Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair.

Drugs targeting the DNA damage response (DDR) are widely used in cancer therapy, but resistance to these drugs remains a major clinical challenge. Here, we show that SYCP2, a meiotic protein in the synaptonemal complex, is aberrantly and commonly expressed in breast and ovarian cancers and associated with broad resistance to DDR drugs. Mechanistically, SYCP2 enhances the repair of DNA double-strand breaks (DSBs) through transcription-coupled homologous recombination (TC-HR). SYCP2 promotes R-loop formation at DSBs and facilitates RAD51 recruitment independently of BRCA1. SYCP2 loss impairs RAD51 localization, reduces TC-HR, and renders tumors sensitive to PARP and topoisomerase I (TOP1) inhibitors. Furthermore, our studies of two clinical cohorts find that SYCP2 overexpression correlates with breast cancer resistance to antibody-conjugated TOP1 inhibitor and ovarian cancer resistance to platinum treatment. Collectively, our data suggest that SYCP2 confers cancer cell resistance to DNA-damaging agents by stimulating R-loop-mediated DSB repair, offering opportunities to improve DDR therapy.

Minimally invasive interval cytoreductive surgery for advanced ovarian cancer.

With the increasing use of neoadjuvant chemotherapy, it has also become apparent that some patients will require a less extensive interval cytoreductive surgery which could be performed as a minimally invasive procedure. This observation, and expertise with minimally invasive surgery for other indications in gynecologic oncology, has driven surgeons in the United States and other countries to perform an increasing portion of interval cytoreductive surgery using minimally invasive techniques. Further observational and trial data will continue to inform which patients are best suited for this approach.

Trends in the use of neoadjuvant chemotherapy for low-grade serous ovarian cancer in the United States.

OBJECTIVE: To describe trends in neoadjuvant chemotherapy (NACT) use for low-grade serous ovarian carcinoma (LGSOC) and to quantify associations between NACT and extent of cytoreductive surgery. METHODS: We identified women treated for stage III or IV serous ovarian cancer in a Commission on Cancer accredited program between January 2004-December 2020. Regression models were developed to evaluate trends in NACT use for LGSOC, to identify factors associated with receipt of NACT, and to quantify associations between NACT and bowel or urinary resection at the time of surgery. Demographic and clinical factors were used for confounder control. RESULTS: We observed 3350 patients who received treatment for LGSOC during the study period. The proportion of patients who received NACT increased from 9.5% in 2004 to 25.9% in 2020, corresponding to an annual percent change of 7.2% (95% CI 5.6-8.9). Increasing age (rate ratio (RR) 1.15; 95% CI 1.07-1.24), and stage IV disease (RR 2.66; 95% CI 2.31-3.07) were associated with a higher likelihood of receiving NACT. For patients with high-grade disease, NACT was associated with a decrease in likelihood of bowel or urinary surgery (35.3% versus 23.9%; RR 0.68, 95% CI 0.65-0.71). For LGSOC, NACT was associated with a higher likelihood of these procedures (26.6% versus 32.2%; RR 1.24, 95% CI 1.08-1.42). CONCLUSION: NACT use among patients with LGSOC has increased from 2004 to 2020. While NACT was associated with a lower rate of gastrointestinal and urinary surgery among patients with high-grade disease, patients with LGSOC receiving NACT were more likely to undergo these procedures.

Association of hospital-level factors with utilization of sentinel lymph node biopsy in patients with early-stage vulvar cancer.

OBJECTIVE: To evaluate utilization of sentinel lymph node biopsy (SLNB) for early-stage vulvar cancer at minority-serving hospitals and low-volume facilities. METHODS: Between 2012-2018, individuals with T1b vulvar squamous cell carcinoma were identified using the National Cancer Database. Patient, facility, and disease characteristics were compared between patients undergoing SLNB or inguinofemoral lymph node dissection (IFLD). Multivariable logistic regression, adjusted for patient, facility, and disease characteristics, was used to evaluate factors associated with SLNB. Kaplan-Meier survival analysis using log rank test and Cox regression was performed. RESULTS: Of the 3,532 patients, 2,406 (68.1%) underwent lymph node evaluation, with 1,704 (48.2%) undergoing IFLD and 702 (19.8%) SLNB. In a multivariable analysis, treatment at minority-serving hospitals (OR 0.39, 95% CI 0.19-0.78) and low-volume hospitals (OR 0.44, 95% CI 0.28-0.70) were associated with significantly lower odds of undergoing SLNB compared to receiving care at non-minority-serving and high-volume hospitals, respectively. While SLNB utilization increased over time for the entire cohort and stratified subgroups, use of the procedure did not increase at minority-serving hospitals. After controlling for patient and tumor characteristics, SLNB was not associated with worse OS compared to IFLD in patients with positive (HR 1.02, 95% CI 0.63-1.66) or negative (HR 0.92, 95% CI 0.70-1.21) nodal pathology. CONCLUSIONS: For patients with early-stage vulvar cancer, treatment at minority-serving or low-volume hospitals was associated with significantly decreased odds of undergoing SLNB. Future efforts should be concentrated toward ensuring that all patients have access to advanced surgical techniques regardless of where they receive their care.

