A pre-operative scoring model to estimate the risk of blood transfusion over an ovarian cancer debulking surgery (BLOODS score): a Memorial Sloan Kettering Cancer Center Team Ovary study.

OBJECTIVES: To develop a pre-operative tool to estimate the risk of peri-operative packed red blood cell transfusion in primary debulking surgery. METHODS: We retrospectively reviewed an institutional database to identify patients who underwent primary debulking surgery for ovarian cancer at a single center between January 1, 2001 and May 31, 2019. Receiver operating characteristic curve and area under the receiver operating characteristic curve (AUC) were calculated. Five-fold cross-validation was applied to the multivariate model. Significant variables were assigned a 'BLOODS' (BLood transfusion Over an Ovarian cancer Debulking Surgery) score of +1 if present. A total BLOODS score was calculated for each patient, and the odds of receiving a transfusion was determined for each score. RESULTS: Overall, 1566 patients met eligibility criteria; 800 (51%) underwent a peri-operative blood transfusion. Odds ratios (OR) were statistically significant for American Society of Anesthesiologists scores of 3 and 4 (OR 1.34, 95% confidence interval (95% CI) 1.09 to 1.63), pre-operative levels of cancer antigen 125 (CA125) (OR 2.43, 95% CI 1.98 to 2.99), platelets (OR 1.59, 95% CI 1.45 to 1.74), obesity (OR 0.76, 95% CI 0.60 to 0.96), presence of carcinomatosis (OR 2.45, 95% CI 1.93 to 3.11), bulky upper abdominal disease (OR 2.86, 95% CI 2.32 to 3.54), pre-operative serum albumin level (OR 0.31, 95% CI 0.24 to 0.40), and pre-operative hemoglobin level (OR 0.56, 95% CI 0.51 to 0.61). The corrected AUC was 0.748 (95% CI 0.693 to 0.804). BLOODS scores of 0 and 5 corresponded to 11% and 73% odds, respectively, of receiving a peri-operative blood transfusion. CONCLUSIONS: We developed a universal pre-operative scoring system, the BLOODS score, to help identify patients with ovarian cancer who would benefit from surgical planning and blood-saving techniques. The BLOODS score was directly proportional to the American Society of Anesthesiologists score, presence of upper abdominal disease, carcinomatosis, CA125 level, and platelets level. We believe this model can help physicians with surgical planning and can benefit patient outcomes.

Folate receptor alpha expression in low-grade serous ovarian cancer: Exploring new therapeutic possibilities.

OBJECTIVE: Mirvetuximab soravtansine may be a potentially effective therapeutic option for ovarian low-grade serous carcinoma (LGSC), but the prevalence of folate receptor alpha (FRα) overexpression in this tumor type is unknown. We sought to characterize FRα expression in LGSC and its association with clinical and molecular features. METHODS: FRα immunohistochemistry was performed on a tissue microarray comprised of 89 LGSCs and 42 ovarian serous borderline tumors (SBTs). Clinical tumor-normal panel-based sequencing was performed on 78 LGSCs. Associations between FRα-high status and clinicopathologic characteristics and survival outcomes were examined. RESULTS: Of 89 LGSCs, 36 (40%) were FRα-high (≥75% of viable tumor cells exhibiting moderate-to-strong membranous expression). Of 9 patients with LGSC and samples from different timepoints, 4 (44%) had discordant results, with conversion from FRα-negative to FRα-high in 3 (33%) cases. There was no association between FRα-high status with age, race, or progression-free/overall survival. A MAPK pathway genetic alteration, most commonly involving KRAS (n = 23), was present in 45 (58%) LGSCs. Those lacking MAPK pathway alterations were more likely to be FRα-high compared to MAPK-altered LGSCs (61% vs 20%, p < 0.001). In SBTs, FRα-high expression was associated with high-risk (micropapillary) histology and/or subsequent LGSC recurrence compared to conventional SBTs without malignant recurrence (53% vs 9%, p = 0.008). CONCLUSIONS: Future studies of FRα-directed therapy in patients with LGSC are warranted. Discordant FRα status at recurrence suggests potential benefit for retesting. A biomarker-driven approach to direct treatment selection in LGSC is recommended. As high FRα expression is more common amongst tumors lacking MAPK pathway genetic alterations, FRα testing to determine eligibility for mirvetuximab soravtansine therapy is particularly recommended for this subgroup.

