Biomarker-driven therapy in endometrial cancer.

This article reviews treatments and targets of interest in endometrial cancer by molecular subtype. The Cancer Genome Atlas (TCGA) classifies four molecular subtypes-mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H); copy number high (CNH)/p53abn; copy number low (CNL)/no specific molecular profile (NSMP); and POLEmut-which are validated and highly prognostic. Treatment consideration by subtype is now recommended. In March and April 2022, respectively, the US Food and Drug Administration (FDA) fully approved and the European Medicines Agency adopted a positive opinion recommending the anti-programmed cell death protein-1 (PD-1) antibody pembrolizumab for advanced/recurrent dMMR/MSI-H endometrial cancer which has progressed on or following a platinum-containing therapy. A second anti-PD-1, dostarlimab, received accelerated approval by the FDA and conditional marketing authorization by the European Medicines Agency in this group. The combination of pembrolizumab/lenvatinib for mismatch repair proficient/microsatellite stable endometrial cancer, including p53abn/CNH and NSMP/CNL, received accelerated FDA approval in conjunction with Australia's Therapeutic Goods Administration and Health Canada in September 2019. The FDA and European Medicines Agency made full recommendations in July 2021 and October 2021. Trastuzumab is National Comprehensive Cancer Network (NCCN) compendium listed for human epidermal growth factor receptor-2-positive serous endometrial cancer, which is primarily within the p53abn/CNH subtype. In addition to hormonal therapy, maintenance therapy with selinexor (exportin-1 inhibitor) showed potential benefit in p53-wildtype cases in a subset analysis and is being investigated prospectively. Other treatment regimens being evaluated in NSMP/CNL are hormonal combinations with cyclin-dependent kinase 4/6 inhibitors and letrozole. Ongoing trials are evaluating immunotherapy in combination with frontline chemotherapy and other targeted agents. Treatment de-escalation is being evaluated in POLEmut cases given its favorable prognosis with or without adjuvant therapy. Molecular subtyping has important prognostic and therapeutic implications, and should guide patient management and clinical trial design in endometrial cancer, which is a molecularly driven disease.

Beyond BRCA: Patterns of risk-reducing surgery for non-BRCA, homologous recombination repair pathway gene variant carriers.

OBJECTIVE: The real-world management of patients with non-BRCA, homologous recombination repair pathway variants with increased or uncertain risks of ovarian cancer is unknown. The objective was to determine the adoption of risk-reducing salpingo-oophorectomy (RRSO) for carriers of variants with increased or uncertain risks of ovarian cancer beyond BRCA. METHODS: This was a retrospective cohort study of patients at three hospitals with non-BRCA, homologous recombination repair pathway variants with increased risk (BRIP1, RAD51C, RAD51D) and uncertain risk (ATM, BARD1, NBN, PALB2) of ovarian cancer. Outcomes of interest were adoption of RRSO and factors associated with adoption of RRSO. Wilcoxon rank-sum, chi-square, and logistic regression were performed with p < 0.05. RESULTS: Of 318 patients, 76 (24%) had pathogenic variants with increased risks of ovarian cancer (BRIP1, 45; RAD51C, 20; RAD51D, 11), and 242 (76%) had variants with uncertain risks of ovarian cancer (ATM, 145; PALB2, 69; NBN, 23; BARD1, 5). Of 64 patients eligible for RRSO by National Comprehensive Cancer Network (NCCN) criteria or family history, 31 (48%) underwent RRSO. Among eligible patients who did not undergo RRSO, 24 (73%) were not referred for gynecologic oncology consultation. Older age at testing (adjusted odds ratio [aOR] 1.08, 95% confidence interval [CI] 1.03-1.13) and referral to gynecologic oncology (aOR 33.48, CI 8.10-138.39) were associated with increased adoption of RRSO when adjusting for personal and family history of breast and ovarian cancer. CONCLUSION: Half of RRSO-eligible patients by NCCN criteria beyond BRCA did not undergo RRSO. Opportunities exist for improving education to increase referrals to facilitate RRSO for these patients.

Missed opportunities in the real-world genetic testing in BRCA gene variant carriers with cancers meeting NCCN criteria.

