Michaela Onstad

Addressing the Role of Obesity in Endometrial Cancer Risk, Prevention, and Treatment

In sharp contrast to many other cancer types, the incidence and mortality of endometrial cancer continue to grow. This unfortunate trend is, in no small part, a result of the worldwide obesity epidemic. More than half of endometrial cancers are currently attributable to obesity, which is recognized as an independent risk factor for this disease. In this review, we identify the molecular mechanisms by which obesity and adipose tissue contribute to the pathogenesis of endometrial cancer. We further discuss the impact of obesity on the clinical management of the disease and examine the development of rational behavioral and pharmaceutical interventions aimed at reducing endometrial cancer risk, improving cancer outcomes, and preserving fertility in an increasingly younger population of patients with endometrial cancer.

Benign Breast Disorders

Full understanding of benign breast disease should enable the obstetrician-gynecologist to appropriately evaluate symptoms, distinguish between benign and malignant processes, determine which benign breast lesions require surgical management, and identify patients who are at increased risk of developing breast cancer. This article reviews nipple discharge, breast pain, palpable breast masses, adolescent breast disorders, inflammatory lesions (including mastitis and breast abscesses), and benign breast abnormality detected on imaging and biopsy. Each topic provides a review of the clinical presentation, a discussion of the appropriate workup, and a further description of specific etiology within each category.

Hereditary breast cancer: an update on risk assessment and genetic testing in 2015

The last 5 years have brought significant innovation and advancement in the genetics of breast cancer. This clinical opinion aims to summarize and update current approaches to the care of women at risk for a hereditary predisposition to breast cancer. Implications of the BRCA mutation and several other hereditary syndromes will be discussed. Risk assessment and criteria for referral to cancer genetic professionals as well as high-risk screening and prophylactic options will be reviewed. Finally, the newly available genetic cancer panels and implications of mutations in some of these lesser known genes will be discussed. As the field of cancer genetics continues to evolve, the education of medical students, residents, and faculty will be paramount to identify appropriate candidates for genetic counseling and testing in conjunction with cancer genetic professionals.

The impact of mastectomy type on the Female Sexual Function Index (FSFI), satisfaction with appearance, and the reconstructed breast’s role in intimacy

BackgroundAs mastectomy rates increase and overall survival for early breast cancer improves, a better understanding of the long-term consequences of mastectomy is needed. We sought to explore the correlation of specific mastectomy type with the Female Sexual Function Index (FSFI), body image satisfaction, and the reconstructed breast’s role in intimacy.MethodsThis study is a secondary analysis of a cross-sectional survey including a retrospective chart review. Patients at least one year from primary surgery were invited to complete the survey between 2012 and 2014. Baseline characteristics and survey responses were compared between three mastectomy groups: total/modified radical (TMRM), skin-sparing (SSM), and nipple-sparing (NSM). All patients underwent reconstruction.ResultsOf 453 invited, 268 (59%) completed the survey. Sixty underwent mastectomy with reconstruction: 16 (27%) TMRM, 36 (60%) SSM, and 8 (13%) NSM. There were no significant differences in median total FSFI scores between groups, yet median FSFI scores for the NSM group indicated sexual dysfunction. After adjusting for receipt of chemotherapy and/or radiation, NSM had the lowest median desire score. There was a trend for the NSM group to be the least satisfied with postoperative appearance, but also more likely to report that the chest was “often” caressed during intimacy. However, nearly 40% of the NSM group reported that caress of the reconstructed breast was unpleasant.ConclusionNSM offers patients the greatest opportunity for preservation of their native skin envelope and potentially enhanced cosmetic outcome, but our results did not demonstrate superior sexual function or body image outcomes in this group. By highlighting surgical consequences of mastectomy preoperatively, surgeons may better set realistic patient expectations regarding both aesthetic and functional outcomes after breast cancer surgery. With clearer expectations, patients will have a better opportunity for improved surgical decision-making.

Endometrial cancers with activating kras mutations have activated estrogen signaling and paradoxical response to MEK inhibition

Objectives The aims of this study were to determine if activating KRas mutation alters estrogen signaling in endometrial cancer (EC) and to explore the potential therapeutic impact of these alterations. Methods The Cancer Genome Atlas was queried for changes in estrogen-regulated genes in EC based on KRas mutation status. In vitro studies were conducted to evaluate estrogen receptor &agr; (ER&agr;) phosphorylation changes and related kinase changes in KRas mutant EC cells. The resulting effect on response to MEK inhibition, using trametinib, was evaluated. Immunohistochemistry was performed on KRas mutant and wild-type EC tumors to test estrogen signaling differences. Results KRas mutant tumors in The Cancer Genome Atlas showed decreased progesterone receptor expression (P = 0.047). Protein analysis in KRas mutant EC cells also showed decreased expression of ER&agr; (P < 0.001) and progesterone receptor (P = 0.001). Although total ER&agr; is decreased in KRas mutant cells, phospho-ER&agr; S118 was increased compared with wild type. Treatment with trametinib in KRas mutant cells increased phospho-ER&agr; S167 and increased expression of estrogen-regulated genes. While MEK inhibition blocked estradiol-stimulated phosphorylation of ERK1/2 and p90RSK in wild-type cells, phospho-ERK1/2 and phospho-p90RSK were substantially increased in KRas mutants. KRas mutant EC tumor specimens showed similar changes, with increased phospho-ER&agr; S118 and phospho-ER&agr; S167 compared with wild-type EC tumors. Conclusions MEK inhibition in KRas mutant cells results in activation of ER signaling and prevents the abrogation of signaling through ERK1/2 and p90RSK that is achieved in KRas wild-type EC cells. Combination therapy with MEK inhibition plus antiestrogen therapy may be necessary to improve response rates in patients with KRas mutant EC.

