Archive for the ‘Hormone Physician’ Category

KENILWORTH, N.J. & WOODCLIFF LAKE, N.J.--(BUSINESS WIRE)--

KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) Combination Demonstrated Statistically Significant Improvement in Overall Survival, Progression-Free Survival and Objective Response Rate Versus Chemotherapy in Patients With Advanced Endometrial Cancer Following Prior Systemic Therapy in Phase 3 Study

Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Eisai today announced that the pivotal Phase 3 KEYNOTE-775/Study 309 trial evaluating the investigational use of KEYTRUDA, Mercks anti-PD-1 therapy, plus LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, met its dual primary endpoints of overall survival (OS) and progression-free survival (PFS) and its secondary efficacy endpoint of objective response rate (ORR) in patients with advanced endometrial cancer following at least one prior platinum-based regimen. These positive results were observed in the mismatch repair proficient (pMMR) subgroup and the intention-to-treat (ITT) study population, which includes both patients with endometrial carcinoma that is pMMR as well as patients whose disease is microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR). Based on an analysis conducted by an independent Data Monitoring Committee, KEYTRUDA plus LENVIMA demonstrated a statistically significant and clinically meaningful improvement in OS, PFS and ORR versus chemotherapy (treatment of physicians choice [TPC] of doxorubicin or paclitaxel). The safety profile of the KEYTRUDA plus LENVIMA combination was consistent with previously reported studies. Merck and Eisai will discuss these data with regulatory authorities worldwide, with the intent to submit marketing authorization applications based on these results, and plan to present these results at an upcoming medical meeting.

Women with advanced endometrial cancer are faced with high mortality rates and limited treatment options following initial systemic therapy, said Dr. Gregory Lubiniecki, Associate Vice President, Oncology Clinical Research, Merck Research Laboratories. These are the first results from a Phase 3 trial of a combination regimen including immunotherapy in advanced endometrial carcinoma that have shown a statistically significant improvement in overall survival, progression-free survival and objective response rate versus chemotherapy. Merck and Eisai are dedicated to continuing to research the KEYTRUDA plus LENVIMA combination and discover new approaches to address unmet needs for devastating diseases such as endometrial carcinoma.

We are encouraged by the data observed in KEYNOTE-775/Study 309, which represent a possible step forward for patients impacted by advanced endometrial carcinoma and support the results seen in the advanced endometrial cancer cohort of KEYNOTE-146/Study 111, said Dr. Takashi Owa, Vice President, Chief Medicine Creation Officer and Chief Discovery Officer, Oncology Business Group at Eisai. As more clinical data from the LEAP (LEnvatinib And Pembrolizumab) program are revealed, we cannot help but be energized by the trajectory of our collaboration with Merck and the benefits we hope to provide to patients together. Most importantly, we are grateful for the trust that the patients and healthcare professionals who participated in this trial have shown us.

KEYNOTE-775/Study 309 is the confirmatory trial for KEYNOTE-146/Study 111, which supported the U.S. Food and Drug Administrations (FDA) 2019 accelerated approval of the KEYTRUDA plus LENVIMA combination for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. This accelerated approval was based on tumor response rate and durability of response and was the first approval granted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among its international partners. Under Project Orbis, Health Canada and Australias Therapeutic Goods Administration (TGA) granted conditional and provisional approvals, respectively, for this indication.

Merck and Eisai are studying the KEYTRUDA plus LENVIMA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in 13 different tumor types across 20 clinical trials, including a Phase 3 trial evaluating the combination in the first-line setting for patients with advanced endometrial carcinoma (LEAP-001).

About KEYNOTE-775/Study 309

KEYNOTE-775/Study 309 is a multicenter, randomized, open-label, Phase 3 trial (ClinicalTrials.gov, NCT03517449) evaluating KEYTRUDA in combination with LENVIMA in patients with advanced endometrial cancer following at least one prior platinum-based regimen. The dual primary endpoints are OS and PFS, as assessed by Blinded Independent Central Review (BICR) per Response Evaluation Criteria in Solid Tumors Version (RECIST) v1.1. Select secondary endpoints include objective response rate (ORR) by BICR per RECIST v1.1 and safety/tolerability. Of the 827 patients enrolled, 697 patients had tumors that were non-MSI-H or pMMR, and 130 patients had tumors that were MSI-H or dMMR. Patients were randomized 1:1 to receive:

About Endometrial Cancer

Endometrial cancer begins in the inner lining of the uterus, which is known as the endometrium and is the most common type of cancer in the uterus. In 2018, it was estimated there were more than 382,000 new cases and nearly 90,000 deaths from uterine body cancers worldwide (these estimates include both endometrial cancers and uterine sarcomas; more than 90% of uterine body cancers occur in the endometrium, so the actual numbers for endometrial cancer cases and deaths are slightly lower than these estimates). In the U.S., it is estimated there will be almost 66,000 new cases of uterine body cancer and nearly 13,000 deaths from the disease in 2020. The five-year survival rate for advanced or metastatic endometrial cancer (stage IV) is estimated to be approximately 17%.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,300 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Endometrial Carcinoma

KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1). All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

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KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) Combination Demonstrated Statistically Significant Improvement in Overall Survival,...

SHANGHAI, China, Dec. 09, 2020 (GLOBE NEWSWIRE) -- Everest Medicines (HKEX 1952.HK), a biopharmaceutical company focused on developing and commercializing transformative pharmaceutical products that address critical unmet medical needs for patients in Greater China and other parts of Asia, today announced that the first patient has been dosed in the Phase 3 registration Asian study EVER-132-002 evaluating TrodelvyTM (sacituzumab govitecan) versus treatment of physicians choice (TPC) in subjects with hormonal receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2) metastatic breast cancer (mBC).

EVER-132-002 is a Phase 3 Asian study designed to assess and compare the efficacy and safety of sacituzumab govitecan versus TPC in Asian patients with HR+/HER2- mBC who received at least two, and no more than four systemic chemotherapy regimens. The trial will enroll up to 330 HR+/HER2- mBC patients in China mainland, Taiwan and South Korea. The primary endpoint is progression free survival (PFS) per RECIST v1.1 by an Independent Review Committee.

HR+/HER2- breast cancer is the most prevalent subtype of breast cancer and accounts for more than 60% of all breast cancer cases. There is a significant unmet need for new treatment options for women with HR+/HER2 mBC who have failed initial standard-of-care chemotherapies, said Dr. Yang Shi, Chief Medical Officerfor Oncology at Everest Medicines. The clinical data generated to date suggested promising clinical activity of sacituzumab govitecan in HR+/HER2 mBC patients who have failed at least two chemotherapy regimens. We are very excited to initiate our Phase 3 registration trial as we believe sacituzumab govitecan has tremendous potential to become the new standard of care in patients with pre-treated HR+/HER2 mBC.

Immunomedics (now part of Gilead Sciences, Inc), which developed sacituzumab govitecan, is currently recruiting patients for the TROPiCS-02 trial, an open-label, randomized, multi-center Phase 3 study to compare the efficacy and safety of sacituzumab govitecan versus the TPC in subjects with metastatic or locally recurrent inoperable HR+/HER2- mBC, after failure of at least two, and no more than four, prior chemotherapy regimens for metastatic disease.

About Sacituzumab Govitecan

Sacituzumab govitecan is a first-in-class antibody-drug conjugate (ADC) directed at TROP-2, a membrane antigen that is over-expressed in many common epithelial cancers. Sacituzumab govitecan was granted accelerated approval by the U.S. FDA in April 2020 for the treatment of patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for metastatic disease. In September 2020 at the ESMO2020 annual conference, Immunomedics (now part of Gilead Sciences, Inc.) presented the confirmatory Phase 3 trial results (ASCENT) demonstrating that sacituzumab govitecan significantly improved progression free survival (PFS) and overall survival (OS) over standard single agent chemotherapy in pre-treated metastatic triple-negative breast cancer (mTNBC) patients with a hazard ratio of 0.41 and 0.48 respectively. Under a licensing agreement with Immunomedics, Everest Medicines has exclusive rights to develop, register, and commercialize sacituzumab govitecan for all cancer indications in Greater China, South Korea, and certain Southeast Asian countries.

In October 2020, sacituzumab govitecan was included in the updated 2020 Guidelines for the Standardized Diagnosis and Treatment of Advanced Breast Cancer in China, compiled by the Breast Cancer Expert Committee of the National Cancer Control Center, the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association, and the Cancer Drug Clinical Research Professional Committee of the Chinese Anti-Cancer Association.

About HR+/HER2- Breast Cancer

Hormone Receptor Positive, HER2 Negative (HR+/HER2-) breast cancer is the most common form of breast cancer in China, representing over 60% of all breast cancer cases. This subtype of breast cancer grows in connection with estrogen or progesteroneand is likely to respond to hormone therapies initially, but almost all HR+/HER2- metastatic breast cancers becomerefractory over time.

About Everest Medicines

Everest Medicines is a biopharmaceutical company focused on developing and commercializing transformative pharmaceutical products that address critical unmet medical needs for patients in Greater China and other Asian markets. The management team of Everest Medicines has deep expertise and an extensive track record of high-quality clinical development, regulatory affairs, CMC, business development and operations both in China and with leading global pharmaceutical companies. Everest Medicines has built a portfolio of eight potentially global first-in-class or best-in-class molecules, many of which are in late stage clinical development. The Companys therapeutic areas of interest include oncology, autoimmune disorders, cardio-renal diseases and infectious diseases. Everest Medicines obtained the development and commercial right in greater China, South Korea and certain Southeast Asian countries of sacituzumab govitecan from Immunomedics in April 2019. For more information, please visit its website at http://www.everestmedicines.com.

Everest MedicinesMedia in US and Europe: Darcie RobinsonVice PresidentWestwicke PR(203) 919-7905darcie.robinson@icrinc.com

Media in China: Edmond LococoManaging DirectorICR Asia+86 (10) 6583-7510edmond.lococo@icrinc.com

Originally posted here:
Everest Medicines Announces First Patient Dosed in Phase 3 Registration Asian Study of TrodelvyTM (sacituzumab govitecan) for Hormone Receptor...

It may be possible for some postmenopausal women to avoid some breast cancer treatment without compromising survival, according to two new studies presented at the San Antonio Breast Cancer Symposium (SABCS), hosted by UT Health San Antonio, the American Association for Cancer Research, and the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine.

The meeting was held virtually December 8 to 11.

One study found that postmenopausal women with early-stage breast cancer who were at low risk of recurrence can skip chemotherapy after surgery. The other found that older patients may be able to skip radiation therapy following breast-conserving surgery.

The studies reflect a resolve in the oncology field to avoid overtreatment of disease, sparing patients from some of the side effects that can accompany treatments like chemotherapy and radiation.

Were looking to move beyond a one-size-fits-all approach, said the presenting author of the first study, Kevin Kalinsky, MD, director of the Glenn Family Breast Center at Winship Cancer Institute of Emory University. This is another step forward in trying to achieve precision medicine.

Dr. Kalinskys study followed women with hormone receptor-positive (HR positive), HER2-negative breast cancer the most common form of breast cancer for about five years following treatment.

The 5,083 study participants had early-stage lymph node-positive cancer (meaning the cancer had spread to one to three lymph nodes) and a recurrence score of 25 or lower.

Breast cancer recurrence scores are based on the presence of 16 cancer-related genes and can range from 0 to 100.

All the study participants received endocrine therapy following surgery, while about half were randomly assigned to receive chemotherapy as well.

The study, which was organized by the SWOG Cancer Research Network and is called RxPONDER, found that while additional chemotherapy improved disease-free survival rates by about 5 percent for premenopausal women, postmenopausal patients gained no added benefit.

This will save tens of thousands of women the time, expense, and potentially harmful side effects that can be associated with chemo infusions, Kalinsky said.

Questions remain about whether chemotherapy has different biological effects based on menopausal status, or simply exerts its effect by shutting down ovarian function.

In the second study, known as PRIME II, researchers found that older patients with HR-positive breast cancer may be able to skip radiation treatment after breast-conserving surgery.

The study enrolled 1,326 women ages 65 and older who had HR-positive breast cancer that had not spread. All of the women had breast-conserving surgery and received hormone therapy. Half of the study participants were assigned to also receive radiation therapy after surgery.

Previous research has suggested a higher risk of cancer recurrence among patients who do not receive radiation therapy. However, the new study found no significant differences in survival, metastasis (disease spread), or new breast cancers among the two groups after five years of follow-up.

The study is important because many postmenopausal women are diagnosed with less-aggressive breast cancers but still receive whole-breast radiation therapy following breast-conserving surgery.

Over half the patients diagnosed with breast cancer in developed countries are over the age of 65 years, said Ian Kunkler, MBBCh, a professor of clinical oncology at the Western General Hospital at the University of Edinburgh in Scotland. We were interested in determining whether older patients with low-risk breast cancer could be spared radiation therapy.

We found that omitting postoperative radiation therapy did not compromise survival or increase the risk of distant metastasis, Dr. Kunkler said. Based on these results, we believe that omission of radiation therapy after breast-conserving surgery should be an option for older patients with localized, HR-positive breast cancer who are receiving adjuvant hormone therapy and meet certain clinico-pathological criteria.

The study findings may not be applicable to patients with high-grade tumors or tumors larger than 3 centimeters, he said, because there were only a few patients with grade-three tumors in the study.

RELATED: Everyday Healths Building a Breast Cancer Community Twitter Chat: Heres What You Missed

A fresh analysis of the landmark phase 3 monarchE clinical trial showed adding Verzenio (abemaciclib) to endocrine therapy significantly benefits patients with high-risk, lymph-node positive, early-stage breast cancer thats classified as HR-positive, HER2-negative.

Many patients with HR-positive, HER2-negative early-stage disease will not experience a recurrence of cancer with endocrine therapy alone, said the study presenter, Priya Rastogi, MD, associate professor in the department of medicine at the University of Pittsburgh and medical director of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation.

But about 20 percent of patients will experience a recurrence of the disease within 10 years of their initial diagnosis. These recurrences are typically diagnosed as incurable metastatic breast cancer, she said.

An earlier release of data from the trial, which includes 5,637 patients, showed the addition of Verzenio to endocrine therapy curbed the risk of invasive disease recurrent by about 25 percent. The new data, which followed patients for longer, showed that those who received Verzenio experienced a 28.7 percent reduced risk of invasive disease.

Since some women experience relapse several years after their initial treatment, it will be important to gather long-term data on the treatment regimen, said SABCS codirector C. Kent Osborne, MD, professor in the department of medicine, hematology, and oncology at Baylor College of Medicine in Houston. Dr. Osborne was not involved in the study.

The study will continue with a longer-term assessment of overall survival rates among the two groups.

RELATED: New Treatment for Aggressive Breast Cancer Announced at ESMO 2020

Women with breast cancer who undergo radiation therapy may have side effects that go unreported or unnoticed by healthcare providers, according to a study from the University of Michigan.

The study was comprised of 9,868 patients with breast cancer who were treated with radiation therapy. Researchers compared the patients reports of side effects with those assessed by their physicians.

The study showed physicians tended to under-recognize pain severity as well as itching (pruritus), swelling, and fatigue. Among the 5,510 patients who reported at least one substantial symptom during radiation therapy, 53.2 percent had under-recognition of at least one of the four symptoms.

Recognition of symptoms is necessary for appropriate supportive care, said Reshma Jagsi, MD, DPhil, the Newman Family Professor and deputy chair of the department of radiation oncology and director of the Center for Bioethics and Social Sciences in Medicine at the University of Michigan in Ann Arbor.

This work reveals that [physicians] systematically miss substantial symptoms in certain patients, including patients who are younger or of Black or other race.

The study points to the need for physicians to improve the way they assess side effects in patients, said SABCS codirector Virginia Kaklamani, MD, a professor of medicine in the division of hematology and medical oncology, University of Texas Health Sciences Center in San Antonio. Dr. Kaklamani was not involved in the study.

Its really quite surprising to me that in 30 percent of cases there was under-recognition compared to what patients are reporting, she said. We need to do a better job.

I think the key here is improving physician-patient communication, she said. That involves a spectrum of potential interventions which begins with addressing our own unintentional biases.

RELATED: Closing the Gap in Breast Cancer Care and Support for Black Women

Read the original post:
Less Treatment May Be Fine for Some Women With Breast Cancer - Everyday Health

Sara M. Tolaney, MD, MPH, discusses where she sees the treatment landscape evolving in the future for the treatment of patients with hormone receptor-positive metastatic breast cancer.

Sara M. Tolaney, MD, MPH, associate director of the Susan F. Smith Center for Womens Cancers; director of Clinical Trials, Breast Oncology; and senior physician at Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, discusses where she sees the treatment landscape evolving in the future for patients with hormone receptor (HR)-positive metastatic breast cancer.

There have been many advancements over the last several years for the treatment of patients with HR-positive metastatic breast cancer, but Tolaney believes there will be a shift towards combination therapy in the future. Current treatment options in the include the combination of endocrine therapy with CDK4/6 inhibition, while physicians may also consider mTOR or PI3K inhibition with endocrine therapy.

In terms of moving forward, Tolaney says 1 major consideration will be combination strategy, which is under exploration in several clinical trials today. These studies are aiming to move the use of CDK4/6 inhibition forward, as well as treatments in the adjuvant setting and treatment with mTOR and PI3K inhibitors as partners for combination strategies. Tolaney says there are many options and new directions for replacing endocrine therapy backbones and perhaps moving into the earlier disease settings. However, first robust data from monotherapy trials are needed.

Continued here:
Combination Strategy May Play Role in Treatment of HR+ Metastatic Breast Cancer - Targeted Oncology

This activity offers CE credits for:

1. Physicians (CME)

2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

ACTIVITY GOAL

The goal of this activity is to inform readers about the possible connections between infertility and mental health disorders.

LEARNING OBJECTIVES:

Understand the prevalence of mood and anxiety disorders in women experiencing infertility and undergoing infertility treatment

Identify patients who may need psychiatric support during infertility treatment

Appreciate factors that may modulate vulnerability to stress, anxiety, and depression in the context of infertility and its treatment

Identify appropriate treatment options for mood and anxiety disorders in women undergoing infertility treatment

TARGET AUDIENCE

This continuing medical education (CME) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve the care of patients with mental health disorders.

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This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Physicians Education Resource, LLC and Psychiatric TimesTM. Physicians Education Resource, LLC is accredited by ACCME to provide continuing medical education for physicians.

Physicians Education Resource, LLC designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded entirely by Physicians Education Resource, LLC. No commercial support was received.

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This CME activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patients medical condition.

The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians Education Resource, LLC.

FACULTY, STAFF, AND PLANNERS DISCLOSURES

Elizabeth Clayton, Ruta Nonacs, MD, PhD, Linda L.M. Worley, MD, FACLP (external reviewer), the staff members of Physicians Education Resource, LLC, and Psychiatric TimesTM have no relevant financial relationships with commercial interests.

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Ms Clayton is an MD candidate (class of 2021) at Tufts University School of Medicine. Dr Nonacs is clinical assistant professor in the Department of Psychiatry at Massachusetts General Hospital and editor in chief at the MGH Center for Womens Mental Health.

Difficulty with conceiving can have many psychological repercussions. Infertility is defined as the inability of a couple to conceive after 12 months of regular intercourse without the use of contraception in women aged 35 years or younger, or after 6 months in women aged 36 years or older. The Centers for Disease Control and Prevention (CDC) reports that 12% of women aged 15 to 44 years have difficulty getting pregnant or carrying a pregnancy to term (Figure). Some form of infertility was reported by 9% of men aged 25 to 44 years. In about 35% of couples surveyed, infertility was due to both male and female factors.1

Infertility can have a profound impact on psychological well-being for both the individual and the couple. A woman may find herself feeling betrayed by her body and may be overcome by emotions, ranging from profound despair to anger and resentment, when a friend announces a pregnancy. Sexual intimacy can morph from an expression of closeness to a demand for conception. Each failed cycle is a multifaceted burden. In vitro fertilization (IVF) is rarely covered by insurance. Some individuals may even become suicidal with recurrent loss of pregnancy.

While we acknowledge that infertility and its treatment are physically and psychologically challenging, there is a paucity of research into the association between psychiatric illness and infertility (Table 1). Additionally, we know little about the psychological impact of infertility and prolonged exposure to infertility treatment on mood and well-being. As the current research stands, it is unclear how mood and anxiety disorders impact fertility and if infertility and its treatment may lead to mood and anxiety disorders.

