Non-serous Subtypes Research Articles

Mucin 13 (MUC13) as a candidate biomarker for ovarian cancer detection: potential to complement CA125 in detecting non-serous subtypes.

Ovarian cancer is the most lethal gynecological malignancy in developed countries. One of the key associations with the high mortality rate is diagnosis at late stages. This clinical limitation is primarily due to a lack of distinct symptoms and detection at the early stages. The ovarian cancer biomarker, CA125, is mainly effective for identifying serous ovarian carcinomas, leaving a gap in non-serous ovarian cancer detection. Mucin 13 (MUC13) is atransmembrane, glycosylated protein with aberrant expression in malignancies, including ovarian cancer. We explored the potential of MUC13 to complement CA125 as an ovarian cancer biomarker, by evaluating its ability to discriminate serous and non-serous subtypes of ovarian cancer at FIGO stages I-IV from benign conditions. We used our newly developed, high sensitivity ELISA to measure MUC13 protein in a large, well-defined cohort of 389 serum samples from patients with ovarian cancer and benign conditions. MUC13 and CA125 serum levels were elevated in malignant compared to benign cases (p<0.0001). Receiver-operating characteristic (ROC) curve analysis showed similar area under the curve (AUC) of 0.74 (MUC13) and 0.76 (CA125). MUC13 concentrations were significantly higher in mucinous adenocarcinomas compared to benign controls (p=0.0005), with AUC of 0.80. MUC13 and CA125 showed significant elevation in early-stage cases (stage I-II) in relation to benign controls (p=0.0012 and p=0.014, respectively). We report the novel role of MUC13 as a serum ovarian cancer biomarker, where it could complement CA125 for detecting some subtypes of non-serous ovarian carcinoma and early-stage disease.

Abstract 6402: Associations of sodium glucose cotransporter-2 (SGLT2), metabolic disorders, and survival following incident epithelial ovarian cancer

Abstract Background: Up to 75% of ovarian cancers will become platinum resistant and survival following the development of resistance is typically less than one year. New therapies with higher curative rates are needed to improve prognosis. There has been increasing interest in inhibitors of sodium glucose cotransporter-2 (SGLT2) in suppressing tumor growth. Use of SGLT2 inhibitors show promise not only due to their ability to inhibit glucose uptake, but also from the subsequent improvements in other metabolic disorders that may affect cancer prognosis. Purpose: We evaluated the associations of tumor SGLT2 protein expression with survival following diagnosis of incident epithelial ovarian cancer (EOC). Methods: Tumor samples were obtained from 492 patients undergoing debulking surgery for primary EOC at Roswell Park Comprehensive Cancer Center between 1995 and 2002. Only incident cases and patients who did not receive neo-adjuvant chemotherapy were included in analyses (n=396). Tissue samples were compiled into tissue microarray blocks that were sectioned, stained, imaged, and analyzed for SGLT2 expression. Data on patient, clinical, and tumor characteristics, along with available information on components of metabolic disorders, were linked to each patient. Multivariate Cox proportional hazards models were performed to determine hazards ratios (HR) and 95% confidence intervals (CI) for EOC-specific and all-cause mortality. Results: In our analysis of 396 EOC patients seen at Roswell Park, we observed significant associations between high SGLT2 expression and decreased risk of both EOC-specific (HR: 0.68; 95% CI: 0.49-0.94) and all-cause mortality (HR: 0.71; 95% CI: 0.53-0.95). In particular, among those with advanced-stage tumors, there was a significant association between high SGLT2 expression and lower risk of EOC-specific (HR: 0.61; 95% CI: 0.42-0.91) and all-cause mortality (HR: 0.64; 95% CI: 0.45-0.90). A lower risk of all-cause mortality was observed among those with high-grade tumors (HR: 0.69; 95% CI: 0.48-0.98). Trends of increasing SGLT2 associated with decreased risk of mortality varied by histological subtype. The inverse association between high SGLT2 and EOC-death was stronger among those with a history of hyperlipidemia (HR: 0.46; 95% CI: 0.19-0.99) and obesity (HR: 0.43; 95% CI: 0.23-0.82) compared to other metabolic syndrome components. These associations were less robust for all-cause mortality. Conclusion: Contrary to our initial hypothesis, higher SGLT2 expression among EOC patients may be associated with more favorable prognosis. This association may be stronger for high grade and advanced stage tumors as well as non-serous subtypes. Identifying other factors associated with levels of expression could aid in the development of potential screening interventions and more personalized treatment. Citation Format: Jennifer M. Mongiovi, Jo L. Freudenheim, Jeff C. Miecznikowski, Susan E. McCann, Ashley E. Stenzel, Wiam Bshara, Agnieszka Witkiewicz, Leighton Stein, Lisa D. Kellenberger, Ahmad Al Sulimani, Kirsten B. Moysich. Associations of sodium glucose cotransporter-2 (SGLT2), metabolic disorders, and survival following incident epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6402.

