Evaluation of Homologous Recombination Deficiency in Ovarian Cancer.

OPINION STATEMENT: Homologous recombination deficiency (HRD) is an important biomarker guiding selection of ovarian cancer patients who will derive the most benefit from poly(ADP-ribose) polymerase inhibitors (PARPi). HRD prevents cells from repairing double-stranded DNA damage with high fidelity, PARPis limit single-stranded repair, and together these deficits induce synthetic lethality. Germline or somatic BRCA mutations represent the narrowest definition of HRD, but do not reflect all patients who will have a durable PARPi response. HRD can also be defined by its downstream consequences, which are measured by different metrics depending on the test used. Ideally, all patients will undergo genetic counseling and germline testing shortly after diagnosis and have somatic testing sent once an adequate tumor sample is available. Should barriers to one test be higher, pursuing germline testing with reflex to somatic testing for BRCA wildtype patients or somatic testing first strategies are both evidence-based. Ultimately both tests offer complementary information, germline testing should be pursued for any patient with a history of ovarian cancer, and somatic testing is valuable at recurrence if not performed in the upfront setting. There is a paucity of data to suggest superiority of one germline or somatic assay; therefore, selection should optimize turnaround time, cost to patients, preferred result format, and logistical burden. Each clinic should implement a standard testing strategy for all ovarian cancer patients that ensures HRD status is known at the time of upfront chemotherapy completion to facilitate comprehensive counseling about anticipated maintenance PARPi benefit.

Functional Analysis of RE1 Silencing Transcription Factor as a Putative Tumor Suppressor in Human Endometrial Cancer.

Uterine cancer is the most common gynecologic malignancy in the United States, with endometrioid endometrial adenocarcinoma (EC) being the most common histologic sub-type. Considering the molecular classifications of EC, efforts have been made to identify additional biomarkers that can assist in diagnosis, prognosis, and individualized therapy. We sought to explore the relationship of Repressor Element 1 (RE1) silencing transcription factor (REST), which downregulates neuronal genes in non-neuronal tissue, along with matrix metalloproteinase-24 (MMP24) and EC. We analyzed the expression of REST and MMP24 in 31 cases of endometrial cancer and 16 controls. We then explored the baseline expression of REST and MMP24 in two EC cell lines (Ishikawa and HEC-1-A) compared to a benign cell line (t-HESC) and subsequently evaluated proliferation, migration, and invasion in the setting of loss of REST gene expression. REST and MMP24 expression were significantly lower in human EC samples compared to control samples. REST was highly expressed in EC cell lines, but decreasing REST gene expression increased proliferation (FC: 1.13X, p < 0.0001), migration (1.72X, p < 0.0001), and invasion (FC: 7.77X, p < 0.05) in Ishikawa cells, which are hallmarks of cancer progression and metastasis. These findings elicit a potential role for REST as a putative tumor suppressor in EC.

The road to long-term survival: Surgical approach and longitudinal treatments of long-term survivors of advanced-stage serous ovarian cancer.

OBJECTIVE: It is unclear if the types of surgical procedures performed on long-term survivors (LTS) of high-grade serous ovarian carcinoma (HGSOC) contribute to prolonged survival. In this case-control study we review the surgical procedures performed on LTS and describe their individual longitudinal disease courses. METHODS: Women with FIGO stage III-IV high-grade serous cancer of the ovary, fallopian tube or peritoneum were selected from the University of Chicago ovarian cancer database. LTS were those surviving >7 years and controls were short-term survivors (STS) living 1-2 years. Patients with non-serous histology, low grade, and low malignant potential tumors were excluded. RESULTS: We identified 450 women with stage III/IV HGSOC including 45 LTS and 78 STS. LTS showed a trend towards lower disease burden, yet underwent more aggressive surgical treatment. Interestingly, only 15 LTS (34%) were debulked to microscopic disease and 9 LTS (21%) underwent suboptimal debulking. Two LTS (5%) recurred within 12 months. LTS had heterogeneous clinical courses with 13 (29%) never experiencing a recurrence with 143 months median follow-up and 32 (71%) experiencing a recurrence with 115 months median follow-up. Of the women who recurred, 19 (59%) underwent at least one surgery for recurrence. CONCLUSIONS: Aggressive surgical treatment intended to achieve microscopic disease, primary debulking surgery, preservation of sensitivity to chemotherapy, and recurrence amenable to secondary debulking are associated with long-term survival. However, clinicopathologic data are insufficient to predict long-term survival of HGSOC. Biologic characterization of these patient's tumors likely holds the key to understanding their unusually favorable courses.

