Nathaniel L. Jones

Vulvar and vaginal melanoma: A unique subclass of mucosal melanoma based on a comprehensive molecular analysis of 51 cases compared with 2253 cases of nongynecologic melanoma

Optimal treatments for vulvar and vaginal melanomas (VVMs) have not been identified. Herein, the authors compare molecular profiles between VVM and nongynecologic melanoma (NGM) subtypes with the objective of identifying novel, targetable biomarkers.

Distinct molecular landscapes between endometrioid and non‐endometrioid uterine carcinomas

Endometrial carcinoma (EC) is traditionally characterized as endometrioid and nonendometrioid based on histopathologic phenotypes. Molecular‐based classifications have been proposed, but are not widely implemented. Herein we examine molecular profiles between EC histologic subtypes. 3133 ECs were submitted between March 2011 and July 2014: 1634 Type I and 1226 Type II. In situ hybridization and immunohistochemistry were used to assess copy number and protein expression of selected genes. Sequenced variants in 47 genes were analyzed using the Illumina TruSeq Amplicon Cancer Panel. Type II EC included 628 cases of uterine serous cancer (USC), 136 cases of clear cell (CC), 361 cases of carcinosarcoma (CS), 38 cases of mucinous, and 36 cases of squamous cell. PI3K/Akt/mTOR pathway was most frequently dysregulated within Type I and mucinous histologies, least altered in CS and squamous. PD‐L1 expression was highest in mucinous, absent in squamous. ER/PR expression was common in Type II, most frequent in USC, mucinous, and squamous. Receptor tyrosine kinase was frequently dysregulated in Type II disease: HER2 amplification highest in USC and CC, EGFR mutations exclusively seen in mucinous EC, KRAS mutations common in mucinous, squamous, and Type I, and c‐MET overexpression high in CC and mucinous. BRCA1 and BRCA2 were most frequently mutated in CS. Grade 3 EC shares features of G1 tumor and Type II disease, most notably resembling CS. Endometrial carcinomas are a molecularly heterogeneous group of tumors. A histology‐based molecular map can identify rational targets to optimize treatment and guide future clinical trials.

Identification of potential therapeutic targets by molecular profiling of 628 cases of uterine serous carcinoma

BACKGROUND Therapeutic options are limited for uterine serous carcinoma (USC). TP53, PIK3CA, FBXW7, and ERBB mutations, as well as HER2 and EGFR overexpression have been reported. We aim to evaluate patterns of molecular, genomic and protein changes in 628USC tumors. METHODS 628 consecutive cases of USC submitted to Caris Life Sciences from Mar, 2011 to July, 2014 were reviewed. These were analyzed using the Illumina TruSeq Amplcon Cancer panel to search for sequenced variants in 47 genes commonly implicated in carcinomatosis. In situ hybridization and immunohistochemistry were also used to assess copy number and protein expression, respectively, of selected genes. RESULTS 31 out of 47 genes of interest harbored mutations, including TP53 (76%), PIK3CA (29%), FBXW7 (12%) and KRAS (9.3%). BRCA1 and BRCA2 were mutated in 9.1% and 6.3%, respectively. ERCC1 and MGMT were absent in 81% and 46% of tumors analyzed, respectively, suggesting potential benefit from platinum and alkylating agents. While not traditionally considered hormone-dependent, our cohort showed high ERα (60%), PR (32%), and AR (27%) expression. HER2 overexpression was 10% via IHC, amplification was 17% via CISH/FISH and mutation was 2% via NGS. While low in PTEN mutation frequency (7%), 45% of USC showed PTEN loss on IHC, and 29% harbored PIK3A mutation, suggesting deregulation of P13K/AKT pathway in a subset of patients. 11% expressed PDL1 and 67% expressed PD1. CONCLUSIONS Our findings suggest hormonal receptors, as well as genes implicated in DNA repair, cell proliferation and cell cycle pathways are of interest in USC.

Physicians' Perspectives and Practice Patterns Toward Opportunistic Salpingectomy in High- and Low-Risk Women

ABSTRACT Background: Opportunistic bilateral salpingectomy (OBS) has been proposed as an ovarian cancer risk-reducing strategy. Methods: A survey was emailed to 300 members of the American College of Obstetricians and Gynecologists. Results: 125 (42%) surveys were returned: 60% female, 88% generalists, 67% private practice. Only 36% correctly identified the lifetime risk of ovarian cancer, only 23% understood the risk-reducing benefit of bilateral salpingo-oophorectomy. 75% perform salpingectomy during hysterectomy, 26–53% use for sterilization depending on approach. Concerns were increased operative time and complications. For BRCA mutations, 64% recommend BSO, 12% recommend a two-step risk-reducing strategy, and 14% refer to gynecologic oncology. Conclusions: We identified broad support and factors limiting willingness to perform OBS.

