To characterize the mutational landscape of mucinous epithelial ovarian cancer (MOC). Data were extracted from the American Association for Cancer Research's (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database version 12.1 via cBioPortal (http://genie.cbioportal.org). This publicly available, multi-institutional database provides next generation sequencing genomic profiles of tumors. We queried this database for MOC samples and descriptively report mutation frequencies of genes for which targeted therapies are either approved or in clinical trials for other cancer types. We include the following genes in our analysis: ERBB2 (HER2) amplifications, homologous recombination (HR) and mismatch repair (MMR) genes, BRAF, KRAS, NRAS, RNF43, ARID1A, PIK3CA, ERBB3, and PTEN mutations. Among 145 MOC samples, the most common somatic mutations were KRAS (98/145, 67.6%), ERBB2 (HER2) amplification (13/90, 14.4%), ARID1A (16/116, 13.8%), CDKN2A (17/141, 12.1%), PIK3CA (13/145, 9.0%), ERBB3 (10/120, 8.3%), RNF43 (7/102, 6.9%), BRAF (4/145, 2.8%), PTEN (4/145, 2.8%), and NRAS (2/145, 1.4%). Mutations in HR and MMR genes were relatively rare, with the most common HR mutations in BRIP 1 (5/114, 4.4%) and BRCA2 (5/122, 4.1%); and the most common MMR mutations in MLH3 (1/44, 2.3%) and MSH3 (1/48, 2.1%).Table: 40MOMutation frequencies of homologous recombination (HR) and mismatch repair (MMR) genes, as well as the TP53 gene in tumor samples from mucinous ovarian cancerNo. of samples with ≥1 mutationNo. of samples profiled for mutationMutation frequencyBRCA151221.6%BRCA251224.1%BRIP151144.4%CHEK211160.9%PALB221161.7%MSH31482.1%MSH611200.8%MLH31442.3%PMS211130.9%TP539114562.8% Open table in a new tab Advanced stage MOC carries a poor prognosis, with only platinum/taxane, anti-VEGF agents, and 5-fluouracil currently available as current standard of care therapies. Here, we demonstrate high mutation rates in targetable genes among MOC samples. Most commonly, these mutations were identified among KRAS/NRAS (targetable with MEK inhibitors), ERBB2 (HER2) (targetable with anti-HER2 agents), ARID1A (targetable with epigenetic modifiers and ATR inhibitors), and PI3CA (targetable with PI3-kinase and AKT inhibitors). Given the frequency of each mutation, genetically targeted clinical trials evaluating the clinical efficacy of their respective agents are warranted.

Objective: In order to fully realize the benefits of cancer genetic testing and disease prevention, genetic testing must be extended to disease-free at-risk relatives with cascade testing. Standard methods for applying cascade testing are lacking, and there is a paucity of literature on rates of testing uptake among disease-free at-risk relatives. The aim of this review was to assess methods and uptake for disease-free at-risk relatives for published strategies of oncologic cascade testing.

Objective: Cascade testing for familial cancer syndromes has historically been difficult to execute. While probands disclose genetic results to more than 80% of at-risk relatives, less than 30% use recommended genetic services. As part of a facilitated cascade testing pathway, we evaluated barriers to completion of cascade testing.

Objective: Despite a growing understanding of familial cancer, multiple studies demonstrate that the quality of family health history as currently collected in a clinic setting is inadequate to assess disease risk. We sought to evaluate the quality of family health history in a gynecologic oncology clinic.

Objective: Cervical cancer in the setting of uterovaginal prolapse is exceedingly rare. Altered anatomy can complicate treatment of underlying cancer. The objective of this study was to evaluate the practice patterns and outcomes regarding cervical cancer associated with procidentia.

Objective: Ovarian cancer can evade immune responses by inducing endoplasmic reticulum stress in intratumoral leukocytes. In the ovarian tumor microenvironment, the endoplasmic reticulum stress-activated transcription factor X-box binding protein 1 (XBP1s) causes immune cell dysfunction and facilitates malignant progression. However, the clinical significance of XBP1s expression in ovarian cancer remains elusive. We sought to evaluate the association between intratumoral XBP1s levels and ovarian cancer patient outcomes.