Uterine lavage for the detection of ovarian cancer using an expanded gene panel

Current screening methods for ovarian cancer have failed to demonstrate a significant reduction in mortality. Uterine lavage catheters have been used to detect tumor-specific TP53 mutations from cells presumably shed from high-grade serous ovarian cancer, but this technique may not identify non-serous subtypes or early-stage disease. We aimed to pilot the combination of deep sequencing methods with an expanded gene panel to improve detection of both early stage and non-serous ovarian cancers.

Uterine lavage for the detection of ovarian cancer using an expanded gene panel

Uterine lavage for the detection of ovarian cancer using an expanded gene panel

Abstract LB047: Uterine lavage for the detection of ovarian cancer using an expanded gene panel

Abstract Objectives: Current screening methods for ovarian cancer have failed to demonstrate a significant reduction in mortality. Uterine lavage catheters have been used to detect tumor-specific TP53 mutations from cells presumably shed from high-grade serous ovarian cancer, but this technique may not identify non-serous subtypes or early-stage disease. We aimed to pilot the combination of deep sequencing methods with an expanded gene panel to improve detection of both early stage and non-serous ovarian cancers. Methods: Lavage of the uterine cavity was performed in 35 consecutive patients undergoing surgery with preoperative concern for an ovarian malignancy. Duplex sequencing, an ultra-accurate error-correction sequencing approach, was used to deeply sequence extracted DNA from lavage samples (average duplex depth ~2500x) with a panel of candidate ovarian cancer driver genes including TP53, ARID1A, PTEN, PPP2R1A, CDKN2A, KRAS (whole genes), CTNNB1, PIK3CA, and BRAF (hotspots only). Tumor DNA was sequenced to identify driver mutations and compare with mutations found in the lavages. The overall mutation frequency in lavage DNA was calculated by dividing identified non-polymorphism mutant alleles by the total number of nucleotides sequenced in coding regions. Results: In total, lavage samples were collected from fourteen women with benign disease, thirteen with high grade serous carcinoma (HGSC), three with clear cell carcinoma, three with endometrioid carcinoma, one with granulosa cell carcinoma and one with carcinosarcoma. Thirteen women had stage I or II disease (including five with stage I or II high grade serous). Processed lavage samples yielded a median DNA of 596.5 ng. Tumor sequencing is ongoing, but of seven fully sequenced lavage/tumor pairs, the tumor-specific mutation was identified in four lavage samples: TP53 mutations found in two HGSC (stage IIb and stage III), an ARID1A mutation from a stage Ic3 clear cell carcinoma, and a PIK3CA mutation from a stage Ia endometrioid carcinoma. The tumor-specific mutation was not identified in lavage samples from two patients with endometrioid and one with clear cell carcinoma. Of 21 lavage samples that have presently undergone duplex sequencing, a total of 596 additional somatic mutations were identified in the nine genes. Lavages from patients with HGSC tended to have increased average mutation frequency of TP53 compared to patients with benign disease (TP53 2.2x10-6 vs 9.2x10-7, p=0.09). Conclusion: Sequencing at high depth and using an expanded gene panel allows for the identification of tumor mutations in uterine lavage samples, including some early stage and non-serous ovarian cancers, as well as identifying significant somatic mutational background. Larger studies are needed to confirm the clinical utility of this method, which may have potential to improve the early detection of ovarian cancer. Citation Format: Talayeh Ghezelayagh, Jeanne Fredrickson, Enna Manhardt, Marc R. Radke, Brendan Kohrn, Heidi J. Gray, Renata R. Urban, Kathryn P. Pennington, John B. Liao, Kemi M. Doll, Elise J. Simons, Jennifer K. Burzawa, Barbara A. Goff, Paul Speiser, Elizabeth M. Swisher, Rosa Ana Risques, Barbara M. Norquist. Uterine lavage for the detection of ovarian cancer using an expanded gene panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB047.

