Correlation of histopathologic findings with clinical predictors of disease recurrence and progression to vulvar carcinoma in patients with differentiated vulvar intraepithelial neoplasia (dVIN).

Objective: To evaluate predictors of recurrence and the risk of progression to carcinoma in patients with dVIN. Methods: 36 self-identified White patients with dVIN from 2011 to 2022 were identified. Demographics, treatment and clinical course were abstracted. Histopathologic features and IHC stains were reviewed by 2 subspecialty pathologists. Standard statistical analyses were applied. Results: Median cohort age was 70 years (range 39-91). Median follow-up was 29.5 months (range 1-123). All patients were Caucasian. 67% had lichen sclerosus (LS) adjacent to dVIN. 56% of patients had recurrent dVIN a median of 11 months from diagnosis. 14 patients had invasive squamous cell carcinoma of the vulva (SCCV) during the study period: 9 (25%) with synchronous dVIN, 5 (14%) developed SCCV after a median of 21.5 months (range 8-57). Patients treated with surgery were more likely to have recurrent/persistent dVIN (p = 0.04) and synchronous or progression to SCCV (p = 0.02) than patients treated with topical therapy. Excluding 9 women with synchronous SCCV, no initial treatment (observation, topical therapy, surgery) was superior at preventing recurrent/ progressive disease in isolated dVIN. Mutation-type p53 expression was identified in 18 (64%) and aberrant GATA3 staining/expression in 20 (56%) of cases. Aberrant GATA3 expression was associated with a higher frequency of synchronous/progression to SCCV (p < 0.05). Conclusion: dVIN has an aggressive clinical course in white patients with a high risk of recurrence/persistence and synchronous/progression to SCCV despite treatment. Close surveillance with a low threshold for additional biopsies is warranted. P53 and GATA3 IHC stains may be useful markers of disease outcome.

Patterns of care and outcomes of risk reducing surgery in women with pathogenic variants in non-BRCA and Lynch syndrome ovarian cancer susceptibility genes.

OBJECTIVES: Guidelines recommend risk-reducing bilateral salpingo-oophorectomy (RRSO) for women with pathogenic variants of non-BRCA and Lynch syndrome-associated ovarian cancer susceptibility genes. Optimal timing and findings at the time of RRSO for these women remains unclear. We sought to characterize practice patterns and frequency of occult gynecologic cancers for these women at our two institutions. METHODS: Women with germline ovarian cancer susceptibility gene pathogenic variants who underwent RRSO between 1/2000-9/2019 were reviewed in an IRB-approved study. All patients were asymptomatic with no suspicion for malignancy at time of RRSO. Clinico-pathologic characteristics were extracted from the medical records. RESULTS: 26 Non-BRCA (9 BRIP1, 9 RAD51C, and 8 RAD51D) and 75 Lynch (36 MLH1, 18 MSH2, 21 MSH6) pathogenic variants carriers were identified. Median age at time of RRSO was 47. There were no occurrences of occult ovarian or fallopian tube cancer in either group. Two patients (3%) in the Lynch group had occult endometrial cancer. Median follow up was 18 and 35 months for non-BRCA and Lynch patients, respectively. No patient developed primary peritoneal cancer upon follow up. Post-surgical complications occurred in 9/101 (9%) of patients. Hormone replacement therapy (HRT) was rarely used despite reported post-menopausal symptoms in 6/25 (23%) and 7/75 (37%) patients, respectively. CONCLUSIONS: No occult ovarian or tubal cancers were observed in either group. No recurrent or primary gynecologic-related cancers occurred upon follow-up. Despite frequent menopausal symptoms, HRT use was rare. Both groups experienced surgical complications when hysterectomy and/or concurrent colon surgery was performed suggesting concurrent surgeries should only be performed when indicated.

Single-cell transcriptomic analysis of endometriosis.