Molecular profiling of primary endometrioid endometrial cancer and matched lung metastases: CTNNB1 mutation as a potential driver.

•Both primary endometrial cancers (ECs) and matched lung metastases shared a common ancestor with independent evolution at each site.•The two endometrioid ECs studied acquired additional mutations during the distant metastatic process.•Subclonal CTNNB1 hotspot mutations in the two primary ECs studied became clonal in the distant metastases.

Regionalizing ovarian cancer cytoreduction to high-volume centers and the impact on patient travel in New York State.

OBJECTIVE: To evaluate the theoretical impact of regionalizing cytoreductive surgery for ovarian cancer (OC) to high-volume facilities on patient travel. METHODS: We retrospectively identified patients with OC who underwent cytoreduction between 1/1/2004-12/31/2018 from the New York State Cancer Registry and Statewide Planning and Research Cooperative System. Hospitals were stratified by low-volume (<21 cytoreductive surgical procedures for OC annually) and high-volume centers (≥21 procedures annually). A simulation was performed; outcomes of interest were driving distance and time between the centroid of the patient's residence zip code and the treating facility zip code. RESULTS: Overall, 60,493 patients met inclusion criteria. Between 2004 and 2018, 210 facilities were performing cytoreductive surgery for OC in New York; 159 facilities (75.7%) met low-volume and 51 (24.3%) met high-volume criteria. Overall, 10,514 patients (17.4%) were treated at low-volume and 49,979 (82.6%) at high-volume facilities. In 2004, 78.2% of patients were treated at high-volume facilities, which increased to 84.6% in 2018 (P < .0001). Median travel distance and time for patients treated at high-volume centers was 12.2 miles (IQR, 5.6-25.5) and 23.0 min (IQR, 15.2-37.0), and 8.2 miles (IQR, 3.7-15.9) and 16.8 min (IQR, 12.4-26.0) for patients treated at low-volume centers. If cytoreductive surgery was centralized to high-volume centers, median distance and time traveled for patients originally treated at low-volume centers would be 11.2 miles (IQR, 3.8-32.3; P < .001) and 20.2 min (IQR, 13.6-43.0; P < .001). CONCLUSIONS: Centralizing cytoreductive surgery for OC to high-volume centers in New York would increase patient travel burden by negligible amounts of distance and time for most patients.

Pathogenic germline variants in patients with endometrial cancer of diverse ancestry.

BACKGROUND: Racial disparities in outcomes exist in endometrial cancer (EC). The contribution of ancestry-based variations in germline pathogenic variants (gPVs) is unknown. METHODS: Germline assessment of ≥76 cancer predisposition genes was performed in patients with EC undergoing tumor-normal Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets sequencing from January 1, 2015 through June 30, 2021. Self-reported race/ethnicity and Ashkenazi Jewish ancestry data classified patients into groups. Genetic ancestry was inferred from Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets. Rates of gPV and genetic counseling were compared by ancestry. RESULTS: Among 1625 patients with EC, 216 (13%) had gPVs; 15 had >1 gPV. Rates of gPV varied by self-reported ancestry (Ashkenazi Jewish, 40/202 [20%]; Asian, 15/124 [12%]; Black/African American (AA), 12/171 [7.0%]; Hispanic, 15/124 [12%]; non-Hispanic (NH) White, 129/927 [14%]; missing, 5/77 [6.5%]; p = .009], with similar findings by genetic ancestry (p < .001). We observed a lower likelihood of gPVs in patients of Black/AA (odds ratio [OR], 0.44; 95% CI, 0.22-0.81) and African (AFR) ancestry (OR, 0.42; 95% CI, 0.18-0.85) and a higher likelihood in patients of Ashkenazi Jewish genetic ancestry (OR, 1.62; 95% CI; 1.11-2.34) compared with patients of non-Hispanic White/European ancestry, even after adjustment for age and molecular subtype. Somatic landscape influenced gPVs with lower rates of microsatellite instability-high tumors in patients of Black/AA and AFR ancestry. Among those with newly identified gPVs (n = 114), 102 (89%) were seen for genetic counseling, with lowest rates among Black/AA (75%) and AFR patients (67%). CONCLUSIONS: In those with EC, gPV and genetic counseling varied by ancestry, with lowest rates among Black/AA and AFR patients, potentially contributing to disparities in outcomes given implications for treatment and cancer prevention. PLAIN LANGUAGE SUMMARY: Black women with endometrial cancer do worse than White women, and there are many reasons for this disparity. Certain genetic changes from birth (mutations) can increase the risk of cancer, and it is unknown if rates of these changes are different between different ancestry groups. Genetic mutations in 1625 diverse women with endometrial cancer were studied and the lowest rates of mutations and genetic counseling were found in Black and African ancestry women. This could affect their treatment options as well as their families and may make disparities worse.

