OBJECTIVE:To examine the association between ovarian cancer and subsequent risk of cardiovascular disease (CVD). METHODS:This retrospective cohort study used deidentified claims data from the Optum Labs Data Warehouse with linked Surveillance, Epidemiology, and End Results (SEER) data. Female patients aged ≥18 with ovarian cancer (2010-2021) who underwent bilateral oophorectomy were propensity score-matched to non-cancer controls who had bilateral oophorectomy for benign indications based on age, cardiovascular risk factors, comorbidities, and oophorectomy year. Outcome measure was incident major adverse cardiovascular events (MACE), a composite of angina, acute myocardial infarction, heart failure, stroke, transient ischemic attack, cardiac arrest, or cardiovascular procedures. Time to first MACE was compared between ovarian cancer and non-cancer patients using Gray's tests and Fine-Gray sub-distribution hazard models accounting for death as a competing risk. RESULTS:A total of 1148 ovarian cancer patients were matched to 2284 non-cancer controls. Median (interquartile range) follow-up was 29 (13-54) months for ovarian cancer patients and 40 (17-70) months for controls. One-, two-, three-, and five-year MACE risks were higher in ovarian cancer patients (7.7%, 12.0%, 17.1%, 24.8%) compared to controls (5.3%, 9.1%, 12.9%, 18.6%). Ovarian cancer was associated with increased MACE risk (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.14-1.56), with a more pronounced association in patients <55 years (HR 1.95, 95% CI 1.01-3.58) than ≥55 years (HR 1.30, 95% CI 1.09-1.53). CONCLUSION:Ovarian cancer is associated with increased CVD risk, particularly among younger patients, calling for mechanistic studies elucidating this relationship.

PURPOSE:Patients with endometrial cancer who progress after chemotherapy/immunotherapy have limited treatment options. We evaluated the activity and safety of sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, in patients with advanced/recurrent endometrial cancer, including carcinosarcoma. PATIENTS AND METHODS:This was a phase II, two-stage, open-label, investigator-initiated trial of patients with persistent/recurrent endometrial cancer who had progressed following ≥1 prior chemotherapy. Patients received SG 10 mg/kg on days 1 and 8 every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Secondary endpoints included clinical benefit rate [CBR = complete response (CR) + partial response (PR) + stable disease ≥ 6 months], duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Trop-2 expression was analyzed by immunohistochemistry as an H-score. RESULTS:Fifty patients were screened, and 21 enrolled during stage 1; 34 patients were screened, and 29 enrolled during stage 2; 84% (n = 42) of the patients harbored serous carcinoma, carcinosarcoma, or grade 3 endometrioid tumors. Patients received a median of two prior therapies (range, 1-4) and 50% had failed pembrolizumab/dostarlimab. At a median follow-up (range) of 11 (2.9-65.5) months, the ORR was 28% [95% confidence interval (CI), 16%-42%], including CRs (4%) and PRs (24%). The median DOR (95% CI) was 9.3 (2-12.9) months, with four still responding. The CBR was 52% (26/50). The median PFS and OS were 5.5 (95% CI, 3.7-7.4) and 17.5 (95% CI, 10.4-22.2) months, respectively. Grade 3 to 4 toxicity occurred in 88% with no attributable deaths. Mean H-scores did not predict response. CONCLUSIONS:SG demonstrated encouraging efficacy in a pretreated population that included biologically aggressive recurrent endometrial cancer. Adverse events were consistent with the known safety profile.

