A SNaPshot of potentially personalized care: Molecular diagnostics in gynecologic cancer.

BACKGROUND: Genetic abnormalities underlie the development and progression of cancer, and represent potential opportunities for personalized cancer therapy in Gyn malignancies. METHODS: We identified Gyn oncology patients at the MGH Cancer Center with tumors genotyped for a panel of mutations by SNaPshot, a CLIA approved assay, validated in lung cancer, that uses SNP genotyping in degraded DNA from FFPE tissue to identify 160 described mutations across 15 cancer genes (AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, IDH1, KIT, KRAS, MAP2KI, NOTCH1, NRAS, PIK3CA, PTEN, TP53). RESULTS: Between 5/17/10 and 8/8/13, 249 pts consented to SNaPshot analysis. Median age 60 (29-84) yrs. Tumors were ovarian 123 (49%), uterine 74(30%), cervical 14(6%), fallopian 9(4%), primary peritoneal 13(5%), or rare 16(6%) with the incidence of testing high grade serous ovarian cancer (HGSOC) halving over time. SNaPshot was positive in 75 (30%), with 18 of these (24%) having 2 or 3 (n=5) mutations identified. TP53 mutations are most common in high-grade serous cancers yet a low detection rate (17%) was likely related to the assay. However, 4 of the 7 purely endometrioid ovarian tumors (57%) harbored a p53 mutation. Of the 38 endometrioid uterine tumors, 18 mutations (47%) in the PI3Kinase pathway were identified. Only 9 of 122 purely serous (7%) tumors across all tumor types harbored a 'drugable' mutation, compared with 20 of 45 (44%) of endometrioid tumors (p<0.0001). 17 pts subsequently enrolled on a clinical trial; all but 4 of whom had PIK3CA pathway mutations. Eight of 14 (47%) cervical tumors harbored a 'drugable' mutation. CONCLUSION: Although SNaPshot can identify potentially important therapeutic targets, the incidence of 'drugable' targets in ovarian cancer is low. In this cohort, only 7% of subjects eventually were treated on a relevant clinical trial. Geneotyping should be used judiciously and reflect histologic subtype and available platform.

Management and outcomes for elderly women with vulvar cancer over time.

OBJECTIVE: To examine changes over time in survival and treatment for women diagnosed with vulvar squamous cell carcinoma included in the Surveillance, Epidemiology, and End Results (SEER) Program. DESIGN: Retrospective analysis. SETTING: USA, data obtained from the SEER Program for 1988-2009. POPULATION: Women with vulvar squamous cell carcinoma. METHODS: Women were stratified by age: <50, 50-64, 65-79, and ≥80 years. Differences in survival and treatment patterns were analysed between age groups. Multivariate logistic regression models were constructed to examine treatment patterns. Kaplan-Meier and Cox proportional hazards survival methods were used to assess survival. MAIN OUTCOME MEASURES: Vital status from the date of diagnosis until death, censoring or last follow-up. RESULTS: The final study group consisted of 8553 women, 1806 (21.12%) <50 years, 2141 (25.03%) 50-64 years, 2585 (30.22%) 65-79 years, and 2021 (23.63%) >80 years old. After adjusting for patient and tumour characteristics, older women were less likely to have surgery and more likely to receive radiotherapy. Compared with women under 50 years, women 50-64 had a two-fold higher risk of death (HR 1.91, 95% CI 1.55-2.34); those 65-79 years had a four-fold higher risk of death (HR 4.01, 95% CI 3.32-4.82), and those ≥80 years had a seven-fold higher risk of death (HR 6.98, 95% CI 5.77-8.46). These trends stayed relatively constant over the time periods studied. CONCLUSIONS: Women over 50 years are at a higher risk of vulvar cancer-specific mortality, which increases with age. These trends stayed relatively constant over the time periods studied.

Multimodality therapy in early-stage neuroendocrine carcinoma of the uterine cervix.

OBJECTIVE: Patients with early-stage neuroendocrine cervical carcinoma (NECC) have a high mortality rate despite aggressive therapy. The rarity of this tumor precludes initiation of a randomized, prospective trial. We reviewed our experience in early stage disease and performed a meta-analysis of the literature to identify prognostic factors and determine optimal multimodality therapy. METHODS: Eleven women with International Federation of Gynecology and Obstetrics (FIGO) early stage (IB--IIA) NECC were treated with surgery and chemotherapy at our institutions between 1978 and 1998. Administration of radiation therapy was recorded, but not required for inclusion in this study. A gynecologic pathologist reviewed all histopathologic sections. Medical records were retrospectively reviewed and clinical data obtained. Twenty-three early-stage NECC patients who were similarly treated during the study interval were identified by a Medline search of the English literature and included in the analysis. The Kaplan--Meier method and log-rank test were used for survival analysis. RESULTS: The overall 2-year survival rate for the 34 patients was 38%. The median age was 37 years (range, 20--75 years). Median cervical tumor diameter was 3.2 cm (range 0.5--11.0 cm). Lymphovascular space invasion was present in 21 (78%) of 27 patients (7 unknown). Fifteen (52%) of twenty-nine had lymph node metastases (5 unknown). Fifteen patients received postoperative platinum/etoposide (PE), seven received vincristine/adriamycin/cyclophosphamide (VAC), two received alternating cycles of VAC and PE, and ten received other chemotherapy regimens. Twenty women were treated with radiation therapy. The presence of lymph node metastases was a poor prognostic factor (P < 0.001). PE and VAC chemotherapy was associated with increased survival (P < 0.01). CONCLUSION: NECC is a highly lethal variant of cervical cancer. The presence of lymph node metastases is the most important prognostic variable. Postoperative VAC or PE appears most likely to improve chances for survival.