Guideline-Discordant Care in Early-Stage Vulvar Cancer.

OBJECTIVE: To describe the use of National Comprehensive Cancer Network guideline-concordant inguinofemoral lymph node (LN) evaluation in individuals with early-stage vulvar cancer. METHODS: This retrospective cohort study identified patients with T1b and T2 vulvar squamous cell carcinoma diagnosed between 2012 and 2018 using the National Cancer Database. Factors associated with LN evaluation were examined using logistic regression analyses, adjusting for patient, disease, and facility-level characteristics. Kaplan-Meier survival analysis using log rank test and Cox regression was performed for the entire cohort and a subgroup of older patients , defined as individuals aged 80 years or older. RESULTS: Of the 5,685 patients with vulvar cancer, 3,756 (66.1%) underwent guideline-concordant LN evaluation. In our adjusted model, age 80 years or older (odds ratio [OR], 0.30; 95% CI 0.22-0.42) and Black race (OR 0.72; 95% CI 0.54-0.95) were associated with lower odds of LN evaluation. High-volume hospitals were associated with increased odds of LN evaluation compared with low-volume hospitals (OR 1.62; 95% CI 1.28-2.05). Older individuals who did not undergo LN evaluation had significantly worse overall survival than those with pathologically negative LNs (hazard ratio [HR] 0.45; 95% CI 0.37-0.55) and similar overall survival as those with pathologically positive LNs (HR 1.05; 95% CI 0.77-1.43). CONCLUSION: Guideline-concordant LN evaluation for early-stage vulvar squamous cell carcinoma is low. Lower utilization is associated with older age, Black race, and care at a low-volume hospital.

NCCN Guidelines® Insights: Ovarian Cancer, Version 3.2022.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.

Lymph node assessment at the time of hysterectomy has limited clinical utility for patients with pre-cancerous endometrial lesions.

OBJECTIVE: The objective of this study was to determine the proportion of patients with a pre-invasive endometrial lesion who meet Mayo criteria for lymph node dissection on final pathology to determine if the use of sentinel lymph node biopsy in patients with pre-invasive lesions would be warranted. METHODS: All women who underwent hysterectomy for a pre-invasive endometrial lesion (atypical hyperplasia or endometrial intra-epithelial neoplasia) between 2009 and 2019 were included for analysis. Relevant statistical tests were utilized to test the associations between patient, operative, and pathologic characteristics. RESULTS: 141 patients met inclusion criteria. 51 patients (36%) had a final diagnosis of cancer, the majority (96%) of which were Stage IA grade 1 endometrioid carcinomas. Seven patients (5%) met Mayo criteria on final pathology (one grade 3, seven size >2 cm, one >50% myoinvasive). Three of these seven patients had lymph nodes assessed of which 0% had metastases. Six of these patients had frozen section performed, and 2 met (33%) Mayo criteria intraoperatively. Of the seven patients in the overall cohort that had lymph node sampling, six had a final diagnosis of cancer and none had positive lymph nodes. Of the 51 patients with cancer, only 10 had cancer diagnosed using frozen section, and only two met intra-operative Mayo criteria. Age > 55 was predictive of meeting Mayo criteria on final pathology (p = 0.007). No patients experienced a cancer recurrence across a median follow up of 24.3 months. CONCLUSIONS: Atypical hyperplasia and endometrial intra-epithelial neoplasia portend low risk disease and universal nodal assessment is of limited value.

Ovarian Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country's fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.

Patient reported outcome measures among patients with vulvar cancer at various stages of treatment, recurrence, and survivorship.