OBJECTIVES:We aimed to examine patterns of diagnostic evaluations for abnormal uterine bleeding (AUB) in a national sample of emergency department (ED) visits and identify potential racial and ethnic differences. METHODS:Using the 2014-2021 National Hospital Ambulatory Medical Care Survey data, we identified 1,049 (unweighted; 7,900,653 weighted) women age ≥18 years without previous cancer diagnosis who visited EDs for non-pregnancy-related AUB. The primary outcomes were whether an ultrasound was provided/ordered and whether referral/follow-up consultation was recommended. The association of race and ethnicity with these outcome measures was examined using multivariable logistic regressions adjusting for other patient/provider characteristics. RESULTS:Multivariable regression analysis showed that non-Hispanic Black patients were less likely than non-Hispanic white patients to receive or have an ultrasound ordered (adjusted odds ratio [aOR] = .58, 95% confidence interval [CI] [.36, .92]). Non-Hispanic Black patients also had a lower likelihood of receiving referral or recommendation for follow-up consultation, compared with non-Hispanic white patients (aOR = .54, 95% CI [.31, .94]). Hispanic patients did not differ significantly from non-Hispanic white patients in these measures. Perimenopausal age (45-54 years) and location in a non-metropolitan area were associated with a lower likelihood of having an ultrasound performed/ordered or a referral/follow-up consultation recommended. Involvement of a consulting physician at the ED visit increased the likelihood of having an ultrasound performed/ordered while reducing the likelihood of referral/recommendation for follow-up consultation. CONCLUSIONS:Among women presenting with AUB at EDs, diagnostic evaluation varied by race, suggesting a need to improve equity in care.

OBJECTIVE:Uterine cancer has no routine screening. Early diagnosis requires timely/appropriate evaluation of symptoms - most commonly postmenopausal bleeding (PMB). We examined initial place of care for PMB and its association with uterine cancer stage at diagnosis. METHODS:Using the Surveillance, Epidemiology and End Results-Medicare database with linked American Medical Association Physician Professional Data, we identified 15,443 patients aged ≥66 with uterine cancer who presented with PMB. Initial place of care was categorized as: office visit to an obstetrician/gynecologist, office visit to a physician of another specialty, or emergency department (ED) visit. Multivariable regressions were used to analyze the relationship between patient characteristics, initial place of care, and stage at diagnosis. RESULTS:Mean age of patients in the sample was 74.5 and 83.1 % were non-Hispanic White. 61.0 %, 27.8 %, and 11.2 % of patients had their first PMB claim filed from an office visit to an obstetrician/gynecologist, an office visit to a physician of another specialty, and an ED visit, respectively. Their median (10th-to-90th percentile) duration from first PMB claim to uterine cancer diagnosis was 20 (0-134), 32 (6-169), and 14 (0-92) days, respectively (P < 0.001). Patients whose first PMB claim was from an ED visit were more likely to have advanced stage cancer (e.g., adjusted OR [95 % CI] for having distant stage = 1.44 [1.16-1.80] compared to obstetrician/gynecologist visits and 1.31 [1.04-1.66] compared to other physician visits). CONCLUSIONS:Initial place of care for PMB was associated with duration to diagnosis. Patients using ED as initial place of care tended to have more advanced uterine cancer.

OBJECTIVE:Ovarian carcinosarcomas, also known as malignant mixed mullerian tumors, are rare, aggressive malignancies with no set standardized chemotherapy regimen. Our retrospective study aims to compare survival outcomes in patients with ovarian carcinosarcomas treated with platinum-based chemotherapy regimens versus non-platinum-based regimens across 2 major academic centers. METHODS:A retrospective chart review was performed on patients diagnosed with ovarian carcinosarcomas between 1995 and 2023 at Yale New Haven Hospital and between 2007 and 2022 at Stanford Hospital. Inclusion criteria were comprised of patients who underwent cytoreductive surgery followed by chemotherapy. The primary outcome was overall survival. Statistical Kaplan-Meier survival curves, log-rank tests, and Cox proportional hazard regression model analyses were conducted using Prism. RESULTS:Overall, 49 patients were included and there were no significant differences in baseline characteristics between the treatment groups. The median age at diagnosis was 65 years (range; 52-87) in the platinum-based group and 72.5 years (range; 57-89) in the non-platinum group. Most patients in both cohorts presented with advanced-stage disease: 28 of 37 (75.7%) in the platinum-based group and 10 of 12 (83.3%) in the non-platinum group had stage III to IV disease. In total, 37 patients (75.5%) received adjuvant platinum-based chemotherapy (predominantly carboplatin/paclitaxel), and 12 patients (24.4%) received adjuvant non-platinum-based regimens. Median overall survival was higher in the platinum-based group (59.8 months) compared to the non-platinum-based group (35.2 months, p < .05). The adjusted hazard ratio for mortality was 0.25 (95% confidence interval 0.08 to 0.77) in the platinum-based chemotherapy. CONCLUSIONS:Our results suggest an observed association between platinum-based chemotherapy and improved outcomes in patients with ovarian carcinosarcoma following optimal cytoreductive surgery. Given that this is a small retrospective analysis, there is a severe selection bias and no formal non-inferiority design. As such, these findings should be considered exploratory and hypothesis-generating. The observed survival difference supports the rationale for further evaluation of platinum-based chemotherapy in ovarian carcinosarcoma in a larger, multi-institutional study designed to clarify its potential as a first-line approach.