Salpingectomy for the Primary Prevention of Ovarian Cancer: A Systematic Review.

Importance: Most ovarian cancers originate in the fimbriated end of the fallopian tube. This has led to the hypothesis that surgical resection of the fallopian tubes at the time of gynecologic and nongynecologic surgical procedures-referred to as an opportunistic salpingectomy-may prevent the development of epithelial ovarian cancer for women at an average risk of developing the disease. Objective: To compile a comprehensive, state-of-the-science review examining the current landscape of performing bilateral salpingectomy for ovarian cancer prevention. Evidence Review: A systematic review of the literature was performed on March 4, 2022, to identify studies examining salpingectomy for ovarian cancer prevention. This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 statement. Four databases were selected: PubMed via the National Library of Medicine's PubMed.gov, Embase via Elsevier's Embase.com, Cochrane Central Register of Controlled Trials (CENTRAL) via Wiley's Cochrane Library, and Northern Light Life Sciences Conference Abstracts via Ovid. A total of 20 gray literature sources, including 1 database, 2 registers, 1 repository, 1 index, 1 archive, 1 preprint server, 1 agency, and 12 organizations, were also searched. Findings: The initial search produced 1089 results; a total of 158 publications were included in the final review. Salpingectomy has been associated with ovarian cancer risk reduction of approximately 80%. Studies have demonstrated that salpingectomy was safe, cost-effective, and was not associated with an earlier age of menopause onset. With widespread implementation, salpingectomy has the potential to reduce ovarian cancer mortality in the US by an estimated 15%. Both physician and patient awareness regarding the adnexa as the origin for most ovarian cancers, as well as the existence of salpingectomy and its potential benefits in reducing ovarian cancer risk, has increased during the past decade. Raising awareness and developing effective implementation strategies are essential. Conclusions and Relevance: The results of this systematic review suggest that bilateral salpingectomy for ovarian cancer prevention was safe and feasible and has the potential to be a cost-effective and cost-saving strategy across the population. Prospective studies to demonstrate long-term survival outcomes and feasibility in nongynecologic surgical procedures are warranted.

Germline Pathogenic Variants and Genetic Counseling by Ancestry in Patients With Epithelial Ovarian Cancer.

PURPOSE: To evaluate rates of germline pathogenic/likely pathogenic variants (PVs) and genetic counseling by ancestry in patients with epithelial ovarian cancer (EOC). METHODS: Patients with pathologically confirmed EOC who underwent clinical tumor-normal sequencing from January 1, 2015, to December 31, 2020, inclusive of germline analysis of ≥76 genes were included. Patients with newly identified PVs were referred for Clinical Genetics Service (CGS) counseling. Ancestry groups were defined using self-reported race/ethnicity and Ashkenazi Jewish (AJ) heritage. Genetic ancestry was inferred computationally using validated algorithms. Logistic regression models were built. RESULTS: Of 1,266 patients, self-reported ancestry (AJ, 17%; Asian, 10%; Black/African American, 5.4%; Hispanic, 6.2%; non-Hispanic White, 57%; other, 0.16%; unknown, 4.0%) correlated with genetic ancestry (AJ ancestry, 18%; admixed, 10%; African, 4%; East Asian [EAS], 6%; European, 56%; Native American, 0.2%; South Asian [SAS], 4%; unknown, 2%). Germline PVs were observed in 313 (25%) patients, including 195 (15%) with PVs in EOC-associated genes. Those with PVs were younger at diagnosis (59 v 62 years; P < .001) and more likely to have high-grade serous ovarian cancer (83% v 72%; P = .009). PV prevalence varied between ancestry groups (P < .001), with highest rates in the AJ (39.9%) and Asian (26.5%) groups and similar rates (>10%) across other ancestry groups. Use of genetic ancestry demonstrated similar findings and further characterized high rates of PV in EAS/SAS groups. Younger age, high-grade serous histology, and self-reported AJ or Asian ancestry were associated with PV in an EOC-associated gene. Rates of CGS counseling for newly identified PVs were high (80%) across ancestry groups. CONCLUSION: Rates of PV, particularly in EOC-associated genes, were high regardless of ancestry, with similar rates of counseling between groups, emphasizing the importance of universal genetic testing in all patients with EOC.

Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer.

OBJECTIVE: To evaluate adverse events (AEs) of combination lenvatinib plus pembrolizumab for the treatment of recurrent endometrial cancer (EC) and to assess outcomes by lenvatinib starting dose. METHODS: We retrospectively reviewed patients with recurrent EC treated with lenvatinib plus pembrolizumab at our institution between 10/1/2019-11/30/2021. Starting dose of lenvatinib was defined as standard (20 mg) or reduced (10 mg/14 mg). AEs were manually extracted through chart review and graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. PFS, overall survival (OS), and duration of response (DOR) were analyzed. RESULTS: Forty-three patients were identified; median age was 67 years (range, 54-85). The most common histologies were serous (35%), endometrioid (23%), and carcinosarcoma (21%). Starting lenvatinib doses were 10 mg (n = 10), 14 mg (n = 10), and 20 mg (n = 23). Median number of cycles received was 8 (range, 1-42). Twenty-four patients (56%) required ≥1 lenvatinib dose reduction; 3 (7%) discontinued lenvatinib, and 1 (2%) discontinued pembrolizumab for intolerance or AE. Thirty-six patients (84%) experienced grade ≥ 3 AEs; hypertension, weight loss, anemia, fatigue, and thrombocytopenia were most common. The standard dose group experienced significantly shorter observed PFS vs the reduced dose group (P = .02). There was no difference in DOR (P = .09) or OS (P = .27) between the groups. CONCLUSION: In clinical practice, AEs associated with combination lenvatinib plus pembrolizumab were common and comparable to Study 309/KEYNOTE-775 findings. AEs were similar regardless of starting lenvatinib dose. Further dose optimization studies of lenvatinib plus pembrolizumab may be indicated in recurrent EC. Clinical trial data remain the gold standard to guide starting lenvatinib dosing.

Germline drivers of gynecologic carcinosarcomas.

OBJECTIVES: To describe the prevalence of germline pathogenic variants (gPVs) in endometrial and ovarian carcinosarcomas and determine if gPVs are drivers of carcinosarcoma. METHODS: Patients with endometrial or ovarian carcinosarcomas who underwent clinical tumor-normal sequencing from 1/1/2015 to 6/1/2021 and consented to germline assessment of ≥76 cancer predisposition genes were included. In patients with gPVs, biallelic inactivation was identified through analysis of loss of heterozygosity and somatic pathogenic alterations. RESULTS: Of 216 patients identified, 167 (77%) were diagnosed with endometrial carcinosarcoma and 49 (23%) with ovarian carcinosarcoma. Overall, 33 gPVs were observed in 29 patients (13%); 20 gPVs (61%) had biallelic loss in tumors. The rate of high-penetrance gPVs overall was 7% (16 of 216); 88% of high-penetrance gPVs had biallelic loss. In the endometrial carcinosarcoma cohort, 22 gPVs were found in 19 (11%) of 167 patients; 12 gPVs (55%) had biallelic loss in tumors, including 8 (89%) of 9 in high-penetrance gPVs. Among the ovarian carcinosarcoma cohort, 11 gPVs were found in 10 (20%) of 49 patients; 8 gPVs (73%) had biallelic loss in tumors, and all evaluable high-penetrance gPVs (n = 6) had biallelic loss. All gPVs in homologous recombination (BRCA1, BRCA2, RAD51C) and Lynch syndrome (MSH2, MSH6) genes had biallelic loss in tumors (n = 15). CONCLUSIONS: gPVs in genes affecting homologous recombination- or Lynch-associated mismatch repair exhibited biallelic inactivation within tumors, suggesting likely drivers of gynecologic carcinosarcoma. Our data support germline testing for patients with gynecologic carcinosarcomas, given implications for treatment and risk-reduction in patients and at-risk family members.