Sleep Characteristics and Risk of Ovarian Cancer Among Postmenopausal Women.

Several studies have assessed the relationship between sleep duration and ovarian cancer risk, but the results are conflicting. Importantly, no studies addressed the relationship between sleep disturbance or sleep quality and ovarian cancer incidence. Moreover, few studies have examined the relationships between sleep measures and subtypes of ovarian cancer. This study included 109,024 postmenopausal women ages 50-79 from the Women's Health Initiative during 1993-1998 and followed through 2018. The Cox proportional hazards model was used to estimate adjusted HRs for the associations between sleep habits and the incidence of ovarian cancer and its subtypes. No association was observed between sleep duration, sleep quality, sleep disturbance, or insomnia and risk of overall ovarian cancer, serous/nonserous, or type I/type II ovarian cancer subtype. However, compared with women with average sleep quality, women with restful or very restful sleep quality had a significantly lower risk of invasive serous subtype [HR: 0.73, 95% confidence interval (CI): 0.60-0.90] while insomnia was associated with a higher risk of invasive serous subtype (HR: 1.36, 95% CI: 1.12-1.66). Associations with insomnia differed significantly by serous and nonserous subtypes, and type I and type II subtypes (P heterogeneity = 0.001 and P heterogeneity <0.001, respectively). This study provides no evidence on association between sleep habits and overall ovarian cancer risk among postmenopausal women. However, restful or very restful sleep quality was associated with a lower risk of invasive serous ovarian cancer, and insomnia was associated with a higher risk of invasive serous ovarian cancer. Associations with insomnia differed by subtypes. PREVENTION RELEVANCE: This study shows no association between sleep duration, sleep quality, or insomnia with the risk of overall ovarian cancer among postmenopausal women. However, restful sleep quality was associated with a lower risk of invasive serous ovarian cancer, and insomnia was associated with a higher risk of invasive serous ovarian cancer.

Abstract B54: Adipogenic chemokines, body mass index, and ovarian cancer survival

Abstract Objectives: Obesity affects more than one-third of US adults and promotes the development and progression of many cancers. One mechanism by which obesity may influence ovarian cancer is via adipocyte-tumor cell communication, including the production of chemotactic cytokines, or chemokines, in the tumor microenvironment. Our goal was to measure adipogenic chemokine expression and examine associations with body mass index (BMI) and ovarian cancer survival. Methods: We selected 25 chemokines from laboratory experiments that modeled adipogenesis, of which 22 had expression data available for 302 high-grade serous ovarian cancer cases from The Cancer Genome Atlas (TCGA). We measured mRNA expression using Taqman quantitative real-time polymerase chain reaction (QPCR) in 50 high-grade serous tumor samples and ascertained BMI from electronic medical records (EMR) from the Vanderbilt University Medical Center (VUMC). We also evaluated peri-diagnosis BMI (± 4 weeks) from EMR for 298 tumor registry-confirmed (165 serous and 133 nonserous) cases. Expression data were log transformed and dichotomized at median values; associations with disease-free survival (DFS) and overall survival (OS) were quantified using proportional hazards regression. Results: In TCGA analyses, two ligands and one receptor had significant associations with better (CCL8 and CXCL13) and worse (CX3CR1) OS, respectively. Higher CXCL13 expression was also associated with better DFS in VUMC tumors, but significance was attenuated after adjustment for clinical covariates. CX3CR1 was not expressed in all tumors but was positively associated with BMI (Pearson’s r=0.69, P=0.019). Finally, among all 298 tumor registry-confirmed VUMC cases, BMI was not associated with OS, although higher BMI was associated with a 4% significantly increased risk of death among 133 nonserous cases. Conclusions: Our findings suggest that obesity impacts chemokine expression in the tumor microenvironment and ovarian cancer survival. Further, differences between serous and nonserous subtypes may influence the relationship between obesity and ovarian cancer prognosis. Citation Format: Sara Duque, Nneka Anyanwu, George Bukenya, Shriya Karam, Deok-Soo Son, Andrew J. Wilson, Marta A. Crispens, Alicia Beeghly-Fadiel. Adipogenic chemokines, body mass index, and ovarian cancer survival [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B54.