Abstract Purpose: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients. Patients and Methods: We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms. Results: Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated. Conclusions: Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted.

Objective. To examine whether uterine cancer symptoms differ between Black and White patients and how this may influence their stage at diagnosis.Methods. Using the Surveillance, Epidemiology and End Results-Medicare database, we identified 2328 Black and 21,774 White patients with uterine cancer in 2008-2017. Their symptoms in the 18 months before diagnosis were categorized as postmenopausal bleeding (PMB) alone, PMB together with other symptoms (e.g., abdominal/pelvic pain, bloating), non-PMB symptoms alone, or no symptoms. Stage at diagnosis was di-chotomized as advanced (i.e., regional/distant) versus localized. The association between race and stage was analyzed using regression models incrementally adjusting for symptoms and other patient characteristics.Results. A larger proportion of Black than White patients experienced PMB together with other symptoms (63.1% versus 58.0%) or experienced non-PMB symptoms alone (13.1% versus 9.4%) (p < 0.001). Black patients had a higher risk of advanced-stage diagnosis than White patients (45.0% versus 30.3%, unadjusted RR = 1.52, 95% CI: 1.44-1.59). Adjusting for Black-White differences in symptoms attenuated the RR to 1.46 (95% CI: 1.39-1.53). Compared to PMB symptoms alone, having additional non-PMB symptoms (RR = 1.21, 95% CI: 1.15-1.26) and having non-PMB symptoms alone (RR = 1.99, 95% CI: 1.88-2.10) were associated with increased risk of advanced-stage diagnosis. Further adjusting for histology and other patient characteristics reduced Black -White disparity in advanced-stage diagnosis to 1.08 (95% CI: 1.03-1.14) but symptoms remained significantly associated with stage at diagnosis.Conclusions. Having non-PMB symptoms was associated with more advanced stage at diagnosis. Non-PMB symptoms were more common among Black than White patients, which might hinder symptom recognition/ evaluation.(c) 2023 Elsevier Inc. All rights reserved.

Abstract Background Ixabepilone may retain activity in paclitaxel-resistant disease. We previously reported improved response rates (ORR), progression-free (PFS), and overall survival (OS) conferred by ixabepilone+bevacizumab (IXA + BEV) compared to monotherapy (IXA) in heavily pre-treated ovarian cancers. We now describe a mature data set. Subset analyses were performed in patients with different taxane sensitivities and dose modifications. Methods Patients previously treated with paclitaxel were stratified by prior BEV and randomized to receive IXA 20 mg/m2 days 1,8,15 ± BEV 10 mg/kg days 1,15 of a 28-day cycle in a multi-site prospective randomized phase 2 trial. Results Thirty-seven patients were randomized to IXA and 39 patients to IXA + BEV. At the final data cutoff (05/27/2023), ORR was higher in the IXA + BEV arm (38.4% vs. 8.1%, p = 0.003). Dose reductions were necessary in most participants but did not diminish PFS/OS benefits. Most patients were paclitaxel-refractory/-resistant (51%, n = 19/37;67%, n = 26/39); the remainder were taxane-sensitive. The addition of BEV to IXA conferred benefit in PFS (5.5 vs. 2.2 mo; HR 0.31, 90%CI 0.20–0.49, p < 0.001) and OS (10.3 vs. 6.0 mo; HR 0.56, 90%CI 0.38–0.84, p = 0.02) that persisted after adjusting for prior taxane response. Conclusions IXA + BEV has activity in heavily pre-treated ovarian cancers and offers significant improvement in ORR and PFS/OS compared to IXA, despite prior taxane response and dose reductions. Clinical Trial Registration NCT03093155