OBJECTIVE: The objective of this study was to determine the proportion of patients meeting the National Comprehensive Cancer Network (NCCN)'s BRCA genetic testing criteria prior to a diagnosis of a BRCA-related cancer. METHODS: This was a cross-sectional study of patients with BRCA pathogenic variants and a diagnosis of a BRCA-related cancer. Patients were included if they had known dates of genetic testing and cancer diagnosis. NCCN criteria (version 2.2021) were applied to determine if patients met criteria for testing before a BRCA-related cancer diagnosis. The outcome of interest was the proportion of patients undergoing genetic testing following a diagnosis of a BRCA-related cancer who qualified for genetic testing based on NCCN criteria. Chi-square, Mann-Whitney U test, and logistic regression were performed with significance at p < 0.05. RESULTS: Of 270 patients with a BRCA-related cancer, 229 (85%) underwent genetic testing after a cancer diagnosis. Most patients (97%) met at least one NCCN criteria for BRCA testing; 166 (73%) of patients who were tested following a BRCA-related cancer diagnosis also met the criteria for testing by family history. Publicly insured or uninsured patients were three times more likely to undergo BRCA testing after a diagnosis of cancer (odds ratio [OR] 3.03, 95% confidence interval [CI] 1.09-8.40). Patients with a family history of pathogenic variants were more likely to undergo testing before a cancer diagnosis (OR 0.10, 95% CI 0.05-0.23). CONCLUSION: Most patients with BRCA-associated cancers undergo genetic testing after their cancer diagnosis. Increased education on genetic testing criteria and novel methods to improve testing are desperately needed.

Poly(ADP-Ribose) Polymerase Inhibitor Inhibition in Ovarian Cancer: A Comprehensive Review.

ABSTRACT: The emergence of clinical trial data for poly(ADP-ribose) polymerase inhibitors (PARPi), in BRCA-associated ovarian cancer (epithelial ovarian cancer [EOC]) in 2009 (Lancet 2010;376:245-251) unleashed a rapid series of additional asset development and clinical trial activation across all lines of EOC treatment, ultimately leading to 8 new approvals of 3 different PARPi in EOC since 2014. Monotherapy iPARPi were approved as frontline maintenance treatment for all patients with EOC who respond to platinum-based chemotherapy irrespective of biomarker (niraparib) and for BRCA-associated cancers (olaparib) (https://www.azpicentral.com/lynparza_tb/lynparza_tb.pdf#page=1; https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf). Combination of olaparib and bevacizumab was approved as maintenance for patients in response to platinum-based and bevacizumab containing frontline therapy whose tumor is characterized as homologous recombination deficient and as approved test by the Food and Drug Administration, inclusive of BRCA-associated cancers (N Engl J Med 2019;381:2416-2428). Niraparib, olaparib, and rucaparib were also approved as maintenance treatment following response to platinum-based therapy in the recurrent setting irrespective of biomarker (https://www.azpicentral.com/lynparza_tb/lynparza_tb.pdf#page=1; https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf; https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf). All 3 PARPi were also approved as treatment in lieu of chemotherapy for patients with BRCA-associated cancers in third line and beyond (https://www.azpicentral.com/lynparza_tb/lynparza_tb.pdf#page=1;https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf) and platinum-sensitive homologous recombination deficient in the fourth line and beyond (https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf), as well as the National Comprehensive Cancer Network listed in combination with bevacizumab for treatment of patients with platinum-sensitive recurrent disease (https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf). Ongoing clinical trials in all lines of treatment are evaluating combinations of therapies to improve efficacy among biomarker negative tumors as well as overcome acquired PARPi resistance due to prior use.

Uptake and timing of risk-reducing salpingo-oophorectomy among patients with BRCA1 and BRCA2 mutations.