Impact of affective disorders on fertility and its treatment

There are conflicting data regarding the impact of depression and anxiety on the reproductive cycle. In one study, it was observed that depressive symptoms were not associated with changes in reproductive hormone levels,2 but other studies have found that self-reported levels of stress do impact hormone levels.3 In a group of young women aged 17 to 20 years,higher ratings of stress were associated with lower estradiol (but not testosterone or progesterone) concentrations. This finding is consistent with previous studies suggesting that prolonged perceived stress may lower overall estradiol production, thus inhibiting ovulation and suppressing reproduction.

Inflammation may also play an important role in infertility, and current research suggests that chronic inflammation may affect fertility and pregnancy outcomes. Chronic stress, depression, and anxiety have all been associated with inflammation and, therefore, may interfere with attempts to conceive. In a study of women and men undergoing infertility treatment, higher stress levels were associated with various markers of inflammation, including higher cervicovaginal inflammatory cytokines. These inflammatory markers were, in turn, associated with a decreased likelihood of achieving pregnancy through IVF.4

It is likely that high levels of cumulative stress associated with recurrent depression and/or anxiety may affect multiple stages of fertilization. That said, normal levels of stress related to infertility treatment probably have minimal effects. A prospective study from Donarelli and colleagues5 examined anxiety and stress levels in women and men pursuing infertility treatment before undergoing ovarian stimulation. The researchers found that neither partners level of treatment-related stress had an impact on the number of ovarian follicles greater than 16 mm, with ovarian follicle size being a predictor of IVF success.

Health care providers can reassure patients that neither partners situational stress will impact follicle stimulation. Additionally, it has been speculated that chronic stress impedes successful implantation, but difficulty with implantation can be overcome using IVF. Although more research is needed, IVF may be a reasonable recommendation for women with mood disorders who are experiencing infertility.6

Although it is unclear whether depression affects fertility, it may have an impact on treatment with assisted reproductive technology (ART). Health care providers should be aware that women with depression are less likely to pursue infertility treatment. A recent prospective study of patients attending a fertility clinic found that women who screened positive for depression were about half as likely to initiate treatment for infertility compared with their nondepressed counterparts.7 Additionally, depression in women has been associated with higher ART dropout rates. One study found that couples with a clinically depressed female partner were 5 times more likely to discontinue treatment than couples with a nondepressed partner.8 Screening for depression is therefore important in couples pursuing infertility treatment, and extra care should be taken to provide appropriate support to patients seeking infertility treatment who screen positive for an affective disorder.

Eating disorders and infertility treatment

Infertility and subfertility may occur in women with anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). In women with active illness, amenorrhea and oligomenorrhea can compromise the likelihood of conception (Table 2). Menstrual irregularities occur most commonly in women with AN, with 39% to 42% experiencing amenorrhea (an absence of menstruation) and an additional 6% to 11% reporting oligomenorrhea (infrequent menstruation); however, 7% to 40% of women with BN report amenorrhea and 36% to 64% experience oligomenorrhea.9

The strongest predictors of amenorrhea in women with eating disorders are low body mass index (BMI), low caloric intake, and higher levels of exercise. Weight restoration is the primary intervention for amenorrhea in women with eating disorders, although amenorrhea may persist even after normal weight has been restored.In addition, polycystic ovarian syndrome (PCOS) may be another factor contributing to menstrual irregularity in this population, as PCOS is common among women with BN and BED. In fact, one study reported polycystic ovaries in 75% of women with BN.9

Women with a current eating disorder may experience fertility problems, especially if they have a low BMI and experience menstrual irregularity. However, data regarding the fertility of women with a history of an eating disorder have yielded mixed results.Many studies, including 2 large, population-based cohort studies, have demonstrated similar rates of successful pregnancy in women with a history of an eating disorder compared with women in the general population.10 At the same time, prospective data from the Avon Longitudinal Study of Parents and Children (ALSPAC) indicate that women with a history of AN or BN were more likely to take longer than 6 months to conceive and were more likely to have conceived with the aid of fertility treatment.11

While we do not have detailed information on the impact of other psychiatric disorders (such as bipolar disorder and schizophrenia) on fertility, it should be noted that certain medications used to treat these disorders may cause menstrual irregularities, including amenorrhea, and may thus negatively affect fertility. For example, antipsychotic agents with strong antagonism of the dopamine D2 receptor, such as risperidone and older antipsychotics, increase levels of prolactin, causing hypogonadotropic hypogonadism and subsequent menstrual dysfunction.12

Finally, drug and alcohol use disorders have well-documented effects on the fetus, but the effects on conception and implantation of an embryo are unclear. Studies have suggested that substance use disorder has a negative impact on female and male fertility, but more research is needed in this area.13 The majority of data have come from animal models. Studies in humans have been observational and are complicated by participants who use multiple substances and different routes of administration. Explicit associations between substance use and fertility is further confounded by lifestyle factors that often accompany substance use, such as overall unhealthy lifestyle, poor decision-making, and comorbid physical and mental health disorders.14

Psychological impact of fertility treatment

The decision to begin ART can be very stressful for couples, and research has shown that stress may increase with each subsequent fertility treatment.15 However, distress can manifest at any point during ART. In a large Dutch study following couples experiencing infertility (who reported undergoing an average of 4.3 fertility treatments over 5 years), a passive-avoidant method of coping (eg, hoping for a miracle) was linked with psychological distress in women, and this effect increased over time. For men, this coping style led to increased marital distress.16 Women who perceived infertility as central to their identity, and who were resistant to realigning their goals, reported greater distress during fertility treatment.17 On the other hand, meaning-based coping strategies, learning to grow from a negative experience, and/or finding other goals in life were associated with decreased distress in women, but not in men. A womans use of meaning-based coping strategies also decreased marital stress for both partners.16 It is important to note that these studies are based in countries where fertility treatment is covered by insurance, which is rare in the United States. American couples undergoing ART have additional stressors, although they would also likely benefit from these coping strategies.

Protective factors have also been identified. For a woman, having a higher level of education and adequate social supports decreases distress during ART. For men, a problem-solving coping strategy was linked to a higher self-reported quality of life (QOL).15 In a study from Israel, where there is a social emphasis on having children, researchers observed that maintaining daily routines and making efforts to feel normal led to a higher QOL and better adjustment to fertility treatment.18 In another study, the Dyadic Adjustment Scale (DAS), a tool that measures relationship distress, was administered to couples currently undergoing fertility treatment. Higher dyadic adjustment was associated with better QOL and less psychological distress in both men and women undergoing ART. However, this protective effect was diminished when infertility persisted for longer than 3 years.15

Although multiple studies have assessed psychological distress in couples undergoing treatment for infertility, far fewer have assessed the prevalence of clinically significant anxiety and depressive symptoms in this population. A large Danish study of couples undergoing ART found severe depressive symptoms in 11.6% of women and 4.3% of men.19 These symptoms correlated to an increase in infertility-related distress. However, there is considerable variation among studies with regard to rates of depression and anxiety in couples pursuing infertility treatment, which may reflect differences in type of ART, duration of infertility, number of failed cycles, cultural considerations, and methods used to assess symptoms.

According to another study, women who conceived through ART showed no difference in anxiety and depressive symptoms compared with pregnant women who conceived naturally. However, rates of depression and anxiety were higher in subfertile, nonpregnant women (57.6% and 15.7%, respectively).20 Comparisons between women undergoing repeated IVF cycles and first-time participants have suggested that ongoing treatment may lead to an increase in depressive symptoms, which may persist for 6 months after a failed ART trial.21

Recent research also suggests that both women and men with a history of major depressive disorder (MDD) are more likely to experience depressive symptoms during ART.22 In a prospective observational study of 25 women with a history of MDD undergoing ART, 44% of the women experienced a depressive relapse; rates of relapse were similar among women who maintained antidepressant use compared with those who discontinued treatment.23

In another study, researchers observed that among 108 women undergoing IVF for the first time, those with a history of unipolar depression or anxiety disorder reported more depressive symptoms than controls without these disorders. The group without psychiatric illness responded to fertility treatment with elevated cortisol levels (compared to baseline), whereas women with a history of mood or anxiety disorder had a blunted cortisol response. These results may indicate that infertile women with Axis I disorders may have chronically elevated levels of cortisol, even before entering into infertility treatment.24

Clinical recommendations

Steps should be taken to screen couples, not just women, for psychiatric disorders and chronic stress prior to beginning infertility treatment, as well as throughout treatment. Although depressive symptoms and anxiety occur frequently in women experiencing infertility, many women do not seek treatment. In fact, many women resist disclosing their mental health status to their reproductive endocrinologist for fear that they would be deemed bad candidates for infertility treatment. Effectively treating eating disorders, substance use disorders (including alcohol and tobacco use), and bipolar disorder from the initiation of infertility treatment will aid in a healthy pregnancy, if conception is successful.

Although there is no evidence to suggest that antidepressants or anxiolytic medications negatively affect fertility or infertility treatment, many women are reluctant to use medication in this setting. Women undergoing infertility treatment may not engage in treatment of anxiety and depression because they already feel overburdened by the demands of infertility treatment on their time and financial resources. In addition, having to pursue psychiatric treatment in this setting may accentuate the shame and stigma many women with infertility often feel.

Providing couples with information normalizes the psychological effects of infertility and its treatment may help patients adjust to and tolerate the process. Clinicians should give guidance when psychological symptoms are more than a normal reaction to a common reaction to failed ART. Counseling patients on the importance of self-care, healthy coping strategies, and improving communication may have a positive impact on both the individual and couple. Patient support can include connecting them with community support resources, such as RESOLVE (a network of groups affiliated with the National Infertility Association), and recommending a consultation with a sex therapist to help the couple maintain a positive connection with each other.

Additionally, targeted psychological interventions may help alleviate the adverse psychological outcomes associated with infertility and its treatment, including anxiety, depressive symptoms, and marital stress (Table 3). According to a recent meta-analysis25 that included 39 studies and a total of 3064 women and 347 men, psychological interventions, most commonly cognitive behavioral therapy (CBT) or mind-body interventions (MBI), may be effective for reducing anxiety (25 studies), as well as depressive symptoms (21 studies). These interventions also appeared to improve rates of pregnancy; in this meta-analysis, women treated with CBT or MBI were about twice as likely to achieve pregnancy compared with women receiving usual care. Of note, larger reductions in anxiety were associated with greater improvements in pregnancy rates.

To date, there is no research that specifically looked at the pharmacologic treatment of depression or anxiety in women with infertility. Thus, the same principles that guide the treatment of women during pregnancy should inform the treatment of women undergoing infertility treatment. There are sufficient data to support the use of selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs), bupropion, and tricyclic antidepressants. Other factors that may influence the selection of an antidepressant include prior response to a particular antidepressant, comorbidity of anxiety symptoms, and adverse effect profile.

Benzodiazepines, including lorazepam and clonazepam, may be helpful for the management of anxiety disorders, treatment-emergent anxiety, and sleep disturbance. Althoughearlier reports suggested an increased risk of cleft lip and palate associated with prenatal benzodiazepine exposure, more recent reports have shown no increase in the overall risk of malformations in children exposed to benzodiazepines during pregnancy.26

Many women question whether the use of these medications may affect fertility or the success of infertility treatment. Although there is no evidence to indicate that antidepressants or benzodiazepines have deleterious effects on fertility, this has not been studied systematically. There have been reports suggesting a small but statistically significant increase in risk of miscarriage in women treated with SSRIs, although this is not a universal finding.27 It is also important to note that women who suffer from mood and anxiety disorders probably carry a slightly higher risk of miscarriage. In fact, women with a history of depression who stop treatment with an antidepressant 3 to 12 months prior to conception have the same risk of miscarriage as women who continue treatment with an antidepressant.28

Although avoiding treatment with a medication may seem like the safest option, untreated anxiety and/or depression in the mother has been associated with negative pregnancy outcomes, including increased risk of preterm birth, low birth weight, and other complications.29 In addition, depression during pregnancy is a robust predictor of postpartum depression. Numerous somatic complaints are treated with medication during pregnancy; psychological complaints can be just as detrimental and should be treated, as well.

Concluding thoughts

Infertility is a common and psychologically distressing experience, both for the individual and the couple. Although there is a dearth of research examining the association between infertility and psychiatric illness, preliminary research indicates that depression, anxiety, and chronic stress may contribute to inflammation and alterations in hormone levels, factors which may affect the likelihood of successful pregnancy outcomes. Additionally, ongoing infertility treatment has been linked to increased depressive symptoms and anxiety and may hinder couples ability to pursue and continue with infertility treatment.As noted, eating disorders can also affect fertility.

Increased psychological support during infertility treatment would be beneficial for this population and may improve the chances of a successful pregnancy. The patient undergoing infertility treatment should be given the same plan of care as any patient with anxiety or depression. Support should include expectation management around the psychological effects of infertility treatment, as well as promotion of healthy coping strategies, such as taking time for self-care. If needed, pharmacotherapy with SSRIs or benzodiazepines is unlikely to have an adverse effect on conception and may decrease ART dropout. However, more research is needed to establish the connection between psychological illness and depression in order to create effective targeted therapies.

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References

1. Reproductive Health: Infertility FAQs. Centers for Disease Control and Prevention. Updated January 16, 2019. Accessed November 7, 2019. https://www.cdc.gov/reproductivehealth/infertility/index.htm

2. Prasad A, Schisterman EF, Schliep KC, et al. Depressive symptoms and their relationship with endogenous reproductive hormones and sporadic anovulation in premenopausal women. Ann Epidemiol. 2014;24(12):920-924.

3. Roney JR, Simmons ZL. Elevated psychological stress predicts reduced estradiol concentrations in young women. Adapt Human Behav Physiol. 2015;1(1):30-40.

4. Haimovici F, Anderson JL, Bates GW, et al. Stress, anxiety, and depression of both partners in infertile couples are associated with cytokine levels and adverse IVF outcome. Am J Reprod Immunol. 2018;79(4).

5. Donarelli Z, Lo Coco G, Gullo S, et al. Infertility-related stress, anxiety and ovarian stimulation: can couples be reassured about the effects of psychological factors on biological responses to assisted reproductive technology? Reprod Biomed Soc Online. 2016;(3):16-23.

6. Zaig I, Azem F, Schreiber S, et al. Womens psychological profile and psychiatric diagnoses and the outcome of in vitro fertilization: is there an association? Arch Womens Ment Health. 2012;15(5):353-359.

7. Crawford NM, Hoff HS, Mersereau JE. Infertile women who screen positive for depression are less likely to initiate fertility treatments. Hum Reprod. 2017;32(3):582587.

8. Pedro J, Sobral MP, Mesquita-Guimares J, . Couples discontinuation of fertility treatments: a longitudinal study on demographic, biomedical, and psychosocial risk factors. J Assist Reprod Genet. 2017;34(2):217-224.

9. Kimmel MC, Ferguson EH, Zerwas S, Bulik CM, Meltzer-Brody S. Obstetric and gynecologic problems associated with eating disorders.Int J Eat Disord. 2016;49(3):260-275.

10. Tabler J, Utz RL, Smith KR, Hanson HA, Geist C. Variation in reproductive outcomes of women with histories of bulimia nervosa, anorexia nervosa, or eating disorder not otherwise specified relative to the general population and closest-aged sisters.Int J Eat Disord. 2018;51(2):102111.

11. Schmidt U, Sharpe H, Bartholdy S, et al. Treatment of anorexia nervosa: a multimethod investigation translating experimental neuroscience into clinical practice. Programme Grants Appl Res. 2017;5(16):95-107.

12. Lania A, Gianotti L, Gagliardi I, Bondanelli M, Vena W, Ambrosio MR. Functional hypothalamic and drug-induced amenorrhea: an overview. J Endocrinol Invest. 2019;42(9):1001-1010.

13. Sansone A, Di Dato C, de Angelis C, et al. Smoke, alcohol and drug addiction and male fertility.Reprod Biol Endocrinol. 2018;16(1):3.

14. de Angelis C, Nardone A, Garifalos F, et al. Smoke, alcohol and drug addiction and female fertility.Reprod Biol Endocrinol. 2020;18(1):21.

15. Zurlo MC, Cattaneo Della Volta MF, Vallone F. Predictors of quality of life and psychological health in infertile couples: the moderating role of duration of infertility. Qual Life Res. 2018;27(4):945-954.

16. Peterson BD, Pirritano M, Christensen U, et al. The longitudinal impact of partner coping in couples following 5 years of unsuccessful fertility treatments. Hum Reprod. 2009;24(7):1656-1664.

17. Neter E, Goren S. Infertility centrality in the womans identity and goal adjustment predict psychological adjustment among women in ongoing fertility treatments. Int J Behav Med. 2017;24(6):880-892.

18. Benyamini Y, Gozlan M, Weissman A. Normalization as a strategy for maintaining quality of life while coping with infertility in a pronatalist culture. Int J Behav Med. 2017;24(6):871-879.

19. Peterson BD, Sejbaek CS, Pirritano M, Schmidt L. Are severe depressive symptoms associated with infertility-related distress in individuals and their partners? Hum Reprod. 2013;29(1):76-82.

20. Joelsson LS, Tydn T, Wanggren K, et al. Anxiety and depression symptoms among sub-fertile women, women pregnant after infertility treatment, and naturally pregnant women. Eur Psychiatry. 2017;45:212-219.

21. Milazzo A, Mnatzaganian G, Elshaug AG, et al. Depression and anxiety outcomes associated with failed assisted reproductive technologies: a systematic review and meta-analysis. PLoS ONE. 2016;11(11): e0165805.

22. Holley SR, Pasch LA, Bleil ME, et al. Prevalence and predictors of major depressive disorder for fertility treatment patients and their partners. Fertil Steril. 2015;103(5):1332-1339.

23. Freeman MP, Lee H, Savella GM, et al. Predictors of depressive relapse in women undergoing infertility treatment. J Womens Health. 2018;27(11):1408-1414.

24. Zaig I, Azem F, Schreiber S, et al. Psychological response to cortisol reactivity to in vitro fertilization treatment in women with a lifetime anxiety or unipolar mood disorder diagnosis. J Clin Psychiatry. 2013;74(4):386-92.

25. Frederiksen Y, Farver-Vestergaard I, Skovgrd NG, et al. Efficacy of psychosocial interventions for psychological and pregnancy outcomes in infertile women and men: a BMJ Open. 2015;5(1):e006592.

26. Andersen JT, Andersen NL, Horwitz H, et al. Exposure to selective serotonin reuptake inhibitors in early pregnancy and the risk of miscarriage. Obstet Gynecol. 2014;124(4):665-61.

27. Grigoriadis S, Graves L, Peer M, et al. Benzodiazepine use during pregnancy alone or in combination with an antidepressant and congenital malformations: systematic review and meta-analysis. J Clin Psychiatry. 2019;80(4).

28. Jarde A, Morais M, Kingston D, et al. Neonatal outcomes in women with untreated antenatal depression compared with women without depression: a systematic review and meta-analysis. JAMA Psychiatry. 2016;73(8):826-837.

29. Wu P, Velez Edwards DR, Gorrindo P, et al. Association between first trimester antidepressant use and risk of spontaneous abortion. Pharmacotherapy. 2019;39(9):889-898.

Read the original here:
The Intertwining Effect of Mood Disorders and Infertility - Psychiatric Times

Hundreds of physicians and other medical professionals in the Abortion Pill Rescue Network aid women who experience regret after starting the chemical abortion process. And each provider has their own story for how they came to help women in this critical situation have a second chance at life for their child.

According to a recent report from the Charlotte Lozier Institute (CLI), a "surge" in chemical abortions is contributing to a rise in abortion rates.

Chemical abortion is a two-pill process. The first chemical, mifepristone (or RU-486) is the first pill used in a chemical abortion and blocks the effects of progesterone, a hormone necessary for a pregnancy to thrive. The second part, misoprostol, expels the baby.

However, some moms take that first chemical abortion pill and then regret doing itwhich is why the Abortion Pill Rescue Network (APRN), managed by Heartbeat International, plays such a critical role.

Available 24/7 through the network for moms who experience such regret, the abortion pill reversal (apr) protocol offers hope that the chemical abortion process may be reversed if initiated within a specific timeframe.

When one of these women connects with Heartbeats Option Line, consultants assist women with immediate needs before referring them to the nearest one of more than 700 Abortion Pill Rescue (APR) providers worldwide in the APRN.

[Click here to subscribe to Pregnancy Help News!]

One of those providers is Karen D. Poehailos, MD, who has been working with the APRN since 2015. She has successfully helped a number of moms and their babiesincluding her very first reversal baby, who recently turned five years old.