OBJECTIVE: Our goal was to pragmatically describe patient reported outcomes (PROs) in a typical clinic population of vulvar cancer patients, as prior studies of vulvar cancer PROs have examined clinical trial participants. METHODS: A prospective PRO program was implemented in the Gynecologic Oncology clinic of a tertiary academic institution in January 2018. Vulvar cancer patients through September 2019 were administered the European Organization for the Research and Treatment of Cancer Quality of life Questionnaire, the Patient Reported Outcome Measurement Information System Instrumental and Emotional Support Scales, and the Functional Assessment of Cancer Therapy-Vulvar questionnaire. Binary logistic regressions were performed to determine adjusted odds ratios for adverse responses to individual questions by insurance, stage, age, time since diagnosis, recurrence, radiation, and surgical radicality. RESULTS: Seventy vulvar cancer patients responded to PROs (85.4% response rate). Seventy-one percent were > 1 year since diagnosis, 61.4% had stage I disease, and 28.6% recurred. Publicly insured women had less support and worse quality of life (QOL, aOR 4.15, 95% CI 1.00-17.32, p = 0.05). Women who recurred noted more interference with social activities (aOR 4.45, 95% CI 1.28-15.41, p = 0.019) and poorer QOL (aOR 5.22 95% CI 1.51-18.10, p = 0.009). There were no major differences by surgical radicality. Those >1 year since diagnosis experienced less worry (aOR 0.17, 95% CI 0.04-0.63, p = 0.008). CONCLUSIONS: Surgical radicality does not affect symptoms or QOL in vulvar cancer patients, whereas insurance, recurrence, and time since diagnosis do. This data can improve counseling and awareness of patient characteristics that would benefit from social services referral.

Circulating Tumor Cells In Advanced Cervical Cancer: NRG Oncology-Gynecologic Oncology Group Study 240 (NCT 00803062).

To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0240, the phase III randomized trial that led directly to regulatory approval of the antiangiogenesis drug, bevacizumab, in women with recurrent/metastatic cervical cancer. CTCs (defined as anti-cytokeratin+/anti-CD45- cells) were isolated from the buffy coat layer using an anti-EpCAM antibody-conjugated ferrofluid and rare earth magnet, and counted using a semiautomated fluorescence microscope. The median pre-cycle 1 CTC count was 7 CTCs/7.5 mL whole blood (range, 0-18) and, at 36 days posttreatment, was 4 (range, 0-17). The greater the declination in CTCs between time points studied, the lower the risk of death [HR, 0.87; 95% confidence interval (CI), 0.79-0.95)]. Among patients with high (≥ median) pretreatment CTCs, bevacizumab treatment was associated with a reduction in the hazard of death (HR, 0.57; 95% CI, 0.32-1.03) and PFS (HR, 0.59; 95% CI, 0.36-0.96). This effect was not observed with low (< median) CTCs. CTCs can be isolated from women with advanced cervical cancer and may have prognostic significance. A survival benefit conferred by bevacizumab among patients with high pretreatment CTCs may reflect increased tumor neovascularization and concomitant vulnerability to VEGF inhibition. These data support studying CTC capture as a potential predictive biomarker.

Understanding and Targeting Apoptotic Pathways in Ovarian Cancer.

Ovarian cancer cells evade the immune system as well as chemotherapeutic and/or biologic treatments through inherent or acquired mechanisms of survival and drug resistance. Depending on the cell type and the stimuli, this threshold can range from external forces such as blunt trauma to programmed processes such as apoptosis, autophagy, or necroptosis. This review focuses on apoptosis, which is one form of programmed cell death. It highlights the multiple signaling pathways that promote or inhibit apoptosis and reviews current clinical therapies that target apoptotic pathways in ovarian cancer.

Screening and surgical prophylaxis for hereditary cancer syndromes with high risk of endometrial and ovarian cancer.

In the era of advanced cancer genomics, our recognition of hereditary cancer mutations continues to increase. Two of these conditions, which carry an increased risk of female cancers including endometrial, ovarian, breast, are hereditary breast and ovarian cancer syndrome and Lynch syndrome. Risk-reducing surgery, such as mastectomy, salpingo-oophorectomy, and hysterectomy may decrease cancer risk for mutation carriers. Background, indications, techniques, and consequences of these surgical procedures are reviewed.

Impact of tumour histology on survival in advanced cervical carcinoma: an NRG Oncology/Gynaecologic Oncology Group Study.