BACKGROUND: In women with BRCA mutations, risk-reducing bilateral salpingo-oophorectomy has been shown to decrease gynecologic cancer-specific and overall mortality. The National Comprehensive Cancer Network recommends that patients with BRCA mutations undergo risk-reducing bilateral salpingo-oophorectomy between the ages of 35 and 40 years for BRCA1 mutation carriers and between the ages of 40 and 45 years for BRCA2 mutation carriers or after childbearing is complete. Currently, uptake and timing of risk-reducing bilateral salpingo-oophorectomy and reasons for delays in risk-reducing bilateral salpingo-oophorectomy are not well understood. OBJECTIVE: We sought to evaluate uptake and timing of risk-reducing bilateral salpingo-oophorectomy among women with BRCA1 and BRCA2 mutations concerning the National Comprehensive Cancer Network guidelines and reasons for delays in risk-reducing bilateral salpingo-oophorectomy. STUDY DESIGN: In this retrospective chart review, we identified women with BRCA1 and BRCA2 mutations who discussed risk-reducing bilateral salpingo-oophorectomy with a provider between 2012 and 2021. Uptake of risk-reducing bilateral salpingo-oophorectomy was documented, and patients were classified as having timely or delay in risk-reducing bilateral salpingo-oophorectomy based on the National Comprehensive Cancer Network guidelines. For those with delay in risk-reducing bilateral salpingo-oophorectomy, reasons cited for delay were collected. Comparative statistical analyses were performed to evaluate characteristics of those with timely vs delayed risk-reducing bilateral salpingo-oophorectomy. A multivariable logistic regression model was used to evaluate the associations among factors related to timing of risk-reducing bilateral salpingo-oophorectomy. RESULTS: We identified 638 BRCA1 and BRCA2 mutation carriers seen between 2012 and 2021. Of these patients, 306 (48.0%) had undergone risk-reducing bilateral salpingo-oophorectomy and 332 (52.0%) had not. When evaluating the timing of risk-reducing bilateral salpingo-oophorectomy, 136 (21.3%) underwent timely risk-reducing bilateral salpingo-oophorectomy, 239 (37.5%) had delays in risk-reducing bilateral salpingo-oophorectomy, and 263 (41.2%) had not undergone risk-reducing bilateral salpingo-oophorectomy but were younger than the National Comprehensive Cancer Network age guidelines; therefore, they were neither timely nor delayed. Patients with delay in risk-reducing bilateral salpingo-oophorectomy were significantly older at the time of genetic testing than those with timely risk-reducing bilateral salpingo-oophorectomy (mean, 49.8 vs 36.3 years; P<.001). Of the 306 patients who underwent risk-reducing bilateral salpingo-oophorectomy, those with delayed risk-reducing bilateral salpingo-oophorectomy had a significantly shorter interval between BRCA identification and risk-reducing bilateral salpingo-oophorectomy than those with timely risk-reducing bilateral salpingo-oophorectomy (median, 8.7 vs 17.6 months; P<.001). Patients with delay in risk-reducing bilateral salpingo-oophorectomy were more likely to have a personal history of cancer than those with timely risk-reducing bilateral salpingo-oophorectomy (49.8% vs 37.5%; P=.028). Of the 239 women with delay in risk-reducing bilateral salpingo-oophorectomy, 188 (78.7%) had delayed BRCA mutation identification, 29 (12.1%) had menopausal concerns, 17 (7.1%) had ongoing cancer treatment, 12 (5.0%) had coordination with breast surgery, 20 (8.4%) had miscellaneous reasons, and 19 (7.9%) had no reason documented. In the multivariate model, older age at BRCA diagnosis (odds ratio, 0.73; 95% confidence interval, 0.68-0.78; P<.001) was significantly associated with delayed risk-reducing bilateral salpingo-oophorectomy timing; those with BRCA2 mutation type were 7.54 times as likely to have timely risk-reducing bilateral salpingo-oophorectomy than BRCA1 mutation carriers (odds ratio, 7.54; 95% confidence, 3.70-16.42; P<.001). CONCLUSION: Nearly 38% of BRCA1 and BRCA2 mutation carriers undergo or have yet to undergo risk-reducing bilateral salpingo-oophorectomy over the recommended National Comprehensive Cancer Network age. The most common reason for the delay in risk-reducing bilateral salpingo-oophorectomy was delayed identification of BRCA mutation, noted in 79% of patients with delayed risk-reducing bilateral salpingo-oophorectomy. Timely genetic testing for eligible patients can increase appropriately timed risk-reducing bilateral salpingo-oophorectomy for the prevention of ovarian cancer and reduction of mortality in BRCA mutation carriers.