In celebration of this milestone, I spoke with Poehailos to learn more about her background, her journey to the pregnancy help community, her experiences as an APRN provider, and the impact this has had upon her life.

Poehailos is a board-certified family physician and the Regional Medical Director for ThriVe Central VA Women's HealthCare, a group of four womens health care centers with locations in Charlottesville, Albemarle, Culpeper and Orange, Virginia. She is also a family physician part-time at WellFamily Medicine in Charlottesville.

Her responsibilities with ThriVe Central Virginia include oversight of the paid and volunteer medical personnelas well as providing and coordinating limited obstetrical ultrasound, medical visits, and testing and treatment for sexually transmitted infections (STIs) and sexually transmitted diseases (STDs).

Poehailos is a graduate of the University of Virginia School of Medicine and its Family Medicine Residency. She has worked in primary care and urgent care settings, and has taken additional training in Natural Family Planning and is a Certified FertilityCare Medical Consultant, working with women on issues like recurrent miscarriage, infertility and irregular cycles without use of IVF or hormonal contraception.

Shes been a practitioner for the APRN since 2015 and a member of the Heartbeat International Medical Advisory Council and the Heartbeat International Abortion Pill Reversal (APR) Advisory Team since 2019.

A native of Baltimore, Poehailos now makes her home in Charlottesville, Virginiawhere she embraced the challenge of raising four sons through Scouts, sports and band carpools while still maintaining a medical practice and volunteer life at her church.

For many years, Poehailos worked off and on as a volunteer for ThriVe Central Virginia. However, in early 2018 she moved into part-time employment, then became a full-time physician there in June of 2018which she says is an unusual arrangement for pregnancy resource centers, since medical directors are usually volunteers or part-time employees.

Acknowledging the significant step forward in faith it took for the centers to commit to offering her a full-time role, she says that although she was excited, she was also nervous about leaving the employer shed been with for 20 years.

I felt like I was leaving my security blanket, she said. It was a step of faith to leave that job, because I love family medicine and I love doing urgent care, but I just kind of felt the nudge from God.

However, in the midst of the transition, she learned that her former employer had decided to close his doorswhich meant she wouldve suddenly been out of a job if shed stayed.

So, God definitely took care of me, she said.

In this context, Poehailos says she can clearly see how God has used a variety of seemingly disparate skills and circumstances to guide her to her current role.

Noting that the four centers now offer STI testing and treatment, she said, Before I went to medical school, I was a medical technologist and did hospital lab work. The fact that I already had a good lab background helped us get that off the ground. And Im actually comfortable drawing blood because I worked in a blood bank for a while.

She says another much-needed skill shes developed in recent years is the ability to perform her own ultrasounds.

I did training in limited OB ultrasounds so I can conduct the scans myself, in addition to reading them, Poehailos said.

Citing Esther 4:14 as one of her favorite verses, she said, You know, this is the moment for which you've been created. I mean, why was I a med tech before I decided to go to medical school? Well, it finally became clear much later.

Poehailos says her journey to becoming an APRN provider started with a natural family planning meeting in Milwaukee in 2010. It was during lunch with two other physicians that she first heard about the use of progesterone after a woman took the first dose of the abortion pill to try to reverse the abortion.

I thought, Wow, that sounds really interesting, she said. But I didn't have that much familiarity with working with progesterone and I kind of filed the information away in my head.

It was a year or so later, Poehailos said, when she took the FertilityCare medical consultant course at the Saint Paul VI Institute in Omaha, and, one of the primary tools in our toolbox was to use progesterone for women with threatened miscarriage and women with certain cycle irregularities. Once I took that course and got comfortable with progesterone, I knew I was ready to join the APRN hotline as a provider.

When she first got involved, the APRN was operated by Dr. George Delgado through Culture of Life Family Services in San Diego. The APRNs operations transitioned to Heartbeat International in 2018.

Poehailos vividly remembers the first call she received in February of 2015. She was with one of her sons, visiting a university campus and walkway over Interstate 81 on a pedestrian bridge.

My phone vibrates in my pocket and I pull it out and theres a text that says, Hi, this is the hotline. We might have a patient for you, she recalled.

After telling her son to go to the next lecture without her, she found a spot in the lobby of a building and talked to the hotline nurse, then called the patient. When they returned to Charlottesville later that afternoon, Poehailos said, I met her at the office, and we started the protocol.

That first patient was also her first successful reversal; the healthy little girl who recently turned five.

Over time, her experiences have taught her how to prepare women regarding what to expect once the reversal process has startedwhich is an important part of helping them cope with everything thats going on in their lives.

We have to remember that whatever circumstances led the woman to start the medical abortionher social situation or whatever was an influencing factor in her decisiondoesn't magically go away when she attempts to rescue that abortion attempt, said Poehailos. So whatever else was stressing her with her family or her boyfriend or whatever is going on, we have to always remember when we're in contact with these women afterwards, that those things didn't magically disappear.

They are going to need more support than the average woman who may be threatening a miscarriage for another reason, she added.

As far as follow-up, she says she tries to stay in contact with women until they can receive care from a local obstetrician.

Our mission is to get them turned over to local OB care, Poehailos explained. I always tell them when I'm seeing them for the ultrasound that they need to get established with an OB physician and Ill be happy to share any needed information.

Poehailos says being an APRN provider has had a big impact on herespecially when she gets good news about how the moms and children have been thriving since her first contact with them.

One reached out to text me a couple of years ago on Mother's Day and said, Happy Mother's Day to you. And thank you. Here's a picture of my baby, said Poehailos. It just makes you want to cry.

She also recalled how five years ago when the first baby she helped was about to enter the world, the mom asked her to come to the hospital to meet the baby after she was born.

She wasnt that far from away from us, Poehailos said, so I was able to go to the hospital at her request, the day of the delivery to see the baby. The mom took a picture of me holding the baby the day she was born. That's a picture for forever.

Poehailos says one of the challenges with APR is the critical timing thats requiredsince the woman needs to be seen right away to start the protocol. Fortunately, the APRN providers help each other out, she said, providing creative support to meet patient needs.

There's nice collaboration between the providers on the network, Poehailos said. One way or another, weve always managed to get it done.

Referring to the APRN as the emergency room for pregnancy resource clinics, Poehailos said, Were like the code team in a hospital. You have to get there now.

Other times, when women come in and they're still considering all their options, it's not as urgent, she said. But with APR theres much more urgency since the process has already been started and we have to stop it. Somebody needs to be there pretty fast to get the ball rolling. We all pitch in to make sure that happens.

Tweet This: With Abortion Pill Rescue theres urgency as the process has been started & we have to stop it. We all pitch in to make sure that happens.

In terms of ongoing needs, Poehailos says she wants to spread the word about the APRNespecially to other providers who may want to become part of something that makes such a difference.

Theres a great need for more local providers, she says, so women who are already in crisis wont be required to travel long distances to access the urgent care thats required.

We have a lot of providers in the network, but were not evenly distributed geographically, Poehailos said.

And even if theres an APRN provider already in a specific area, Poehailos said it would be a big help to have more than one, so they could back each other up to meet local needs.

If one provider isnt available when a woman needs their services, it would be awesome to have another provider in that same city, said Poehailos, instead of making the woman drive several hours to receive care.

Poehailos says shes been grateful for the increased resources that became available when the Heartbeat International assumed oversight of the APRN.

The people who started APR did an amazing job to get the ball rolling, said Poehailos. Im grateful Heartbeat International was able to step in and put the strength of their network and Option Line behind the network, because we really needed that to have the increased reach.

If you are a woman in need of Abortion Pill Rescue care, representatives are available 24/7 through Option Line to speak with you. Click HERE, call 1-800-712-4357 or text HELPLINE to 313131.

If you are a healthcare provider interested in becoming part of the APRN, you can learn more by visiting the Abortion Pill Rescue Network page.

Editor's note: Heartbeat International manages the Abortion Pill Rescue Network, Option Line and pregnancy Help News.

Go here to see the original:
A nudge from God one doctor's journey to serving other women through Abortion Pill Rescue - Pregnancy Help News

For patients with hormone receptor (HR)positive, HER2-negative breast cancer, research reported that adding ribociclib (Kisqali) to endocrine therapy significantly improved overall survival (OS) while delaying subsequent chemotherapy when compared with placebo, regardless of endocrine partner, according to results presented during the 2020 San Antonio Breast Cancer Symposium.1

An updated analysis of the phase 3 MONALEESA-7 trial (NCT02278120) reported a median follow-up of 53.5 months (range, 46.9-66.4), and the median OS with ribociclib plus endocrine treatment was 58.7 months vs 48.0 months with placebo/endocrine therapy (HR, 0.763; 95% CI, 0.608-0.956), translating to a 24% relative reduction in the risk of death with the CDK4/6 inhibitor.

Moreover, data from a subgroup analysis examining survival in relation to endocrine partner, results showed that patients who received a nonsteroidal aromatase inhibitor (NSAI) experienced a median OS of 58.7 months with ribociclib/endocrine therapy vs 47.7 months with placebo/endocrine therapy (HR, 0.798; 95% CI, 0.615-1.04). In those who received tamoxifen, the median OS had not yet been reached with ribociclib vs 49.3 months with placebo (HR, 0.705; 95% CI, 0.453-1.097).

A consistent significant OS benefit with ribociclib plus endocrine therapy was demonstrated after a longer median follow-up of 53.5 months. With a median OS of 58.7 months in the ribociclib arm, this is the longest median OS [that we have seen] among the phase 3 trials for HR-positive, HER2-negative advanced breast cancer, Debu Tripathy, MD, professor and chairman of the Department of Breast Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, said in a poster presentation during the meeting. Therefore, this exploratory analysis confirms the benefit and continued use of ribociclib in the first-line setting for pre- or perimenopausal patients with HR-positive, HER2-negative advanced disease.

In the multicenter, double-blinded, placebo-controlled phase 3 MONALEESA-7 trial, investigators set out to evaluate the efficacy of ribociclib in pre- and perimenopausal patients with HR-positive, HER2-negative advanced breast cancer. To be eligible to participate, patients needed to have received at least 1 previous line of chemotherapy for advanced disease and they could not have been administered prior endocrine treatment.

A total of 672 patients were randomized 1:1 to receive either ribociclib at a daily dose of 600 mg 3-weeks-on/1-week-off (n = 335) or placebo (n = 337) in combination with goserelin plus either a NSAI or tamoxifen. The primary end point of the trial was progression-free survival (PFS), and key secondary end points comprised OS, health-related quality of life, overall response rate (ORR), time to definitive deterioration of the ECOG performance status, PFS2, and safety, among others.

Patient characteristics were found to be well balanced between the 2 treatment arms. The median age of participants in the investigational arm was 43 years.2 Moreover, 55.8% were white, 29.6% were Asian, and 8.7% were black, Native American, or other. The race of 6.0% of patients was unknown. The ECOG performance status of 73.1% of patients was 0; it was 1 in 26.0%, and unknown for the remaining 0.9%. More than half, or 57.6%, of patients had visceral metastases, with 24.2% of them having bone-only metastases.

Earlier data showed that ribociclib plus endocrine therapy was found to significantly improve PFS and OS compared with placebo/endocrine therapy in this patient population. Specifically, the median PFS was 23.8 months in the investigational arm vs 13.0 months in the control arm (HR, 0.55; 95% CI, 0.44-0.69; P < .0001).3,4 At a median follow-up of 34.6 months, the median OS reported in the final protocol-specified OS analysis had not yet been reached in the ribociclib arm vs 40.9 months in the placebo arm (HR, 0.71; 95% CI, 0.54-0.95; P = .00973).

After the prior analysis, patients were unblinded and 15 patients in the placebo arm crossed over to receive ribociclib, Amy S. Clark, MD, MSCE, assistant professor of medicine at the Hospital of the University of Pennsylvania, commented in a poster spotlight session during the meeting. The median OS had not been reached in the ribociclib group in that initial OS analysis, so I do think it was important to continue to follow these results.

Results from an exploratory subgroup analysis presented at the meeting proved to be consistent with the OS data reported for the overall patient population. However, investigators noted that this should be interpreted with caution because of the small numbers of patients, relatively wide confidence intervals, and a lack of statistical power, said Tripathy.

As of the June 29, 2020 data cutoff, 21.2% of patients on the ribociclib/endocrine therapy arm and 9.2% of those on the placebo arm were still receiving treatment. Almost 80% (78.8%) of patients on the investigative arm had ended treatment vs 90.8% of those on the control arm.

On the ribociclib arm, the majority of patients, or 62.7%, discontinued due to disease progression, noted Tripathy. Additionally, 6.3% of these patients discontinued due patient/guardian decision, 3.6% due to physician decision, 4.8% due to an adverse effect (AE), 0.9% due to death, and 0.6% were lost to follow-up.

Moreover, 77.3% of those on the ribociclib/endocrine therapy arm vs 78.1% of those on the placebo/endocrine therapy arm went on to receive subsequent therapy. The most common first subsequent therapies were chemotherapy alone and hormone therapy alone.

Subsequent treatments received in the investigative and control arms included chemotherapy (22.3% vs 28.4%, respectively), chemotherapy plus hormone therapy or other therapy (10.2% vs 10.1%), hormone therapy alone (27.7% vs 18.3%), hormone therapy plus other therapy (15.2% vs 18.0%), or other treatment (1.9% vs 3.3%).

Moreover, more patients on the placebo arm went on to receive a CDK4/6 inhibitor following treatment discontinuation. Almost 13% of patients on the investigative arm went on to receive another CDK4/6 inhibitor vs 26.1% of those on the control arm. Among the patients on the investigative arm, 9.5% received palbociclib (Ibrance), 2.3% received ribociclib, and 1.5% received abemaciclib (Verzenio). In the control arm, 21.9%, 3.9%, and 0.7% of patients received palbociclib, ribociclib, or abemaciclib, respectively.

The median time to chemotherapy was 50.9 months with ribociclib plus endocrine therapy vs 36.8 months with placebo plus endocrine therapy (HR, 0.694; 95% CI, 0.556-0.867). Moreover, the median chemotherapy-free survival in the investigative and control arms was 42.4 months vs 26.4 months, respectively (HR, 0.666; 95% CI, 0.550-0.808). Lastly, the median PFS2 with ribociclib was 44.2 months vs 31.0 months with placebo (HR, 0.683; 95% CI, 0.560-0.834).

The toxicities in the safety population proved to be consistent with those observed in the primary and final OS analyses, according to Tripathy. AEs of special interest in the ribociclib and placebo arms included all-grade neutropenia (77.9% vs 10.7%, respectively), leukopenia (35.5% vs 5.9%), anemia (22.7% vs 11.6%), hepatobiliary toxicity (29.3% vs 23.7%), QTc prolongation (12.8% vs 6.5%), and interstitial lung disease/pneumonitis (0.6% vs 0%, respectively).

The most commonly reported grade 3 or higher AE in the ribociclib arm was neutropenia (53.1%, grade 3; 11.6%, grade 4). In the control arm, hepatobiliary toxicity was the most frequently experienced grade 3 effect (6.8%), while neutropenia (0.9%) was the most common grade 4 toxicity.

The OS benefit of those receiving ribociclib and endocrine therapy, regardless of the endocrine therapy partner, was sustained in this longer-term follow-up, concluded Clark. The addition of ribociclib also lengthens time to chemotherapy and chemotherapy-free survival, which I think is an incredibly important outcome for these patients who live for many years and who would like to delay the time to chemotherapy for as long as possible. I believe that these data are continued evidence that ribociclib should be considered for use in pre- and perimenopausal women with newly diagnosed [estrogen receptor]positive metastatic breast cancer.

References:

1. Tripathy D, Im S-A, Colleoni M, et al. Updated overall survival (OS) results from the phase III MONALEESA-7 trial of pre- or perimenopausal patients with HR+/HER2- advanced breast cancer (ABC) treated with endocrine therapy (ET) +/- ribociclib. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract PD2-04. https://bit.ly/33WH2ly.

2. Tripathy D, Im S-A, Colleoni M, et al. First-line ribociclib or placebo combined with goserelin and tamoxifen or a nonsteroidal aromatase inhibitor in premenopausal women with hormone receptorpositive, HER2-negative advanced breast cancer: results from the randomized phase 3 MONALEESA-7 trial. Presented at: 35th Annual Miami Breast Cancer Conference; March 8-11, 2018; Miami, FL. Abstract 626.

3. Tripathy D, Im S-A, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904-915. doi:10.1016/S1470-2045(18)30292-4.

4. Im S-A, Lu Y-S, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316. doi:10.1056/NEJMoa1903765.

Excerpt from:
Significant Survival Benefit Found with Ribociclib to Treat HR+/HER2- Breast Cancer - Cancer Network

Imagine being a doctor and having a precocious resident permanently by your side, giving you brilliant insight into disease and helping you to identify the best treatment path for your patients.

A team at Salesforce Research believes this scenario is closer to reality than you might think, as a result of a series of exciting developments in AI vision technology and machine learning.

Breast cancer affects more than two million women worldwide each year, with around one in eight women in the United States developing breast cancer over the course of their lifetime. There were also 2,550 new cases of breast cancer in men in the U.S. in 2018. Alarmingly, rates of breast cancer are increasing in nearly every region globally.

Salesforce Research collaborated with the Ellison Institute to develop ReceptorNet, a deep-learning algorithm that can determine hormone-receptor status - a crucial biomarker for clinicians when deciding on the appropriate treatment path for breast cancer patients - with excellent sensitivity and specificity numbers. This work has been published in the journal Nature Communications under the title 'Deep learning-enabled breast cancer hormonal receptor status determination from base-level H&E stains.'

While using AI to try to improve outcomes for breast cancer patients is not new, efforts up until now - such as Google's AI breast cancer screening tool - have largely focused on diagnosing cancer.

What makes ReceptorNet unique is that it focuses on improving the way treatment decisions are made for breast cancer patients. Specifically, ReceptorNet predicts hormone-receptor status from an inexpensive and ubiquitous tissue image. That's in contrast to the current standard of care, which requires both a more expensive, less widely available type of tissue image - and a trained pathologist to review those images.

Crucially, because it is a less expensive and quicker way of determining hormone-receptor status than the system used commonly today in countries like the U.S., it could potentially help make high-quality decision-making for breast cancer therapies more accessible - allowing patients globally to receive the best possible treatment path, regardless of the expertise available in their healthcare system.

The development of ReceptorNet originated in conversations between Salesforce researchers and Dr. David Agus, Founding Director and CEO of the Lawrence J. Ellison Institute for Transformative Medicine of USC.

Dr. David Agus, Founding Director & CEO, Lawrence J. Elison Institute for Transformative Medicine of USC

Dr. Agus is a renowned oncologist and a professor of medicine and engineering. He explains that there has long been a belief among cancer doctors that tumor cells contain crucial information about cancer that the human brain can't quite extract.

'The human brain is very good at determining whether or not there is cancer based on looking at patterns in cells,' says Dr. Agus, 'but it can't determine the subtle differences in these patterns that correlate with the outcome of the cancer. In other words, what the molecular on/off switch is.'

This means that a patient might be diagnosed with cancer but then have to wait weeks for the results of molecular studies to determine what treatment they should receive.

'Our team has been working on using AI to understand patterns of cells and help make treatment decisions for several years. We had this notion that maybe we could find the answer to those molecular questions instantaneously with AI and machine learning,' Dr. Agus says.

That's where the Salesforce Research team came in. 'We have a world-class AI research team,' says Nikhil Naik, Lead Research Scientist at Salesforce Research and the first author on this study, adding that, 'the collaboration also matched our philosophy of developing technology that doesn't just serve the purpose of the company, but also has a positive impact on people and on the world.'

With a PhD in computer vision from MIT, Naik says he realized early on that Salesforce would be in an ideal position to help.

The algorithm is able to determine subtle patterns the human eye can't possibly perceive.

The team developed an AI solution that is able to extract vital clues about breast cancer by learning to spot patterns in images of tumors, using a cheap and widely available imaging process. Naik gives a simple analogy.

Say you have an accident and you think you may have broken your arm. What if, instead of having to go to the hospital for an X-ray, you could just take a photo of your arm on your cell phone and an AI algorithm could determine whether or not you had a fracture?

'That is very similar to what we are doing. We are replacing an expensive, time-consuming process that requires specialized technology with a simpler, more widely available technology for imaging, using artificial intelligence.'[MC(2]

So how does this work in practice? Typically, when a patient is diagnosed with breast cancer, a pathologist will analyze their tumor tissue under a microscope using a process called immunohistochemistry (IHC) staining, to look for the presence of hormone receptors that allow the cancer to grow. This helps them to decide on the best course of treatment, such as hormone therapy or chemotherapy.