Resilience in the Face of Pandemic: The Impact of COVID-19 on the Psychologic Morbidity and Health-Related Quality of Life Among Women With Ovarian Cancer.

PURPOSE: The COVID-19 pandemic has created new challenges for ovarian cancer survivors. This study aims to evaluate the psychologic morbidity and alterations in medical care caused by the pandemic. METHODS: Advanced-stage ovarian cancer survivors at our institution were contacted for participation in a cross-sectional telephone-based quantitative survey study assessing pandemic-related psychologic morbidity. Psychologic domains using validated measures were explored: health-related quality of life (HRQOL; functional assessment of cancer therapy [FACT-G7]), anxiety (generalized anxiety disorder-7 [GAD7]), depression (Patient Health Questionnarie-2 [PHQ2]), global health Patient-Reported Outcomes Measurement Information System - Global Physical Health/Global Mental Health (PROMIS-GMH/GPH), resilience (brief resilience scale), and loneliness (English Longitudinal Study on Aging). Novel COVID-19 pandemic questions were drawn from a larger survey developed in our department. RESULTS: Fifty-nine percent (61 of 104) of contacted patients completed the survey. One quarter of respondents had high resilience, with only 10% reporting low resilience. Only one patient screened positive for depression, and two for anxiety. Increased loneliness was reported by 43% of respondents. Patients' overall HRQOL was good (median = 21; range = 6-28). Few patients experienced treatment delays, with only four experiencing chemotherapy interruption and two reporting surgical delays. Multiple regression analyses revealed that high FACT-G7 HRQOL was predicted by age > 65 years, high self-reported mental health, high resilience, and being off chemotherapy. Lower COVID-19 concern was predicted by recurrent cancer and high resilience. CONCLUSION: Despite the far-reaching impact of the COVID-19 pandemic, ovarian cancer survivors' HRQOL has been maintained. Older age, high resilience, high mental health, and being off chemotherapy predicted better HRQOL. Ovarian cancer survivors remain resilient in the face of the pandemic, and the support of clinicians to preserve this invaluable personal resource is critical for well-being.

A molecular atlas of the human postmenopausal fallopian tube and ovary from single-cell RNA and ATAC sequencing.

As part of the Human Cell Atlas Initiative, our goal is to generate single-cell transcriptomics (single-cell RNA sequencing [scRNA-seq], 86,708 cells) and regulatory (single-cell assay on transposase accessible chromatin sequencing [scATAC-seq], 59,830 cells) profiles of the normal postmenopausal ovary and fallopian tube (FT). The FT contains 11 major cell types, and the ovary contains 6. The dominating cell type in the FT and ovary is the stromal cell, which expresses aging-associated genes. FT epithelial cells express multiple ovarian cancer risk-associated genes (CCDC170, RND3, TACC2, STK33, and ADGB) and show active communication between fimbrial epithelial cells and ovarian stromal cells. Integrated single-cell transcriptomics and chromatin accessibility data show that the regulatory landscape of the fimbriae is different from other anatomic regions. Cell types with similar gene expression in the FT display transcriptional profiles. These findings allow us to disentangle the cellular makeup of the postmenopausal FT and ovary, advancing our knowledge of gynecologic diseases in menopause.

Neoadjuvant Chemotherapy Induces Genomic and Transcriptomic Changes in Ovarian Cancer.