PARP inhibition as frontline therapy in ovarian cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors have been rapidly integrated into clinical practice for women with ovarian cancer. Currently, PARP inhibitors are approved as frontline maintenance treatment for patients with and without BRCA-associated cancers, and they are listed by the National Comprehensive Cancer Network (NCCN) as a treatment option for all high-grade serous and endometrioid cancers with or without bevacizumab. PARP inhibitors are also approved as maintenance treatment following a response to platinum-based therapy in the recurrent setting, irrespective of biomarker status. Additionally, PARP inhibitors are approved as third-line treatment and beyond in lieu of chemotherapy for patients with BRCA-associated cancers, and as fourth-line treatment and beyond for patients with platinum-sensitive homologous recombination-deficient tumors. They are also listed by the NCCN in combination with bevacizumab for the treatment of patients who have platinum-sensitive recurrent disease. The first part of this 2-part review focuses on the changing paradigm of frontline therapy options resulting from the recent approvals of PARP inhibitors; the second part considers the role of PARP inhibition in recurrent ovarian cancer.

Multi-disciplinary summit on genetics services for women with gynecologic cancers: A Society of Gynecologic Oncology White Paper.

OBJECTIVE: To assess current practice, advise minimum standards, and identify educational gaps relevant to genetic screening, counseling, and testing of women affected by gynecologic cancers. METHODS: The Society of Gynecologic Oncology (SGO) organized a multidisciplinary summit that included representatives from the American College of Obstetricians and Gynecologists (ACOG), the American Society Clinical Oncology (ASCO), the National Society of Genetic Counselors (NSGC), and patient advocacy groups, BrightPink and Facing our Risk of Cancer Empowered (FORCE). Three subject areas were discussed: care delivery models for genetic testing, barriers to genetic testing, and educational opportunities for providers of genetic testing. RESULTS: The group endorsed current SGO, National Comprehensive Cancer Network (NCCN), and NSGC genetic testing guidelines for women affected with ovarian, tubal, peritoneal cancers, or DNA mismatch repair deficient endometrial cancer. Three main areas of unmet need were identified: timely and universal genetic testing for women with ovarian, fallopian tube, and peritoneal cancers; education regarding minimum standards for genetic counseling and testing; and barriers to implementation of testing of both affected individuals as well as cascade testing of family members. Consensus building among all stakeholders resulted in an action plan to address gaps in education of gynecologic oncology providers and delivery of cancer genetics care.

Multigene panels in Ashkenazi Jewish patients yield high rates of actionable mutations in multiple non-BRCA cancer-associated genes.

OBJECTIVE: To evaluate the results of multigene panel testing among Ashkenazi Jewish compared with non-Ashkenazi Jewish patients. METHODS: We reviewed the medical records for all patients who underwent multigene panel testing and targeted BRCA1/2 testing at a single institution between 6/2013-1/2015. Clinical actionability for identified pathogenic mutations was characterized based on the National Comprehensive Cancer Network (NCCN) guidelines and consensus statements and expert opinion for genes not addressed by these guidelines. RESULTS: Four hundred and fifty-four patients underwent multigene panel screening, including 138 Ashkenazi Jewish patients. The median patient age was fifty-two years. Three hundred and fifty-four patients (78%) had a personal history of cancer. Two hundred and fifty-one patients had breast cancer, 49, ovarian cancer, 26, uterine cancer and 20, colorectal cancer. We identified 62 mutations in 56 patients and 291 variants of uncertain significance in 196 patients. Among the 56 patients with mutations, 51 (91%) had actionable mutations. Twenty mutations were identified by multigene panels among Ashkenazi Jewish patients, 18 of which were in genes other than BRCA1/2. A review of targeted BRCA1/2 testing performed over the same study period included 103 patients and identified six mutations in BRCA1/2, all of which occurred in Ashkenazi Jewish patients. Among all Ashkenazi Jewish patients undergoing genetic testing, 25/183 (14%) had a mutation, 24/25 of which were actionable (96%) and 17/25 patients (68%) had mutations in non BRCA1/2 genes. CONCLUSIONS: With the rapid acceptance of multigene panels there is a pressing need to understand how this testing will affect patient management. While traditionally many Ashkenazi Jewish patients have undergone targeted BRCA1/2 testing, our data suggest consideration of multigene panels in this population as the majority of the results are clinically actionable and often in genes other than BRCA1/2.