Mutational heterogeneity in non-serous ovarian cancers

Epithelial ovarian cancer is a leading cause of death in gynecological cancers. While several systematic studies have revealed the mutation landscape of serous epithelial ovarian cancer, other non-serous subtypes of the disease have not been explored as extensively. Here we conduct exome sequencing of nine non-serous epithelial ovarian tumors (six endometrioid and three mucinous) and their corresponding normal DNA as well as a tumor-only granulosa cell sample. We integrated the exome data with targeted gene sequencing for 1,321 genes selected for their involvement in cancer from additional 28 non-serous ovarian tumors and compared our results to TCGA ovarian serous cystadenocarcinoma and uterine corpus endometrial carcinomas. Prevalence of TP53 mutations in non-serous was much lower than in serous epithelial OC, whereas the prevalence of PIK3CA, PIK3R1, PTEN, CTNNB1, ARID1A, and KRAS was higher. We confirmed the high prevalence of FOXL2 and KRAS mutations in granulosa cell tumors and in mucinous tumors, respectively. We also identified POLE proofreading domain mutations in three endometrioid ovarian tumors. These results highlight mutational differences between serous and non-serous ovarian cancers, and further distinguish different non-serous subtypes.

Epigenetic reprogramming of fallopian tube fimbriae in BRCA mutation carriers defines early ovarian cancer evolution.

The exact timing and contribution of epigenetic reprogramming to carcinogenesis are unclear. Women harbouring BRCA1/2 mutations demonstrate a 30–40-fold increased risk of high-grade serous extra-uterine Müllerian cancers (HGSEMC), otherwise referred to as ‘ovarian carcinomas', which frequently develop from fimbrial cells but not from the proximal portion of the fallopian tube. Here we compare the DNA methylome of the fimbrial and proximal ends of the fallopian tube in BRCA1/2 mutation carriers and non-carriers. We show that the number of CpGs displaying significant differences in methylation levels between fimbrial and proximal fallopian tube segments are threefold higher in BRCA mutation carriers than in controls, correlating with overexpression of activation-induced deaminase in their fimbrial epithelium. The differentially methylated CpGs accurately discriminate HGSEMCs from non-serous subtypes. Epigenetic reprogramming is an early pre-malignant event integral to BRCA1/2 mutation-driven carcinogenesis. Our findings may provide a basis for cancer-preventative strategies.

Highlights of This Issue

Uptake of human papillomavirus (HPV) vaccine is low in the United States, but in certain areas, like Appalachia, where rates of cervical cancer are higher, rates should be higher to address this disparity in cancer mortality. Paskett and colleagues tested a multilevel intervention (MLI) targeting clinics, providers, and parents of girls aged 9 to 17 years to try to increase uptake of the vaccine in girls who needed it in a group randomized trial design in 12 counties in Appalachian Ohio. The results indicated that while uptake of the first shot of the HPV vaccine was significantly higher in the intervention group (P = 0.002 at 6 months), rates of uptake in both groups were very low (13.1% vs 6.5%, intervention and comparison groups, respectively). Study design limitations restricted the authors' access to patients from the intervention clinics, and thus, future studies should test MLIs in a pragmatic trial design so that clinics may feel more comfortable in fully participating at all levels.Many hormonal factors are associated with ovarian cancer, but previous studies evaluating associations between endogenous sex-steroid hormone levels and ovarian cancer were inconclusive. Trabert and colleagues evaluated the association between 15 prediagnostic serum estrogens and subsequent ovarian cancer risk among women not currently using menopausal hormones. The study demonstrated striking heterogeneity of estrogen associations with ovarian cancer subtypes. While the authors observed no association with serous tumors, most estrogens were associated with at least a doubling in risk of nonserous subtypes (endometrioid, clear cell, mucinous), with many remaining after correction for multiple comparisons. The results further support the heterogeneous etiology of ovarian cancer.The role of the immune system response in carcinogenesis is an area of active investigation, and there is a need to identify immune circulating biomarkers that are specific indicators of cancer development and progression. In this prospective investigation from the Atherosclerosis Risk in Communities Study, Prizment and colleagues report that a higher concentration of circulating beta-2 microglobulin (B2M), a marker of increased cell turnover, is associated with elevated risk of colorectal cancer development independent of other risk factors. Further research should determine whether circulating B2M is marking increased turnover of tumor or immune cells, i.e., whether it reflects local or systemic response.Statins, commonly used to lower cholesterol, demonstrate anticancer and antiviral properties in experimental models. Limited epidemiologic data also suggest that statins may improve the outcome of hepatocellular carcinoma (HCC), particularly in patients with hepatitis C. Jeon and colleagues analyzed statin prescription filling patterns and survival data in over 1,000 elderly patients with stage I or II HCC residing in the U.S. Statin treatment after HCC diagnosis was not associated with survival in this population, after correction for immortal time bias and confounding. The study does not lend support to treating elderly HCC patients with statins for lengthening survival.

