Anuj Suri

Factors associated with an increased risk of recurrence in women with ovarian granulosa cell tumors

INTRODUCTION Studies demonstrate that patient factors such as race, body composition, medical co-morbidities, and medications may be associated with cancer related outcomes independent of the patients malignancy and related therapies for the cancer. The goal of this study is to determine demographic and prognostic factors affecting disease recurrence in women with early stage ovarian granulosa cell tumors (GCT). MATERIALS AND METHODS This study used a dual-institution retrospective analysis of women diagnosed with GCT between 1995 and 2010. Demographics including age, race, body mass index (BMI), stage, diabetes (DM), adjuvant treatment, and progression-free survival (PFS) were extracted. Hazard ratios for recurrence were estimated by univariate and multivariate Cox regression models. RESULTS One hundred and four women were identified with a median age of 50 years (range 12-87 years). Fifty-five (58.5%) were Caucasian, 29 (30.9%) African American, and 10 (10.2%) others. Median BMI was 29 kg/m(2) (range 12-57 kg/m(2)). Twenty-one patients had DM. The majority of women had clinical stage I disease (95.0%), 5 (6.4%) had stage II/III disease, and 5 were unstaged. In univariate analysis among early stage disease, DM showed the strongest association with recurrence (HR=3.37, 95% CI=1.38-8.20). In multivariate analysis, DM was associated with an HR of 3.19 for recurrence (95% CI=1.08-9.44). CONCLUSIONS Our results emphasize that diabetes is one of the strongest predictors of recurrent disease in patients with ovarian GCTs. As this disease is characterized by long disease-free intervals prior to recurrence, this may serve as a potential chemopreventive strategy in patients felt to be at higher risk for recurrence.

Pre-operative imaging with CA125 is a poor predictor for granulosa cell tumors

OBJECTIVE To determine the radiographic characteristics of ovarian granulosa cell tumors (GCTs) and to evaluate the use of CA125 levels >35 in combination with imaging as an algorithm for preoperative diagnosis. METHODS A retrospective analysis of women from two academic medical centers who were diagnosed with ovarian GCT between January 1998 and August 2012 was conducted. Clinical data included tumor appearance on pre-operative imaging and CA125 levels. Ovarian cysts were defined as complex if imaging exhibited multicystic areas, hemorrhagic, solid, or cystic and solid components. A CA125 level >35 was abnormal. RESULTS One hundred and fifteen women were diagnosed with GCTs, of whom 63 underwent pre-operative imaging. Median age at surgery was 46 years (12-87). Forty women had preoperative ultrasounds, 43 had CT scans and 20 underwent both modalities. GCTs were almost exclusively classified as complex cysts in 62 (98%) cases. The most common morphology was solid and cystic (n=44 (70%)). Forty-four (70%) patients had tumors >10 cm. Forty-two patients had a pre-operative CA125 performed. Eighteen (43%) patients had complex masses and CA125 >35. Twenty-three (55%) had CA125 <35 with a complex mass, and one (2%) had a unilocular cyst with a CA125 >35. CONCLUSIONS In this study, there was a near equal distribution of patients with complex masses and CA125 levels > or <35. If established strategies to predict malignancy are applied to GCTs, we will frequently fail to make the diagnosis pre-operatively. Additional research is necessary to generate an appropriate algorithm to guide pre-operative referral to a gynecologic oncologist.

The effect of celecoxib on tumor growth in ovarian cancer cells and a genetically engineered mouse model of serous ovarian cancer

Our objective was to evaluate the effect of the COX-2 inhibitor, celecoxib, on (1) proliferation and apoptosis in human ovarian cancer cell lines and primary cultures of ovarian cancer cells, and (2) inhibition of tumor growth in a genetically engineered mouse model of serous ovarian cancer under obese and non-obese conditions. Celecoxib inhibited cell proliferation in three ovarian cancer cell lines and five primary cultures of human ovarian cancer after 72 hours of exposure. Treatment with celecoxib resulted in G1 cell cycle arrest, induction of apoptosis, inhibition of cellular adhesion and invasion and reduction of expression of hTERT mRNA and COX-2 protein in all of the ovarian cancer cell lines. In the KpB mice fed a high fat diet (obese) and treated with celecoxib, tumor weight decreased by 66% when compared with control animals. Among KpB mice fed a low fat diet (non-obese), tumor weight decreased by 46% after treatment with celecoxib. In the ovarian tumors from obese and non-obese KpB mice, treatment with celecoxib as compared to control resulted in decreased proliferation, increased apoptosis and reduced COX-2 and MMP9 protein expression, as assessed by immunohistochemistry. Celecoxib strongly decreased the serum level of VEGF and blood vessel density in the tumors from the KpB ovarian cancer mouse model under obese and non-obese conditions. This work suggests that celecoxib may be a novel chemotherapeutic agent for ovarian cancer prevention and treatment and be potentially beneficial in both obese and non-obese women.