The problem with IHC staining is that it is expensive, time-consuming, and not readily available in many parts of the world, particularly in developing countries.

ReceptorNet has learned to determine hormone receptor status by using a much less expensive and simpler imaging process - hematoxylin and eosin (H&E) staining - that analyzes the shape, size, and structure of cells.

ReceptorNet has been trained on several thousand H&E image slides, each containing billions of pixels, from cancer patients in dozens of hospitals across the world.

'The algorithm is able to look at individual pixels and determine subtle patterns that the human eye can't possibly perceive,' says Andre Esteva, Head of Medical AI, and co-author on the study, explaining that patterns can yield vital clues about how to treat the cancer.

An illustrative interpretation of how AI can spot what the human eye can't see

Since early 2019, Naik and Esteva have been leading a team at Salesforce that focuses on delivering AI applications for social good, primarily in the areas of medicine and science. Recently, the team created search engines for COVID-19 to help researchers and clinicians find information faster.

'There's a significant benefit to doing this kind of AI research in industry, as opposed to academia. AI teams tend to flourish when provided with industrial scale compute capabilities - and industrial scale budgets - because those elements make it much easier to rapidly experiment,' says Esteva.

'I think the most impactful applications of AI will be in healthcare,' adds Research Scientist Ali Madani, who assisted on the computer vision algorithm that powers ReceptorNet.

Madani talks passionately about the transformative impact AI could have on people's lives. 'There are direct applications that could improve society as a whole,' he says. 'That's the underlying motivation which has drawn me to AI and healthcare.'

An algorithm that's only 80% accurate is not good enough for a critical application, like determining which cancer therapy to give to a patient.

So, what could this mean for clinicians and patients? The ability to determine hormone-receptor status from H&E stains could make treatment less expensive and more readily available, particularly in developing countries.

It could also, says Dr. Agus, mean patients are spared an agonizing wait between diagnosis and the initiation of treatment.

Proposing a future use case of this new technology, Dr. Agus said to, 'Imagine when a woman comes in for her diagnosis and we can tell her right there on the spot what her treatment should be. Or in a third-world country (where molecule tests aren't available), imagine potentially being able to, just by scanning a slide, tell a woman that she can get a pill that could put her breast cancer under control. All of a sudden there's a transformation in medicine.'

In order for AI in medicine to deliver its full potential, clinicians must first have confidence in its accuracy.

'An algorithm that's only 80% accurate is not good enough for a critical application, like determining which cancer therapy to give to a patient,' acknowledges Naik.

In the test phase of the ReceptorNet project, when the algorithm was tested on images it had never seen before, it achieved 92% accuracy for hormone receptor determinations, which indicates its potential for future clinical deployment.

Numerous small, incremental changes were made to ensure the algorithm was able to deliver accurate predictions, regardless of differences in the preparation of the tissue samples it was analyzing. Crucially, the algorithm has also been able to deliver reliable performance across different demographic groups.

There have long been concerns that healthcare and evidence-based medicine can be biased against certain groups, because they are often underrepresented in the evidence base. However, during the development of ReceptorNet, researchers were able to achieve accurate results across a variety of different groups, which could be vital in order to build confidence in the performance of the AI among healthcare professionals.

Naik says, 'We analyzed this by splitting the data based on things like age, race, and location, and statistically there was no difference in the performance of the algorithm.'

Throughout the design process, the Salesforce team worked closely with Dr. Agus, Dr. Dan Ruderman, and Dr. Michael F. Press at The Ellison Institute, to ensure they were aware of any possible biases that could exist in the data that was fed into the model. This close collaboration also helped to ensure that the objectives of the team were closely aligned with the clinical workflows and questions that clinicians, doctors, and nurses would be interested in.

Despite this, the team was aware that not every medical professional would be easily convinced that AI could be relied upon.

Naik says that the pathologists they spoke to were initially skeptical, explaining that this kind of prediction based on an H&E slide is not something pathologists could do on their own.

'However, when they saw that the algorithm was working so well, they were really impressed that it was able to make these predictions just by learning from thousands of images - and also that it was able to confirm their suspicions about what kinds of patterns could be predictive. That was very impressive and exciting for them.'

Dr. Agus agrees. 'When we first started looking at how we could answer molecular questions instantaneously with AI and machine learning, we achieved some good results. But when we teamed up with Salesforce, those results went from good to great.'

But when we teamed up with Salesforce, those results went from good to great.

From a clinical perspective, this technology could eventually lead to a number of positive impacts. In a developed country such as the U.S., it could reduce the cost of care and the time it takes to initiate breast cancer treatment, because it uses much less expensive imaging technology and automated decision-making. It could also improve accuracy and deliver better outcomes for patients.

In developing countries where there is limited access to IHC staining, it could have a big impact in terms of broadening access to treatment.

The immediate effect of this work is to lay a foundation for future studies to compare the clinical workflow of a pathologist with and without this type of AI, in order to better understand its full potential.

Dr. Agus says that, 'This is just the tip of the iceberg with what we're going to be able to do with AI in cancer care. It's just a pilot project to show what's doable. Now, we can get deeper and deeper, and I can envisage a day not too far away, when just by looking at a slide, I can tell, with the help of AI, tell somebody 'you're going to get Drug X and not Drug Y because of how the cells are arranged'.'

For Esteva, one of the most exciting things about this project is that it has shown how AI can do more than just mimic the role of a doctor.

'What we're doing here is actually training AI to do something that the physician can't do, as an added capability to their repertoire. The AI can see patterns that are essentially invisible to the physician, and potentially critical for the patient.'

AI could ultimately also have a positive impact on the doctor-patient relationship. With access to AI-powered insights, doctors could have more informed conversations with their patients at an early stage in their treatment path, giving them a fuller, data-driven picture of what may lie ahead in terms of treatment and therapy.

What gets me really excited is thinking, 'where is this going to go in the next five or 10 years?'

Esteva is keen to stress that AI will help augment the role of a doctor, not replace it.

'What gets me really excited is thinking, 'where is this going to go in the next five or 10 years?' Unfortunately, many of us can relate to situations where someone we love was given the wrong therapy or misdiagnosed. You end up asking yourself how their lives could have been different if a slightly better decision was made. A single moment can have a ripple effect in a patient's life for years or decades.'

'Physicians should be able to make the best possible decisions based on all available medical knowledge. If you can build AI that can help doctors make the right decisions, by harnessing the collective intelligence of physicians and medical data, that's incredibly powerful.'

Dr. Agus adds, 'AI and machine learning are going to herald a new era, with potential to be applied to diseases beyond cancer and ultimately create better outcomes for patients. It won't happen overnight, and it will be a slow, step-by-step process, but we're embarking on a journey over the next decade to improve every aspect of what we do, through data. That's really exciting.'

Disclaimer

salesforce.com Inc. published this content on 10 December 2020 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 10 December 2020 16:20:03 UTC

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AI at Work: How Salesforce AI Could Make Therapeutic Decision-Making for Breast Cancer More Accurate, Affordable and Accessible - marketscreener.com

Pune, India, Dec. 10, 2020 (GLOBE NEWSWIRE) -- The global heparin market size is expected to reach USD 11.43 billion by 2027, exhibiting a CAGR of 3.9% during the forecast period. The market size stood at USD 8.39 billion in 2019. The increasing cases of cardiovascular diseases such as deep vein thrombosis & pulmonary embolism are expected to spur demand for heparin in the forthcoming years, states Fortune Business Insights, in a report. The market size in North America stood at USD 4.28 billion in 2019. The growth in the region is attributed to the prevalence of cardiovascular diseases such as pulmonary embolism. The higher adoption of advanced heparin products will have an excellent effect on the market in the region.

Key Development:

May 2019: Pfizer, Inc. announced that it has received the approval from the U.S. FDA for the administration of its heparin product offering, Fragmin to minimize the recurrence of symptomatic venous thromboembolism (VTE) in pediatric patients aged one month and above.

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Rising Incidence of Chronic Disorders to Incite Business Development

The increasing prevalence of cardiovascular diseases around the world, including heart attacks and strokes will spur opportunities for the market. As per the American Heart Association (AHA) Heart Disease and Stroke Statistics, an estimated 5.3 million Americans suffered from atrial fibrillation in 2019.

The growing demand for heparin among patients can have an excellent impact on the market. As per the Centers for Disease Control and Prevention, coronary heart disease is the most common type of heart disease, killing 365,914 people in 2017.4. About18.2 million adultsage 20 and older have CAD (about 6.7%). Moreover, 2 in 10 deaths from CAD happen in adults less than 65 years old. The increasing awareness about the benefits of heparin in the treatment and management of heart diseases will improve the prospects of the market in the foreseeable future.

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Minimal Impact on the Market During COVID-19

The limitations on non-essential medical procedures and consultations has had a drastic impact on the global market amid COVID-19. The healthcare industry has observed a decline in other medical services besides coronavirus. The increased emphasis on COVIDs vaccine has reduced the demand for other therapeutics.

Furthermore, the lack of supply and production of heparin will simultaneously limit the scope of the market. However, government initiatives, including heavy investments and free medical aid will influence the healthy growth of the market in the time of the pandemic.

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High Adoption of Advanced Products to Boost Market in North America

The market size in North America stood at USD 4.28 billion in 2019. The growth in the region is attributed to the prevalence of cardiovascular diseases such as pulmonary embolism. The higher adoption of advanced heparin products will have an excellent effect on the market in the region.

The increasing healthcare expenditure is expected to foster the healthy growth of the market in North America. The presence of major companies can further enhance the development of the market in the region. Europe is expected to hold the largest share owing to the acceptance of technologically advanced products in the region. The rising number of patients suffering from a range of cardiovascular diseases will further spur opportunities in the region.

Asia Pacific is expected to experience a rapid growth rate owing to the growing patient population. The surging healthcare expenditure in the developing nations will have a tremendous effect on the market in Asia Pacific.

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Heparin Market to Hit USD 11.43 Billion with a CAGR of 3.9% by 2027; Rising Prevalence of Chronic Diseases to Propel Business, states Fortune Business...

Dublin, Dec. 08, 2020 (GLOBE NEWSWIRE) -- The "Prostate Cancer Disease Coverage Forecast and Market Analysis to 2036" report has been added to ResearchAndMarkets.com's offering.

Newly approved therapies for castration-resistant prostate cancer are set to create a shift in the way that the disease is treated, while creating a competitive environment for new market entrants.

Latest Key Takeaways

The report estimates that in 2018, there were 1.3 million incident cases of prostate cancer worldwide in males aged 40 years and older, and forecasts that number to increase to 1.5 million cases by 2027.

In the US, prostate cancer is the most common non-cutaneous malignancy diagnosed in men, and is the second-leading cause of cancer mortality in men behind lung cancer.

The overall likelihood of approval of a Phase I prostate cancer asset is 4.9%, and the average probability a drug advances from Phase III is 51.5%. Prostate cancer drugs, on average, take 9.0 years from Phase I to approval, compared to 9.5 years in the overall oncology space.

Pfizer's next-generation androgen receptor (AR) inhibitor Xtandi is the market leader in prostate cancer due to its established efficacy across prostate cancer segmentations and a lack of near-term generic competition. Bolstered by recent and planned expansions into additional prostate cancer segments, Xtandi will continue to be the leading option in this indication. Future expansion opportunities include potential use in combination with PARP inhibitors Talzenna or Rubraca in metastatic castration-resistant prostate cancer (mCRPC) patients.

Xtandi is also being trialed in combination with leuprolide in the Phase III EMBARK study for non-metastatic hormone-sensitive prostate cancer patients progressing on definitive therapy. Potential expansion into this segment represents a significant opportunity to improve outcomes earlier in the treatment paradigm, but the combination will have to demonstrate a significant benefit over existing localized treatment options to justify the additional clinical and financial toxicity of Xtandi treatment.

Since the launch of generic abiraterone in the US in November 2018, sales of Johnson & Johnson's cytochrome P450c17 inhibitor Zytiga have begun to erode. Further generic erosion is expected in the EU and Japanese markets in the next few years, decimating sales of the multi-blockbuster. Although branded Zytiga will continue to decrease in market share, use of abiraterone as part of standard regimens will continue and may expand to include several novel combinations.

The PARP inhibitors Rubraca and Lynparza were both approved in the US in May 2020 for the treatment of mCRPC patients following AR inhibitor therapy. Rubraca received accelerated conditional approval in mCRPC with a deleterious BRCA mutation (germline and/or somatic), while Lynparza received full approval for use in the broader homologous recombination deficient (HRD) population. To potentially differentiate the PARP assets, both are being trialed in the first-line setting of mCRPC; Rubraca in combination with Xtandi against Xtandi alone, and Lynparza with abiraterone against abiraterone alone. There is potential synergy with these combinations as its hypothesized that AR inhibitors may sensitize tumors to PARP treatment by reducing DNA damage repair (DDR) expression.

Late-phase PARP inhibitors Zejula and Talzenna are also being developed in combination with next-generation treatments and will join a crowded PARP treatment space. Zejula is being tested in combination with abiraterone against abiraterone alone as first-line therapy for mCRPC patients. Similarly, Talzenna is being studied in combination with physician's choice of Xtandi or enzalutamide in mCRPC patients, also as a first-line option. The potential synergy of the PARP inhibitors with AR modulators is promising, but a strong benefit will have to be seen to justify use in the front-line setting of mCRPC. If approved, it is likely that these regimens will be limited to the HRD or even BRCA populations, where they will have strong utility but somewhat limited commercial impact due to the relatively small prevalence of these biomarkers.

Next-generation AR inhibitors Nubeqa and Erleada have shifted the treatment paradigm to include these therapies in earlier segments of disease such as non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC). Expansion into earlier segments and lines of therapy is ongoing. Bayer is looking to expand Nubeqa's label to include use in very high-risk localized patients and metastatic hormone-sensitive patients. Johnson & Johnson will continue to try and differentiate Erleada with an aggressive development plan that includes potential expansions into chemotherapy-naive mCRPC patients as part of a combination with abiraterone, as well as into the localized setting for patients treated with prostatectomy or radiation therapy.

Akt inhibitors ipatasertib and capivasertib are a potential new mechanistic addition to the prostate cancer space, but the efficacy/tolerability profile of these PI3K/Akt/mTOR pathway inhibitors may prevent approval and potential usage. Ipatasertib is a pan-Akt inhibitor from Roche currently in development for asymptomatic or mildly symptomatic mCRPC patients with PTEN loss as part of a combination with abiraterone. PTEN loss is not a standard target in this indication, but represents a significant market opportunity as it is estimated to occur in approximately 20% of primary prostate cancers and up to 50% of castration-resistant tumors. However, ipatasertib is beset by known class toxicities of PI3K/Akt/mTOR pathway inhibitors such as diarrhea, rash, and ALT/AST elevations that could be detrimental to its regulatory chances. AstraZeneca's Akt inhibitor capivasertib has also demonstrated mixed results in prostate cancer.

In the Phase I/II ProCAID trial, capivasertib in combination with docetaxel failed to meet the primary endpoint of improved progression-free survival in mCRPC patients. However, the combination did improve overall survival in these patients irrespective of PI3K/Akt/mTOR pathway mutations. This has led to initiation of the Phase III CAPItello-281 trial testing capivasertib in combination with abiraterone in de novo mHSPC with PTEN loss.

Several checkpoint inhibitors are in development for prostate cancer, but late-phase data from ongoing combination trials are needed to fully determine their relative outlook in the indication. Merck is pursuing an aggressive late-phase development strategy for Keytruda in prostate cancer that includes combinations with Lynparza, Xtandi, and docetaxel for the treatment of mCRPC patients. Opdivo is also in late-phase development as part of a combination with docetaxel in mCRPC patients after failure on a next-generation hormone therapy. Finally, Roche's Tecentriq, the lone anti-PD-L1 antibody in late-phase development for prostate cancer, is currently in Phase III development in combination with Xtandi or in combination with Cabometyx in mCRPC patients after failing on a next-generation hormone therapy.

Myovant's relugolix is a GnRH receptor antagonist that is differentiated from available GnRH antagonist Firmagon by its oral formulation, which will facilitate use in patients undergoing localized definitive therapy who also need ADT and may also allow use of an intermittent ADT option in advanced hormone-sensitive patients looking to mitigate side effects and maintain quality of life.

Key Topics Covered:

OVERVIEW

DISEASE BACKGROUND

TREATMENT

EPIDEMIOLOGY

MARKETED DRUGS

PIPELINE DRUGS

KEY REGULATORY EVENTS

PROBABILITY OF SUCCESS

LICENSING AND ASSET ACQUISITION DEALS

CLINICAL TRIAL LANDSCAPE

DRUG ASSESSMENT MODEL

MARKET DYNAMICS

FUTURE TRENDS

CONSENSUS FORECASTS

RECENT EVENTS AND ANALYST OPINION

KEY UPCOMING EVENTS

KEY OPINION LEADER INSIGHTS

BIBLIOGRAPHY

APPENDIX

For more information about this report visit https://www.researchandmarkets.com/r/jj2ao6

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Global Prostate Cancer Disease Coverage Forecast and Market Analysis 2020-2036 - Xtandi will Remain the Best-selling Therapy Over the Next Decade -...

Possible TMI alert: You know that sleepless feeling when youre curled up on your sleeping side and one nostril is so stuffed you cant breathe so you switch to the other side to give it a break then that one stuffs too? Tired of this cycle, I met with Jason Erdan, the head herbalist at Alchemist Kitchen in NYC, a botanical dispensary dedicated to connecting you with the power of plants. to find out the best supplements to fight fall allergies.

The benefit of herbalism is that often one can find a plant based equivalent for manyeven mostallopathic (or Western) remedies with fewer side effects, says Erdan. When it comes to finding relief for allergies, Erdan explains that the first step is to know exactly what youre up against. Seasonal allergies are the bodys immune responses to common allergens entering your system. This results in your body releasing T-cells (parts of the immune system that attack foreign particles) to clean up and remove the invader. This stimulates the inflammatory response and releases histamine, causing allergic symptoms. To find the internal balance to both relieve and prevent these symptoms, Erdan says one has to understand the symptoms, the system, and the individual. Allergies arent coming to me for a consultation, the person that has them is, says Erdan. And they want a personalized plan based on everything from their current habits, exercise routine, supplement regimen, sleep schedule, and diet.

While both over-the-counter and prescribed antihistamines are helpful to combating allergens, they can often come with side effects like drowsiness. Erdans main recommendation for the majority of individuals struggling with seasonal allergies is to consult with ones physician first, and then incorporate adaptogens like ashwagandha, and mushrooms, like reishi, into ones diet.

Why? Ashwagandha is an adaptogen that helps manage stress and inflammation in the body by controlling our cortisol (or stress hormone) and blood sugar levels. This means if the immune system is depressed, this anti-inflammatory, immune-boosting adaptogen enhances the immune response. If the immune system is overactivelike with allergiesit helps to regulate and promote homeostasis (the balance of bodily functions).

Reishi mushrooms (Ganoderma lucidum), known as lingzhi in Chinese, are also high in antioxidants and can act as natures natural antihistamine. They are stimulants that help regulate the Th1 levels, which are responsible for battlingintracellular parasites within the body and inhibiting inflammatory compounds.

Erdan always recommends discussing any large changes with your physician, but he stresses that along with all of the more clinical remedies that we often turn to, the foods that you do and dont eat are a huge contributing factor to combating inflammation of all kinds, especially seasonal allergies. After taking Erdans advice, my ever-present allergy attacks have become more and more sporadic and much less aggressive, and I couldnt be more grateful. So the next time you feel those peskyor in my case, debilitatingallergies coming along, make sure to talk to your doc, but also take a peek at your diet and try to squeeze some adaptogens and healthy mushrooms into your routine.

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The Two Things an Herbalist Wants You To Take To Stop Cold-Weather Allergies in Their Tracks - Well+Good

Medicine is ever-evolving on a daily basis. Keeping track of the changes can be an almost-full-time job.Stacker looked at a number of medical journals and media sources to discover the biggest breakthroughs the year you were born, from 1921 to the current day.

From diseases that have been around for decades, such as diabetes and the flu, to cutting-edge tools like artificial intelligence and 3D printing, explore how medical and scientific professionals continually conduct research and clinical trials to improve the lives of patients. Sometimes advances arent immediately adopted, as with the Pap smearthat wasnt integrated into womens health care for 16 years after it was invented. But other times the path from laboratory to everyday use is much more abbreviated, like with insulin, which was used to treat diabetes only a year after it was discovered.