Abstract 1535: Omentin: A novel adipokine linking visceral obesity to ovarian cancer progression

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Advanced stage serous ovarian cancer metastasizes preferentially to the omentum, which is a major site of intra-abdominal fat accumulation, suggesting that the omental microenvironment is a favorable niche for ovarian cancer cells. The 5-year survival drops to below 50% for the cancer cases that spread beyond the pelvis to the omentum. It has also become apparent that obesity contributes to a poor clinical outcome. The mechanisms by which omental adipose tissue promotes tumor growth and disease progression are not entirely clear. Using transcriptome profiling analysis on the microdissected adipose tissue from patients with benign gynecologic diseases and from patients with advanced high-grade serous ovarian cancer (HGSOC), we found that a novel adipokine called omentin (Intestinal Lactoferrin Receptor ITLN1) was significantly down-regulated in ovarian cancer associated adipose tissue compared with the normal adipose tissue. Survival correlation studies demonstrated that patients with serum ITLN1 levels of >350 ng/mL at the time of first treatment experienced longer survival times than those with lower levels of ITLN1. We showed that ITLN1 suppressed the ovarian cancer cell migration ability and invasion potential in vitro. To delineate the underlying molecular mechanisms, RNA sequencing and pathway analyses were performed on ITLN1 treated ovarian cancer cells and we identified MMP1 as one of the potential mediators. It has been shown that MMP1 expression was induced by lactoferrin, which is abundant in ascites. We hypothesized ITLN1 could abrogate the effect of lactoferrin on ovarian cancer motility and invasion potential. Our preliminary data suggested that secreted ITLN1 may sequester lactoferrin in the ascites, thereby preventing it from binding to the low-density-lipoprotein-receptor-related-protein-1 (LRP-1) on ovarian cancer cell surface and thus inactivate downstream signaling pathways that control MMP1 expression. The study provides the first evidence that ovarian cancer cells modify the visceral adipose tissue through down-regulation of omentin to facilitate their growth in the omental microenvironment. Citation Format: Chi Lam Au Yeung, Ngai Na Co, Michaela Onstad, Tsz-Lun Yeung, Cecilia S. Leung, Rosemarie Schmandt, Karen H. Lu, Samuel C. Mok. Omentin: A novel adipokine linking visceral obesity to ovarian cancer progression. [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 1535. doi:10.1158/1538-7445.AM2015-1535

Abstract 4887: Omentin: A novel adipokine in the omental microenvironment associated with ovarian cancer progression

Advanced stage serous ovarian cancer metastasizes preferentially to the omentum, which is a well-vascularized fold of peritoneal tissue and is a major site of intra-abdominal fat accumulation, suggesting that the omental microenvironment is a favorable niche for ovarian cancer cells. The 5-year survival drops to below 50% for the cancer cases that spread beyond the pelvis to the omentum. It has also become apparent that obesity contributes to a poor clinical outcome. The mechanisms by which omental adipose tissue promotes tumor growth and disease progression are not entirely clear. Using transcriptome profiling analysis on the microdissected adipose tissue from patients with benign gynecologic diseases and from patients with advanced high-grade serous ovarian cancer (HGSOC), we identified a gene signature for ovarian cancer associated omental adipose tissue, suggesting that alteration of these genes in the ovarian cancer associated omental adipose tissue may generate a permissive microenvironment to support ovarian cancer growth. Among genes that are significantly up- or down-regulated in ovarian cancer associated adipose tissue compared with the normal adipose tissue, we seek to focus on evaluating the role of omentin (Intestinal Lactoferrin Receptor ITLN1) in ovarian cancer progression since it is a novel adipokine that is predominantly expressed and secreted by visceral adipose tissue and is barely detectable in subcutaneous fats. Our data showed for the first time that omentin was expressed predominantly by the mesothelial cells covering the visceral adipose tissue but not by other cell types in the omental adipose tissue. Interestingly, we showed that circulating omentin level is significantly lower in patients with HGSOC compared with those in the BMI matched healthy individuals. In addition, using monolayer culture models, we demonstrated that omentin suppressed ovarian cancer motility and invasion potential directly and ovarian cancer growth only in the presence of adipocytes. We also showed that omentin can increase insulin-dependent glucose up-take in adipocytes and omentin expression can be down-regulated by co-culturing with ovarian cancer cells and in the presence of TNF-α. The study provides the first evidence that ovarian cancer cells modify the visceral adipose tissue through down-regulation of omentin to facilitate their growth in the omental microenvironment. Citation Format: Chi Lam Au Yeung, Ngai Na Co, Michaela Onstad, Tsz-Lun Yeung, Cecilia S. Leung, Rosemarie Schmandt, Karen H. Lu, Samuel C. Mok. Omentin: A novel adipokine in the omental microenvironment associated with ovarian cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4887. doi:10.1158/1538-7445.AM2014-4887