Faculty Bibliography

PURPOSE OF REVIEW:This article reviews treatment strategies in endometrial cancer by molecular subtype. RECENT FINDINGS:The Cancer Genome Atlas (TCGA) classifies four molecular subtypes of endometrial cancer - 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. FDA-approved immune checkpoint inhibitors (ICIs) include pembrolizumab and dostarlimab for previously treated dMMR/MSI-H EC, and pembrolizumab/lenvatinib for mismatch repair-proficient/microsatellite-stable endometrial cancer, including CNH/p53abn and CNL/NSMP. ICIs are being studied as first-line therapy in advanced/recurrent endometrial cancer by MMR status, as well as in combination with other targeted agents. Trastuzumab is NCCN compendium listed for HER2-positive serous endometrial cancer, which are primarily p53-abnormal. Antibody-drug conjugates targeting low and high HER2 levels show promise in breast cancer, and are beginning to be studied in endometrial cancer. In addition to hormonal therapy, maintenance therapy with selinexor (XPO1-inhibitor) showed potential benefit in p53 -wildtype endometrial cancer and is being investigated prospectively. Multiple prospective trials are evaluating de-escalation of care for POLEmut endometrial cancer given favorable survival regardless of adjuvant therapy. SUMMARY:Molecular subtyping has important prognostic and therapeutic implications and should be guiding patient management and clinical trial design in endometrial cancer.

BACKGROUND:Tumor next-generation sequencing can identify potential germline pathogenic variants associated with cancer susceptibility. OBJECTIVE:To describe the frequency of tumor sequencing results that met European Society of Medical Oncology (ESMO) recommendations for further germline genetic testing, and the frequency of germline variants among a cohort with gynecologic cancer. METHODS:Patients with gynecologic cancer who underwent tumor sequencing between September 2019 and February 2022 in a large healthcare system in New York City were retrospectively identified. Eligible patients with suspected germline pathogenic variants on tumor sequencing were identified based on ESMO guidelines. Logistic regression was used to explore variables associated with referral and completion of germline testing. RESULTS:Of 358 patients with gynecologic cancers who underwent tumor sequencing, 81 (22.6%) had ≥1 suspected germline variant according to ESMO guidelines. Of the 81 patients with qualifying tumor sequencing results, 56 (69.1%) received germline testing: 41/46 (89.1%) eligible patients with ovarian cancer and 15/33 (45.5%) with endometrial cancer. In the endometrial cancer cohort, 11/33 (33.3%) eligible patients were not referred for germline testing and the majority of these patients had tumor variants in genes commonly known to cause hereditary cancer. Of the 56 patients who underwent germline testing, 40 (71.4%) had pathogenic germline variants. In multivariable analysis, race/ethnicity other than non-Hispanic white was associated with lower odds of germline testing referral and completion (OR=0.1, 95% CI 0.01 to 0.5 and OR=0.2, 95% CI 0.04 to 0.6, respectively). CONCLUSION/CONCLUSIONS:Given the high rate of pathogenic germline variant detection and the importance of identifying such variants for both patients and their family, it is imperative that eligible patients undergo germline testing. Additional education for providers on multidisciplinary guidelines and development of clinical pathways to ensure germline testing of suspected pathogenic variants identified on tumor sequencing is warranted, especially in light of the racial/ethnic inequity observed.

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.

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/CONCLUSIONS: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.

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/CONCLUSIONS: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.

Objectives Minority U.S. populations are underrepresented in oncologic clinical trials. In an urban NCI-designated Comprehensive Cancer Center, we evaluated enrollment in gynecologic cancer trials by race/ethnicity pre and post the June 2020 NCI call-to-action for increased diversity in clinical trials. Methods Enrollment data in 22 therapeutic clinical trials from January 2018-May 2022 was analyzed. Chi-square/Fisher's exact analysis compared proportions of accrued patients by race/ethnicity pre and post the NCI call-to-action. Results Over the study period 205 patients were enrolled in gynecologic cancer trials: 129 (62.9%) ovarian, 52 (25.4%) endometrial, 24 (11.7%) cervical. Overall racial/ethnic distribution of patients in clinical trials was: 112 (54.6%) non-Hispanic White, 33 (16.1%) Hispanic, 32 (15.6%) Black, 28 (13.7%) Asian. Although not statistically significant, accrual of underrepresented populations increased from pre call-to-action (45/108, 41.7%) to post (48/97, 49.5%). Significantly more Black patients were accrued post NCI call-to-action (8/108, 7.4% vs 24/97, 24.7%, p=0.001). However, significantly fewer Asian patients were accrued post NCI call-to-action (21/ 108, 19.4% vs 7/97, 7.2%, p=0.01). Conclusions Overall accrual of Black patients in gynecologic cancer clinical trials increased following the NCI call-to-action, but accrual of Asian patients decreased. Further efforts are needed to ensure all racial/ethnic groups are represented in clinical trials