Another recurring theme in medical history is the repurposing of medicines that have worked for one disease in the past, to see how theyll work with another. A number of drugs and vaccines are being re-explored to manage COVID-19. Not all the heroes of medical research come from a traditional backgroundone was an electric engineer who worked for a major record label. Some were recognized with the highest honors, but others still have little visibility decades after their death. Funding for the research behind the breakthroughs is always a considerationsometimes it comes from foundations and government entities, but other times via donations from individuals and enterprises.

The dark side of medical history shown here includes unethical behavior by researchers in the past, which explains why some in the Black community arent exactly early adopters when it comes to clinical trials and new treatment options.

Advances noted here focus not only on the body, but also the mind. Explore this slideshow to see all the ways that health care has changed over the past century.

You may also like: Countries with the best life expectancy

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Medical history from the year you were born - The Elkhart Truth

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About nine years ago, California-based longhaul truck driver Richard Hall was in for a big surprise when he got his first Department of Transportation medical exam.

You should be in a coma, the medical examiner said, looking at the results of Halls bloodwork. He told me my blood sugar level was 392, and that Im diabetic.

Needless to say Hall, 50, a former physically active construction worker before becoming a truck driver, was shocked. Like many truck drivers, Hall had no idea he was diabetic, or that his blood sugar levels were dangerously high.

Nine years ago, Richard Hall was suprised to learn he had Type 2 diabetes.(Courtesy Hall)

Doctors and diabetes experts say Hall is one of a growing number of truck drivers and Americans in general who either have no clue they have Type 2 diabetes by far the most common form of diabetes or might be ignoring some of the more common signs of the so-called lifestyledisease. Unfortunately, even some drivers who have been diagnosed with diabetes are taking chances by not watching their weight, not eating right and not exercising, according to experts.

Diabetes is a disease in which the bodys ability to produce or respond to the hormone insulin is impaired, resulting in abnormal metabolism of carbohydrates and elevated levels of glucose-surge in the blood and urine. It can be detected in a urine or blood test, or at home by pricking a finger, putting a drop of blood onto a test strip, and inserting it into a glucose monitor.

Early on, youll feel fine, until one day, boom, your body is going to crash, said Kay Pfeiffer, senior vice president at TrueLifeCare of Brentwood, Tenn., a firm that helps employers and employees wrestle with the impact of diabetes.

Pfeiffer

Medications are a temporary solution, Pfeiffer told Transport Topics. Diabetes not managed, sooner or later, something is going to happen.

For instance, untreated diabetes is one of the leading causes of blindness.

If blood sugar is too high for too long, you run the risk of having damage to the eyes, the kidneys and the heart, said Natalie Hartenbaum, a medical doctor and recognized expert in occupational fitness and truck driver health. Those that cant control their blood sugar will generally end up on insulin.

Hall says diabetes has not interfered with his driving. But he only drives about nine hours a day to avoid getting fatigued.

RELATED: Options Abound for Elevating Drivers Health and Wellness

Because of his diagnosis, Hall was only given a one-year medical card, rather than the two-year card that a healthier diver is typically given after passing a medical exam administered by one of the more than 50,000 certified Federal Motor Carrier Safety Administration examiners. About 43% of drivers have a medical certification of one year or less, according to David Thorpe, a Fayetteville, N.Y., chiropractor who has trained more than 5,000 FMCSA certified medical examiners in his career. Thorpe has focused his medical practice on drivers and occupational medicine for over 30 years.

Thorpe

So why is diabetes such a prominent issue among drivers? The answer is its a stressful job, a lot of time away from home, poor eating habits, drivers are notoriously overweight, and in poor health in general. Plus it's an aging population, Thorpe told TT.

Thorpe said that diabetic drivers can sometimes be managed without drugs, but its not uncommon for them to receive oral medications. Oftentimes they work very well, other times they dont, he said. Even when taking drugs, Type 2 diabetics need to take care of their health, Thorpe said.

Really, we dont know that much about Type 2 diabetes, Pfeiffer said.

The medical experts do know this: There is no cure for Type 2 diabetes. Its a disease that requires those who have it to eat healthy, keep their weight in check, and exercise. You have to get in front of diabetes. You have to have the will to manage diabetes, Pfeiffer, a former hospital nurse, told Transport Topics.

Type 1 diabetics, believed to be only about 5% of the U.S. diabetic population, are dependent on insulin to stay healthy and risk almost certain death if not taking it.

But in a way, Type 2 diabetics have a tougher battle ahead of them because they must radically alter their daily lives.

While about 7% to 10% of the U.S. population is believed to diabetic, a 2014 FMCSA survey of longhaul drivers self-reported higher rates of diabetes for drivers 14.1%. The study also concluded that the prevalence of obesity is more than twice as high (69% vs. 31%) in longhaul drivers as the general population, and the prevalence of morbid obesity is more than twice as high as well (17% vs. 7%).

About 25% of truck drivers over the age of 54 are diabetic, according to numbers compiled by TrueLifeCare.

This past June, an FMCSA-sponsored Virginia Tech Transportation Institute study, Commercial Driver Safety Risk Factors, used data from more than 21,000 drivers to help understand the impact of health and other challenges for those sitting behind the wheel.

While the study concluded that treated diabetic truck drivers are at no greater risk of accidents, it noted that those same treated drivers were 38% more likely to be convicted of a moving violation compared to drivers who do not have diabetes or elevated blood sugar.

The study further concluded that diabetic drivers not being medicated for the disease had a threefold increased crash risk.

Larry Wolfe, retired medical doctor

While there are many good reasons for drivers such as Hall to keep their blood sugar in control, diabetes is an issue for the whole country, not just truck drivers, said Larry Wolfe, a retired medical doctor who specialized in endocrinology nearly his entire career. Wolfe was a staff doctor at the Vanderbilt University Diabetes Center for 10 years.

Its almost an epidemic, he told TT. Truck drivers tend to be obese, dont exercise, they eat wrong, so their diabetes is a real problem to manage, even under the best of circumstances. The major fear always was that they could experience hypoglycemia and lose consciousness while they are driving.

The common signs of Type 2 diabetes include profuse sweating, irritability, a lack of coordination, blurry vision and shaky hands. Ignoring the signs of Type 2 diabetes can lead to ulcers on the feet or legs that can ultimately result in amputations.

Pfeiffer said when some drivers feel symptoms of the disease, they sometimes stop at a convenience store and get a Coke.

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Theyll say to themselves, Ive gotten used to it, she said. But its very, very dangerous.

Thats why Hall, who spends three months at a time away from home hauling dry goods across much of the country in his tractor-trailer, says he tries to eat mostly chicken and fish and avoids sweets to do the best job he can to control his blood sugar. And when he gets home, he visits his doctor.

To get exercise, I even walk around the truck three times to do my pre-trip, Hall said. The last time he checked his blood sugar level, it was 182, a little high, but he has registered up to 249. The American Diabetes Association (ADA) says a normal blood sugar reading for an individual fasting is 100 or lower. If the level is 126 or higher after fasting for eight hours or more, a person could be diabetic.

There also is another problematic issue related to diabetes: It adds costs to an employers bottom line, according to the most recent diabetes report by the Health Care Cost Institute. The per capita annual spend in 2014 for people with diabetes enrolled in employer health plans was $16,021 (combined employer and employee). Thats nearly four times the $4,396 per capita spend for health plan members without diabetes.

How did turkey-to-table change this year? What obstacles were suppliers going through to get turkeys to grocery stores? Join us as we talk with J.J. Smith, President of Valley Proteins, about how staying open-minded and flexible helped his business of delivering turkeys persevere.Hear a snippet, above, and get the full program by going to RoadSigns.TTNews.com.

The ADA states that people with diabetes typically will experience three additional days of absenteeism and have 12 days of lost productivity each year associated with the disease.

Diabetes goes along with the epidemic of obesity, Wolfe said. And unfortunately, we wont be able to get a good handle on the treatment of Type 2 diabetes until we get a handle on how to treat obesity. Thats the real problem that we dont know how to get people to lose weight. If we could, there would be a whole lot less Type 2 diabetes.

Wolfe said a person can have Type 2 diabetes for 10 years and not know it. Since it is possible for drivers to not have symptoms, the easiest thing for some of them to do is deny having the disease. Its a very frustrating practice to take care of truck drivers, he said.

Wolfe added, Its a disease where the patient has to assume a lot of the responsibility for treatment. Its a complicated disease because it requires you to think about it every day of your life. If you dont take it seriously, no doctor in the world is going to help you.

What was really sad for me as a physician was when the poor patient was in the position of having to choose between his health and making a living, Wolfe said.

From a regulatory standpoint, FMCSA relies on a drivers treating physician and the medical examiners to ensure that drivers who take insulin and those who dont take it all have a stable medication and treatment regimen prior to medically qualifying them to get a medical card.

Federal regulations require that insulin-treated diabetics fill out an assessment form in which the drivers treating clinician must attest that the driver has a stable insulin regimen and well-controlled diabetes. The form poses a series of diabetes management-related questions that can aid the medical examiner in deciding if a driver is fit to get behind the wheel.

Hartenbaum

Hartenbaum said she believes that since there are no specific federal guidelines for medical examiners, the so-called best practices used by medical examiners to qualify a driver can vary.

Because of the lack of specific federal guidance, Hartenbaum said she is very concerned that there may be an increased crash risk for diabetics. But it hasnt shown up yet, she said.

FMCSA doesnt monitor medical conditions, Hartenbaum said. They dont monitor sleep apnea, they dont monitor blood pressure, they dont monitor heart disease. They have medical standards and medical guidelines. But its up to the medical examiner to evaluate whether the individual is at risk of sudden or gradual incapacitation due to a medical condition, and whether a study is needed to evaluate that.

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Diabetes: The Bump in the Road for the Longhaul Truck Driver - Transport Topics Online

In 1992 when investigators began testing trastuzumab (Herceptin) in women with HER2-positive breast cancer, many observers predicted failureand they kept on predicting failure throughout the trial process. Even after the FDA approved the drug in 1998, some observers scoffed at the modest survival benefit it had demonstrated to that point and predicted that targeted therapy would never be a major form of cancer treatment. There was a great deal of skepticism about targeted monoclonal antibodies back in the 1990s. People didnt believe that it would be possible to make antibodies that bound specifically to cancer cells or, if it was possible, that the antibodies would kill the cancer cells. Its hard to imagine now, but those first trastuzumab trials I did in the mid-90s were actually controversial, said Howard A. Skip Burris III, MD, president of clinical operations and chief medical officer at Sarah Cannon in Nashville, Tennessee.

It wasnt until the subsequent trials that used trastuzumab in women with early-stage breast cancers, trials that showed a much bigger survival benefit than the trials in metastatic cancers, that everyone saw trastuzumab as a major breakthrough, and many people realized that targeted therapies might proliferate quickly, he said.

There was, of course, reason for skepticism. A small number of successful targeted therapies existed longbefore trastuzumab, but none of them launched a new class of cancer treatments that successfully fought a wide range of tumor types.

Indeed, physicians have known since the 1940s that iodine-131 therapy can selectively target thyroid cancer and that androgen deprivation therapy can selectively target prostate cancer. Hormone deprivation did find one other major use in the 1970s, when tamoxifen (Soltamox) was approved for hormone receptorpositive breastncancer, but neither iodine-131 nor any other elemental radioisotopes have become major treatment types.

Thus, many people doubted that the approval of the first 2 monoclonal antibodies, trastuzumab and rituximab (Rituxan), signified an explosion in new targeted therapies, and if not for rapid advances in genetics, proteomics, and molecular synthesis, the doubters may have been right.

But the 2001 approval of a third novel targeted therapy, imatinib mesylate (Gleevec), turned many skeptics into believers. Unlike trastuzumab and rituximab, imatinib is a small molecule drug, but it is a highly specific inhibitor of tyrosine kinase enzymes that are overactive in a number of cancers that are Philadelphia chromosome positive. It was also obvious, from the very first trials, that imatinib was an incredibly effective treatment, particularly for chronic myelogenous leukemia (CML). A phase 1 trial launched in 1998 reported that the drug caused CML to quickly disappear in the vast majority of patients with early-stage disease, and a 5-year follow-up found that 98% of patients were still in remission.1

Within a decade of trastuzumabs initial approval, the FDA approved another 23 targeted cancer therapies. More than 80 targeted cancer therapies are now available to patients.2

Its been an amazingly rapid proliferation, and its happened because weve made huge technical advances on 2 distinct fronts, Burris said. When trastuzumab arrived, we were still working to sequence one human genome at a cost of many billions of dollars. Systematically analyzing tumors for druggable driver mutations seemed unrealistically expensive, but then, over the course of just a few years, the technology became so much faster and so much cheaper that it was entirely feasible. The other big advance has been on the chemistry side. Pharmaceutical and biotech companies have gotten much better at creating molecules that will bind to their intended targets. Better chemistry has allowed medications to bind to many targets like KRAS that were once considered undruggable.

Monoclonal Antibodies

The first attempt to develop a targeted monoclonal antibody treatment for cancer dates back to 1980, when a team led by Lee Marshall Nadler, MD, treated a patient affected by non-Hodgkin lymphoma with the murine monoclonal antibody AB 89. The treatment, however, did not produce a significant clinical response.3

Several other research groups tested monoclonal antibodies against hematological cancers over the next decade, but none of them worked well enough for FDA approval. In fact, many of these murine formulations induced immune reactions that both created adverse effects and reduced therapeutic half-life.4

The first monoclonal antibody to demonstrate itself safe and effective enough for FDA approval was rituximab, which kills B cells by targeting the surface antigen CD20. The drug, which was first approved in 1997 for B-cell lymphoproliferative disorders, is currently indicated, alone or in various combinations, to treat forms of non-Hodgkin lymphoma and chronic lymphocytic leukemia.

Trastuzumab, which was approved a year later, is a genetically engineered, humanized monoclonal antibody that fights cancer 2 ways. First, it inhibits HER2, a glycoprotein receptor with tyrosine kinase activity that promotes breast cancer cell growth. Second, it induces cancer cell death via antibodydependent cell-mediated cytotoxicity.

Trastuzumab was developed at the University of California, Los Angeles (UCLA) by a team led by Dennis Slamon, MD, PhD. Slamon identified the HER2-positive subtype of breast cancer in the early 1980s, demonstrated that this subtype was particularly deadly and aggressive, and hypothesized that a HER2 inhibitor would extend life. The team spent several years developing drug candidates, and the very first human trials were conducted at UCLA in 1990.

Trastuzumab has since shown significantand often dramaticbenefit when used in a variety of ways against HER2-positive breast cancer. For example, a 2005 trial of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer found that after a median follow-up of one year, 1693 women assigned to the observation group had nearly twice as many events (recurrence, contralateral breast cancer, second nonbreast malignant disease, or death) as the 1694 women assigned to the trastuzumab group.5

In the early 1990s, women with the HER2-positive subtype had an average life expectancy after diagnosis of 3 to 5 years. Today, an estimated 3 million patients have an average life expectancy of 7 to 10 years, thanks largely to receiving trastuzumab.6

The next targeted therapy to reach patients was gefitinib (Iressa), an EGFR tyrosine kinase inhibitor (TKI) approved in 2003 for the treatment of nonsmall cell lung cancer (NSCLC). Studies published the following year showed that a particular subset of patients with EGFR mutation positive NSCLC were far more likely than others to respond to gefitinib7 and a second EGFR TKI approved in 2004, erlotinib (Tarceva).8

The phase 3 trial that led to erlotinibs approval found that only 8.9% of patients responded to the drug and that it increased median overall survival (OS) by just 2 months to 6.7 months,9 but the subgroup analysis found traits ranging from female sex to never smoking to EGFR expression that predicted response.

Later research demonstrated that EGFR TKIs greatly increase survival in patients with EGFR-positive NSCLC. Combination chemotherapy in advanced NSCLC typically results in a median OS of 8 to 12 months and a median progression-free survival (PFS) of 5 to 6 months.10 Among 137 patients with EGFR-mutant metastatic lung adenocarcinoma treated with erlotinib or gefitinib at Dana-Farber Cancer Institute between 2002 and 2009, however, median PFS and OS were 12.1 months and 30.9 months, respectively. Twenty patients (14.6%) were 5-year survivors.11

Even though targeted therapies had already proven themselves effective against other tumor types, especially imatinib against CML, a lot of people were still skeptical that they would work against lung cancer, said Paul Bunn, MD, distinguished professor of medicine-medical oncology and the James Dudley Chair in Cancer Research at the University of Colorado School of Medicine in Aurora, Colorado. But the skeptics were quickly silenced. The trial results were pretty convincing.

Shortly after the FDA approved erlotinib, it also approved bevacizumab (Avastin), the first example of another novel form of targeted therapies called antiangiogenics, which are designed to deprive tumors of blood.

Many targeted therapies were conceived long before they were approved, including antiangiogenics. The idea of fighting cancer by starving tumors of blood first occurred to Judah Folkman, MD, in 1963, when he and Fred Becker, MD, were comparing possible substitutes for blood transfusions. During those experiments, the 2 young doctors injected adult mouse melanoma cells into isolated, perfused thyroid glands taken from dogs and noticed that while tumors did form, they never developed blood vessels or grew beyond 2 mm in diameter.12

Other investigators had already made similar observations, but Folkmans efforts to understand his findings led him to complete a few more experiments and then to hypothesize, via a 1971 piece in the New England Journal of Medicine, 13 several very new ideas:

The paper drew such negative response that it quickly made Folkman a pariah.

The approval of bevacizumab in 2004 was a triumph for Folkman, but because he died in 2008, he did not live long enough to see how broadly the use of antiangiogenics would expand. Bevacizumab alone is now approved as monotherapy or in combination with other medications to treat 7 different tumor types,14 and more than a dozen other angiogenesisinhibiting medications have subsequently been approved as cancer treatments.15

Many of them work by binding to VEGF, preventing it from activating the VEGF receptor, and blocking the formation of new blood vessels. The first 2 approved drugs that targeted this pathway were sorafenib (Nexavar), which was approved in 2005, and sunitinib malate (Sutent), which was approved in 2006.16,17

Oddly, an antiangiogenic drug had already been approved for use in most of the world (just not the United States) slightly before Folkman first devised the idea in 1963, but it was approved to treat sleeplessness and morning sickness rather than cancer. That drug, of course, was thalidomide (Synovir, Thalomid), which was later approved to treat multiple myeloma, many decades after the discovery that it causes birth defects.

Molecules that inhibit PARPs, which play a major role in DNA damage repair, were another form of targeted therapy that existed long before FDA approval to treat cancer. PARP-inhibiting substances, such as nicotinamide, have been used for various indications over the decades. In the 1970s, some thought these substances might prime patients for better response to chemotherapy or radiation.18

The FDA, however, did not support a PARP inhibitor for cancer treatment until 2014, when it approved olaparib (Lynparza) for advanced ovarian cancer with a deleterious or suspected deleterious germline BRCA mutation.19 It has since approved more PARP inhibitors, including rucaparib (Rubraca), niraparib (Zejula), and talazoparib (Talzenna) across a wide variety of tumors, including metastatic prostate cancer and certain subtypes of breast cancer (TABLE19-22).20-22

Immunotherapies are another type of targeted cancer treatment that were hypothesized many decades before they were realized. A German physician working in the mid-19th century noticed that tumors tended to regress when cancer patients were infected by erysipelas, so in 1868, he intentionally infected a patient with erysipelas to treat their cancer.23

In the 19th century, the American doctor William Coley began directly injecting tumors with mixtures of live and inactivated Streptococcus pyogenes and Serratia marcescens. He reported more than 1000 regressions or cures over the course of his career, but he was poorly esteemed among researchers of the day and his findings were largely ignored.24

The work that laid the foundation for todays immunotherapies took place in 1982, nearly a century after Coleys first efforts at immunotherapy, when James Allison, PhD, and colleagues identified and described tumor-specific antigens in a mouse model of T-cell lymphoma. 25 A year later, they described the first T-cell antigen receptor.

The first immune checkpoint molecule was discovered in 1987 and named CTLA-4. Just one year later, the first CTLA-4blocking antibody was discovered, and in 2011, the first CTLA-4blocking drug, ipilimumab (Yervoy), was approved by the FDA.26

The sheer number of targeted therapies that have been approved in the [past] 20 years is amazing, even if youre just looking at my specialty of lung cancer, said Bunn, who is a past president of the American Society of Clinical Oncology. And thanks to those treatments, along with earlier diagnosis, survival rates have improved considerably, from roughly 4 to 6 months untreated to a year with chemotherapy to 5 years or more with TKIs. But theres still work to be done because neither the TKIs nor the immunotherapies, or anything else, tends to produce complete responses or absolute cures. We need to find things we can pair with TKIs to kill the cancer cells they dont, and there are a large number of combinations that are currently being investigated.