Chemotherapy response in low-grade serous ovarian carcinoma at a comprehensive cancer center: Readdressing the roles of platinum and cytotoxic therapies.

BACKGROUND: Data on platinum sensitivity of low-grade serous ovarian carcinoma (LGSOC) in the upfront setting is lacking, and there is limited and contradictory information on chemotherapy responses in recurrent disease. METHODS: Patients with LGSOC seen at a comprehensive cancer center from January 1, 1998 to September 30, 2021 were identified from institutional databases. Response to neoadjuvant chemotherapy (NACT) or adjuvant platinum-based chemotherapy and to second- to fifth-line regimens was retrospectively characterized by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Wilcoxon rank-sum and two-tailed Fisher exact tests were employed. RESULTS: Of 50 patients, 12 received platinum doublets for suboptimal residual disease and 11 as NACT. Of 12 patients with suboptimal residual disease, seven (58%) achieved objective responses (five partial responses [PRs] and two complete responses); of the 11 patients who underwent NACT, one (9%) achieved a PR (p = .027). The 15 remaining patients had stable disease on first-line platinum chemotherapy. Of 44 patients who recurred, 20 had RECIST-evaluable responses to second-line and 27 to third-line chemotherapy. Objective response rates to platinum-based chemotherapy were 22% (two of nine) in the second line and 10% (one of 10) in the third. In second and third lines, highest response rates were observed with nonplatinum chemotherapy with bevacizumab, at 100% (two of two) and 30% (three of 10), respectively. CONCLUSIONS: Primary platinum-based chemotherapy has moderate activity in LGSOC and minimal activity in the recurrent setting, suggesting standard definitions of platinum sensitivity may not apply in LGSOC. In the second and third lines, nonplatinum chemotherapy/bevacizumab elicited the highest response rates.

Comprehensive analysis of germline drivers in endometrial cancer.

BACKGROUND: We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features. METHODS: Germline assessment of at least 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing from January 1, 2015, to June 30, 2021. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using nonparametric tests. RESULTS: Of 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high penetrance; 39 [17%] moderate penetrance; and 117 [51%] low, recessive, or uncertain penetrance). Compared with those without gPVs, patients with gPVs were younger (P = .002), more often White (P = .009), and less obese (P = .025) and had differences in distribution of tumor histology (P = .017) and molecular subtype (P < .001). Among 231 gPVs, 74 (32%) exhibited biallelic inactivation within tumors. For high-penetrance gPVs, 63% (47 of 75) of ECs had biallelic alterations, primarily affecting mismatch repair (MMR) and homologous recombination related genes, including BRCA1,BRCA2, RAD51D, and PALB2. Biallelic inactivation varied across molecular subtypes with highest rates in microsatellite instability-high (MSI-H) or copy-number (CN)-high subtypes (3 of 12 [25%] POLE, 30 of 77 [39%] MSI-H, 27 of 60 [45%] CN-high, 9 of 57 [16%] CN-low; P < .001). CONCLUSIONS: Of unselected patients with EC, 13% had gPVs, with 63% of gPVs in high-penetrance genes (MMR and homologous recombination) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention.

Current Evidence-Based Systemic Therapy for Advanced and Recurrent Endometrial Cancer.