Objective: E-cadherin is an important cell-cell adhesion molecule in epithelial tissues. Previous literature has demonstrated an association with E-cadherin deficiency and progression of different malignancies, including squamous cell carcinoma of the cervix. However, there have been no studies investigating the relationship between E-cadherin expression and adenocarcinoma in situ (ACIS) or adenocarcinoma (AC) of the cervix. We sought to determine whether E-cadherin immunohistochemistry (IHC) can be a valuable marker in screening for ACIS and AC.

Fragestellung Um die Vorteile des genetischen Testens und der Krebsprävention vollständig zu nutzen, sind genetische Screens mittels Cascade testing auch auf Risikoverwandte (RV) auszuweiten. Momentan fehlen Standardmethoden und es findet sich wenig Literatur zur Nutzungsrate von genetischen Tests bei RV. Das Ziel dieser Studie war es, Methoden für Cascade testing und Testungsraten von RV in bisher publizierten Studien zu erheben.

Objective: The ultimate impact of genetic testing is the ability to identify relatives carrying the mutation before they develop cancer, maximizing disease prevention and early detection. However, there is a paucity of literature on quality of life (QOL) in this testing context. We sought to evaluate the QOL implications for at-risk relatives undergoing cascade testing.

Objective: Cascade genetic testing is essential for identifying inherited cancer-associated mutation in at-risk relatives. However, the new diagnosis of a pathogenic mutation can lead to anxiety and distress, and strategies to mitigate this have not been well studied. We sought to evaluate immediate and long-term distress and anxiety among at-risk relatives found to have a pathogenic mutation on cascade genetic testing.

Previous studies evaluating the impact of race on survival in triple-negative breast cancer (TNBC) have come to inconsistent conclusions. In this study we further explore relative survival by race within a TNBC population receiving care in the controlled settings of clinical trials. Phase II and III open-label breast cancer studies having completed their primary analysis were selected from the Medidata Enterprise Data Store comprised of 19,000+ historical clinical trials, for de-identified aggregate analyses. The Synthetic Control Database (SCD) for this study contains 1215 patients with metastatic TNBC enrolled in trials between 2010 and 2017. Patients were stratified by race. Overall survival (OS), progression-free survival (PFS) and duration of response (DOR) were assessed using a Kaplan-Meier analysis. Baseline covariates were compared using Wilcoxon and Chi-Square tests. We assessed the potential impact of additional factors on survival including age, body mass index (BMI), baseline leukocytes, dose adjustments and adverse events. The racial breakdown of the SCD population was 12% Black and 88% Non-Black (NB). Black study participants had a higher BMI than NB patients (median 30.3 vs. 25.8, p<0.001) and were slightly older at time of enrollment (54 vs. 51 years of age, p=0.11). The proportion of patients experiencing a complete or partial remission were similar between groups (34% Black vs. 33% NB), however, the unadjusted OS, PFS and DOR were consistently shorter (but not statistically different) in Black patients: median OS of 349 v. 362 days (hazard ratio 0.91, 95% CI: 0.74, 1.11), PFS of 128 vs. 140 days (HR 0.93, CI: 0.78, 1.12) and DOR of 140 days vs. 172 days (HR 0.82, CI: 0.59, 1.13). Although not statistically significant, Black patients had lower leukocyte levels upon study entry than NBs (median 5.6 vs. 6.0 x 109/L) and also experienced more dose modifications (p=0.05). Compared to their NB counterparts, Black patients with TNBC demonstrated a slightly shorter OS, PFS and DOR that lacked statistical significance. This analysis also suggests that Black patients experience more dose modifications on study. These findings are intriguing and suggest that further investigation of possible racial disparity in TNBC outcomes is required.

