Clinical implications of tumor-based next-generation sequencing in high-grade epithelial ovarian cancer.

BACKGROUND: Tumor-based next-generation sequencing is used inconsistently as a tool to tailor treatment of ovarian cancer, yet beyond detection of somatic BRCA1 and BRCA2 mutations, the clinical benefit is not well established. This study aimed to assess the clinical relevance of tumor-based next-generation sequencing (tbNGS) in patients with ovarian cancer. METHODS: This retrospective study included patients with high-grade epithelial ovarian carcinoma. tbNGS results were identified in the electronic medical record using optical character recognition and natural language processing. Genetic, clinical, and demographic information was collected. Progression-free survival (PFS) and overall survival were calculated and compared using log-rank tests. Multivariate Cox regression and clustering analyses were used to identify patterns of genetic alterations associated with survival. RESULTS: Of 1092 patients in the described population, 409 (37.5%) had tbNGS results. Nearly all (96.1% [393/409]) had one or more genetic alterations. In 25.9% (106/409) of patients, an alteration that aligned with a targeted treatment was identified, and in an additional 48.7% (199/409), tbNGS results suggested eligibility for an investigational agent or clinical trial. The most frequent alterations were TP53, PIK3CA, and NF1 mutations, and CCNE1 amplification. Together, BRCA1 and BRCA2 mutations were associated with longer PFS (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.42-0.92; p = .02), whereas AKT2 amplification was associated with shorter PFS (HR, 3.86; 95% CI, 1.002-14.88; p < .05). Multivariate Cox regression and clustering analyses identified several combinations of genetic alterations that corresponded to outcomes in patients with high-grade serous carcinoma. CONCLUSIONS: tbNGS often yields clinically relevant information. Detailed analysis of population-level tumor genomics may help to identify therapeutic targets and guide development of clinical decision support tools. PLAIN LANGUAGE SUMMARY: Although more and more patients with ovarian cancer are undergoing tumor-based next-generation sequencing to identify genetic mutations in their tumors, the benefits of such testing are not well established. In a group of over 400 patients with ovarian cancer who underwent tumor-based next-generation sequencing in the course of their treatment, nearly all patients had one or more genetic alterations detected, and one out of four patients had a mutation that qualified them for a personalized treatment option.

Intraoperative Radiation Therapy in the Management of Gynecologic Malignancies.

OBJECTIVE: The aim of this study was to review the experience with intraoperative radiation therapy (IORT) in the treatment of gynecologic cancers at the Massachusetts General Hospital. METHODS: From January 1, 1994 to December 31, 2011, 32 patients were treated with IORT at Massachusetts General Hospital. Hospital, pathology, and office medical records and radiation oncology records were reviewed. The Kaplan-Meier method was used to generate disease-free survival and overall survival (OS) data. RESULTS: In 27 patients (84.4), surgical resection margins were microscopically positive. In 5 patients (15.6%), margins were grossly positive. For patients with microscopic disease, 5-year disease-free survival was 40.9% (57 mo), compared with 9.1% (23 mo) for those with gross residual disease (P=0.001). Five-year OS was also statistically improved for patients with microscopic residual disease, when compared with OS among patients with gross residual disease, 77.3% (93 mo) and 54.5% (40 mo), respectively (P=0.001). The risk of distant metastases in patients with gross residual disease was 87%, compared with 28% in patients with microscopic disease (P=0.02). CONCLUSIONS: Volume of residual disease before IORT is an important prognostic indicator. Local recurrence and distant metastases were more common among patients with gross residual disease left in situ at time of IORT. Our institutional experience with IORT further supports the importance of complete surgical resection.

Changing Trends in Lymphadenectomy for Endometrioid Adenocarcinoma of the Endometrium.

OBJECTIVE: To describe trends in the use of lymphadenectomy for endometrioid adenocarcinoma of the endometrium between 1998 and 2012. METHODS: A time-trend analysis was conducted using a population-based cancer registry covering 28% of the population of the United States. To quantify differences over the study period time, the frequency of lymphadenectomy and nodal metastasis among women who underwent surgical treatment of endometrioid endometrial adenocarcinoma was compared among consecutive 3- to 4-year periods. Biannual frequency of lymphadenectomy was modeled with Joinpoint regression to identify when potential changes in trends occurred and calculate annual percentage change. RESULTS: A total of 74,365 women who underwent surgery between 1998 and 2012 were analyzed. Frequency of lymphadenectomy increased by 4.2% annually (95% confidence interval [CI] 3.7-4.6) from 1998 to 2007, after which the frequency declined by 1.6% per year (95% CI 0.9-2.2). Between 1998-2000 and 2007-2009, the frequency of lymphadenectomy rose from 48.7% to 65.5% (risk difference 16.8%, 95% CI 15.4-18.1), the proportion of women found to have nodal metastasis increased by 1.1% (95% CI 0.4-1.7), and the frequency of negative lymphadenectomy increased by 15.7% (95% CI 14.3-17.1). The decline in frequency of lymphadenectomy after 2007 was associated a 3.1% (95% CI 2.1-4.1) decline in the rate of negative lymphadenectomy, but no change in the proportion of women found to have nodal metastasis (P=.17). CONCLUSION: The frequency of lymphadenectomy in the surgical treatment of endometrioid endometrial cancer increased by 4.2% annually from 1998 to 2007 and decreased by 1.6% annually from 2007 to 2012. LEVEL OF EVIDENCE: II.