Endometrial cancer (EC) is the most common gynecologic malignancy, with worldwide increasing incidence and disease-associated mortality. Although most patients with EC are diagnosed with early-stage disease, systemic treatment options for patients with advanced or recurrent EC have historically been limited. EC-focused clinical trials and the ensuing therapeutic landscape have expanded since The Cancer Genome Atlas (TCGA) identified 4 distinct EC subgroups associated with differential survival. This endeavor revolutionized our understanding of the genomic characterization of EC as well as molecular drivers of this heterogeneous malignancy, leading to precision oncology approaches to therapeutics and advancement in treatment options. This review describes the current status of and recent advancements in therapeutic options for patients with advanced and recurrent EC. The NCCN Guidelines for Uterine Neoplasms provide detailed recommendations regarding the diagnosis, workup, and management of EC.

Ten-year conditional probability of survival for patients with ovarian cancer: A new metric tailored to Long-term survivors.

OBJECTIVES: We assessed a conditional probability of survival (CPS) model to determine the probability of living 10 years after ovarian cancer diagnosis after having already survived 5 years. METHODS: We identified patients newly diagnosed with high-grade epithelial ovarian cancer from 1/1/2001-12/31/2009 and treated at our institution. Patients with <3 years follow-up were excluded. CPS was defined as the probability of surviving additional years (y) based on the condition a patient had already survived a given time (x): S(x + y)/S(x). Confidence intervals were estimated using a variation of Greenwood's formula. RESULTS: Of 916 patients meeting inclusion criteria, 473 (52%) were diagnosed from 2001 to 2005 and 443 (48%) from 2006 to 2009. Median age at diagnosis was 60 years (range, 25-95). The conventional 10-year OS rate for all patients was 29% (95% CI: 26%-32%)-75% (95% CI: 68%-82%) for stage I/II disease, 22% (95% CI: 19%-26%) for stage III, and 6.9% (95% CI: 3.9%-12%) for stage IV. For patients <65 years, the 10-year CPS for 5-year survivors was 65% (95% CI: 59%-70%); for those ≥65 years, it was 48% (95% CI: 38%-57%). For patients <65 years, the 10-year CPS for 5-year survivors by stage was: stage I/II, 89% (95% CI: 81%-94%); stage III, 58% (95% CI: 50%-66%); and stage IV, 26% (95% CI: 12%-42%). For patients ≥65 years, rates by stage were 78% (95% CI: 53%-91%), 42% (95% CI: 30%-53%), and 29% (95% CI: 7%-56%), respectively. CONCLUSIONS: For long-term survivors with high-grade epithelial ovarian cancer, CPS provides better prediction of survival than conventional methods.

The use of fertility preservation services for cancer patients: a single institution experience.

Objective: To analyze the use of services regarding fertility preservation (FP) in cancer patients at a single institution. Design: A retrospective cohort study. Setting: Academic medical center. Patients: A total of 208 FP referrals. Interventions: None. Main Outcome Measures: Method of FP; time from referral to FP intervention. Results: A total of 553 patients were referred to a reproductive specialist for FP in the setting of a medical diagnosis from 2011 to 2016. Of these, 208 patients satisfied the inclusion criteria and met with a reproductive specialist. Ninety patients underwent FP services. The average age at referral was 30.9 ± 7.9 years. Breast cancer (n=94, 45%) and leukemia/lymphoma (n=62, 30%) were the most prevalent cancer diagnoses. A 68.9% of patients underwent oocyte cryopreservation (n=62), 26.7% underwent embryo cryopreservation (n=24) and 4.4% underwent ovarian tissue preservation (n=4). The time interval from the referral to the FP intervention ranged from 1 to 810 days, with a median of 17 days. Conclusions: In the setting of a cancer diagnosis, most patients undergoing FP intervention underwent oocyte cryopreservation, were <35 years old, and underwent FP intervention in <30 days from referral. Whereas FP should ideally be initiated at the time of cancer diagnosis, all patients with a cancer diagnosis should be referred to a reproductive specialist and counseled on options for FP to preserve the optionality for the reproductive future they desire.

Management of patients with early-stage ovarian clear cell carcinoma: risk stratification and fertility conservation.