Abstract Background: Denosumab is a monoclonal antibody that inhibits RANKL and is approved for the prevention of fractures in patients with osteoporosis or bone metastases. The RANKL signaling pathway is also involved in BRCA1-associated mammary tumorigenesis via a progesterone-induced paracrine effect of RANKL on luminal progenitor cells. Pre-clinical studies have demonstrated that RANKL inhibition resulted in reduced proliferation of mammary tumors. Early findings from an ongoing pre-surgical study demonstrated that denosumab treatment resulted in decreased Ki67 proliferation index in benign breast tissue. Based on these data, denosumab is being pursued as a potential preventive agent for breast cancer in BRCA1 mutation carriers. While promising, the effect of RANKL inhibition on gynecologic tissues such as the ovaries and fallopian tubes, in which progesterone has a protective effect, is unknown. Trial design: We will conduct a multicenter, open-label randomized pilot study of presurgical administration of denosumab versus no treatment in premenopausal women with BRCA1/2 mutations undergoing risk-reducing salpingo-oophorectomy (RRSO). A total of 60 women will be randomized 1:1 to Arm 1) 3-4 doses of 120 mg denosumab subcutaneously every 4 weeks or Arm 2) No treatment. Participants will be stratified by 1) BRCA1 versus BRCA2 mutation status and 2) Use of hormonal contraceptives within the past 3 months (yes/no). Assuming a 10% unevaluable rate, we expect to have 54 evaluable participants (27 per arm). Eligibility criteria: 1) Premenopausal women (defined as < 3 months since last menstrual period OR serum follicle-stimulating hormone (FSH) < 20 mIU/mL), age > 18 years; 2) Documented germline pathogenic mutation or likely pathogenic variant in the BRCA1 or BRCA2 gene; 3) Plan for RRSO with or without hysterectomy; 4) ECOG performance status ≤ 1 (Karnofsky ≥ 70%); 5) Normal organ and marrow function; 6) Negative pregnancy test and use of adequate contraception; 7) Willingness to take supplemental oral calcium and vitamin D3; 8) Dental examination within 6 months of enrollment and no evidence of active dental issues; 9) Ability to understand and willingness to provide informed consent. Specific aims: Our primary objective is to compare the effect of denosumab to no treatment on Ki67 expression in the fimbrial end of the fallopian tube. Secondary objectives are to assess Ki67 in ovary and endometrium; cleaved caspase-3, RANK/RANKL, ER/PR, CD44, and STAT3/pSTAT3 expression in fallopian tube, ovary, and endometrium; gene expression profiling in the fallopian tube and ovary; serum markers (progesterone, estradiol, C-terminal telopeptide) and denosumab levels; and toxicity. Statistical methods: The primary endpoint is post-treatment Ki67 expression in the fimbrial end of the fallopian tube in the denosumab arm compared to the no treatment arm. Assuming a standard deviation of 5.0%, we will have 82% power to detect a 4.0% absolute difference (or effect size of 0.8) in Ki67 proliferation index between the denosumab and no treatment groups by applying a 2-sample t-test at a 0.05 significance level. Target accrual: 60 participants, to be activated in Summer 2018. Citation Format: Trivedi MS, Samimi G, Wright JD, Holcomb K, Garber JE, Horowitz NS, Arber N, Friedman E, Wenham RM, House M, Parnes H, Lee JJ, Abutaseh S, Vornik LA, Heckman-Stoddard BM, Brown PH, Crew KD. Pilot study of denosumab in BRCA1/2 mutation carriers scheduling for risk-reducing salpingo-oophorectomy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-09-01.

Objective: For patients diagnosed with a germline cancer-associated mutation, informing at-risk relatives (ARR) is a critical but challenging task. As part of a prospective facilitated cascade genetic testing strategy, we assessed patients’ attitudes toward cascade testing.

Objective: Following the 2013 Supreme Court ruling invalidating exclusive license rights to isolated human genes and genetic testing, and subsequent rapid integration of multigene panel testing, we sought to evaluate changes in genetic assessment modalities among Ashkenazi Jewish (AJ) patients from June 2013 to December 2016.

Objective: Risk-reducing salpingo-oophorectomy (RRSO) is recommended to BRCA mutation carriers to prevent ovarian cancer by age 35 years or at completion of childbearing. Surgical menopause is a consequence, leaving many women symptomatic. Controversy exists around use of hormonal replacement therapy (HRT) in this population because of concern for increased breast cancer risk, although recent studies have proven its safety. We evaluated trends in HRT use among BRCA patients at a single institution.

Objective: Tumor-infiltrating lymphocytes (TILs) are the host immune response against cancer cells and have been determined to play a role in ovarian cancer outcomes. The quantification of TIL levels has yet to be developed into a clinical scoring system. The aim of this study was to assess CD3+/CD8+ TIL levels as a predictor of high-grade serous ovarian cancer (HGSOC) prognosis.

Objective: Screening for DNA mismatch repair (MMR) in endometrial carcinomas (EC) identifies patients at risk for Lynch syndrome (LS). Patients with MMR-deficient tumors and negative germline LS genetic testing have been described as having Lynch-like syndrome. We aimed to compare clinicopathologic features of EC in patients with intact MMR, Lynch-like syndrome, and LS.