BACKGROUND: Based primarily on studies concerning early-stage tumours (treated surgically), and locally advanced disease (treated with chemoradiation), the prognosis for women with adenocarcinoma (AC) or adenosquamous (AS) carcinoma has been reported to be poorer than those with squamous cell carcinoma (SCCA) of the cervix. It is unclear whether differences in prognosis also persist in the setting of recurrent or metastatic disease treated using chemotherapy doublets with or without bevacizumab. METHODS: Cases were pooled from three Gynaecologic Oncology Group randomised phase III trials of chemotherapy doublets. Pearson's test was used to evaluate response rate (RR) of AC/AS vs SCCA, Kaplan-Meier method to estimate progression-free survival (PFS) and overall survival (OS), and Cox proportional hazards model to estimate the impact of histology on PFS and OS. RESULTS: Of 781 evaluable patients, 77% (N=599) had SCCA and 23% (N=182) AC/AS. There were no significant differences in RRs between histologic subgroups. The adjusted hazard ratio (HR) for death for SCCA vs AC/AS was 1.13 (95% CI 0.93, 1.38 P=0.23). When comparing SC/AS (N=661, 85%) to AC alone (N=120, 15%), the adjusted HR for death was 1.23 (95% CI 0.97, 1.57, P=0.09). CONCLUSIONS: AC/AS and SCCA have similar survival in recurrent or metastatic cervical carcinoma when treated with chemotherapy doublets.

Reproductive counseling, contraception, and unplanned pregnancy in fertile women treated by gynecologic oncologists.

We sought to identify how gynecologic oncologists approach reproductive counseling for their fertile, reproductive age patients, and their experience with unplanned pregnancies. Members of the Society of Gynecologic Oncology (SGO) were surveyed electronically regarding consistency of counseling patterns of contraception and fertility concerns, most and least common contraceptive methods utilized, referral patterns, and incidence of unplanned pregnancy. Of the 1424 SGO members identified, 261 participated in the questionnaire, yielding a response rate of 18%. Eighty-two percent of respondents agreed unplanned pregnancy is a potential problem, but only 57% believed their patients understood unplanned pregnancy is possible during treatment. Half of respondents report "always" in terms of frequency that contraception is addressed among their high-risk patients. After adjustment for gender, we found that the odds of reporting providing fertility counseling were nearly three times higher among attendings as compared to fellows [AOR = 2.72; 95% CI = (1.44, 5.12), three times higher in women as compared to men [AOR = 2.80; 95% CI = (1.46, 5.38)], as well as in individuals 50 + years as compared to those < 40 years old [AOR = 4.91; 95% CI = (2.05, 11.74)]. Ninety-six percent reported < 5 unplanned pregnancies, to their knowledge, in the previous five years of clinical practice. Most providers acknowledge that unplanned pregnancy is a potential risk in fertile gynecologic oncology patients, but only half believe their patients understand an unplanned pregnancy is possible. An opportunity exists to provide more directed counseling regarding fertility during and after cancer therapy, and to educate patients and providers regarding more reliable, long acting contraceptive methods.

A pilot study of topical imiquimod therapy for the treatment of recurrent extramammary Paget's disease.

OBJECTIVE: The objective of this prospective pilot study was to assess the clinical and histologic effects of topical imiquimod therapy on recurrent extramammary Paget's disease of the vulva. METHODS: Patients with biopsy-proven recurrent extramammary Paget's disease presenting to the gynecology outpatient services at two participating institutions were recruited for conservative treatment with 5% imiquimod cream from 2007 to 2011. The topical cream was to be applied 3 times per week for 12weeks. Punch biopsy and photography were performed at baseline and at the 12-week time point. RESULTS: Eight patients from two institutions were enrolled. Complete clinical and histologic response was achieved in 6 (75%) patients by the 12-week follow-up appointment. Of the two remaining patients, one had a complete clinical response but no significant histologic response; the other patient was removed from the study protocol secondary to intolerable local irritation. Two patients continue to have no evidence of disease after a median follow-up of 35months. Five are alive with disease. No patients progressed to invasive cancer while receiving therapy. CONCLUSION: Topical 5% imiquimod cream is a safe and feasible option for women suffering from recurrent extramammary Paget's disease of the vulva, and should be considered as a viable alternative to surgical management. Given the rare nature of this disease, additional multi-institutional prospective studies should be conducted to explore the efficacy of this treatment regime.

A Prospective, Comparative Study for the Evaluation of Postoperative Pain and Quality of Recovery in Patients Undergoing Robotic Versus Open Hysterectomy for Staging of Endometrial Cancer.