OBJECTIVE: We sought to describe clinicopathologic and treatment factors associated with oncologic outcomes in patients with early-stage ovarian clear cell carcinoma undergoing complete staging and in a sub-set of these patients undergoing fertility-conserving surgery. METHODS: We retrospectively identified patients with ovarian clear cell carcinoma initially treated at our institution from January 1, 1996 to March 31, 2020. Survival was estimated using Kaplan-Meier curves and compared by log-rank test. Survival-associated variables were identified by Cox proportional hazards regression. RESULTS: Of 182 patients, mismatch repair and p53 protein expression were assessed by immunohistochemistry on 82 and 66 samples, respectively. There were no significant differences in progression-free survival or overall survival between mismatch repair-deficient (n=6, including 4 patients with Lynch syndrome; 7.3%) and mismatch repair-proficient patients, whereas aberrant p53 expression (n=3; 4.5%) was associated with worse progression-free (p<0.001) and overall survival (p=0.01). Patients with stage IA/IC1 disease had a 95% 5-year overall survival rate (95% CI 88% to 98%); patients with stage IC2/IC3 disease had a similar 5-year overall survival rate (76%; 95% CI 54% to 88%) to that of patients with stage IIA/IIB disease (82%; 95% CI 54% to 94%). There was no difference in 5-year overall survival in patients with stage IA/IC1 undergoing chemotherapy versus observation (94% vs 100%). Nine patients underwent fertility-sparing surgery and none experienced recurrence. Of five patients who pursued fertility, all had successful pregnancies. CONCLUSIONS: In patients with completely staged ovarian clear cell carcinoma, those with stage IA/IC1 disease have an excellent prognosis, regardless of chemotherapy. Aberrant p53 expression may portend worse outcomes. Additional investigation is warranted on the safety of fertility conservation in patients with stage IA/IC1 disease.

Small cell neuroendocrine carcinoma of the cervix: Analysis of prognostic factors and patterns of metastasis.

Objectives: To describe characteristics and outcomes of patients with small cell neuroendocrine carcinoma of the cervix (SCNCC) and determine the staging system most predictive of outcome-the two-tier (limited-stage [LS] vs. extensive-stage [ES]) or International Federation of Gynecology and Obstetrics (FIGO) staging system. Methods: Patients with SCNCC evaluated at our institution from 1/1/1990-6/30/2021 were included. Medical records were reviewed for variables of interest. Appropriate statistical tests were performed to determine associations. Survival curves were created using the Kaplan-Meier method. Concordance probability estimates (CPEs) were calculated to evaluate the prediction probability of the staging systems. Results: Of 63 patients, 41 had LS and 22 ES SCNCC. Patients with ES disease were significantly older than those with LS disease (median, 54 and 37 years, respectively; p < 0.001). Smoking status, race, and history of HPV were not associated with stage or outcomes. Forty-eight patients had metastatic disease (24 [50%] at initial diagnosis). The most common first sites of metastasis were lung (n = 20/48, 42%), lymph nodes (n = 19/48, 40%), and liver (n = 13/48, 27%). Nine patients had brain metastasis (8 symptomatic at recurrence; 1 asymptomatic at initial diagnosis). Both staging systems were associated with progression-free and overall survival. Adjusted CPE found the FIGO staging system was more predictive of outcomes than the two-tier staging system. Conclusions: Providers should have a low threshold to obtain brain imaging for patients with SCNCC, especially in the presence of visceral metastases. FIGO staging should be used to classify SCNCC. Further research is necessary to understand prognostic factors of this rare disease.

Microsatellite Instability-High Endometrial Cancers with MLH1 Promoter Hypermethylation Have Distinct Molecular and Clinical Profiles.