Obesity, lymphadenectomy and survival outcomes in intermediate to high-risk, early-stage endometrial cancer patients.

AIM: Lymphadenectomy or lymph node dissection is a topic of controversy in endometrial cancer (EC) treatment. MATERIALS & METHODS: Associations between lymph node dissections and clinical factors were retrospectively examined in obese, endometrioid endometrial cancer patients with early-stage disease between 1995 and 2005. Overall, EC-specific and recurrence-free survival were also evaluated. RESULTS: Out of 192 patients, 61 (32%) did not have a lymph node examination, 55 (29%) had less than ten lymph nodes removed and 76 (39%) had ≥10 removed. Lymph node dissection count was not significantly associated with overall, EC-specific or recurrence-free survival. CONCLUSION: Analysis revealed no significant associations between ≥10 dissected lymph nodes and survival outcomes among obese, EC patients, which supports the need for additional investigation of the merit of lymphadenectomy among these patients.

Adnexal mass in the postmenopausal patient.

The adnexal mass in a postmenopausal patient poses an important diagnostic and management dilemma for primary care providers and gynecologists. Postmenopausal women are at a significantly increased risk of gynecologic malignancy; yet even in this population the majority of adnexal masses are benign. Evaluation and management of these lesions centers on the identification of malignancy, especially ovarian cancer, while avoiding unnecessary intervention in patients with benign lesions. Tumor markers and imaging can help in the evaluation of adnexal mass in postmenopausal women. Transvaginal ultrasound has long been considered the imaging modality of choice for the evaluation of adnexal masses. Particularly in the setting of high frequency utilization of transvaginal probes, which project high quality images allowing for detailed descriptions of the macroscopic appearance of the mass, and remains the least expensive of all imaging modalities currently available. For adnexal masses that are highly suspicious for cancer, women should be referred a gynecologic oncologist and facility for optimal care.

Retrospective cohort study evaluating the impact of intraperitoneal morcellation on outcomes of localized uterine leiomyosarcoma.

BACKGROUND: Uterine leiomyosarcoma (ULMS) is identified in 0.1% to 0.2% of hysterectomy specimens of presumed leiomyoma. To date, there is no preoperative technique that reliably differentiates ULMS from uterine leiomyoma. Increasing use of minimally invasive approaches for the management of leiomyomas may result in inadvertently morcellated ULMS with resultant intraperitoneal dissemination of tumor. The objective of this study was to assess the impact of intraperitoneal morcellation on the outcomes of patients with ULMS. METHODS: In this retrospective cohort study, all patients with ULMS who attended the authors' institutions from 2007 to 2012 were reviewed. Demographics and outcomes were compared between those who underwent morcellation or total abdominal hysterectomy (TAH) as their first surgery for uterus-limited ULMS. RESULTS: In total, 58 patients were identified, including 39 who underwent TAH and 19 who underwent intraperitoneal morcellation. Intraperitoneal morcellation was associated with a significantly increased risk of abdominal/pelvic recurrences (P = .001) and with significantly shorter median recurrence-free survival (10.8 months vs 39.6 months; P = .002). A multivariate adjusted model demonstrated a > 3 times increased risk of recurrence associated with morcellation (hazard ratio, 3.18; 95% confidence interval, 1.5-6.8; P = .003). CONCLUSIONS: Intraperitoneal morcellation of presumed leiomyoma worsens the outcomes of women with ULMS. Because there are no reliable preoperative techniques to distinguish ULMS from benign leiomyoma, all efforts to minimize intraperitoneal uterine morcellation should be considered. [See editorial on pages 000-000, this issue.]

Casein kinase I epsilon interacts with mitochondrial proteins for the growth and survival of human ovarian cancer cells.

Epithelial ovarian cancer is the leading cause of death among gynaecologic cancers in Western countries. Our studies have shown that casein kinase I-epsilon (CKIε), a Wnt pathway protein, is significantly overexpressed in ovarian cancer tissues and is associated with poor survival. Ectopic expression of CKIε in normal human ovarian surface epithelial cells and inhibition of CKIε in ovarian cancer cells and in xenografts demonstrated the importance of CKIε in regulating cell proliferation and migration. Interestingly, CKIε function did not seem to involve ß-catenin activity. Instead, CKIε was found to interact with several mitochondrial proteins including adenine nucleotide translocase 2 (ANT2). Inhibition of CKIε in ovarian cancer cells resulted in suppression of ANT2, downregulation of cellular ATP and the resulting cancer cells were more susceptible to chemotherapy. Our studies indicate that, in the context of ovarian cancer, the interaction between CKIε and ANT2 mediates pathogenic signalling that is distinct from the canonical Wnt/ß-catenin pathway and is essential for cell proliferation and is clinically associated with poor survival.