STUDY OBJECTIVE: To measure and compare postoperative pain and patient satisfaction in patients undergoing either robotic or open laparotomy for surgical staging of endometrial cancer. DESIGN: Prospective, comparative study (Canadian Task Force classification II). SETTING: University hospital. PATIENTS: A total of 142 patients undergoing either robotic or open laparotomy for surgical staging of endometrial cancer. INTERVENTIONS: Patients scheduled for surgical staging of endometrial cancer at a single institution were identified. The patients underwent either robotic or open hysterectomy for staging of endometrial cancer. The choice of operative approach (robotic vs laparotomy) was made by the faculty physician before enrollment. Patients participated in the study for up to 48 hours for pain assessments and up to 10 ± 3 days postoperatively for quality of recovery assessments. MEASUREMENTS AND MAIN RESULTS: The following measurements were performed: postoperative pain with the visual analog scale (VAS), 24-hour opioid consumption, and quality of recovery using the Quality of Recovery Questionnaire (QoR-40). The study was terminated owing to futility, given the lack of open procedures at our institution. Despite that lack of statistically significant difference between VAS scores at rest and with leg extension, there was a significant decrease in 24-hour opioid consumption in the robotic group. In addition, the QoR-40 showed an increased perception of recovery in patients within the robotic group compared with the laparotomy group. CONCLUSION: Patients with endometrial cancer who underwent robotic surgery had decreased postoperative opioid consumption and improved quality of recovery compared with those who underwent surgery via laparotomy.

Documentation of Pregnancy Risk Assessment and Pregnancy Among Women Presenting for Gynecologic Oncology Consultation.

OBJECTIVE: The aim of the study was to describe pregnancy risk assessment, reproductive goals, and incidence of pregnancy among the reproductive age population seen by gynecologic oncologists at a tertiary care center. METHODS: A retrospective chart review was conducted among 18- to 45-year-old women evaluated by a gynecologic oncologist from January 2000 to December 2011. Data abstracted included the following: diagnosis, cancer treatment, parity, pregnancy risk factors (eg, menstrual patterns, sexual activity, and use of contraception), reproductive goals, type of referral, and pregnancy. Descriptive statistics were used to describe the characteristics of the population. RESULTS: Five hundred seventeen women were eligible and included in the review. Median age was 31 years with most common diagnoses being cervical cancer, endometrial cancer, and premalignant disease. Most patients are multiparous. Seventy percent were treated surgically, with 58% experiencing surgical sterility. Completeness of reproductive data documented at initial visit included the following: 47% with a contraception plan, 54% sexual activity/practices, and 37% with personal reproductive goals reviewed. Fifteen patients were pregnant at the initial visit, and 21 patients pregnant during follow-up, representing 43 pregnancies (9 patients had more than 1 pregnancy). For those maintaining fertility after the initial visit, there was a median (range) of 2 (0-25) visits with 32% documenting a contraception plan at follow-up visits. CONCLUSIONS: A patient's reproductive goals and risk factors for pregnancy are inconsistently addressed during initial consultation with the gynecologic oncologist. This lack of consistency potentially increases patients' risk for unplanned pregnancy during evaluation and treatment of a gynecologic cancer diagnosis and potentially results in a missed opportunity for fertility preservation. Planned and unplanned pregnancy occurs in this population at a rate similar to that of US women of reproductive age, underscoring the need for reproductive counseling in this population.

Emerging therapies: angiogenesis inhibitors for ovarian cancer.

INTRODUCTION: Patients with epithelial ovarian cancer (EOC) have a high rate of recurrence, and overall survival remains at ∼ 25%. There is a need for new treatments that can increase progression free survival and quality of life. Recent clinical trials focus on angiogenesis, VEGFs, and tyrosine kinase inhibitors that play a role in recurrence, metastasis, and ascites in EOC. AREAS COVERED: This review summarizes clinical rationale, mechanisms of action, and clinical data for angiogenesis inhibitors under evaluation in Phase II and III trials for EOC. Anti-angiogenesis agents reviewed in this paper include aflibercept, bevacizumab, cediranib, fosbretabulin, imatinib, nintedanib, pazopanib, saracatinib, sorafenib, sunitinib, and trebananib. EXPERT OPINION: These agents have particular rationale for potential use in EOC due to the molecular changes associated with EOC tumorigenesis, namely a significant increase in angiogenic activity. Due to the costs and toxicities associated with anti-angiogenics, biomarker or molecular signature selection strategy for patients who will most benefit would be ideal but no such strategy has been validated to date.