Background: Median age of EC diagnosis is 62 y, yet most EC deaths occur in pts >65 y (median 70 y). Unmet need in older pts is not addressed by current standard of care. Dostarlimab is an anti-programmed death receptor 1 (PD-1) antibody. We report a post-hoc analysis of dostarlimab antitumor activity and safety by age in pts with dMMR/microsatellite instability high (MSI-H) EC and MMR proficient (MMRp)/MS stable (MSS) EC.
Method(s): GARNET (NCT02715284) is a Phase I, single-arm study of dostarlimab in pts with advanced/recurrent (A/R) solid tumors. Pts with dMMR/MSI-H EC were enrolled in Cohort A1 and pts with MMRp/MSS EC in Cohort A2. Pts were stratified: <65 y, >=65 to <75 y, or >=75 y at baseline. Antitumor activity and safety were assessed. Data cut was March 1, 2020.
Result(s): In Cohort A1 (n=129), 51.2% of pts were <65 y, 39.5% were >=65 to <75 y, and 9.3% were >=75 y. In Cohort A2 (n=161), 43.5% were <65 y, 44.7% were >=65 to <75 y, and 11.8% were >=75 y. In the efficacy-evaluable population (measurable disease at baseline; >=24 w follow up), objective response rates (ORRs) (95% confidence interval [CI]) per RECIST v1.1 assessed by BICR were similar across age groups for pts with dMMR/ MSI-H EC (<65 y: 45.3% [31.6-59.6] vs >=65 to <75 y: 43.9% [28.5-60.3] vs >=75 y: 45.5% [16.7-76.6]) and for pts with MMRp/MSS EC (<65 y: 9.1% [3.4-18.7] vs >=65 to <75 y: 16.9% [9.0-27.7] vs >=75 y: 21.1% [6.1-45.6]). There were few Grade >=3 treatment-related adverse events (TRAEs) (for pts with dMMR/MSI-H EC [n=129]: 13.6% vs 13.7% vs 8.3%, respectively) and for MMRp/MSS EC [n=161]: 22.9% vs 19.4% vs 5.3%, respectively); observed TRAEs were similar between groups.
Conclusion(s): Dostarlimab antitumor activity and safety for pts with dMMR/MSI-H EC and MMRp/MSS EC were comparable across age groups, with low Grade >=3 TRAE incidence. Older pts with A/R dMMR/ MSI-H EC experienced broadly similar treatment benefits as younger pts

Objectives UpRi is a first-in-class NaPi2b ADC with a novel scaffold-linker-payload that enables high drug-to-antibody ratio and controlled bystander effect. NaPi2b is a sodium-dependent phosphate transporter protein broadly expressed in high-grade serous ovarian cancer (HGSOC), with limited expression in healthy tissues. Interim data from the Phase 1b expansion cohort of heavily pretreated patients with recurrent HGSOC has been reported. These data demonstrated clinically meaningful activity, notably in patients with NaPi2b-high tumors (TPS>=75). Effective and well-tolerated treatments for PROC remains an unmet medical need. The standard of care, singleagent chemotherapy, has limited efficacy, significant toxicities, and short duration of response. UPLIFT was designed as a single- arm Ph2 registrational trial for UpRi monotherapy in PROC. Methods UPLIFT is enrolling patients with PROC with up to 4 prior LoT. Prior bevacizumab is required for patients with 1-2 prior LoT only; it's not required for patients with 3-4 prior LoT. Patients may enroll regardless of NaPi2b expression; <= Grade 2 peripheral neuropathy is permitted. Primary platinum refractory patients are excluded. UPLIFT will enroll ~180 patients globally, including ~100 patients with high NaPi2b expression. UpRi is dosed IV at 36 mg/ m2 up to ~80 mg dose maximum Q4W. Baseline tumor samples (fresh or archived) will be collected for central analysis of NaPi2b expression. The primary endpoint is ORR in NaPi2b-high expressing patients. The cut-off for high NaPi2b expression is TPS>=75. Secondary endpoints include ORR in the overall population, duration of response, and safety. UPLIFT is conducted in collaboration with ENGOT (ENGOT-ov67) and GOG (GOG-3048). NCT03319628 Results trialinprogress Conclusions trialinprogress

Objectives Patterns of recurrence on PARP inhibitor maintenance therapy are unclear and may affect treatment choices for subsequent therapy, including secondary cytoreductive surgery (SCS). This analysis of PRIMA/ENGOT-OV26/GOG-3012 evaluated patterns of recurrence on niraparib maintenance therapy. Methods This post hoc subgroup analysis included 314 patients treated with niraparib maintenance monotherapy following first-line chemotherapy and who had no lesions identified by CT/MRI (or by investigator assessment) at baseline. Number and site(s) of initial recurrent lesions at the time of investigator-assessed RECIST-defined progressive disease (PD) were evaluated. Results As of the primary data cut, May 17, 2019, with a median follow-up of 13.8 months (range <1-28), 141/ 314 (45%) patients developed investigator-assessed PD, with an average 1.9 (standard deviation 0.9) lesions at PD. At the time of recurrence, 62 patients (44%) had 1 lesion, 46 (33%) had 2 lesions, 24 (17%) had 3 lesions, and 9 (6%) had 4-5 lesions. The five most common sites with >=1 lesion at PD were the peritoneum (n=45), lymph nodes (n=36), liver (n=34), other (n=26), and pelvis (n=20). Conclusions For patients who received niraparib maintenance monotherapy after first-line chemotherapy and had no lesions at baseline, <50% had recurrent disease after a median 13.8 months of follow-up and >75% of patients with recurrence progressed in 1-2 sites. Prospective evaluation is required to determine whether patients with oligoprogressive disease have improved outcomes with local therapies, like SCS, in addition to systemic therapy