High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D / MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4 , a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib ( P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies.

Representative microscopic images of paired cervical biopsies at enrollment at 6 months follow-up.

Objective To explore patient experiences with the diagnosis process for uterine cancer and the perceived barriers that may affect early diagnosis and racial disparities in stage at diagnosis. Methods We conducted semi-structured interviews to ascertain the diagnostic journey of 11 non-Hispanic Black (“Black”) and 11 non-Hispanic White (“White”) patients who were diagnosed with uterine cancer in the past six months. All interviews were audio-recorded, professionally transcribed, and analyzed using thematic analysis. Findings were presented to patients and community advocates for critical review and feedback before being finalized. Results Respondents had a median age of 64 years. Thirteen (59.1 %) had stage I tumor, whereas nine (40.9 %) had stage II-IV disease. Respondents were attentive to their symptoms but unaware that they could indicate uterine cancer. This was compounded by women's conditioned acceptance of discomfort and disconnection from gynecological care after reproductive age. Respondents often viewed racial disparities in diagnosis through other social determinants of health, including gender, age, and healthcare access. These overlapping social experiences, coupled with respondents' concentration on recovery, may mask their perceptions about systemic racism. Although few respondents noted negative experiences in their own evaluations leading to the diagnosis of uterine cancer, Black respondents often described how previous discriminatory experiences informed a wariness of healthcare systems. Conclusion Lack of public awareness of uterine cancer, gendered expectations for discomfort, and disconnection from gynecologic care all interfered with early diagnosis of uterine cancer. Discriminatory experiences in prior healthcare further complicate Black patients' engagement with the healthcare system.

Study Objective The purpose of this study was to assess the long-term risk of hysterectomy following endometrial ablation and to identify risk factors for endometrial ablation failure. Design We performed a retrospective cohort study of all patients who underwent endometrial ablation from January 1, 2011 to January 1, 2021 at a single academic institution. Setting N/A. Patients or Participants 1072 patients who met inclusion criteria and were included in the analysis. Interventions N/A. Measurements and Main Results Of the 1072 patients who underwent an endometrial ablation, 191 (17.8%) went on to have a hysterectomy. The majority of these hysterectomies were performed for persistent abnormal uterine bleeding and pelvic pain. Forward stepwise logistic regression was used to account for the effect of specific categorical variables on the probability of hysterectomy after ablation. Patients who required a hysterectomy were more likely to have a higher BMI and identify as Black or African-American (p<0.01). Over 16% of final hysterectomy specimens showed evidence of adenomyosis. Conclusion Endometrial ablation has become a popular choice for treatment of abnormal uterine bleeding, given its minimally invasive nature and cost-effectiveness. When counseling patients for treatment with endometrial ablation, it is important to inform them of the risk of treatment failure and the need for hysterectomy. Our study aimed to identify risk factors that lead to endometrial ablation failure to improve patient counseling. Previous studies have quoted a 12-13% risk of hysterectomy following endometrial ablation, however our study found a higher rate of hysterectomy – approaching 18%. Our results indicate that women with higher BMI and those who are Black or African-American are more likely to fail an endometrial ablation. In addition, adenomyosis was present in a large proportion of final hysterectomy specimens. These findings can be used to enhance patient counseling and selection of appropriate candidates for endometrial ablation.