Endometriosis is a common condition in women that causes chronic pain and infertility and is associated with an elevated risk of ovarian cancer. We profiled transcriptomes of >370,000 individual cells from endometriomas (n = 8), endometriosis (n = 28), eutopic endometrium (n = 10), unaffected ovary (n = 4) and endometriosis-free peritoneum (n = 4), generating a cellular atlas of endometrial-type epithelial cells, stromal cells and microenvironmental cell populations across tissue sites. Cellular and molecular signatures of endometrial-type epithelium and stroma differed across tissue types, suggesting a role for cellular restructuring and transcriptional reprogramming in the disease. Epithelium, stroma and proximal mesothelial cells of endometriomas showed dysregulation of pro-inflammatory pathways and upregulation of complement proteins. Somatic ARID1A mutation in epithelial cells was associated with upregulation of pro-angiogenic and pro-lymphangiogenic factors and remodeling of the endothelial cell compartment, with enrichment of lymphatic endothelial cells. Finally, signatures of ciliated epithelial cells were enriched in ovarian cancers, reinforcing epidemiologic associations between these two diseases.

DNA methylation and transcriptomic features are preserved throughout disease recurrence and chemoresistance in high grade serous ovarian cancers.

BACKGROUND: Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC). METHODS: We performed whole genome bisulfite sequencing and transcriptome sequencing in 62 primary and recurrent tumors from 28 patients with stage III/IV HGSOC, of which 11 patients carried germline, pathogenic BRCA1 and/or BRCA2 mutations. RESULTS: Landscapes of genome-wide methylation (on average 24.2 million CpGs per tumor) and transcriptomes in primary and recurrent tumors showed extensive heterogeneity between patients but were highly preserved in tumors from the same patient. We identified significant differences in the burden of differentially methylated regions (DMRs) in tumors from BRCA1/2 compared to non-BRCA1/2 carriers (mean 659 DMRs and 388 DMRs in paired comparisons respectively). We identified overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival (P = 0.006) in these BRCA1/2 carriers. CONCLUSION: These findings indicate methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even after extensive chemotherapy treatment, and that changes in methylation and gene expression are unlikely to serve as drivers for chemoresistance in HGSOC.

A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes.

Endometriosis is associated with increased risk of epithelial ovarian cancers (EOCs). Using data from large endometriosis and EOC genome-wide association meta-analyses, we estimate the genetic correlation and evaluate the causal relationship between genetic liability to endometriosis and EOC histotypes, and identify shared susceptibility loci. We estimate a significant genetic correlation (rg) between endometriosis and clear cell (rg = 0.71), endometrioid (rg = 0.48), and high-grade serous (rg = 0.19) ovarian cancer, associations supported by Mendelian randomization analyses. Bivariate meta-analysis identified 28 loci associated with both endometriosis and EOC, including 19 with evidence for a shared underlying association signal. Differences in the shared risk suggest different underlying pathways may contribute to the relationship between endometriosis and the different histotypes. Functional annotation using transcriptomic and epigenomic profiles of relevant tissues/cells highlights several target genes. This comprehensive analysis reveals profound genetic overlap between endometriosis and EOC histotypes with valuable genomic targets for understanding the biological mechanisms linking the diseases.

Prenatal telemedicine during COVID-19: patterns of use and barriers to access.

OBJECTIVE: To evaluate patient experience with a prenatal telemedicine visit and identify barriers to accessing telemedicine among rural pregnant people in northern New England during the beginning of the COVID-19 pandemic. MATERIALS AND METHODS: We conducted a postvisit electronic survey of pregnant people who successfully participated in a prenatal telemedicine visit at a rural academic medical center in Northern New England. Nineteen questions were included in 5 domains: (1) engagement with prenatal care; (2) barriers to telemedicine and in person healthcare; (3) experience of prenatal care; (4) remote pregnancy surveillance tools; and (5) sources of COVID-19 information. RESULTS: Responses were obtained from 164 pregnant people. Forty percent of participants had participated in an audio-only telemedicine visit, and 60% in a video telemedicine visit. The visit was easy or somewhat easy for 79% of respondents and somewhat difficult or difficult for 6.8%. The most common barrier to accessing telemedicine was poor internet or phone connectivity, followed by childcare responsibilities, lack of equipment, and lack of privacy. Participants also engaged in additional remote prenatal care including phone calls with registered nurses (7.6%), communication with the obstetrics team through a secure health messaging portal (21.1%), and home health monitoring (76.3%). DISCUSSION AND CONCLUSIONS: In this survey, evaluating the experience of pregnant people participating in a prenatal telemedicine visit during the COVID-19 pandemic, respondents had a positive experience with telemedicine overall, but also identified significant barriers to participation including issues with connectivity and lack of equipment for the visit. Most participants used telemedicine in combination with other tools for remote self-care.