Burris is also excited to see so many new targeted treatmentsand combinations of targeted treatmentsin trials right now. He is particularly optimistic about antibody-drug conjugates, therapies that combine antibodies that bind to tumors with a second agent that attacks the tumor. The most successful such product may be ado-trastuzumab emtansine (Kadcyla), which combines trastuzumab with a cytotoxic drug thats released after the molecule binds to the cancer.

When you see what big pharmaceutical companies are paying to acquire the makers of antibody- drug conjugates, you get a good sense of how promising the technology is, Burris said. The technology for binding the antibody and the cytotoxic agent, for getting the antibody to bind with the tumor, and for releasing the cytotoxic agent at the right time all keep improving. This is a promising strategy for attacking a wide range of tumors that dont have a druggable driver mutation.

References:

1. Druker BJ, Guilhot F, OBrien SG, et al; IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J. Med. 2006;355(23):2408-2417. doi: 10.1056/NEJMoa063867

2. Targeted therapies: overview of targeted therapies for cancer. My Cancer Genome. Updated May 27, 2019. Accessed November 2, 2020. https://bit.ly/385txmr

3. Nadler LM, Stashenko P, Hardy R, et al. Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen. Cancer Res. 1980;40(9):3147-3154.

4. Dillman RO, Beauregard JC, Halpern SE, Clutter M. Toxicities and side effects associated with intravenous infusions of murine monoclonal antibodies antibodies. J Biol Response Mod. 1986;5(1):73-84.

5. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659-1672. doi:10.1056/NEJMoa052306

6. UCLA oncologist Dennis Slamon wins 2019 Lasker Award for clinical medical research. UCLA newsroom. September 9, 2019. Accessed November 2, 2020. https://bit.ly/2TKzvkt

7. Paez JG, Jnne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-1500. doi:10.1126/science.1099314

8. Tsao M-S, Sakurada A, Cutz J-C, et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med. 2005;353(2):133-144. doi:10.1056/NEJMoa050736

9. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated nonsmall-cell lung cancer. N Engl J Med. 2005;353(2):123-132. doi:10.1056/NEJMoa050753

10. Schiller JH, Harrington D, Belani CP, et al; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced nonsmall- cell lung cancer. N Engl J Med. 2002;346(2):92-98. doi:10.1056/NEJMoa011954

11. Lin JJ, Cardarella S, Lydon CA, et al. Five-Year survival in EGFR-mutant metastatic lung adenocarcinoma treated with EGFR-TKIs. J Thorac Oncol. 2016;11(4):556-565. doi:10.1016/j.jtho.2015.12.103

12. Folkman J, Long DM Jr, Becker FF. Growth and metastasis of tumor in organ culture. Cancer. 1963;16:453-467. doi:10.1002/1097-0142(196304)16:4<453::aid-cncr2820160407>3.0.co;2-y

13. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182-1186. doi:10.1056/NEJM197111182852108

14. Bevacizumab. National Cancer Institute. October 5, 2006. Updated September 10, 2020. Accessed November 2, 2020. https://bit.ly/2TKcNcn

15. Angiogenesis inhibitors. National Cancer Institute. Updated April 2, 2018. Accessed November 2, 2020. https://bit.ly/325ldQ0

16. Nexavar. Prescribing information. Bayer HealthCare Pharmaceuticals Inc; 2010. Accessed November 2, 2020. https://bit.ly/360eQid

17. Sutent. Prescribing information. Pfizer Inc; 2011. Accessed November 2, 2020. https://bit.ly/2I0jzbr

18. Clark JB, Ferris GM, Pinder S. Inhibition of nuclear NAD nucleosidase and poly ADP-ribose polymerase activity from rat liver by nicotinamide and 5-methyl nicotinamide. Biochim Biophys Acta. 1971;238(1):82-85. doi:10.1016/0005-2787(71)90012-8

19. FDA approves olaparib tablets for maintenance treatment in ovarian cancer. FDA. Updated August 17, 2017. Accessed November 3, 2020. https://bit.ly/324l5Ah

20. FDA grants accelerated approval to new treatment for advanced ovarian cancer. News release. FDA. December 19, 2016. Accessed November 3, 2020. https://bit.ly/34Pzsu7

21. Niraparib (Zejula). FDA. Updated May 30, 2017. Accessed November 2, 2020. https://bit.ly/36bQT7J

22. FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. FDA. Updated December 14, 2018. Accessed November 2, 2020. https://bit.ly/3jUsp7r

23. Busch W. Aus der Sitzung der medicinischen Section vom 13 November 1867. Berlin Klin Wochenschr. 1868;5:137. (Ger).

24. Dobosz P, Dziecitkowski T. The intriguing history of cancer immunotherapy. Front Immunol. 2019;10:2965. doi:10.3389/fimmu.2019.02965

25. Allison JP, McIntyre BW, Bloch D. Tumor-specific antigen of murine T-lymphoma defined with monoclonal antibody. J Immunol. 1982;129(5):2293-2300.

26. Yervoy. Prescribing information. Bristol Myers Squibb; 2018. Accessed November 2, 2020. https://bit.ly/2HQsQT7

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A Look Back Prompts Memories of Initial Skepticism for Targeted Agents Shattered by Positive Efficacy Trials - Targeted Oncology

If youre a woman in the menopause transition, hot flashes and night sweats arent the only things that should grab your attention. It turns out that the stage of fluctuating hormones leading to your final period is a risky time for your heart health.

Thats the consensus of nearly a dozen experts who reviewed the research on the topic for the American Heart Association. They published theirscientific statement on November 30 in the journal Circulation.

RELATED: 10 Ways to Beat Menopausal Belly Fat

This phase of a womans life is a time of accelerated cardiovascular risk at multiple dimensions, including changes in lipids, body fat, metabolic syndrome, and vascular health, saysSamar R. El Khoudary, PhD, MPH, an associate professor of epidemiology at the University of Pittsburgh and the chair of this AHA statement writing committee.

These changes significantly raise the potential for heart disease later in life, and this is why women and their doctors must see themenopause transitionas a crucial time for intervention, rather than wait until women are older and experiencing disease, Dr. El Khoudary says.

The AHA committee undertook their thorough review because many more studies on women going through the menopause transition are available now than previously, especially since the last AHA guidelines on treating women were written, in 2011.

Some of the best studies have followed women during their midlife years. This includes the Study of Womens Health Across the Nation (SWAN), the Melbourne Womens Midlife Health Project, and the Penn Ovarian Aging Study (POAS).

RELATED: 5 Things Weve Learned From the Most Important Menopause Study

Other, especially older, studies have tended to group women into before menopause and after, leaping over the important phase that occurs as they shift from one time of life to the other, El Khoudary says.

Still, even more research is needed, she says, especially studies testing specific cardiovascular interventions, such as medications, during this stage.

Understanding these processes is so important, because heart disease is the leading cause of death for women. If you didnt know that, youre not alone. Only 56 percent of women are aware of this fact, El Khoudary observes.

Cardiologists dont sufficiently focus on this, either. While most know that a womans risk of heart disease increases once the protective effects of estrogen cease after menopause, many dont intervene soon enough to make a difference, she says.

More cardiologists are becoming aware of this important window. But we are behind because of this notion that women dont get cardiovascular disease until later in life, and that they have different symptoms than men, says Ruwanthi Titano, MD, an assistant professor of cardiology at the Icahn School of Medicine at Mount Sinai in New York, who was not involved with the review.

Doctors need to view the menopause transition as a risk factor akin to high cholesterol and hypertension, Dr. Titano says.

RELATED: Coping With Hot Flashes and Other Menopausal Symptoms: What 9 Celebrities Said

A woman is considered post-menopausal only after she has gone a full year without a single period. During the transition period, known as perimenopause, a woman can go months without a menstrual bleed, but then menstruate, resetting the clock.

During this time, hormones fluctuate greatly. One of the main hormones is estrogen. It is this hormone that is thought to provide the key heart protection women experience earlier in life.

Once a woman becomes post-menopausal, her estrogen level remains low.

RELATED: What Are Irregular Periods?

And that's by no means the only change that happens in the body during the menopause transition. They cumulatively raise the potential for heart troubles down the road, El Khoudary says. Its not like a button you press that quickly increases your mortality. But, accumulated together, the changes women experience increase her risks for cardiovascular disease.

During this period, blood cholesterol levels start to rise. The carotid artery begins to thicken (a subclinical measure of atherosclerosis, El Khourdary says). Excess weight moves from being stored around the thighs and buttocks to around the abdominal organs and the heart more dangerous locations. And metabolic syndrome symptoms increase, the committee found.

All these factors can set the stage for later heart attacks or strokes.

RELATED:What Experts Want BIPOC Women Know About Menopause

Even once-healthy HDL cholesterol levels seem to take a destructive turn.

HDL, or good cholesterol, is considered to be cardioprotective. But once a woman transitions to menopause, it actually seems to become bad for you, El Khoudary says, citing her own soon-to-be published research.

This has led to the hypothesis that HDL experiences some dysfunctionality as women transition through menopause, causing it to stop functioning the way it used to, she says.

Doctors erroneously think of menopause as a point of demarcation, El Khoudary says. One day youre menstruating, then youre not. But menopause is actually a lengthy and varied process, with hormonal fluctuations sometimes lasting years.

Its connection to heart disease is especially complex. Age of menopause, the stage of menopause youre in, and even your race may play a role, the paper states. For instance, women who experience menopause at an earlier age, typically before 45, have a higher risk for later heart disease.

Socioeconomic indicators, prior cardiovascular health, and other factors are associated with a younger transition. Black, Hispanic, and Native Hawaiian women tend to experience the menopause transition at a younger age.

Women whose ovaries are surgically removed when theyre younger are also more likely to face increased cardiovascular problems, the paper states.

So, too, are women who suffer severe vasomotor symptoms, including hot flashes and night sweats.

The analysis reveals the importance of monitoring womens health during midlife and using the menopausal transition as a critical window for intervention.

Women and their doctors need to understand how the body changes during this time, and the ways that can boost your heart disease risk, El Khoudary says.

Your doctor might prescribe medications to keep blood pressure, cholesterol, and blood sugar in check, critical parts of the AHAs Lifes Simple 7 heart campaign.

My message for perimenopausal women is to engage in your healthcare. Get your yearly checkup with your physician or see your cardiologist if you have one. Your doctor should be looking more closely at your lipid panel, because maybe numbers that were acceptable before arent good enough anymore, Titano says.

RELATED:Fitness After 40 and Beyond: What to Know About Midlife Exercise Needs

Sufficient physical exercise is key. El Khoudary was stunned to learn that just 7.2 percent of women past menopause are meeting physical activity guidelines.

RELATED:7 Fun Ways to Move More in Midlife

Similarly, adopting a healthy eating plan, one that becomes part of your life rather than a short-term fad, can protect your heart. But post-menopausal women dont seem to be doing this either, with only 20 percent saying they consistently maintain a healthy diet.

Other important actions to protect your heart include getting sufficient sleep, adopting stress-reduction techniques, and quitting smoking if you havent already.

RELATED: Having Multiple Severe Menopause Symptoms Is Linked to Increased Risk for Heart Disease

While it might seem that properly dosed and timed menopausal hormone therapy (MHT) could lower womens heart disease risk, this has not been proved in research.

The last major study of hormone therapy, the Womens Health Initiative, was stopped in 2002 when participants were found to have a small increase in heart disease, blood clots, cancer, and stroke. But these women were older, generally many years past their menopause transition.

We dont know what would happen in terms of heart disease if you gave hormone therapy to women during the transition, El Khourdary says. We dont have the clinical trials for women in their forties or fifties.

Still, some smaller studies, many of them observational ones, indicate that newer formulations of hormone therapy, especially those taken via skin patches or sprays rather than pills, may offer some heart protection, she says.

RELATED: Timing and Type of Hormone Therapy Impacts Its Effectiveness in Preventing Heart Disease

The Circulation paper notes the promise, but also indicates that the AHA may not be ready to recommend that women take hormone therapy for their heart.

The literature supporting a critical role for the time of initiation of MHT use relative to menopause, with initiation at <60 years of age or within 10 years of menopause appearing to be associated with reduced CVD risk, strongly calls for further research assessing MHT use, including potential contrasts by form, route, and duration of administration, on cardiometabolic effects in women traversing menopause, the paper states.

RELATED: Hormone Therapy May Prevent UTIs in Post-Menopausal Women

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The Menopause Transition Poses Heart Disease Risk - Everyday Health

(UroToday.com) At the second prostate cancer session at the 2020 Annual Meeting of the Society of Urologic Oncology (SUO), Dr. Maha Hussain presented the results of the PROfound study, Study of Olaparib (Lynparza) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer (PROfound Study), which demonstrated the superiority of olaparib, a poly (adenosine diphosphate-ribose) polymerase inhibitor, for treatment of metastatic castrate-resistant prostate cancer (mCRPC).

After a brief discussion of the ToPARP trial and some of the rationale which lead to the genesis of the PROfound study, Dr. Hussain launched into a discussion of the trial itself. In this trial, published in the New England Journal of Medicine in May 20201 with an update in the same journal in September2, patients with the following characteristics were enrolled:

There were no restrictions based on ECOG status, volume or location of metastases, or prior taxane therapy.

Patients with mutations in BRCA1, BRCA2, ATM were called and cohort A and were the primary population for the analysis.

These patients were randomized to olaparib 300mg twice-daily vs the physician's choice of abiraterone or enzalutamide. The primary endpoint was imaging-based progression-free survival in cohort A based on blinded central review.

Overall the results were resoundingly positive, with olaparib showing superiority in progression-free survival (7.4 mo vs 3.6 mo, HR 0.34 0.25-0.47, P<0.001), the median time to pain progression (HR 0.44 0.22-0.91, P <0.02), andoverall survival (19.1 months vs 14.7 mo, HR 0.69 9.50-0.97 P =0.02)in cohort A. This overall survival difference is particularly impressive given an 81% cross over from the control to the olaparib arm after progression in these patients.

Results in the full population were similar, as were results from numerous prespecified subgroup analyses, including patients with and without prior taxane use, bone only and visceral metastases, and baseline ECOG score of 0 and 1.

This data lead to the United States Federal Drug Administration (FDA) to approve olaparib for patients with mCRCP with deleterious or suspected deleterious germline or somatic homologous recombination repair mutations who have progressed on enzalutamide or abiraterone. This recommendation was similarly adopted in theNational Comprehensive Cancer Network (NCCN) guidelines.

(Similar approval was given to rucaparib based on the TRITON2 study, though this was limited to tumors with deleterious BRCA mutations and men previously treated with taxane chemotherapy.)

As Dr. Daniel Spratt argued in his counterpoint, however, this approval may be overly broad.

When analyzing patients by which genes were altered, the 95% CI of patients with BRCA2 mutations was the only one not to cross 1 (HR 0.21 0.12-0.32) for progression-free survival despite there being similar numbers of patients with ATM and CDK12 mutations. The signal of benefit was generally much stronger in BRCA mutations for both OS and PFS, with very little signal of benefit in the remaining patients, so it may be wise to limit clinical use to patients with these mutations.

Dr. Spratt also pointed out that there now exists a large body of evidence suggesting there is very little benefit in using abiraterone after progression on enzalutamide (or similar) and vice versa. Thus, for the 44.7% (173/387) patients who received docetaxel only, and certainly for the 34% who had received no prior chemotherapy (133/387), olaparib cannot be said to have been compared to the current standard of care in this trial.

Thus even for patients with BRCA mutations, which seem to confer the most favorable responses to olaparib, it remains very much unclear whether olaparib should be chosen before exhausting the numerous alternative available therapies.

Presented by: Maha H.A. Hussain, MD, FACP, FASCO, Genevieve Teuton Professor of Medicine, Division of Hematology-Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine

Daniel Spratt, MD, Professor, Laurie Snow Research Professor of Radiation Oncology, University of Michigan

Written by: Marshall Strother, MD, Society for Urologic Oncology Fellow, Division of Urologic Oncology, Fox Chase Cancer Center, Philadelphia PA, @mcstroth duringthe 2020 Society of Urologic Oncology Annual Meeting December 2-5, 2020 Washington, DC

References:

1. de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 May 28;382(22):2091-2102. doi: 10.1056/NEJMoa1911440. Epub 2020 Apr 28. PMID: 32343890.

2. Hussain M, Mateo J, Fizazi K, et al. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. Published online September 20, 2020:NEJMoa2022485.

Related ContentPatients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Can Be Preselected to Maximize Benefit of Olaparib - Maha Hussain

Continued here:
SUO 2020: New Second Line Therapy for mCRPC: PARPi: Results from the PROfound Study - UroToday

Polycystic ovary syndrome (PCOS) is a medical condition that affects an estimated 8 to 13 percent of women who are of reproductive age.

PCOS can cause:

While these dont happen to every woman with PCOS, there are changes from a lifestyle perspective that can help reduce the likelihood these effects will occur.

This article will focus on some of the changes you can implement today, such as diet and exercise routines. As always, if you have specific questions, talk to your doctor who helps you manage your PCOS.

Women with PCOS experience higher rates of insulin resistance compared to women who dont have the condition. Insulin resistance affects your bodys ability to use blood sugar for energy.

Doctors have connected a lack of physical activity and excess body weight as potential contributing factors to insulin resistance, according to the National Institute of Diabetes and Digestive and Kidney Diseases.

Not all women with PCOS have overweight. The good news is physical exercise is something you can do for your health when you have PCOS, regardless of your weight.

A meta-analysis of 16 studies related to PCOS and exercise found that vigorous intensity aerobic exercise was the most likely to reduce body mass index (BMI) and insulin resistance in women with PCOS, according to an article in the journal Frontiers in Physiology.

The researchers compared moderate exercise to vigorous exercise. They also found that vigorous exercise and healthy diet interventions resulted in the greatest decreases in BMI.

A research review of lifestyle interventions in PCOS published in the journal Best Practice & Research Clinical Obstetrics & Gynaecology found that exercise helped to reduce weight, abdominal fat, and fasting insulin levels.

The review also found exercise could help women of all weight levels with PCOS either lose or maintain their weight to help them look and feel healthier.

A literature review of studies published in the journal Sports Medicine regarding types of exercises, such as strength training and aerobic activity, did not find one specific exercise type was the most beneficial to women with PCOS.

Some of the studies reviewed aerobic exercise and resistance training, riding a stationary bicycle versus riding a bicycle outside, and treadmill walking or jogging at a moderate intensity versus vigorous intensity. The authors did find there are many exercise types that could benefit women with PCOS.

The message from these and other studies is that exercise can usually help you when you have PCOS, and the best exercise is what you will do regularly. Bonus points if the exercise can be something you enjoy doing.

Here are some exercise types to consider:

These are just some examples of exercises you can do with minimal equipment and space.

Researchers have completed several studies regarding the best diet types for those with PCOS to follow. The Androgen Excess and PCOS Society used this research to make recommendations for women, which include:

If you arent sure where to start with incorporating these changes to your diet, talk to your doctor. Your doctor also may recommend seeing a dietitian to create an eating plan specific to women with PCOS.

Exercise to improve your PCOS doesnt have to take hours a week. Studies have found exercise sessions ranging from 30 minutes a day, three times a week, to three total hours per week improved metabolic and reproductive symptoms associated with PCOS.

The Androgen Excess and PCOS Society recommends getting at least 30 minutes of moderate to vigorous physical activity a day and increasing your activity effort when you can. Some of the ways you can incorporate exercise in your life include the following:

If boredom is a factor in your commitment to an exercise routine, utilize a combination of these exercise types, such as completing a different exercise session type three times a week.

Try to incorporate the following habits for healthy eating with each meal and snack:

Using these guidelines, you can often stay within recommended daily calorie requirements given your overall height, health level, and weight.

When you have PCOS, its always a good idea to talk to your doctor about the lifestyle changes you can make to improve your health. When it comes to exercise for your PCOS, its especially important you talk to your doctor if you have other medical conditions that could affect your ability to exercise. Examples include arthritis or heart-related conditions.

If you have been sedentary for some time or dont have a solid foundation in exercise safety or proper form, it may be a good idea to consult a personal trainer. Your personal trainer should have a fitness certification from an accredited organization. Examples include:

Your trainer should be experienced and emphasize safety.