PURPOSE: Microsatellite instability-high (MSI-H) endometrial carcinomas are underpinned by distinct mechanisms of DNA mismatch repair deficiency (MMR-D). We sought to characterize the clinical and genetic features of MSI-H endometrial cancers harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph). EXPERIMENTAL DESIGN: Of > 1,100 patients with endometrial cancer that underwent clinical tumor-normal sequencing, 184 had MSI-H endometrial cancers due to somatic MMR mutations or MLH1ph, or harbored pathogenic germline MMR mutations. Clinicopathologic features, mutational landscape, and tumor-infiltrating lymphocyte (TIL) scores were compared among MMR-D groups using nonparametric tests. Log-rank tests were used for categorical associations; Kaplan-Meier method and Wald test based on Cox proportional hazards models were employed for continuous variables and survival analyses. RESULTS: Compared with patients with germline (n = 25) and somatic (n = 39) mutations, patients with MLH1ph endometrial cancers (n = 120) were older (P < 0.001), more obese (P = 0.001) and had more advanced disease at diagnosis (P = 0.025). MLH1ph endometrial cancers were enriched for JAK1 somatic mutations as opposed to germline MMR-D endometrial cancers which showed enrichment for pathogenic ERBB2 mutations. MLH1ph endometrial cancers exhibited lower tumor mutational burden and TIL scores compared with endometrial cancers harboring germline or somatic MMR mutations (P < 0.01). MLH1ph endometrial cancer patients had shorter progression-free survival (PFS) on univariate analysis, but in multivariable models, stage at diagnosis remained the only predictor of survival. For stage I/II endometrial cancer, two-year PFS was inferior for patients with MLH1ph endometrial cancers compared with germline and somatic MMR groups (70% vs. 100%, respectively). CONCLUSIONS: MLH1ph endometrial cancers likely constitute a distinct clinicopathologic entity compared with germline and somatic MMR-D ECs with potential treatment implications.

Treatment of ovarian clear cell carcinoma with immune checkpoint blockade: a case series.

BACKGROUND: Although immune checkpoint blockade has demonstrated limited effectiveness against ovarian cancer, subset analyses from completed trials suggest possible superior efficacy in the clear cell carcinoma subtype. OBJECTIVE: To describe the outcomes of patients with ovarian clear cell carcinoma treated with immune checkpoint blockade. METHODS: This was a single-institution, retrospective case series of patients with ovarian clear cell carcinoma treated with a programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor with or without concomitant cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition between January 2016 and June 2021. Demographic variables, tumor microenvironment, molecular data, and clinical outcomes were examined. Time to treatment failure was defined as the number of days between start of treatment and next line of treatment or death. RESULTS: A total of 16 eligible patients were analyzed. The median treatment duration was 56 days (range 14-574); median time to treatment failure was 99 days (range 27-1568). The reason for discontinuation was disease progression in 88% of cases. Four patients (25%) experienced durable clinical benefit (time to treatment failure ≥180 days). One patient was treated twice with combined immune checkpoint blockade and experienced a complete response each time. All 12 patients who underwent clinical tumor-normal molecular profiling had microsatellite-stable disease, and all but one had low tumor mutation burden. Multiplex immunofluorescence analysis available from pre-treatment biopsies of two patients with clinical benefit demonstrated abundant tumor-infiltrating lymphocytes expressing PD-1. CONCLUSION: Our study suggests a potential role for immune checkpoint blockade in patients with clear cell carcinoma of the ovary. Identification of genetic and microenvironmental biomarkers predictive of response will be key to guide therapy.

MAPK Pathway Genetic Alterations Are Associated with Prolonged Overall Survival in Low-Grade Serous Ovarian Carcinoma.

PURPOSE: To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSC). EXPERIMENTAL DESIGN: Patients with LGSC tumors who underwent panel-based sequencing of up to 505 genes were identified. Data on somatic and germline mutations; copy-number alterations; and clinicopathologic features, including age at diagnosis, platinum sensitivity, and overall survival (OS), were collected. RESULTS: Following central pathology rereview, 119 patients with LGSC were identified for analysis. Of these, 110 (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; MAPK pathway alterations were found in 60% (n = 71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis more than 50 years (P = 0.02) and platinum-sensitive disease (P = 0.03). On multivariate analysis, MAPK pathway alterations (P = 0.02) and platinum sensitivity (P = 0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; seven pathogenic germline mutations were identified: MUTYH (n = 2), BAP1 (n = 1), RB1 (n = 1), CHEK2 (n = 1), APC (n = 1), and FANCA (n = 1). There were no germline BRCA1/2 mutations. One germline MUTYH-associated LGSC harbored loss-of-heterozygosity at the MUTYH locus, and the patient with the germline BAP1 mutation also harbored a somatic BAP1 frameshift mutation. CONCLUSIONS: This study showed that MAPK pathway alterations in LGSC, including KRAS mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC. See related commentary by Veneziani and Oza, p. 4357.