David A. Iglesias

Understanding obesity and endometrial cancer risk: opportunities for prevention

Worldwide, obesity has become a major public health crisis. Overweight and obesity not only increase the risk of cardiovascular disease and type-2 diabetes mellitus but also are now known risk factors for a variety of cancer types. Among all cancers, increasing body mass index is associated most strongly with endometrial cancer incidence and death. The molecular mechanisms underlying how adipose tissue and obesity contribute to the pathogenesis of endometrial cancer are becoming better understood and have revealed a number of rational strategies, both behavioral and pharmaceutical, for the prevention of both primary and recurrent disease.

Another Surprise from Metformin: Novel Mechanism of Action via K-Ras Influences Endometrial Cancer Response to Therapy

Metformin is an oral biguanide commonly used for the treatment of type II diabetes and has recently been demonstrated to possess antiproliferative properties that can be exploited for the prevention and treatment of a variety of cancers. The mechanisms underlying this effect have not been fully elucidated. Using both in vitro and in vivo models, we examined the effects of metformin on endometrial tumors with defined aberrations in the PI3K/PTEN/mTOR and MAPK signaling pathways to understand metformin mechanism of action and identify clinically useful predictors of response to this agent. In vitro assays of proliferation, cytotoxicity, and apoptosis were used to quantify the effects of metformin on endometrial cancer cell lines with mutations in the PI3K/PTEN/mTOR and MAPK signaling pathways. The in vivo effects of oral metformin on tumor progression were further examined using xenograft mouse models of endometrial cancer. K-Ras localization was analyzed by confocal microscopy using GFP-labeled oncogenic K-Ras and by immunoblot following subcellular fractionation. Metformin inhibited cell proliferation, induced apoptosis, and decreased tumor growth in preclinical endometrial cancer models, with the greatest response observed in cells harboring activating mutations in K-Ras. Furthermore, metformin displaces constitutively active K-Ras from the cell membrane, causing uncoupling of the MAPK signaling pathway. These studies provide a rationale for clinical trials using metformin in combination with PI3K-targeted agents for tumors harboring activating K-Ras mutations, and reveal a novel mechanism of action for metformin. Mol Cancer Ther; 12(12); 2847–56. ©2013 AACR.

Role of Minimally Invasive Surgery in Staging of Ovarian Cancer

Opinion statementSince the introduction of laparoscopy and robotic surgery in gynecologic practice in the last several decades, use of these minimally invasive surgical techniques has increased dramatically. The role of minimally invasive surgical techniques continues to expand because they offer reduced intraoperative and postoperative complications, less intraoperative blood loss, and a shorter postoperative recovery. Despite initial concerns about the use of minimally invasive surgery in gynecologic oncology, this approach has been shown to be safe and effective in the management of uterine and cervical cancer, and minimally invasive surgical management of these malignancies is now commonplace. Concerns remain regarding the use of minimally invasive surgery for the staging and management of ovarian cancer, including concerns regarding the adequacy of abdominal exploration and staging with minimally invasive approaches compared to traditional laparotomy and the risks and implications of intra-operative tumor cyst rupture and port-site metastases. However, several case series, retrospective reviews, and case–control studies have demonstrated that minimally invasive surgery is both safe and effective for the staging of borderline ovarian tumors and early-stage epithelial ovarian cancer when performed by a trained gynecologic oncologist. Data to support the role of minimally invasive surgery for advanced epithelial ovarian cancer are scant and use of minimally invasive surgery in this setting is not recommended.

The Search Continues

Objective PI3K/mammalian target of rapamycin (mTOR) pathway aberrations occur in 40% to 80% of endometrial cancer. Prior studies suggest KRAS mutations are associated with resistance to mTOR inhibitors in solid tumors. The objective of this study was to determine if biomarker expression in the PI3K/mTOR pathway or KRAS mutations would predict response to therapy with everolimus, an mTOR inhibitor. Methods Specimens from a phase II study of everolimus in recurrent endometrioid endometrial cancer were utilized. The primary end point was clinical benefit rate (CBR: objective response and nonprogression at 20 weeks). Correlative studies evaluating PTEN expression and phospho-S6 ribosomal protein (pS6rp) status by immunohistochemistry and KRAS mutational analysis were performed. Results Six of 28 evaluable patients achieved prolonged stable disease (SD) at 20 weeks (CBR, 21%). Loss of PTEN expression did not predict CBR (P = 0.62) with a positive predictive value (PPV) of 0.13. Five (83%) of 6 patients with SD maintained PTEN expression. Neither pS6rp expression (P = 0.65) nor KRAS mutation (P = 0.99) predicted CBR; the PPV was 0.14 for each. Eighty percent (4/5) of those with SD were KRAS wild type. Combined analysis of pS6rp expression and KRAS mutation provided 100% PPV (95% confidence interval, 39.6%–100%), suggesting no chance of CBR for these individuals with 100% specificity (95% confidence interval, 46.3%–100%). Conclusions S6rp phosphorylation, loss of PTEN expression, and presence of KRAS mutations alone did not correlate with CBR. However, positive pS6rp staining combined with KRAS mutation performed with 100% PPV and specificity to predict nonresponse. Identifying patients who will not benefit from mTOR inhibitors can direct therapy and reduce exposure to agents that add toxicity without clinical benefit.