Breast cancer surveillance following ovarian cancer in BRCA mutation carriers.

OBJECTIVES: BRCA 1 or 2 mutation carriers have increased risk of developing breast cancer (BC) and serous epithelial ovarian cancer (EOC). The incidence of BC over time after EOC is unknown. Optimal BC surveillance for BRCA mutation carriers following EOC has not been defined. METHODS: A multi-institutional retrospective chart review was performed. Patients with BRCA -associated EOC diagnosed between 1996 and 2016 were followed for an average of 80 months. Women with previous bilateral mastectomy were excluded; women with prior BC and an intact breast were included. Descriptive statistics, Chi Square, and univariate survival analysis were performed. RESULTS: 184 patients with BRCA -associated EOC were identified. Eighteen (10%) were diagnosed with BC a median of 48 months following EOC. Two (1%) with prior BC developed contralateral BC and 16 (9%) developed primary BC. The majority of BC (55%) was diagnosed 3 years following EOC. The 3-, 5- and 10-year incidence of BC was 5.6%, 9.5% and 33.3%. Annual mammography was performed in 43% and MRI in 34%. Twenty-eight (15%) women underwent risk-reducing mastectomy (RRM). There was no statistically significant difference in BC screening between women with, and without, a prior BC. BC was most commonly detected on mammogram. Three (17%) women had occult BC at the time of RRM. Nine (50%) had DCIS, and 8 (44%) had stage I/II BC. Median 5- and 10-year survival was 68% and 43% and was comparable between groups. CONCLUSIONS: Ten percent of women developed BC after EOC. The incidence of BC following EOC in BRCA carriers increases over time, and surveillance is recommended given their enhanced survival of EOC. Timely genetic testing for women with EOC is imperative to better triage BC screening resources and treatment.

Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer.

OBJECTIVE: To evaluate the combination of pembrolizumab, cisplatin and gemcitabine in recurrent platinum-resistant ovarian cancer. METHODS: Patients received six cycles of chemotherapy with gemcitabine and cisplatin on day 1 and day 8 of a 21-day treatment cycle. Pembrolizumab was administered on day 1 of cycles 3-6 and as maintenance monotherapy in cycles 7-34. Palliative radiation to a non-target symptomatic lesion was allowed. The primary objective was overall response rate by RECIST 1.1 criteria. Secondary objectives included safety, progression-free survival, time to progression, duration of response and overall survival. RESULTS: An interim analysis for futility was performed at 18 evaluable patients. Overall response rate was 60%, duration of response was 4.9 months and time to progression was 5.2 months. Progression-free survival at 6 and 12 months was 43% and 5%. Median progression-free survival was 6.2 months and median overall survival was 11.3 months. In all patients, CA125 levels reflected response and progression. There were no pseudoprogression events. After receiving palliative radiation during pembrolizumab maintenance, a patient with recurrent ovarian clear cell carcinoma had an exceptional and durable response that is ongoing for greater than 2 years. After consultation with the sponsor, based on the modest duration of response observed at the interim analysis for futility, the decision was made to close the trial to further accrual. CONCLUSIONS: The addition of pembrolizumab to cisplatin and gemcitabine did not appear to provide benefit beyond chemotherapy alone in patients with recurrent platinum-resistant ovarian cancer.

Short-term impact of surgically induced menopause on cognitive function and wellbeing in women at high risk for ovarian cancer following risk-reducing bilateral salpingo-oophorectomy.