Abstract A63: The importance of cyclooxygenase 1 and 2 expression in ovarian cancer survival: Notable differences by histologic subtype.

Abstract Background: Cyclooxygenase (COX) enzymes catalyze key reactions of prostaglandin biosynthesis. COX-2 is implicated in inflammation, and high expression has been associated with lower survival from several malignancies, including ovarian cancer. COX-1 is thought to contribute primarily to normal physiology, so cancer outcomes have been evaluated less frequently. However, COX-1 is highly expressed in ovarian cancer, and both COX enzymes have differences in expression across histologic subtypes of disease. This study was undertaken to evaluate COX-1 and COX-2 expression in relation to ovarian cancer survival, including differences between serous and non-serous disease subtypes. Methods: A tissue microarray was created from primary ovarian, fallopian, or peritoneal cancers diagnosed at the Vanderbilt University Medical Center. COX-1 (Santa Cruz Biotechnology, Dallas, TX) and COX-2 (Thermo Fisher Scientific, Inc., Waltham, MA) immunostaining was performed; semi-quantitative measurement was conducted using the automated Ariol® SL-50 Platform. Outcomes and clinical characteristics, including age, stage, grade, histologic subtype, residual disease, and race were collected by medical record abstraction. Progression-free and overall survival were evaluated using proportional hazards regression to calculate Hazard Ratios (HR) and Confidence Intervals (CI). Results: Among 191 epithelial ovarian cancer cases, 57 had documented disease progression, and 121 deaths occurred. COX expression was categorized into tertiles; significant differences were found in regards to histologic subtype, disease stage, and residual disease. In multivariate models among all cases, increasing tertiles of COX-2 expression was significantly associated with increased hazards of disease progression (HR: 1.43, 95% CI: 1.01-2.02) but not death (HR: 1.02, 95% CI: 0.79-1.30). Among serous subtypes, higher COX-2 expression was significantly associated with worse overall survival (HR: 1.53, 95% CI: 1.04-2.23). Among non-serous subtypes, higher COX-1 expression was associated with better overall survival (HR: 0.46, 95% CI: 0.24-0.90). Differences by histology were suggestive for COX-2 (P-value for interaction=0.090) and significant for COX-1 (P-value for interaction=0.013). Conclusions: This single institution retrospective study demonstrates distinct associations between COX enzymes and ovarian cancer disease outcomes across histologic subtypes. If replicated, these findings imply that histologic subtype of disease may be important for the appropriate selection and application of COX inhibitors for ovarian cancer treatment. Citation Format: Alicia Beeghly-Fadiel, Meral El Ramahi, Andrew Wilson, Spencer Keene, Oluwole Fadare, Marta A. Crispens, Dineo Khabele. The importance of cyclooxygenase 1 and 2 expression in ovarian cancer survival: Notable differences by histologic subtype. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A63.

Abstract B13: Discovery of novel subtype-specific ovarian cancer biomarkers via integrated tissue proteomics.