Exercise can be an important part of your PCOS management. Not only does it improve your physical health, exercise can help you manage your stress levels.

If you arent sure where to start, seeing your doctor and finding a personal trainer can help set you on a safe pathway. Exercising at least three times a week and sticking with it can help you improve symptoms from PCOS.

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Exercise For PCOS: Sample Plan, Types of Exercise, and More - Healthline

SGF proudly welcomes Dr. Jennifer Hsu to its Woodbridge practice.

FAIRFAX, Va. (PRWEB) December 03, 2020

Shady Grove Fertility (SGF) announced today that reproductive endocrinologist, Jennifer Hsu, M.D., has joined the practice and will begin seeing patients in SGFs Woodbridge location late December 2020. As a University of Virginia Cavalier alumna, Dr. Hsu is proud to return to the state where her medical journey began.

The 85,000 babies and counting born at SGF is nothing short of a miracle, says Dr. Hsu. I am immensely proud to be a part of this team of people who are all 100% dedicated to the goal of building families and making dreams a reality.

Dr. Hsu will provide comprehensive fertility services to patients, including:

Dr. Hsu earned a full undergraduate merit scholarship from UVA, where she continued her graduate studies and earned a medical degree. As a medical student, Dr. Hsu extended her research efforts abroad in Quetzaltenango, Guatemala, and was ultimately honored with the Medical Alumni Association (MAA) Outstanding Medical Student Award. Her time in Central America allowed Dr. Hsu to exercise her fluency in Spanish.

She then completed her residency at Columbia University Medical Center, followed by a move to Boston where Dr. Hsu completed her fellowship in reproductive endocrinology and infertility at Massachusetts General Hospital. Today, she is board eligible in obstetrics and gynecology as well as reproductive endocrinology and infertility.

When patients are hurting, my vow is to stay by their side and help them through it, shares Dr. Hsu. Whether they need someone to listen, grieve with, or help them make a plan, I will be there. The journey to parenthood can be difficult, but I hope my patients never feel that they are alone.

Dr. Hsu is very active in the medical community. She is an experienced lecturer and oral examiner at Harvard Medical School and has spent time in Appalachia providing free medical and womens health services to residents. Additionally, Dr. Hsu is an accomplished researcher, having contributed to more than 15 presentations across the country on topics including intrauterine insemination (IUI), anti-Mullerian hormone (AMH), and polycystic ovary syndrome (PCOS). She has also served as a peer-reviewer for several publications including the Journal of Assisted Reproduction and Genetics.

Dr. Hsu is a very bright and compassionate physician who, on behalf of SGF, were very thankful to have part of our team, says Eric Widra, M.D., Chief Medical Officer at SGF.

Patients may schedule a new patient virtual physician consultation with Dr. Hsu by calling 1-877-761-1967 or submitting this brief form. Patients also have access to SGF Woodbridges unique financial options, such as the 100% refund program for IVF, that help make fertility treatment more affordable.

About Shady Grove Fertility (SGF)SGF is a leading fertility and IVF center of excellence with more than 85,000 babies born and 5,000+ 5-star patient reviews. With 37 locations throughout FL, GA, MD, NY, PA, VA, D.C., and Santiago, Chile, we offer patients virtual physician consults, deliver individualized care, accept most insurance plans, and make treatment affordable through innovative financial options, including 100% refund guarantees. More physicians refer their patients to SGF than any other center. Call 1-888-761-1967 or visit ShadyGroveFertility.com.

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Shady Grove Fertility (SGF) Welcomes Reproductive Endocrinologist, Jennifer Hsu, MD, to the Northern Virginia Physician Team - PR Web

Nearly 40 percent of Type-2 diabetics are meeting the amount of aerobic exercise recommended, but only 14 percent are meeting the resistance training standard.

NEW ORLEANS Mayoclinic.org says that type 2 diabetes also referred to as adult onset diabetes is a chronic condition that affects the way your body metabolizes glucose (blood sugar) resulting in your body either resisting the effects of the hormone insulin that regulates the movement of sugar into your cells, or doesn't produce enough insulin to maintain normal glucose levels.

Mayo comments that, type 2 diabetes develops, when the body becomes resistant to insulin or when the pancreas is unable to produce enough insulin. Exactly why this happens is unknown, although genetics and environmental factors, such as being overweight and inactive, seem to be contributing factors.

Research has demonstrated that exercise improves glycemic control in people with type 2 diabetes, alone, or the result of weight loss, improved insulin sensitivity, and modifications in cardiovascular risk factors like elevated blood pressure and triglycerides a blood fat associated with an excess of simple carbohydrates in the diet.

The American Diabetes Association recommends that people with type 2 diabetes attain a minimum of 150 minutes per week of aerobic exercise and at least two weekly resistance exercise sessions, while minimizing sedentary time.

A study Significant Dose-Response Between Exercise Adherence and Hemoglobin A1c Change which appears in the September 2020 issue of Medicine & Science in Sports & Exercise, examining the physical activity level in individuals with type 2 diabetes over the age of 65 years in the United States, found that only 25% met the American Diabetes Association 2007 guideline recommendations for total physical activity.

A separate study of physical activity levels in the United States reported that, 41.1% of individuals with type 2 diabetes met the aerobic exercise recommendations compared with only 12.4% for resistance training.

Canadian authors of this Medicine & Science study chose to examine, whether a doseresponse relationship existed between the level of adherence to prescribed exercise over a 6-month exercise intervention and glycemic control (specifically, change in hemoglobin A1c [HbA1c]) in patients with type 2 diabetes. And, if

this association was affected by any of the following factors: modality of exercise, age, sex, or glycemic control before participating in exercise training.

A HbA1c test, according to Medlineplus.gov, measures the amount of glucose attached to hemoglobin. Hemoglobin is the part of your red blood cells that carries oxygen from your lungs to the rest of your body. An HbA1c test shows what the average amount of glucose attached to hemoglobin has been over the past three months.

The Canadian researchers used data from the Diabetes Aerobic and Resistance Exercise (DARE) trial, a single-center, randomized controlled trial designed to evaluate in type 2 diabetes the effect of aerobic, resistance, and combined aerobic and resistance exercise training compared with no exercise training on glycemic control over 26 wk.

The aerobic exercise participants utilized a gradual intensity-based progression with a duration to 45 min at 75% of maximum heart rate per session, while the resistance participants worked up to three sets of eight repetitions of seven exercises at an intensity of eight maximal repetitions. The combined exercise training group completed both the aerobic and resistance training components.

The control group were encouraged to maintain their usual pretrial level of physical activity from baseline to the end of the intervention period.

Dietary guidelines were recommended from the Canadian Diabetes Association meeting 90% of the energy intake to maintain their weights during the study. HbA1c changes from baseline and the end of the 6-month supervised exercise intervention were evaluated.

It was concluded that, a doseresponse relationship between exercise adherence and change in HbA1c for aerobic and combined exercise but not for resistance exercise training. These results suggest that an increased volume of aerobic or combined aerobic and resistance exercise is associated with greater improvement in glycemic control.

If you have type 2 diabetes or are pre-diabetic, check with your physician first for guidelines, before you begin a new exercise program.

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Mackie: Type-2 diabetics need strength exercises in addition to aerobic - WWLTV.com

CARLSBAD, Calif., Dec. 2, 2020 /PRNewswire/ --Qualigen Therapeutics, Inc. (Nasdaq: QLGN) announcesthat it has completed the recertification of its supply of AS1411, and has begun final formulation and filling for use in the Company's proposed Phase 2a efficacy trials of AS1411 for the treatment of patients with COVID-19. Qualigen plans to seek U.S. Food and Drug Administration (FDA) approval for and to begin these trials in the first half of calendar 2021.

Qualigen's lead compound AS1411 is a nucleolin-targeting DNA aptamer drug candidate for the treatment of COVID-19 and other viruses. Preclinical studies at the University of Louisville's (UofL) Center for Infectious Disease have demonstrated the ability of AS1411 to protect cells from the damaging effects of the novel coronavirus. In addition, AS1411 holds potential as a broad antiviral therapeutic agent, which could expand its applications and market potential.

"Even with the roll-out of COVID-19 vaccines, we see this virus being around for many years to come in different forms. The mechanism by which AS1411 is believed to work, by blocking the ability of viruses to replicate in the body, may make our therapeutic effective against future mutations in COVID-19 as well as against other dangerous viruses including the flu," stated Michael Poirier, President, Chief Executive Officer and Chairman of Qualigen.

Mr. Poirier added: "Recertification of our AS1411 inventory represents another critical step in advancing our antiviral development program in a cost-efficient manner. We continue to move forward with our IND-enabling studies and are on track to commence the efficacy stage of human trials in the first half of next year, upon obtaining IND approval from the FDA. We believe there is great potential for this drug to be an effective therapeutic for COVID-19, in addition to other viral infections."

In June 2020, Qualigen signed an exclusive license agreement with UofL for U.S. patent rights covering the treatment of COVID-19 with AS1411, adding to Qualigen's other AS1411 license exclusivities. Qualigen intends to work with UofL to complete investigational new drug (IND)-enabling studies and plans to file an IND application with the FDA in early calendar 2021. Qualigen's aim is to initiate a Phase 2a clinical study in COVID-19 patients in the first half of calendar 2021.

About Qualigen Therapeutics, Inc.Qualigen Therapeutics, Inc. is a biotechnology company focused on developing novel therapeutics for the treatment of cancer and infectious diseases, as well as maintaining and expanding its core FDA-approved FastPack System, which has been used successfully in diagnostics for 20 years. The Company's cancer therapeutics pipeline includes ALAN (AS1411-GNP), RAS-F and STARS. ALAN (AS1411-GNP) is a DNA coated gold nanoparticle cancer drug candidate that has the potential to target various types of cancer with minimal side effects. The foundational nucleolin-targeting DNA aptamer of ALAN, AS1411, is also a drug candidatefor use in treating COVID-19 and other viral-based infectious diseases. RAS-F is a family of RAS oncogene protein-protein interaction inhibitor small molecules for preventing mutated RAS genes' proteins from binding to their effector proteins; preventing this binding could stop tumor growth, especially in pancreatic, colorectal and lung cancers. STARS is a DNA/RNA-based treatment device candidate for removal from circulating blood of precisely targeted tumor-produced and viral compounds. Because Qualigen's therapeutic candidates are still in the development stage, Qualigen's only products that are currently commercially available are FastPack System diagnostic instruments and test kits, used in physician offices, clinics and small hospitals around the world. The FastPack System menu includes rapid point-of-care diagnostic tests for cancer, men's health, hormone function, vitamin D status and antibodies against SARS-CoV-2. Qualigen's facility in Carlsbad, California is FDA and ISO Certified and its FastPack product line is sold worldwide by its commercial partner Sekisui Diagnostics, LLC. For more information on Qualigen Therapeutics, Inc., please visit https://www.qualigeninc.com/.

Forward-Looking StatementsThis news release contains forward-looking statements by the Company that involve risks and uncertainties and reflect the Company's judgment as of the date of this release. These statements include those related to potential future development, testing, efficacy, approval, manufacturing and commercialization of product candidates, including the possible effectiveness of AS1411 against COVID-19 or other viral infections and the approval and timing of clinical trials. Actual events or results may differ from the Company's expectations. For example, there can be no assurance that clinical trials will be approved to begin by or will proceed as contemplated by any projected timeline; that the Company will successfully develop any drugs or therapeutic devices; that preclinical or clinical development of the Company's drugs or therapeutic devices will be successful; that future clinical trial data will be favorable or that such trials will confirm any improvements over other products or lack negative impacts; that any drugs or therapeutic devices will receive required regulatory approvals or that they will be commercially successful; that patents will issue on the Company's owned and in-licensed patent applications; that such patents, if any, and the Company's current owned and in-licensed patents would prevent competition; that the Company will be able to procure or earn sufficient working capital to complete the development, testing and launch of the Company's prospective therapeutic products; that the Company will be able to maintain or expand market demand and/or market share for the Company's diagnostic products generally, particularly in view of COVID-19-related deferral of patients' physician-office visits and FastPack reimbursement pricing challenges; that adoption and placement of FastPack PRO System instruments (which are the only FastPackinstruments on which the Company's SARS-CoV-2 IgGtest kits can be run) will be widespread; that the Company will be able to manufacture the FastPack PRO System instruments and SARS-CoV-2 IgGtest kits successfully; that any commercialization of the FastPack PRO System instruments and SARS-CoV-2 IgGtest kits will be profitable; or that the FDA will ultimately approve an Emergency Use Authorization for the Company's SARS-CoV-2 IgG test. The Company's stock price could be harmed if any of the events or trends contemplated by the forward-looking statements fails to occur or is delayed or if any actual future event otherwise differs from expectations. Additional information concerning these and other risk factors affecting the Company's business (including events beyond the Company's control, such as epidemics and resulting changes) can be found in the Company's prior filings with the Securities and Exchange Commission, available atwww.sec.gov. The Company disclaims any intent or obligation to update these forward-looking statements beyond the date of this news release, except as required by law. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

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Qualigen Therapeutics Completes Recertification of Existing AS1411 Drug Supply for Use in Upcoming Clinical Trials - PRNewswire

It is normal for females to experience fluctuations in sexual desire throughout life. However, a substantial or total loss of interest in sex, or difficulty responding to stimulation, may indicate female sexual interest/arousal disorder (FSIAD).

FSIAD is a type of sexual dysfunction. A person with the condition may experience a lack of sexual desire, a lack of physical arousal, or both.

As with other types of sexual dysfunction, FSIAD can be distressing. It can affect a persons self-esteem, relationships, and overall well-being.

In this article, we explore FSIAD and its symptoms, causes, and treatments.

FSIAD describes a loss or significant reduction in sexual desire or physical arousal in females. It is a relatively new term that first appeared in the Diagnostic and Statistical Manual of Mental Health Disorders (DSM-5).

Previously, FSIAD was split into two separate disorders:

FSAD used to refer to a lack of lubrication and swelling in the female genitals, which researchers focused on as a cause for sexual dysfunction.

However, some experts argue that this is a flawed concept, as low levels of lubrication does not necessarily indicate female arousal, nor does it always prevent sex.

There is a close link between sexual desire and physical arousal. As a result, the DSM-5 combined the two conditions.

It is unclear how many people experience FSIAD specifically. However, sexual dysfunction is highly common in males and females.

A 2016 meta-analysis suggests that around 40.9% of premenopausal women worldwide experience at least one type of sexual dysfunction. Of those, 28% reported low sexual desire.

However, compared to some types of sexual dysfunction in males, such as erectile dysfunction, FSIAD is far less well-known.

According to the DSM-5, a person must have three of the following symptoms to have FSIAD:

They must also have:

In addition to this, people with FSIAD can experience symptoms in different ways. The condition may be:

Partners may notice that a person with FSIAD does not want to engage in sex most of the time and that they talk about it less, or not at all.

It is important to note that FSIAD is different from asexuality.

Asexuality is an umbrella term for sexual orientations that involve varying degrees of sexual and romantic attraction towards others. It is not a medical condition.

Some asexual people have lifelong preferences for nonsexual relationships. While a lifelong lack of interest in sex can occur due to sexual dysfunction, this is not always the case.

According to the DSM-5, for an FSIAD diagnosis to apply, a person must show signs of clinically significant distress about their lack of desire.

A person who identifies as asexual, does not feel distressed by it, and has no problem developing close relationships, does not meet the criteria for FSIAD.

Sexual desire and arousal are complex. Many factors influence the amount and type of sexual desire a person has and how their body responds to intimacy.

While a single cause is often difficult to identify, the DSM-5 notes that people with FSIAD often have other sexual or emotional difficulties, some of which are explored below.

A 2018 review found that relationship dissatisfaction was a risk factor for sexual dysfunction in females. This may be the result of communication problems, a lack of emotional intimacy, or unresolved conflict.

The mental and physical health of partners may also have an impact. If a person desires sex more often than their partner or partners, or they have sexual dysfunction themselves, this may influence the development of FSIAD.

A negative self-image, lack of confidence in ones body or appearance, and mood disorders are also associated with FSIAD.

Negative body image, or body dysmorphic disorder, may make the prospect of removing clothes or sexual activity stressful. Stress, anxiety, and depression can also reduce a persons desire to have sex.

However, it is important to note that low self-esteem, stress, and mental health conditions can occur as a result of FSIAD, and may not be the direct cause.

Some people with FSIAD have previously experienced emotional or sexual abuse. A 2020 study suggests that sexual trauma, such as childhood sexual abuse, can lead to shame surrounding sex, which may then contribute to sexual dysfunction.

Personal, cultural, and religious beliefs can play a role in FSIAD.

People who believe in traditional gender roles may feel they should not play an active role in sex or that they should not enjoy it. This may create feelings of shame surrounding sex.

If a person does not have much experience or knowledge about sex, they may have unrealistic ideas about what is normal in terms of sexual desire. They may also struggle to explain what they like or dislike, or be unaware of different sexual techniques.

It is important that people have access to quality sex education that normalizes sexual desire, and teaches that sex has a positive role in a persons well-being.

The 2018 review notes that sex education and feeling that sex is important in a relationship are both protective factors against sexual dysfunction.

Many people with FSIAD may also experience other types of sexual difficulties, such as:

Treating these conditions may help with improving a persons FSIAD symptoms.

Learn about the causes of pain during sex.

Other factors that may cause changes to a persons sexual desire and arousal include:

There are several ways to approach treatment for FSIAD. These include:

Talking with a sex therapist, psychotherapist, or counselor specializing in female sexual health can help someone identify factors contributing to their FSIAD.

A sex therapist or psychotherapist can help someone:

If relationship difficulties contribute to FSIAD, a therapist may also recommend relationship counseling sessions, where the persons partner also attends.

Medication options for FSIAD include Vyleesi (bremelanotide), which activates receptors in the brain that influence sexual behavior and desire.

Hormone therapy may help treat low sexual desire in people going through menopause or who have hormone imbalances.

These medications will not be appropriate for everyone. It is important to discuss the safety, interactions, and side effects of these treatments with a doctor before trying them.

If a persons sexual desire or physical response to sexual stimulation has changed since they developed a mental or physical health condition, or since they began taking a certain medication, this may be a factor.

A person can discuss the following options with a doctor:

If a person notices they have lower sexual desire than usual, or do not seem to respond to sexual stimulation as they used to, they can seek help from a physician or healthcare professional specializing in sexual function.

It can be difficult to talk about sexual dysfunction, but there is no shame in doing so. It is a medical condition, which can get better with treatment.

Being specific about any concerns or changes in desire or arousal will help a doctor advise on the next steps.

FSIAD is a type of sexual dysfunction that occurs when a persons sexual desire or arousal is much lower than usual. It can cause significant distress. However, sexual dysfunction is prevalent in females, and it is treatable.

Many factors may contribute to FSIAD, so a person may benefit from trying several treatment approaches. Options include individual therapy, trauma therapy, relationship counseling, or medication.

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What is female arousal disorder? Symptoms and treatment - Medical News Today

ALBANY Monique and Fred Wilson are lovingly known as the King and Queen of Phoebe, Fred as the familiar friendly face who greets visitors to the hospital and gives them rides through the massive parking lot and Monique as, among other duties, the face-to-face coordinator for the regions Young Survivors Coalition.

Its fitting, then, for the thousands of hospital employees and patients whove been treated there that Monique Wilson has been honored as the tree-lighter for the Phoebe Foundations annual Lights of Love celebration. And while the annual heart-felt ceremony was altered to a virtual celebration this year in deference to the coronavirus pandemic, that does little to dampen the enthusiasm of the woman chosen to represent the cancer survivors as the tree-lighter.

Even though we pre-recorded the (tree-lighting) event as a safety precaution and will show the ceremony later, it was still very moving for me, Monique Wilson, who is the survivorship data coordinator at Phoebe, said. Even filming it ahead of time, I was very nervous at first. But it was such a beautiful ceremony even with the social distancing that I got caught up in it. Ill never forget it.

Wilson was selected as the tree-lighter for the Lights of Love celebration, which is sponsored annually by the Phoebe Foundation and raises funds for cancer-related projects, as a breast cancer survivor. She was diagnosed in June of 2016 and is today cancer-free.

My husband and I were coming back from a trip to New Jersey, when I felt something strange (in my breast), she said. When we got home to Georgia, I rechecked the spot, and it was still there. No one on either side of my family has ever had breast cancer, so one of the things Ive learned from all this is that cancer does not discriminate ... it will impact anyone.