Characteristics, treatment and outcomes of women with immature ovarian teratoma, 1998–2012

OBJECTIVE To explore the presentation, management and outcomes of adult women diagnosed with immature ovarian teratoma. METHODS The National Cancer Database (NCDB) was used to identify women≥18years of age diagnosed with an immature teratoma from 1998 to 2012. We analyzed demographic, clinical and tumor characteristics, and treatment trends. Multivariable models were employed to examine predictors of adjuvant chemotherapy use and survival. RESULTS We identified a total of 1045 adult women with immature teratoma. The median age of diagnosis was 27years and most were diagnosed between ages 18 and 39 (88.9%). The majority presented with early-stage (I/II) disease (76.0%), underwent unilateral salpingo-oophorectomy (52.5%) and received adjuvant chemotherapy (56.8%). The probability of receiving chemotherapy increased with stage, grade, and treatment at academic compared to community based centers (P<0.05.). Older age, advanced stage, and grade III histology were associated with worse survival (P<0.05). Five-year survival rates were: 98.3% (95% CI 96.8-99.1), 93.2% (95% CI 82.8-97.4), 82.7% (95% CI 74.3-88.5), and 72.0% (95% CI 50.1-85.5) for stages I, II, III, and IV disease, respectively. CONCLUSIONS The incidence of immature teratoma is highest in young adults aged 18 to 39. Most patients present with early-stage disease, are managed with fertility sparing surgery and chemotherapy and have an excellent prognosis. Later age at diagnosis, advanced stage, and high-grade histology confer a worse prognosis.

National trends in total pelvic exenteration for gynecologic malignancies

OBJECTIVE: Total pelvic exenteration (TPE) is a radical procedure involving en bloc resection of the pelvic viscera. The procedure may be performed as primary treatment for gynecologic malignancies or as a salvage therapy in women with a pelvic recurrence. It is unclear how improvements in radiation and chemotherapy have impacted the use of TPE. We performed a population-based analysis to examine the annual rate of TPE among women with cervical and uterine cancer.

The “value” of value in gynecologic oncology practice in the United States: Society of Gynecologic Oncology evidence-based review and recommendations

a Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Ohio State University College of Medicine, Columbus, OH, United States b Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania Health System, Pennsylvania Hospital, Philadelphia, PA, United States c Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States d Division of Gynecologic Oncology, Columbia University College of Physicians and Surgeons and New York Presbyterian Hospital, New York, NY, United States e Virginia Commonwealth University, Richmond, VA, United States f Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University, Durham, NC, United States

Abstract 4023: Notch3 signal activation promotes tumorigenesis in a mouse model of peritoneal epithelial ovarian cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA This study investigates how Notch3 signal activation affects ovarian cancer metastatic growth in order to provide insight into the mechanisms of ovarian cancer progression. Ovarian cancer is often detected at late stages after peritoneal metastasis, at which point prognosis is poor. TCGA defined the Notch signaling pathway as detectably altered in 22% of high-grade serous ovarian cancers, and NOTCH3 in particular is commonly overexpressed. Patients with NOTCH3-high recurrent tumors exhibit worse prognosis and decreased survival. NOTCH3 expression is correlated with resistance to platinum-based chemotherapy. To investigate the mechanisms by which Notch3 signaling functions to promote ovarian cancer, we performed experiments using the ID8 IP2 luciferase mouse ovarian surface epithelial line. This low-Notch3 expressing line was lentivirally infected with Notch3 intracellular domain (N3IC), an activated form of the Notch3 receptor. Increase in N3IC expression and Notch signal activation were confirmed with a dual luciferase reporter assay and via quantitative PCR for N3IC and downstream HES and HEY family targets. We then compared Notch3 activated ID8 IP2 cells to control cells using in vitro assays to evaluate growth properties of the cells, and in vivo intraperitoneal implants in NCR-nu/nu athymic mice to assess metastatic potential. In vitro N3IC and control cells were found to be morphologically similar, and assessment of N3IC cells demonstrated no significant effect on proliferation rate. Anchorage independent growth was also not significantly altered upon activation of Notch3. In addition, the effect of platinum therapy response was assessed in N3IC and control lines. When tested in a DIMSCAN cytotoxicity assay with cisplatinum doses raging from 2-16 μM, no significant difference in sensitivity to platinum treatment, as measured by IC50, was observed. In vivo, however, preliminary results indicate that activation of Notch3 signaling leads to acceleration of ascites accumulation and tumorigenesis. Ascites derived from mice with Notch3 activated tumors had a notably higher blood content indicating alteration of tumor vasculature. Finally, mice display a significant reduction in overall survival with Notch3 activation. We conclude that Notch3 signal activation in ID8 IP2 cells promotes metastatic growth in the peritoneum and ascites accumulation. Notch3 activation was associated with a decreased overall survival of tumor bearing mice. The growth properties of cultured ID8 IP2 cells were not noticeably altered due to Notch3 activation. We propose that Notch3 activation promotes increased tumorigenesis by influencing interaction between cancer cells and the host environment. Citation Format: Jessica Price, Nathaniel Jones, Jan Kitajewski. Notch3 signal activation promotes tumorigenesis in a mouse model of peritoneal epithelial ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4023. doi:10.1158/1538-7445.AM2015-4023