Robert Neff

Is bariatric surgery an option for women with gynecologic cancer? Examining weight loss counseling practices and training among gynecologic oncology providers

OBJECTIVE The objective of this study was to evaluate gynecologic oncology provider (GOP) practices regarding weight loss (WL) counseling, and to assess their willingness to initiate weight loss interventions, specifically bariatric surgery (WLS). METHODS Members of the Society of Gynecologic Oncology were invited to complete an online survey of 49 items assessing knowledge, attitudes, and behaviors related to WL counseling. RESULTS A total of 454 participants initiated the survey, yielding a response rate of 30%. The majority of respondents (85%) were practicing GOP or fellows. A majority of responders reported that >50% of their patient population is clinically obese (BMI ≥ 30). Only 10% reported having any formal training in WL counseling, most often in medical school or residency. Providers who feel adequate about WL counseling were more likely to offer multiple WL options to their patients (p<.05). Over 90% of responders believe that WLS is an effective WL option and is more effective than self-directed diet and medical management of obesity. Providers who were more comfortable with WL counseling were significantly more likely to recommend WLS (p<.01). Approximately 75% of respondents expressed interest in clinical trials evaluating WLS in obese cancer survivors. CONCLUSIONS The present study suggests that GOP appreciate the importance of WL counseling, but often fail to provide it. Our results demonstrate the paucity of formal obesity training in oncology. Providers seem willing to recommend WLS as an option to their patients but also in clinical trials examining gynecologic cancer outcomes in women treated with BS.

The mutational spectrum of FOXA2 in endometrioid endometrial cancer points to a tumor suppressor role

BACKGROUND Forkhead box protein A2 (FOXA2) plays an important in development, cellular metabolism and tumorigenesis. The Cancer Genome Atlas (TCGA) identified a modest frequency of FOXA2 mutations in endometrioid endometrial cancers (EEC). The current study sought to determine the relationship between FOXA2 mutation and clinicopathologic features in EEC and FOXA2 expression. METHODS Polymerase chain reaction (PCR) amplification and sequencing were used to identify mutations in 542 EEC. Western blot, quantitative reverse transcriptase PCR (qRT-PCR) and immunohistochemistry (IHC) were used to assess expression. Methylation analysis was performed using combined bisulfite restriction analysis (COBRA) and sequencing. Chi-squared, Fishers exact, Students t- and log-rank tests were performed. RESULTS Fifty-one mutations were identified in 49 tumors (9.4% mutation rate). The majority of mutations were novel, loss of function (LOF) (78.4%) mutations, and most disrupted the DNA-binding domain (58.8%). Six recurrent mutations were identified. Only two tumors had two mutations and there was no evidence for FOXA2 allelic loss. Mutation status was associated with tumor grade and not associated with survival outcomes. Methylation of the FOXA2 promoter region was highly variable. Most tumors expressed FOXA2 at both the mRNA and protein level. In those tumors with mutations, the majority of cases expressed both alleles. CONCLUSION FOXA2 is frequently mutated in EEC. The pattern of FOXA2 mutations and expression in tumors suggests complex regulation and a haploinsufficient or dominant-negative tumor suppressor function. In vitro studies may shed light on how mutations in FOXA2 affect FOXA2 pioneer and/or transcription factor functions in EEC.

Bariatric surgery as a means to decrease mortality in women with type I endometrial cancer — An intriguing option in a population at risk for dying of complications of metabolic syndrome

OBJECTIVE To estimate the cost-effectiveness and utility of a strategy of offering weight loss surgery (WLS) to women with low risk stage I endometrial cancer (EC) and BMI≥40kg/m(2). METHODS A modified Markov state transition model was designed to compare routine care to WLS for women with low risk stage I endometrioid EC, age<70, with a mean BMI 40. A time horizon of 15years was used to simulate the overall survival (OS) of 96,232 women treated from 1988-2010 from SEER*Stat data. To simulate the effects of WLS on OS, a hazard ratio (0.76, 95% CI 0.59-0.99) representing the OS improvement achieved from this intervention (derived from a prospective trial) was modeled. We assumed that 90% of women undergoing bariatric procedures would experience a reduction in BMI. We assumed that 5% of women not undergoing WLS would achieve weight loss to a BMI of 35. Costs of treatment for obesity-related chronic diseases and quality of life (QOL)-related utilities were modeled from published reports. RESULTS The mean cost-effectiveness for each strategy was:

Management of a rapidly enlarging new adnexal mass: a rare case of desmoplastic small round cell tumor of the ovary arising in pregnancy

69,295 and 8.10 quality-adjusted life years (QALYs) for routine care versus

Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers: Neff et al.

100,675 and 9.30 QALYs for WLS. WLS had an incremental cost-effectiveness ratio (ICER) of

Recurrent low grade serous ovarian cancer in a 20 year old woman: A case from the Ohio State University College of Medicine

26,080/QALY compared to routine care. At a willingness to pay threshold of

Perceptions of weight management counseling among gynecologic cancer survivors: opportunities for enhancing survivorship care

50,000/QALY, WLS was the strategy of choice in 100% of simulations. CONCLUSIONS WLS is a potentially cost-effective intervention in women with low risk, early stage EC, at least in part due to improved quality of life with weight reduction.

Are gynecologic oncology patients interested in weight loss surgery

Background Desmoplastic small round cell tumor (DSRCT) is an extremely rare sarcomatous tumor, which is most commonly seen in men. Clinicians managing a patient with a rapidly enlarging mass in pregnancy should be aware of the risk for malignancy. Case A 31-year-old woman was found to have a newly enlarged ovarian mass in the second trimester. She subsequently underwent a laparotomy for removal, with chemotherapy for presumed poorly differentiated ovarian malignancy. Ultimately she was diagnosed with a desmoplastic small round cell tumor of the ovary and had progression at time of delivery. Following cesarean delivery, she had a tumor reductive surgery. She has completed 12 cycles of intensive chemotherapy and is alive with disease at 14 months. Conclusion Care should be taken not to delay evaluation of a rapidly enlarging mass in pregnancy. While this tumor type is extremely rare, a malignancy in pregnancy must be ruled out in this clinical scenario.

Survivorship care and weight management: Assessing patient attitudes and preferences toward provider involvement.

FOXA2, a member of the forkhead family of DNA‐binding proteins, is frequently mutated in uterine cancers. Most of the mutations observed in uterine cancers are frameshifts and stops. FOXA2 is considered to be a driver gene in uterine cancers, functioning as a haploinsufficient tumor suppressor. The functional consequences of FOXA2 mutations, however, have not yet been determined. We evaluated the effects that frameshift mutations and a recurrent missense mutation have on FOXA2 transcriptional activity. Recurrent N‐terminal frameshifts resulted in truncated proteins that failed to translocate to the nucleus and have no transcriptional activity using an E‐cadherin/luciferase reporter assay. Protein abundance was reduced for the recurrent p.S169 W mutation, as was transcriptional activity. A C‐terminal frameshift mutation had increased FOXA2 levels evidenced by both Western blot and immunofluorescence. Given that FOXA2 is a recognized activator of E‐cadherin (CDH1) expression and E‐cadherins potential role in epithelial‐to‐mesenchymal transition in a wide range of cancer types, we tested the hypothesis that FOXA2 mutations in primary uterine cancer specimens would be associated with reduced CDH1 transcript levels. qRT‐PCR revealed significantly lower levels of CDH1 expression in primary tumors with FOXA2 mutations. Our findings in vitro and in vivo suggest that reduced transcriptional activity associated with FOXA2 mutations in uterine cancers is likely to contribute to protumorigenic changes in gene expression.

Functional characterization of recurrent FOXA2 mutations in endometrial cancer

A 20 year old with recurrent low-grade serous carcinoma (LGSC) is discussed. The differential diagnosis, pathology, epidemiology, treatment options are discussed. Focus on the molecular pathways of LGSC and the implications of the diagnosis on fertility are highlighted.