I called my family physician the next day, and she scheduled a mammogram. I got the phone call on June 26 that it was breast cancer. On the same day, the Carlton Breast Center called and said I needed to come in immediately for an ultrasound and biopsy. I told them I was going away for a birthday weekend, and the person who called said, Did you hear what I just said? I told her, Yes, and did you hear what I just said? I had my weekend but scheduled an appointment for the ultrasound and biopsy the next Monday.

Wilsons cancer was detected early (Stage 1) but was found to be invasive, so she began a series of 33 radiation treatments. Shes in the midst of a 10-year regimen of hormone blockers, but she is now cancer-free.

Sure, there was some depression and anxiety during the treatment, but I never lost faith, Wilson said.

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Now, her experience allows her to give a first-hand accounting to young cancer patients as they face their own battle.

We have women as young as 27 and as old as 49, and my having been through this gives me an opportunity to give them some honest answers that often comforts them, she said of the Young Survivors Coalition.

In addition, both Fred and Monique Wilson participate in their Tour de Pink, an annual 200-mile bike ride they take part in in New Jersey to raise funds to support and increase awareness of breast cancer treatment and prevention.

We do the Tour de Pink to raise funds for other women and even men who will be diagnosed with breast cancer and for those who have passed on, Monique Wilson said.

This years virtual tree-lighting ceremony will be unveiled on Phoebes Facebook and YouTube channels Thursday at 7 p.m. And, since the annual Lights of Love event is a fundraiser for the Phoebe Foundation, that groups Mandy Tedder said the broadcast will include an opportunity for the community to donate to the foundation.

Tedder said she doesnt think the pandemic will stop supporters from giving.

I believe people are going to come across, she said. This is their opportunity to be part of something extra special. This is the 37th year for Lights of Love, and while people know they cant come out for the celebration, they can gather with their immediate family and still be a part of this community tradition.

Funds raised through Lights of Love have been used to purchase a van that has taken cancer patients to and from treatments and to purchase radiation equipment. Tedder said this years funds will top off efforts to re-open the Light House, which was destroyed by straight-line winds in January of 2017. The newly built Light House, which provides respite opportunities for families of cancer patients, will be opened early next year at the corner of Second Avenue and Monroe Street.

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Monique Wilson tree-lighter for Phoebe's virtual Lights of Love - The Albany Herald

Amcenestrant (SAR439859), a new oral form of endocrine therapy that has shown early signs of efficacy, is being evaluated against the current standards of care in patients with estrogen receptor (ER) positive, HER2-negative locally advanced or metastatic breast cancer.

The agent, a selective estrogen receptor degrader (SERD), is being compared with physicians choice of endocrine therapy in the open label, phase 2 trial AMEERA-3 trial (NCT04059484). The control treatment involves choosing monotherapy from a list of agents with different mechanisms of action: anastrozole, letrozole, or exemestane, which are aromatase inhibitors; tamoxifen, a selective estrogen receptor modulator; or fulvestrant (Faslodex), a SERD (Figure).1

Figure. SAR439859 in Locally Advanced or Metastatic Breast Cancer

Amcenestrant is a next-generation SERD that, in preclinical studies, has demonstrated antitumor efficacy and regression in ER-positive breast cancer models and can be administered as an oral therapy because of its favorable pharmacokinetic profile.2 Fulvestrant, which has been available since 2002, must be administered via intramuscular injection because of limitations including low solubility and weak permeation.3

Its exciting to have a potential SERD that is oral and has potentially better bioavailability than fulvestrant. So many of us wondered whether these [novel] agents could substitute for fulvestrant in the future and potentially be a better option, said Sara M. Tolaney, MD, MPH, principal investigator for the AMEERA-3 trial, in an interview with OncLive.

SERDs work by serving as competitive antagonists to the ER, inducing conformational changes that lead to degradation of the receptors. They have dual functions. I think this accounts for their ability to block the signaling in ER-dependent tumors that may be potentially resistant to other endocrine therapies, said Tolaney, who is associate director of the Susan F. Smith Center for Womens Cancers and director of Clinical Trials in Breast Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts.

Amcenestrant has shown activity in patients regardless of ESR1 mutation status, which makes it very intriguing, added Tolaney, who also is an associate professor of medicine at Harvard Medical School in Boston. It is blocking the estradiol and binding to the estrogen receptor, which promotes inactivation and degradation. Its thought to do so more potently than fulvestrant does.

The goal of AMEERA-3 is to demonstrate that amcenestrant is superior to the endocrine therapy of physicians choice in patients who are refractory to endocrine therapy and have metastatic hormone receptor (HR)positive breast cancer, Tolaney said. The primary end point is progression-free survival (PFS). Secondary end points include overall survival (OS), objective response rate (ORR), disease control rate, clinical benefit rate (CBR), and duration of response (DOR).

Tolaney said the trial design takes into account the options available to patients with HR-driven breast cancer. In the first-line setting for metastatic hormonal receptorpositive disease, patients get a different endocrine backbone. Some patients are getting an aromatase inhibitor with CDK4/6 inhibition; some are getting fulvestrant with CDK4/6 inhibition. This trial allows for the flexibility for the physician to choose what is most appropriate for the patient based on their prior exposure to endocrine treatment, Tolaney said.

Amcenestrant is being administered at 400 mg daily in 28-day cycles until unacceptable toxicity, progression, death, investigator decision, or patient request.3 The comparators are being given based on approved labeling.4

In terms of eligibility requirements, the trial limits participants to 1 prior targeted therapy with a CDK4/6 inhibitor or 1 prior treatment with chemotherapy for advanced or metastatic disease. The criteria also require patients outside of China to receive a prior CDK4/6 inhibitor if they can get reimbursed for it; the number of participants without previous CDK4/6 inhibitor therapy will be capped at 20%. It has become standard of care to use CDK4/6 inhibitors with endocrine treatment in the first-line setting for metastatic, hormone receptorpositive disease, Tolaney noted.

Additionally, eligible patients are required to have progressed after 6 or more months of continuous endocrine therapy for advanced disease or to have relapsed while on adjuvant endocrine treatment for 2 or more years or within 12 months of receiving that therapy. Patients with brain metastases are excluded, as well those who previously received an mTOR inhibitor or a SERD other than fulvestrant, which must be stopped at least 3 months before randomization.

The trial seeks to enroll 282 patients through 126 worldwide locations. An extension is planned with an additional 90 Chinese participants expected to be enrolled. Tolaney said the trial is more than halfway accrued. It was a little delayed because of COVID [coronavirus disease 2019], but it has been doing well otherwise, she said. She anticipates enrollment will be completed early in 2021.

The rationale for AMEERA-3 stems from findings from an ongoing first-in human phase 1/2 study (NCT03284957) testing amcenestrant as monotherapy and in combination with other agents in postmenopausal women with ER-positive, HER2-negative metastatic breast cancer.

Investigators presented results for patients who received amcenestrant monotherapy in 2 cohorts of the study at the 2020 American Society of Clinical Oncology Virtual Scientific Program. The pooled data included women who received from 150 mg to 600 mg daily in part A of the study and those who took 400 mg daily in part B of the study. The primary end point in part B was ORR, documented by RECIST v1.1 criteria; secondary end points included overall safety profile; ORR based on ESR1 status (mutated or wild type); and CBR defined as complete and partial responses plus stable disease for 24 weeks or more.5

All patients in the study (N = 62) had received prior endocrine therapy in the advanced setting; 48.4% had 3 or more previous lines of therapy. Among 59 evaluable patients, the ORR was 6.8% (90% CI, 2.3%-14.8%), all partial responses. The CBR was 35.6% (90% CI, 25.1%-47.1%), which study investigators said was similar to that of fulvestrant in less heavily pretreated patients. Patients with wild-type ESR1 (n = 30) had better responses than those with mutant ESR1 (n = 28) for ORR (10.0% vs 3.6%, respectively) and CBR (40.0% vs 32.1%).

In a subset of women without prior treatment with a SERD, CDK4/6 inhibitor, or mTOR inhibitor (n = 14), the antitumor activity of amcenestrant was substantially greater and compared favorably with historical results for fulvestrant. The ORR was 21.4% (90% CI, 6.1%-46.6%) and the CBR was 64.3% (90% CI, 39.0%-84.7%).

Amcenestrant had a favorable safety profile with limited treatment-related adverse effects (TRAEs); 61.3% of women in the study had adverse effects, and all were grade 1 or 2, most commonly hot flush (16.1%); constipation (9.7%); and arthralgia (9.7); decreased appetite, vomiting, diarrhea, nausea and decreased appetite (all 8.1%); and fatigue (6.5%). No patients discontinued because of TRAEs.

Amcenestrant has the potential to become the best-in-class endocrine backbone across treatment lines in HR-positive breast cancer, according to Paul Hudson, chief executive officer of Sanofi, the company developing the drug.6

Amcenestrant also is being evaluated in comparison with letrozole in an ongoing phase 2 window of opportunity study (NCT04191382) in newly diagnosed ER-positive, HER2-negative breast cancer.7 In this study, patients are being randomized to receive amcenestrant at 400 mg or 200 mg daily, or to receive letrozole at 2.5 mg daily for 14 days prior to surgery. Biopsies will be taken before and after therapy to assess tumor biomarkers.

The primary end point is a change in Ki-67 after a 14-treatment period compared with baselines levels via immunohistochemistry assessment in tumor tissue. Secondary end points include the proportion of patients with relative decrease from baseline in Ki-67 of 50% or more, change in ER expression compared with baseline, and safety and tolerability. Ki-67 is a biomarker of cellular proliferation, and expression of Ki-67 in 14% or more of tumor nuclei is associated with poor prognosis in early breast cancer, investigators noted. This study began enrolling patients in December 2019 and is being conducted at 16 sites worldwide.7

Another study, AMEERA-5 (NCT04478266)8, is testing amcenestrant in combination with palbociclib (Ibrance), a CDK4/6 inhibitor, versus letrozole plus palbociclib as a firstline therapy for patients with ER- positive, HER2-negative breast cancer. The study, which aims to recruit 810 patients, has a primary end point of PFS and secondary end points of OS, ORR, DOR, and CBR.

Additionally, the Quantum Leap Healthcare Collaborative announced in June 2020 that amcenestrant was selected to be part of a new I-SPY 2 study arm.7 The study, known as the I-SPY 2 Endocrine Optimization Protocol (EOP), is focused on patients with molecularly low-risk, clinically high-risk, HR-positive, HER2-negative clinical stage II or III invasive breast cancer. Amcenestrant will be tested as a monotherapy and in combination with up to 3 other agents.

The I-SPY program was designed to identify therapies that are most effective in specific patient subgroups based on biomarker signatures. Sanofi is supplying the drug and providing financial support.9

See the article here:
Next-Generation Endocrine Therapy Moves Forward in Breast Cancer Trial - OncLive

The human endocrine system consists of a number of glands, which release hormones to control many different functions.

When the hormones leave the glands, they enter the bloodstream and are transported to organs and tissues in every part of the body.

The adrenal, or suprarenal, glands are located on top of the kidneys. They are divided into two regions. The right gland is triangular, and the left is crescent-shaped.

The adrenal glands secrete:

Both men and women have some androgen, but men have higher levels. Androgens control the development of characteristics associated with males, like facial hair and a deeper voice.

The hypothalamus is located just above the brain stem and below the thalamus.

This gland activates and controls involuntary body functions, including respiration, heart rate, appetite, sleep, temperature, and the circadian cycles, or daily rhythms.

The hypothalamus links the nervous system to the endocrine system via the attached pituitary gland.

The ovaries are located on either side of the uterus in females. They secrete the hormones estrogen and progesterone.

These hormones promote sexual development, fertility, and menstruation.

The testicles are located in the scrotum, below the penis in males. They secrete androgens, mainly testosterone.

Androgens control sexual development, puberty, facial hair, sexual behavior, libido, erectile function, and the formation of sperm cells.

Located in the abdomen, the pancreas is both an endocrine gland and a digestive organ.

It releases:

Diabetes and digestive issues can result if there are problems with the pancreas.

This is a small endocrine gland located deep in the brain. It secretes melatonin and helps control the bodys sleep patterns and moderate levels of reproductive hormones.

An endocrine gland attached to the hypothalamus at the base of the brain.

It is sometimes called the main endocrine master gland because it secretes hormones that regulate the functions of other glands, as well as growth and several other bodily functions.

The anterior, or front, pituitary secretes hormones that affect sexual development, thyroid function, growth, skin pigmentation, and adrenocortical function.

If the anterior pituitary is underactive, it can lead to stunted growth in childhood and underactivity in other endocrine glands.

The posterior, or rear, pituitary secretes oxytocin, a hormone that increases contractions of the uterus and antidiuretic hormone (ADH) which encourages the kidneys to reabsorb water.

The thymus is an endocrine gland located beneath the breastbone, or sternum.

T lymphocytes, a type of immune cell, mature and multiply in the thymus gland early in life. After puberty, the gland shrinks.

The thymus gland plays a role in the immune system, which protects the body against disease and infection.

A butterfly-shaped gland located just below the Adams apple in the neck, the thyroid produces hormones that play a key role in regulating blood pressure, body temperature, heart rate, metabolism, and how the body reacts to other hormones.

The thyroid gland uses iodine to create hormones.

The two main hormones it produces are thyroxine and triiodothyronine.

It also produces calcitonin, which helps strengthen bones and regulates the metabolism of calcium.

Below is a 3-D model of the endocrine system, which is fully interactive.

Explore the model using your mouse pad or touchscreen to understand more about the endocrine system.

During the first visit, the doctor will ask the patient a series of questions to help reach a diagnosis.

These might cover:

It can help to list any existing symptoms before the visit.

The endocrinologist might ask about symptoms that do not seem to be related, or that seem unnecessary.

This is because hormone levels affect so many different systems in the body that just small changes in one gland can impact parts of the body far from the site of the glands themselves.

They will check the patients heart rate and blood pressure, and look at the condition of their skin, hair, teeth, and mouth.

Blood and urine samples may be taken.

Following diagnosis, the endocrinologist will suggest a treatment plan. This will depend on which underlying condition is causing the symptoms.

Link:
Endocrinologist: Why would I visit and what can I expect?

by Dr. Elizabeth Lee Vliet

SARS-CoV-2 virus was virtually unknown when it hit in early 2020. COVID-19, as the disease is known, now has more than 60,000 National Library of Medicine citations, as the internet disseminates information at the speed of light. Recently President Trump was treated early for COVID-19, with rapid success.

What are the lessons learned from the scientific research?

Lesson 1: COVID-19 is not the death sentence we had at first thought. For healthy 74-year-olds who do not smoke tobacco, dont drink alcohol, and have no serious medical conditions such as heart disease, lung disease, diabetes, kidney disease, or morbid obesity, recovery rate is better than 95%.

Lesson 2: Early treatment at first sign of symptoms is critical. Thousands of frontline physicians in the US and around the world have been saying this from the beginning. Early treatment is the principle that guides almost all medical practicefrom heart disease to diabetes to cancer. In viral diseases, early treatment is critical. Patients need antiviral medicines, vitamins, minerals, known immune boosters, fresh air, and sunshine.

Studies confirm early treatment for COVID-19. In more than 130 studies compiled at c19study.com, the early-treatment studies using hydroxychloroquine (HCQ) showed a favorable effect of HCQ with other antivirals, with a median improvement of 64 percent. We accept 30-40 percent as a success with flu vaccine. Why wouldnt 64 percent improvement with antiviral medicines be considered a huge success? Even the majority of late treatment studies in very sick hospitalized patients showed around 25% improvement with HCQ.

Lesson 3: Doctors have now learned what medicines work, and when to use them. Many physicians across Americamyself included--are using a combination approach to early treatment for COVID, keeping patients at home for treatment with family and loved ones around them helping to implement the physicians recommendations.

A peer-reviewed algorithm by lead author Baylor cardiologist Peter McCullough, M.D. and colleagues from major US and Italian medical centers shows the widely available, safe medicines targeted for each stage of COVID-19 illness. Doctors already use these generic medicines day in and day out for many conditions. They now show impressive success with COVID-19.

Dr. McCulloughs team of experts recommend cheap, safe, FDA-approved medicineshydroxychloroquine (HCQ) with azithromycin or doxycycline, possibly ivermectin or colchicine, inhaled budesonide or the more potent oral prednisone, anticoagulants, supplemental zinc, vitamin C and vitamin D, and home oxygen concentrators.

With the possible exception of mechanical ventilation, almost all the treatment modalities treatment used in hospitals can be implemented at homefaster, better tailored to the individual, at lower risk of other infections common in hospitals, and at dramatically lower cost.

Lesson 4: LATE stage treatment of COVID carries a high risk of ICU admission, mechanical ventilation and death. The failed Fauci model telling patients to go home, self quarantine, do nothing, and go to the ER if they sickerexacerbated by the FDAs statements discouraging HCQ use, has caused the US COVID death rate to be in the worlds top ten.

Lesson 5: Widespread use of home therapy could prevent thousands of deaths and hospitalizations. The pathophysiological rationale and protocol published in the prestigious American Journal of Medicine gives much needed hope for physicians and patients around the world. Dr. McCullough is not just theorizing. He is actually treating COVID patients who remain in their own homes.

This is not just theory for me either. I have personally collaborated with Dr. McCullough using this home-based model of care for my own seriously ill COVID patients who live in other states. TeleHealth allows visually checking the patient, remote access to vital signs, and electronic ordering of medications and medical equipment such as oxygen concentrators when needed. In my experience, early aggressive outpatient treatment can usually be handled with oral medicines, but home health services can provide intravenous medicines if necessary. One of my seriously ill COVID patients in Virginia, a 63-year-old health care worker, is alive today and avoided hospitalization because of early treatment at home following Dr. McCulloughs algorithm.

But patients and physicians suffer as the FDA continues to erect barriers to early home-based treatment for COVID-19. FDA refuses to retract its negative statements on HCQ or release the national stockpile of HCQ donated by Big Pharma to help save American lives.

In a letter delivered August 19 to FDA Commissioner Stephen Hahn, Sen. Ron Johnson (R-Wis.), Chairman of the Senate Oversight Committee on Government Affairs and National Security, with Sen. Ted Cruz (R-Tex.) and Sen. Mike Lee (R-Utah) requested the FDAs data used to claim HCQ given within the first seven days of COVID symptoms might be harmful in outpatients. The FDAs reply deadline was August 25.

The FDA stonewalled until October 6, when the Senators finally received a response letter that completely ignored the questions asked by the Senators. FDA failed to produce any data at all that showed use of HCQ for early outpatients had no clinical effect or caused harm.

Whom is the FDA protecting by stonewalling, using a false narrative of outpatient harm with HCQthat even the FDA itself cannot support with its data? Are they preserving profits for Big Pharma with new high-cost medicines still on patentfor example, Gileads costly experimental drug remdesivir, or Regeneron, another high cost experimental drug given to President Trump?

Americans have the right to know why low-cost medicine, widely used for other conditions for decades, are suddenly too dangerous to be used for COVID-9 so people can stay at home to be treated and get well quickly.

Enormous financial conflicts exist within NIH, CDC and FDAand all receive payments from pharmaceutical companies and vaccine manufacturers, as well as income from patents on new vaccine adjuvants and processes. Dr. McCulloughs editorial, The Great Gamble of Covid-19 Vaccine Development, explained this multibillion-dollar financial incentive to preserve vaccine windfall profits in wealthy countries.

Print Dr. McCulloughs article. This can save your life. Learn your options before you get sick. Make a copy for your doctor. This entire model of care can be implemented by your local physician, in your own home, with minimal cost, and gives you the best chance of rapid recovery.

I know these doctors are right from my own experience treating patients. If you get admitted to hospital, you will likely be a prisoner with no visits from family, clergy, or the doctor of your choiceand at high risk of complications and death. For most patients, hospitalization is unnecessary.

Patients and physicians must take the initiative from the start, use the home-based methods that work, instead of trusting in FDA-promoted no-treatment standard of care, waiting in fear for a vaccine magic bullet.

(Dr. Vliet has been a leader in patient centered, individualized medical care. Since 1986, she has practiced medicine independent of insurance contracts that interfere with patient-physician relationships and decision-making. Dr. Vliet focus is medical freedom and free market approaches to healthcare. Dr. Vliet is the founder of Vive Life Center and Hormone Health Strategies with medical practices in Tucson AZ and Dallas TX, specializing in preventive and climacteric medicine with an integrated approach to evaluation and treatment of women and men with complex medical and hormonal problems from puberty to late life.)

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There is hope and help for treating COVID-19 at home - Gasconade County Republican