OBJECTIVE: Risk-reducing bilateral salpingo-oophorectomy (RRSO) is an effective strategy to prevent pelvic serous carcinoma for women at high risk of developing ovarian cancer; however, it results in premature menopause. Data is lacking to adequately counsel these women about potential effects of premature menopause on cognition and quality of life. METHODS: A prospective study in premenopausal women at high risk of ovarian cancer to determine changes in cognition over time after RRSO and the impact of hormone therapy (HT) on cognition. Participants were surveyed before and after surgery using the Functional Assessment of Cancer Therapy-Cognitive questionnaire and questions regarding domains of wellbeing at 6, 12 and 18 months. Data was tested for changes across time using mixed model regression and logistic regression. RESULTS: Fifty-seven women were included. Sixty-three percent of participants used HT. At 6 months postoperatively, perceived cognitive impairment declined by 5.5 points overall (4.4 in non-HT users and 6 in HT users), P = 0.003. The other domains of cognition assessed did not change significantly over time and the use of HT did not impact scores. Sleep disruption was common in this cohort and was not mitigated by HT. Self-reported depression improved after RRSO (P = 0.004). CONCLUSION: Women at high risk of ovarian cancer who choose RRSO may experience declines in cognition within the first 6 months of surgical menopause. HT may cause small declines in perceived cognitive impairment at 6 months after RRSO. Women can expect more sleep disruption after menopause, which is not mitigated by HT.

Video Summary:http://links.lww.com/MENO/A697.

Breast Cancer Surveillance Following Ovarian Cancer in BRCA Mutation Carriers.

BRCA1 or 2 mutations result in higher cancer risk for breast cancer (BC) and epithelial ovarian cancer (EOC) for carriers than exists in the general population. Optimal breast imaging surveillance in these patients has not been well defined. An Institutional Review Board-approved, multi-institutional retrospective chart review was performed. Patients diagnosed with BRCA-associated EOC between 1990-2015 were identified; demographic and clinical data were collected and analyzed. 192 BRCA mutation-positive patients with EOC were identified. 16/192 (8.3%) women were diagnosed with BC following EOC, at a median of 50 (range 5-327) months following EOC diagnosis and median age 59.5 (45-84) years. Breast cancer was most commonly detected on mammogram 7/16 (44%) or clinical exam 7/16 (44%). 2/16 (12.5%) had occult BC found during risk-reducing mastectomy. 14 (88%) had early-stage (0-2) disease. At mean follow-up of 8.1 years, 6 (37.5%) patients with BC following EOC had died due to EOC. The risk of BC diagnosis following EOC in BRCA mutation carriers is low; most of these BCs are early stage and diagnosed with mammography or physical exam. Overall, survival in BRCA mutation carriers is dominated by EOC-related mortality. Breast cancer surveillance in BRCA mutation carriers following EOC should prioritize nonsurgical strategies.

Clinical outcomes in ovarian cancer patients receiving three versus more cycles of chemotherapy after neoadjuvant treatment and interval cytoreductive surgery.

OBJECTIVES: To compare clinical outcomes for stage IIIC and IV ovarian cancer patients receiving neoadjuvant chemotherapy and interval cytoreductive surgery followed by up to three versus more cycles of post-operative chemotherapy. METHODS: We conducted a multi-institution retrospective cohort study of patients treated from January 2005 to February 2016 with neoadjuvant platinum-based therapy followed by interval surgery and post-operative chemotherapy. The following were exclusion criteria: more than four cycles of neoadjuvant chemotherapy, bevacizumab with neoadjuvant chemotherapy, non-platinum therapy, prior chemotherapy, and elevated CA125 values after three post-operative chemotherapy cycles. Progression-free and overall survival and toxicity profiles were compared between groups receiving up to three cycles versus more that three cycles post-operatively. RESULTS: A total of 100 patients met inclusion criteria: 41 received up to three cycles and 59 received more than three cycles. The groups were similar in terms of age, body mass index, performance status, tumor histology, optimal cytoreduction rates, and median number of neoadjuvant chemotherapy cycles. Median progression-free survival was 14 vs 16.6 months in those receiving up to three cycles versus more than three cycles, respectively (HR 0.99, 95% CI 0.58 to 1.68, p=0.97). Similarly, median overall survival was not different at 47.1 vs 69.4 months, respectively (HR 1.96, 95% CI 0.87 to 4.42, p=0.10). There were no differences in grade 2 or higher chemotherapy-related toxicities. CONCLUSIONS: Extending post-operative chemotherapy beyond three cycles in patients receiving neoadjuvant chemotherapy and interval cytoreductive surgery with normalization of CA125 levels was not associated with improved survival or greater toxicity. Future study in a larger cohort is warranted to define optimal length of cytotoxic treatment.