The search continues: looking for predictive biomarkers for response to mammalian target of rapamycin inhibition in endometrial cancer.

Objective PI3K/mammalian target of rapamycin (mTOR) pathway aberrations occur in 40% to 80% of endometrial cancer. Prior studies suggest KRAS mutations are associated with resistance to mTOR inhibitors in solid tumors. The objective of this study was to determine if biomarker expression in the PI3K/mTOR pathway or KRAS mutations would predict response to therapy with everolimus, an mTOR inhibitor. Methods Specimens from a phase II study of everolimus in recurrent endometrioid endometrial cancer were utilized. The primary end point was clinical benefit rate (CBR: objective response and nonprogression at 20 weeks). Correlative studies evaluating PTEN expression and phospho-S6 ribosomal protein (pS6rp) status by immunohistochemistry and KRAS mutational analysis were performed. Results Six of 28 evaluable patients achieved prolonged stable disease (SD) at 20 weeks (CBR, 21%). Loss of PTEN expression did not predict CBR (P = 0.62) with a positive predictive value (PPV) of 0.13. Five (83%) of 6 patients with SD maintained PTEN expression. Neither pS6rp expression (P = 0.65) nor KRAS mutation (P = 0.99) predicted CBR; the PPV was 0.14 for each. Eighty percent (4/5) of those with SD were KRAS wild type. Combined analysis of pS6rp expression and KRAS mutation provided 100% PPV (95% confidence interval, 39.6%–100%), suggesting no chance of CBR for these individuals with 100% specificity (95% confidence interval, 46.3%–100%). Conclusions S6rp phosphorylation, loss of PTEN expression, and presence of KRAS mutations alone did not correlate with CBR. However, positive pS6rp staining combined with KRAS mutation performed with 100% PPV and specificity to predict nonresponse. Identifying patients who will not benefit from mTOR inhibitors can direct therapy and reduce exposure to agents that add toxicity without clinical benefit.

Pelvic Exenteration: Impact of age on surgical and oncologic outcomes

OBJECTIVE To evaluate whether preoperative age impacts surgical outcomes, complication rates, and/or recurrence in women undergoing pelvic exenteration. METHODS All women who underwent a pelvic exenteration for any gynecologic indication at our institution from 1993 to 2010 were included. Women were stratified into groups based on age in years (young: ≤ 50, middle: 51-64, and senior: ≥ 65). Baseline characteristics, surgical outcomes, early (<60 days) and late (≥ 60 days) postoperative complications, and recurrence/survival outcomes were ascertained. Fishers exact test or Kruskal-Wallis test was performed. Kaplan-Meier survival curves were compared. RESULTS 161 patients were included (58 young, 62 in the middle, and 41 senior). Women in the young group predominately had a diagnosis of cervical cancer (82.8%) while women in the senior group primarily had a diagnosis of vulvar or vaginal cancer (70.7%). Senior women were also more likely to have hypertension (p < 0.0001) and pulmonary disease (p = 0.040). Operative time was significantly shorter for women in the senior group (8.5h) compared with the middle (9.5h) and young group (10.1h) (p = 0.0089). There were no significant differences in early or late complications when stratified by age. The overall survival did not differ between age groups (p = 0.3760). CONCLUSION Although hypertension and pulmonary disease were more frequent in the senior age group, duration of surgery, blood loss, length of hospital stay and complication rates did not increase with age. Advanced chronological age should not be considered a contraindication to a potentially curative surgical procedure.