Abstract Introduction and Objectives: It is evident that ovarian cancer (OvCa) is not a single disease but is made up of several distinct subtypes, including serous, endometrioid, clear cell and mucinous. The gold-standard biomarker CA125 performs well in serous but not in the other histotypes. We hypothesize that a more focused discovery effort (on non-serous OvCa biomarkers and/or markers that can complement serum CA125) may bring about a sensitivity that is acceptable for all histotypes and be suitable for early diagnosis of OvCa. Methods: Tissues from patients diagnosed with endometrioid (EC), clear cell (CC), and mucinous ovarian carcinoma (MC), as well as from their appropriate controls (endometriosis and healthy endometrium for EC and CC; mucinous cystadenoma for MC) were subjected to proteomic analysis using a label-free, offline 2-dimensional liquid chromatography tandem mass spectrometry-based approach. Discovery candidates were then filtered using an in-house developed algorithm combining publicly-available resources with our own warehouse of transcriptomic and proteomic sets. Results and Discussion: Over 8000 unique proteins were identified in this proteomic exercise; specifically, approximately 1500 protein unique to MC, 1100 unique to CC, and 3000 unique to EC were identified when comparing the appropriate cases and controls. A curated list of 60 high-potential candidates was generated after using a range of bioinformatics tools to ensure criteria based on factors including (but not limited to) tissue specificity, cellular localization and transcriptional upregulation were met. These 60 candidates represent putative subtype-specific markers which will be further analyzed and validated in serum cohorts. Conclusions: The identification and validation of markers specific to the non-serous subtypes of OvCa remains an unmet clinical need. With our list of putative subtype-specific markers, we aim to develop a novel biomarker panel able to detect all OvCa histotypes with greater sensitivity and specificity than any existing clinical tools. Citation Format: Felix Leung, Marcus Q. Bernardini, Blaise Clarke, Marjan Rouzbahman, Eleftherios P. Diamandis, Vathany Kulasingam. Discovery of novel subtype-specific ovarian cancer biomarkers via integrated tissue proteomics. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B13.

Physical activity in different periods of life, sedentary behavior, and the risk of ovarian cancer in the NIH-AARP diet and health study.

Physical activity and sedentary behavior may influence ovarian cancer risk, but clear evidence is lacking. We prospectively investigated the relations of self-reported physical activity and sedentary behavior to ovarian cancer incidence in a cohort of 148,892 U.S. women ages 50-71 years at baseline (1995-1996), who were followed through 2006. Multivariate Cox proportional hazard models were used to estimate relative risks (RR) and 95% confidence intervals (CI). We also conducted analysis by hormone use, body mass index (BMI), and cancer subtype. We identified 753 incident epithelial ovarian cancers. Overall, neither physical activity nor sedentary behavior at baseline was associated with ovarian cancer risk. Compared with women who never or rarely engaged in vigorous physical activity in the past year, women who reported more than 5 times/week of vigorous physical activity had an RR of 1.05 (95% CI, 0.84-1.32). Women who sat 7+ hours/day had an RR of 1.05 (95% CI, 0.80-1.37) compared with those reporting <3 hours of sitting. The associations were not modified by hormone use or BMI and were similar for both serous and non-serous subtypes. Physical activity and sedentary behavior in middle and older ages were not associated with ovarian cancer risk. We found no clear support for a role of physical activity and sedentary behavior in ovarian cancer risk.

Revisiting the Role of Radiation Treatment for Non-serous Subtypes of Epithelial Ovarian Cancer

Except for its palliative use, radiation has been largely abandoned in the management of ovarian cancers because of the recognized efficacy of chemotherapy agents. Whole abdominal irradiation (WAR), however, has been shown to be of adjuvant and curative value in ovarian cancer with microscopic or minimal residual disease in the pelvis, the so-called "intermediate risk group." Recent hypothesis generating data from the use of adjuvant radiation following adjuvant chemotherapy in ovarian cancer has shown an incremental survival benefit for the rarer non-serous ovarian subtypes including clear cell, endometrioid, and mucinous. No incremental benefit was observed for the more common serous subtype. A retrospective examination of early trials using WAR as the sole postoperative treatment in ovarian cancer has determined that the majority of patients in these studies and cured by radiation actually had the non-serous subtypes. The recognition that the non-serous subtypes differ from the serous cancers in their stage of presentation, their molecular characteristics, their response to classic chemotherapy, and their outcomes suggest the non-serous subtypes should be treated as rare and different cancers. In addition to specific targeting therapies that may be developed, radiation should be reconsidered as part of the treatment armamentarium for these diseases.