Prognostic role of pathologic response and cytoreductive status at interval debulking surgery after neoadjuvant chemotherapy for advanced epithelial ovarian cancer.

BACKGROUND: We sought to determine if complete pathologic response (cPR) and cytoreductive status at interval debulking surgery (IDS) after neoadjuvant chemotherapy (NACT) are associated with improved clinical outcomes in ovarian cancer. METHODS: We evaluated 91 patients with advanced ovarian cancer who underwent NACT and IDS. Pathologic response, cytoreductive status, and outcomes were determined. Descriptive statistics, bivariate analysis, and Kaplan-Meier survival probabilities were calculated. RESULTS: cPR occurred in 9 (10%), microscopic pathologic response (microPR) in 18 (20%), and macroscopic pathologic response (macroPR) in 64 (70%) patients. Median progression-free survival (PFS) for patients with cPR was significantly improved compared with patients with any pathologic residual disease (microPR/macroPR; undefined vs 10.9 months, P = .01); whereas, microPR was not associated with significantly improved PFS compared with macroPR (16.3 months vs 10 months, P = .08). Cytoreduction to no gross residual disease was associated with improved PFS (undefined vs 7.5 months vs 5.5 months, P < .01) and overall survival (undefined vs 38.7 months vs 12 months, P < .01) compared with visible residual disease less than or equal to 1 cm or suboptimal. CONCLUSIONS: cPR is uncommon (10%) after NACT for advanced ovarian cancer. Better pathologic response and cytoreductive status are associated with improved PFS, emphasizing the importance of both chemotherapy response and surgical effort.

Ultrasound guided transversus abdominis plane (TAP) block utilization in multimodal pain management after open gynecologic surgery.

Transversus abdominis plane (TAP) block is a peripheral nerve block directed at the nerves in the anterior abdominal wall. We sought to determine whether TAP block reduces post-operative narcotic use or length of stay after open gynecologic surgery. Among 98 women who underwent an open hysterectomy between July 2016 - July 2017 by a gynecologic oncologist, 73 (74.5%) received a TAP block. The majority of patients who received a TAP block had a vertical incision (86.3%) while the majority of patients who did not receive TAP block had a transverse incision (64%). More patients in the TAP block group underwent cancer debulking compared to the no TAP block group (65.7% versus 8%). The two groups did not differ in post-operative pain scores on day 1, 2, or 3, cumulative narcotic use by post-operative day 3, length of stay, or ileus. We found TAP block after vertical skin incision results in comparable pain scores, narcotic use, and length of stay compared to patients undergoing transverse incisions without TAP block.

Aspirin use correlates with survival in women with clear cell ovarian cancer.