The effect of body mass index on surgical outcomes and survival following pelvic exenteration

OBJECTIVE We sought to evaluate whether preoperative body mass index (BMI) impacts surgical outcomes, complication rates, and/or recurrence rates in women undergoing pelvic exenteration. METHODS All women who underwent pelvic exenteration for gynecologic indications at our institution from 1993 through 2010 were included. Women were stratified into 3 groups based on BMI. Baseline characteristics, surgical outcomes, early (<60 days) and late (≥ 60 days) postoperative complications, and recurrence/survival outcomes were collected. Multivariate logistic regression analyses were performed. Kaplan-Meier survival curves were compared using log-rank test. RESULTS 161 patients were included (59 normal weight, 44 overweight, 58 obese). Median follow-up times were 22, 29, and 25 months. Most patients underwent total pelvic exenteration (68%); 64.6% had a vaginal reconstruction. On multivariate analysis, both overweight and obese patients had a higher risk of early superficial wound separation compared to normal weight patients - OR 10.74 (3.33-34.62, p<0.001) and OR 4.35 (1.40-13.52, p=0.011), respectively. Length of surgery was significantly longer for overweight (9.6h, OR 1.26, 1.02-1.55, p=0.032) and obese (10.1h, OR 1.24, 1.04-1.47, p=0.014) patients than for normal weight patients (8.7h). Late postoperative complications for patients in the normal weight, overweight, and obese groups were 47.5%, 45.5%, and 43.1% (p=0.144). There were no differences in time to recurrence (p=0.752) or overall survival (p=0.103) between groups. CONCLUSION Although operative times were longer and risk for superficial wound separation was significantly higher, pelvic exenteration appears to be feasible and safe in overweight and obese women with overall complication rates and survival outcomes comparable to normal weight women.

Successful incorporation of robotic surgery into gynecologic oncology fellowship training

BACKGROUND The increasing role of robotic surgery in gynecologic oncology may impact fellowship training. The purpose of this study was to review the proportion of robotic procedures performed by fellows at the console, and compare operative times and lymph node yields to faculty surgeons. METHODS A prospective database of women undergoing robotic gynecologic surgery has been maintained since 2008. Intra-operative datasheets completed include surgical times and primary surgeon at the console. Operative times were compared between faculty and fellows for simple hysterectomy (SH), bilateral salpingo-oophorectomy (BSO), pelvic (PLND) and paraaortic lymph node dissection (PALND) and vaginal cuff closure (VCC). Lymph nodes counts were also compared. RESULTS Times were recorded for 239 SH, 43 BSOs, 105 right PLNDs, 104 left PLNDs, 34 PALND and 269 VCC. Comparing 2008 to 2011, procedures performed by the fellow significantly increased; SH 16% to 83% (p<0.001), BSO 7% to 75% (p=0.005), right PLND 4% to 44% (p<0.001), left PLND 0% to 56% (p<0.001), and VCC 59% to 82% (p=0.024). Console times (min) were similar for SH (60 vs. 63, p=0.73), BSO (48 vs. 43, p=0.55), and VCC (20 vs. 22, p=0.26). Faculty times (min) were shorter for PLND (right 26 vs. 30, p=0.04, left 23 vs. 27, p=0.02). Nodal counts were not significantly different (right 7 vs. 8, p=0.17 or left 7 vs. 7, p=0.87). CONCLUSIONS Robotic surgery can be successfully incorporated into gynecologic oncology fellowship training. With increased exposure to robotic surgery, fellows had similar operative times and lymph node yields as faculty surgeons.

Loss of LKB1 in high-grade endometrial carcinoma

Liver kinase B1 (LKB1) is a serine/threonine kinase that functions as a tumor suppressor and regulates cell polarity, proliferation, and metabolism. Mutations in LKB1 are associated with Peutz‐Jeghers syndrome as well as sporadic cervical and lung cancers. Although LKB1‐null mice develop invasive endometrial cancers, the role and regulation of LKB1 in the pathogenesis of human endometrial cancer are not well defined and are the focus of these studies.

Loss of LKB1 in high-grade endometrial carcinoma: LKB1 is a novel transcriptional target of p53

Liver kinase B1 (LKB1) is a serine/threonine kinase that functions as a tumor suppressor and regulates cell polarity, proliferation, and metabolism. Mutations in LKB1 are associated with Peutz‐Jeghers syndrome as well as sporadic cervical and lung cancers. Although LKB1‐null mice develop invasive endometrial cancers, the role and regulation of LKB1 in the pathogenesis of human endometrial cancer are not well defined and are the focus of these studies.