Revisiting the Role of Radiation Treatment for Non-serous Subtypes of Epithelial Ovarian Cancer

Except for its palliative use, radiation has been largely abandoned in the management of ovarian cancers because of the recognized efficacy of chemotherapy agents. Whole abdominal irradiation (WAR), however, has been shown to be of adjuvant and curative value in ovarian cancer with microscopic or minimal residual disease in the pelvis, the so-called "intermediate risk group." Recent hypothesis generating data from the use of adjuvant radiation following adjuvant chemotherapy in ovarian cancer has shown an incremental survival benefit for the rarer non-serous ovarian subtypes including clear cell, endometrioid, and mucinous. No incremental benefit was observed for the more common serous subtype. A retrospective examination of early trials using WAR as the sole postoperative treatment in ovarian cancer has determined that the majority of patients in these studies and cured by radiation actually had the non-serous subtypes. The recognition that the non-serous subtypes differ from the serous cancers in their stage of presentation, their molecular characteristics, their response to classic chemotherapy, and their outcomes suggest the non-serous subtypes should be treated as rare and different cancers. In addition to specific targeting therapies that may be developed, radiation should be reconsidered as part of the treatment armamentarium for these diseases.

Type II Diabetes Mellitus and the Incidence of Epithelial Ovarian Cancer in the Cancer Prevention Study-II Nutrition Cohort

Despite consistent associations of type II diabetes mellitus with hormonally related cancers such as breast and endometrium, the relation between type II diabetes mellitus and ovarian cancer risk is unclear. Associations of type II diabetes mellitus status, duration, and insulin use with epithelial ovarian cancer overall, and with serous and nonserous histologic subtypes were examined in the Cancer Prevention Study-II Nutrition Cohort, a prospective study of U.S. men and women predominantly aged 50 years and older. Between 1992 and 2007, 524 incident epithelial ovarian cancer cases were identified among 63,440 postmenopausal women. Multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI) were computed using extended Cox regression to update diabetes status and bilateral oophorectomy status during follow-up. Type II diabetes mellitus status (RR = 1.05; 95% CI, 0.75-1.46) and duration were not associated with epithelial ovarian cancer risk. Although not statistically significantly different (P(difference) = 0.39), the RR was higher for type II diabetes mellitus with insulin use (RR = 1.28; 95% CI, 0.74-2.24) than for type II diabetes mellitus without insulin use (RR = 0.96; 95% CI, 0.64-1.43). Diabetes seemed to be more strongly associated with nonserous (RR = 1.41; 95% CI, 0.70-2.85) than serous (RR = 0.71; 95% CI, 0.41-1.23) histologic subtypes. Type II diabetes mellitus was not associated with risk of epithelial ovarian cancer, although higher risks with nonserous subtypes and among insulin users cannot be ruled out. Larger studies are needed to clarify associations of type II diabetes mellitus with or without insulin use with risk of ovarian cancer overall and by histologic subtypes.

Secondary cytoreductive surgery for recurrent mullerian adenocarcinomas: A comparison of serous and non-serous subtypes.

e15544 Background: The aim of the study was to evaluate the effects of secondary cytoreductive surgery on survival in patients with recurrent epithelial ovarian, tubal, and peritoneal cancer. Methods: Among all patients who underwent primary therapy for epithelial ovarian, tubal, and peritoneal cancer between 1994 and 2006 at our insitution, the medical records of all patients who were submitted to secondary cytoreductive surgery were retrospectively investigated. Survival analysis was estimated by Kaplan-Meier methods. Results: In total, 34 patients met the inclusion criteria, of whom, 26 had serous, 4 had endometrioid and 4 had clear cell type adenocarcinomas. Median age at treatment for recurrence was 57 years (range 47-76). Following primary surgical and systematic treatment, recurrence was diagnosed after a median treatment free interval of 10 months (range 2-137). Complete cytoreduction was achieved in 24 of the patients (75%). At the end of a median follow-up of 36 months after treatment for recurrence, 12 patients were alive and well, 6 alive with disease and 16 were dead and median post-recurrence survival was 60 months. When compared between histological subtypes, overall post-recurrence survival of serous adenocarcinoma was significantly worse than that of non-serous (p = 0.048). Conclusions: In the present study, the impact of secondary cytoreductive surgery on a significant survival benefit was identified especially for non-serous type. Further analyses are needed to better define the role of surgery in these patients. No significant financial relationships to disclose.