The growing use of neoadjuvant chemotherapy to treat advanced stage high-grade serous ovarian cancer (HGSOC) creates an opportunity to better understand chemotherapy-induced mutational and gene expression changes. Here we performed a cohort study including 34 patients with advanced stage IIIC or IV HGSOC to assess changes in the tumor genome and transcriptome in women receiving neoadjuvant chemotherapy. RNA sequencing and panel DNA sequencing of 596 cancer-related genes was performed on paired formalin-fixed paraffin-embedded specimens collected before and after chemotherapy, and differentially expressed genes (DEG) and copy-number variations (CNV) in pre- and post-chemotherapy samples were identified. Following tissue and sequencing quality control, the final patient cohort consisted of 32 paired DNA and 20 paired RNA samples. Genomic analysis of paired samples did not reveal any recurrent chemotherapy-induced mutations. Gene expression analyses found that most DEGs were upregulated by chemotherapy, primarily in the chemotherapy-resistant specimens. AP-1 transcription factor family genes (FOS, FOSB, FRA-1) were particularly upregulated in chemotherapy-resistant samples. CNV analysis identified recurrent 11q23.1 amplification, which encompasses SIK2. In vitro, combined treatment with AP-1 or SIK2 inhibitors with carboplatin or paclitaxel demonstrated synergistic effects. These data suggest that AP-1 activity and SIK2 copy-number amplification are induced by chemotherapy and may represent mechanisms by which chemotherapy resistance evolves in HGSOC. AP-1 and SIK2 are druggable targets with available small molecule inhibitors and represent potential targets to circumvent chemotherapy resistance. SIGNIFICANCE: Genomic and transcriptomic analyses identify increased AP-1 activity and SIK2 copy-number amplifications in resistant ovarian cancer following neoadjuvant chemotherapy, uncovering synergistic effects of AP-1 and SIK2 inhibitors with chemotherapy.

The Effects of Chemotherapeutics on the Ovarian Cancer Microenvironment.

High-grade serous ovarian cancer (HGSOC) is characterized by a complex and dynamic tumor microenvironment (TME) composed of cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and adipocytes. Although most approved therapies target cancer cells, a growing body of evidence suggests that chemotherapeutic agents have an important role in regulating the biology of the diverse cells that compose the TME. Understanding how non-transformed cells respond and adapt to established therapeutics is necessary to completely comprehend their action and develop novel therapeutics that interrupt undesired tumor-stroma interactions. Here, we review the effects of chemotherapeutic agents on normal cellular components of the host-derived TME focusing on CAFs. We concentrate on therapies used in the treatment of HGSOC and synthesize findings from studies focusing on other cancer types and benign tissues. Agents such as platinum derivatives, taxanes, and PARP inhibitors broadly affect the TME and promote or inhibit the pro-tumorigenic roles of CAFs by modifying the bidirectional cross-talk between tumor and stromal cells in the tumor organ. While most chemotherapy research focuses on cancer cells, these studies emphasize the need to consider all cell types within the tumor organ when evaluating chemotherapeutics.

Tissue Adhesive Compared With Sterile Strips After Cesarean Delivery: A Randomized Controlled Trial.

OBJECTIVE: To assess whether tissue adhesive after closure of Pfannenstiel incision for cesarean delivery lowers the risk of wound complications when compared with sterile strips. METHODS: In this multicenter randomized controlled trial, women undergoing cesarean delivery using Pfannenstiel skin incision were randomized to receive tissue adhesive (2-octyl cyanoacrylate) compared with sterile strips after closure of the skin incision. The primary outcome was a composite of wound complications (drainage, cellulitis, abscess, seroma, hematoma, or isolated wound separation) within 8 weeks of delivery. Secondary outcomes included operative time, readmission, office or emergency department visits, or antibiotic use for wound complications, and patient satisfaction with the cesarean scar. With 80% power and a 95% CI, a sample size of 432 per group (n=864) was required to detect a 50% reduction in the primary outcome. A planned interim analysis was performed after 500 patients delivered. A conditional power analysis revealed that the probability of showing a benefit with tissue adhesive was extremely low (6.2%), and the study was halted owing to futility. RESULTS: Between November 2016 and April 2018, 504 patients were randomized, and follow-up was achieved in 479 (95%). Wound complications occurred in 18 out of 238 patients (7.6%) in the tissue adhesive group and 19 out of 241 patients (7.9%) in the sterile strips group (relative risk 0.96; 95% CI 0.51-1.78). There were no significant differences with regard to types of wound complications, operative time, readmission, office or emergency department visits, antibiotics prescribed for wound complications, or patient scar assessment scores of pain, stiffness, and irregularity between the two groups. However, tissue adhesive performed slightly better in regard to itchiness of scar and overall scar satisfaction. CONCLUSION: Compared with sterile strips, tissue adhesive after closure of Pfannenstiel incision for cesarean delivery is unlikely to lower the risk of wound complications. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02838017.