Ovarian cancer screening and early detection in the general population.

Worldwide, the estimated annual incidence of ovarian cancer is 204,000, with 125,000 deaths. In developed countries, ovarian cancer remains the most lethal of all gynecologic malignancies. One of the reasons for the high fatality rate is that more than 70% of women with ovarian cancer are diagnosed with advanced disease. There is a close correlation between stage at presentation and survival; therefore, early detection of ovarian cancer represents the best hope for mortality reduction and long-term disease control. There is preliminary evidence that screening can improve survival, but the impact of screening on mortality from ovarian cancer is still unclear. The proteomic approach has yielded encouraging preliminary findings, but these findings are not mature enough for clinical use. At this time, clear recommendations cannot be made on the basis of the available data.

Understanding barriers to cervical cancer screening among Hispanic women.

OBJECTIVE: We investigated issues affecting Papanicolaou smear screening access, health services utilization, acculturation, social networking, and media venues most conducive to acquiring health information among Hispanics. STUDY DESIGN: Self-identified Hispanics were surveyed. Participants were stratified based on age, time living in the United States, and Papanicolaou screening frequency. RESULTS: Of 318 participants, Hispanics aged 30 years or older and living in the United States less than 5 years prefer speaking Spanish. Women with 5 or more lifetime Papanicolaou smears were 1.610 times more likely to have lived in the United States 5 or more years, 1.706 times more likely to speak a second language, and 1.712 times less likely to need a translator during their health care encounter. CONCLUSION: Age and years living in the United States may be independent risk factors for participation in Papanicolaou screening programs. Social difficulties inherent to acculturation inform health behavior and translate to health disparity among Hispanics. Our results may help design federally funded and community-level programs.

Risk for developing gestational diabetes in women with twin pregnancies.

OBJECTIVE: To examine the risk of developing gestational diabetes mellitus (GDM) in women with twin compared with singleton pregnancies. RESEARCH DESIGN AND METHODS: We examined a cohort of 23,056 pregnant women who gave birth to a live infant between 1 September 1998 and 31 December 2006, 553 of whom had twin pregnancy. The primary exposure was twin versus singleton pregnancy, and the primary outcome was the development of GDM. Standard univariate analyses were performed, as were multivariable analysis with logistic regression to control for potential confounding variables. GDM was diagnosed using criteria of the National Diabetes Data Group. RESULTS: Patients with twin pregnancies had a higher rate of GDM when compared with singleton pregnancies (3.98% vs. 2.32%; p = 0.01). In a multiple regression analysis after adjusting for age, race/ethnicity, body mass index, maximal systolic and diastolic blood pressure, smoking and parity, twin pregnancy was associated with an approximately two-fold increase in risk for developing GDM (OR 2.2, 95% CI 1.4-3.6). In a stratified analysis, women between the ages of 25 and 30 years and African-American women had the highest risk of developing GDM in twin pregnancies. When compared with twins of non-diabetic mothers, twins of gestational diabetics had a higher rate of admission to the neonatal intensive care unit (37%vs. 52%; p = 0.05), had longer hospitalisation (8 +/- 0.5 vs. 16 +/- 4 days; p = 0.01) and higher rate for respiratory distress syndrome (7% vs. 27%; p = 0.001). CONCLUSION: There is a significant increase in the incidence of GDM in twin pregnancies versus singleton pregnancies. The risk is highest in African-American and young women.

HPV vaccine: A comparison of attitudes and behavioral perspectives between Latino and non-Latino women.

OBJECTIVE: Recent scientific advances have lead to the development of a prophylactic, quadrivalent HPV vaccine conferring. We surveyed Latino and non-Latino women directly to examine what motivates them to vaccinate themselves, their daughters, and their sons. METHODS: A written survey was administered to 86 Latinas and 141 non-Latinas, ages 18-55, and attending a general medicine, gynecology, or pediatric unit at an academic center. The instrument included questions on demographics, knowledge and attitudes toward the HPV vaccine, attitudes toward HPV vaccination for the respondents' daughters and/or sons, and the effect of vaccine acceptability on women's attitudes towards their sexual behavior and cervical cancer screening practices. RESULTS: Acceptance for the HPV vaccine was high, with 73% of non-vaccinated, eligible women stating that they would vaccinate themselves. Cervical cancer prevention was the primary motivation for seeking vaccination. Most respondents reported that vaccination should still be accompanied by cervical cancer screening. Seventy-percent of eligible respondent agreed to vaccinate their daughters (97% of Latino and 68.2% of non-Latino mothers, p=0.0078). Eighty-six percent of eligible participants agreed to vaccinate their sons (92.3% of Latino and 76.9% of non-Latino mothers, p=0.0490). Cervical cancer prevention and anal/penile cancer prevention were the primary motivation reported for accepting the vaccine in their daughters and sons, respectively. Fewer than 20% of eligible respondents cited protection of women against developing cervical cancer as the motivation to vaccinate their son(s). CONCLUSIONS: Among vaccine-eligible women, HPV vaccination acceptance for themselves, their daughters, and potentially their sons is high and primarily motivated by cancer prevention for the individual vaccinated.