Data from colon, breast and prostate cancers suggest that aspirin users have reduced mortality. While the direct mechanism remains uncertain, aspirin can suppress the COX-dependent and independent pathways involved in tumor progression. We hypothesized that aspirin users with clear cell ovarian cancer would have improved survival outcomes. We performed a retrospective review of patients with clear cell ovarian cancer diagnosed between 1995 and 2010, and followed outcomes through 2016. Patients underwent primary cytoreductive surgery followed by platinum-based chemotherapy. Aspirin use was defined by medication documentation in two records more than six months apart. Statistical tests included Fisher's exact, Kaplan-Meier and Cox regression analyses. Seventy-seven patients met inclusion criteria. Fifty-four patients (70%) had stage I-II disease. Thirteen patients (17%) used aspirin. Aspirin users had a statistically longer disease-free survival compared to non-users (HR 0.13, p = .018). While median disease-free survival was not reached for either group, 1 of 13 (8%) aspirin users recurred at 24 months, compared to 18 of 64 (28%) non-users. Aspirin users demonstrated longer overall survival (HR 0.13, p = .015). Median survival was not reached for aspirin users, compared to 166 months for non-users. Aspirin use retained significance (HR 0.13, p = .044) after controlling for age, stage and cytoreductive status. In this small cohort of women with clear cell ovarian cancer, aspirin use correlated with improved disease-free and overall survival, and retained independent significance as a positive prognostic factor. Further research is warranted to confirm these findings before considering aspirin as a therapeutic intervention.

Language as a barrier to cancer clinical trial accrual: assessing consenting team knowledge and practices for cancer clinical trial consent among low English fluency patients

Background: Low English fluency in large culturally diverse institutions may contribute to meager minority accrual. Our objective was to: 1) Assess knowledge of proper consenting procedures among the research team when consenting a low English fluency patient. 2) Assess the enrollment rate of participants in cancer therapeutic trials who identify a preferred language other than English. Methods: An anonymous web-based survey was distributed at a single institution to investigators, research staff and translator services to assess knowledge of consenting procedures. Patient enrollment data was retrieved from the clinical trials enrollment tracking system from January 2011 ­ October 2014 and matched to registration data indicating preferred language (N = 1521). The number and type of cancer cases from January 2011­October 2014 were retrieved from the institutional cancer registry and matched to registration data indicating preferred language. Results: Although there are many organizational in-person and web-based trainings focused on the requirements for consenting low English fluency patients, members of the research team responded correctly to only 64.8% (σ = 24.6%) of the knowledge-based portion of the survey. Of the 12,538 index cancer cases indentified, 10% preferred a language other than English. Trial enrollment rates for cancer clinical trials were similar for English (13%), Spanish (11%), and, Armenian (10%) speakers. Populations speaking Russian and Arabic had the lowest participation at 5% each. Conclusions: In order to increase enrollment into clinical trials, institutions must explore more effective training opportunities for research staff, engage interpreters and adopt recruitment and study materials in different languages (AU)

Occult and subsequent cancer incidence following risk-reducing surgery in BRCA mutation carriers.

OBJECTIVE: To report the frequency and features of occult carcinomas and the incidence of subsequent cancers following risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers. METHODS: 257 consecutive women with germline BRCA mutations who underwent RRSO between January 1, 2000 and December 31, 2014 were identified in an Institutional Review Board approved study. All patients were asymptomatic with normal physical exams, CA 125 values, and imaging studies preoperatively, and had at least 12months of follow-up post-RRSO. All patients had comprehensive adnexal sectioning performed. Patient demographics and clinico-pathologic characteristics were extracted from medical and pathology records. RESULTS: The cohort included 148 BRCA1, 98 BRCA2, 6 BRCA not otherwise specified (NOS), and 5 BRCA1 and 2 mutation carriers. Occult carcinoma was seen in 14/257 (5.4%) of patients: 9 serous tubal intraepithelial carcinomas (STIC), 3 tubal cancers, 1 ovarian cancer, and 1 endometrial cancer. Three patients (1.2%) with negative pathology at RRSO subsequently developed primary peritoneal serous carcinoma (PPSC), and 2 of 9 patients (22%) with STIC subsequently developed pelvic serous carcinoma. 110 women (43%) were diagnosed with breast cancer prior to RRSO, and 14 of the remaining 147 (9.5%) developed breast cancer following RRSO. Median follow-up of the cohort was 63months. CONCLUSION: In this cohort, 5.4% of asymptomatic BRCA mutation carriers had occult carcinomas at RRSO, 86% of which were tubal in origin. The risk of subsequent PPSC for women with benign adnexa at RRSO is low; however, the risk of pelvic serous carcinoma among women with STIC is significantly higher.