Discussion: ‘Ovarian epithelial carcinoma with pelvic endometriosis,’ by Wang et al

In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Wang S, Qui L, Lang JH, et al. Clinical analysis of ovarian epithelial carcinoma with coexisting pelvic endometriosis.

Abstract 4663: The cyclooxygenase-2 inhibitor, celecoxib, suppresses proliferation and induces apoptosis in endometrial cancer cells

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL INTRODUCTION: Obesity is associated with increased risk and worse outcomes for women with endometrial cancer. Inflammation may play a critical role in obesity-driven cancers; thus, the anti-inflammatory effects of COX-2 inhibitors may be a novel treatment strategy that is particularly beneficial in endometrial cancer patients. As a result, our objective was to evaluate the effect of COX-2 inhibitors on proliferation and apoptosis in endometrial cancer cell lines. METHODS: Two endometrial cancer cell lines (ECC-1 and Ishikawa) were used in these studies. Cell proliferation was assessed by MTT assay after exposure to the COX-2 inhibitor, celecoxib. Cell cycle progression was evaluated by flow cytometry. Apoptosis was assessed by ELISA for caspase-3. hTERT mRNA expression was assessed by real-time PCR. Western immunoblotting was performed to determine the effect of celecoxib on COX-2 expression in the endometrial cancer cell lines. RESULTS: Celecoxib significantly inhibited proliferation in a dose-dependent manner in both endometrial cancer cell lines (IC50 5-10 μM for ECC-1, 10-20 μM for Ishikawa; p<0.005 for each). Treatment with celecoxib resulted in G1 cell cycle arrest, induction of apoptosis and inhibition of hTERT mRNA expression. Western immunoblot analysis demonstrated that celecoxib treatment suppresses COX-2 expression in both endometrial cancer cell lines. CONCLUSION: Celecoxib potently inhibits cell growth via G1 arrest, decreases telomerase activity and increases apoptotic cell death in endometrial cancer cells. This work suggests that celecoxib may be a novel chemotherapeutic agent for endometrial cancer prevention and treatment, especially given the interplay between obesity, inflammation and cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4663. doi:1538-7445.AM2012-4663

Abstract 504: Metformin potently inhibits cell proliferation, adhesion and invasion in ovarian cancer cells

ABSTRACT Objectives: Metformin is an anti-diabetic drug that has been shown to have anti-tumorgenic effects by behaving as a novel mTOR inhibitor. Metformin has been shown to suppress cancer cell growth, but little is known of its potential to halt metastatic spread. Thus, our goal was to assess the effect of metformin on proliferation, adhesion and invasion in ovarian cancer cell lines. Methods: Four ovarian cancer cell lines, SKOV3, CAOV3, OVCAR3 and IGROV1 were used. Cell proliferation was assessed by MTT assay after exposure to metformin. Cell cycle progression was evaluated by flow cytometry. Apoptosis was assessed by Annexin V-FITC assay. hTERT expression was determined by real-time RT-PCR. Western immunoblotting was performed to determine the expression of the downstream targets of metformin, including AMPK and the ribosomal protein S6. Inhibition of adhesion and invasion by metformin was assessed by in vitro adhesion assay and ChemoTx® invasion assay. Results: Metformin potently inhibited growth in a dose-dependent manner in all four ovarian cancer cell lines (IC 50 of 0.1-1 mM) (p=0.00001-0.0121). Treatment with metformin resulted in G1 arrest, induction of apoptosis and decreased hTERT expression. Western immunoblot analysis demonstrated that metformin induced phosphorylation of AMPK, its immediate downstream mediator, and decreased phosphorylation of the S6 protein, a key target of the mTOR pathway, within 24 hours of exposure. Metformin inhibited cellular adhesion in the ovarian cancer cell lines by 10-23% at 1 mM (p=0.04-0.00001) and 25-35% at 10 mM (p=0.05-0.00001). In addition, metformin decreased invasion by 7-21% at 1 mM (p=0.03-0.0009) and 29-42% at 10 mM (p=0.03-0.0012). Conclusions: We report that metformin is a potent inhibitor of cell proliferation and exhibits anti-metastatic effects in ovarian cancer cells. Thus, metformin may have potential as a targeted chemotherapeutic agent in the treatment of ovarian cancer. More work is needed to determine if metformin will be universally beneficial in all ovarian cancer patients versus selectively efficacious in a subset of ovarian cancer patients, such as those women who are obese and/or diabetic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 504. doi:1538-7445.AM2012-504

Discussion: 'Surgical staging in early ovarian carcinoma' by Garcia-Soto et al.

In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research.