Jennifer K. Burzawa

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.

Prospective evaluation of insulin resistance among endometrial cancer patients

OBJECTIVE Obesity and estrogen are strong risk factors for endometrial cancer (EC). Whereas diabetes also increases the risk, little is known about related insulin resistance (IR). The purpose of this study was to determine the prevalence of IR in newly diagnosed EC patients. STUDY DESIGN EC patients from a large, metropolitan county were prospectively enrolled from 2005 to 2008. Fasting serum was analyzed for glucose and insulin. IR was defined as a history of diabetes or a quantitative insulin sensitivity check index (QUICKI) (1/[log fasting insulin + log fasting glucose]) value of less than 0.357. RESULTS Among 99 patients, diabetes was present in 30, and an abnormal QUICKI was found in 36 additional patients. Increased risk of IR was significantly associated with higher body mass index (P < .001), lower socioeconomic status (P = .007), and nulliparity (P = .029). CONCLUSION IR was highly prevalent in endometrial cancer patients, including nonobese women. Better characterization of metabolic risks in addition to obesity may provide avenues for targeted cancer prevention in the future.

Risk of Thromboembolic Disease in Patients Undergoing Laparoscopic Gynecologic Surgery

OBJECTIVE: To estimate the incidence of venous thromboembolism among patients undergoing gynecologic laparoscopy and characterize the risk of venous thromboembolism among patients with gynecologic malignancy. METHODS: Data were collected for patients who underwent laparoscopic gynecologic surgery from January 2000 to January 2009. Incidence of deep vein thrombosis (DVT) or pulmonary embolism diagnosed within 6 weeks of surgery was estimated. Fishers exact test was used to estimate the association between the presence of perioperative venous thromboembolism and categorical variables. RESULTS: Six (of 849) patients developed symptomatic venous thromboembolism (0.7%, 95% confidence interval: 0.024–1.44%). The median time to diagnosis of venous thromboembolism was postoperative day 15.5 (range, 1–41 days), median body mass index was 25.4 kg/m2 (range, 18.4–50 kg/m2), median operative time was 176 minutes (range, 53–358 minutes), and median estimated blood loss was 125 mL (range, 10–250 mL). Five of 430 (1.2%) patients with a history of gynecologic malignancy developed postoperative thromboembolic events. Venous thromboembolism was diagnosed in three of 662 (0.5%) patients undergoing intermediate complexity procedures and three of 106 (2.8%) patients undergoing high-complexity procedures. Three patients with venous thromboembolism (50%) had a history of at least one previous modality of cancer treatment before laparoscopy. One patient (17%) had DVT only, four (67%) had pulmonary emboli without an identified DVT, and one (17%) had both. There were no associated mortalities. CONCLUSION: The incidence of thromboembolism in patients undergoing low- and intermediate-complexity, minimally invasive surgery was low, even among patients with a gynecologic malignancy. Patients undergoing high-complexity, minimally invasive procedures may benefit from postoperative anticoagulation. LEVEL OF EVIDENCE: II

Use of social media to conduct a cross-sectional epidemiologic and quality of life survey of patients with neuroendocrine carcinoma of the cervix: a feasibility study.

OBJECTIVE To determine the feasibility of using social media to perform cross-sectional epidemiologic and quality-of-life research on patients with rare gynecologic tumors, we performed a survey of patients with neuroendocrine tumors of the cervix using Facebook. METHODS After approval from our Institutional Review Board, a support group of patients with neuroendocrine tumors of the cervix was identified on Facebook. Group members were asked to complete a survey comprising 84 questions evaluating clinical presentation; treatment; recurrence; quality of life; and sexual function. RESULTS The survey was posted for 30 days, during which 57 women responded from 8 countries across 4 continents treated at 51 centers. All respondents provided a detailed clinical and tumor history. The mean age was 38.5 years. The stage distribution was stage I, 36 patients (63%); II, 13 (23%); III, 2 (4%); and IV, 6 (11%). Forty-nine patients (86%) had small cell and 8 (14%) had large cell tumors. Forty-five of the respondents (79%) had completed primary therapy and were without evidence of disease. Five (9%) had recurrence, 3 (5%) had persistent disease after therapy, and 4 (7%) were still under treatment. Forty-one patients (72%) reported symptoms at time of presentation. Thirty-seven patients (65%) received multimodality primary therapy. Quality of life instruments demonstrated high scores for anxiety and a negative impact of anxiety and cancer on functional and emotional well-being. Sexual function scores did not differ significantly between respondents and the PROMIS reference population. CONCLUSIONS Use of a social media network to perform epidemiologic and quality of life research on patients with rare gynecologic tumors is feasible and permits such research to be conducted efficiently and rapidly.

Molecular pathogenesis of endometrial cancers in patients with Lynch syndrome

The authors hypothesized that Lynch syndrome (LS)‐associated endometrial cancer (EC) develops from morphologically normal endometrium that accumulates enough molecular changes to progress through a continuum of hyperplasia to carcinoma, similar to sporadic EC. The primary objective of the current study was to determine whether LS‐associated EC involves progression through a preinvasive lesion. The secondary objective was to identify molecular changes that contribute to endometrial carcinogenesis in patients with LS.

Prospective Study of Combined Colon and Endometrial Cancer Screening in Women With Lynch Syndrome: A Patient-Centered Approach

BACKGROUND Endometrial and colorectal cancers are the most common cancers in Lynch syndrome. Consensus guidelines recommend annual endometrial biopsy (EMB) and regular colonoscopies. We assessed the feasibility of concurrently performing EMB and colonoscopy and evaluated womens perception of pain, satisfaction, and acceptability. METHODS From July 2002 to December 2009, women who had a gene mutation for Lynch syndrome, met the Amsterdam II criteria, or had a high-risk situation that required screening were prospectively enrolled. After conscious sedation, the procedures were sequentially performed. Patients completed pre- and postprocedure questionnaires assessing pain, level of satisfaction, and acceptability. The Wilcoxon rank test and Mann-Whitney test were used to compare pain scores. RESULTS Forty-two women completed the study. Median age was 37 years (range, 25 to 73). Nineteen had previously had an EMB in the office setting. Women reported significantly lower median levels of pain in the combined procedure compared with previous office setting biopsies (P < .001). Regardless of parity, women reported significantly less pain for an EMB as part of the combined screen compared with an office EMB (parous, P = .003; nulliparous, P = .026). Women also reported a high level of satisfaction and more convenience in the combined procedure. All participants preferred combined to separately scheduled procedures and would recommend the combined procedure to their relatives. CONCLUSION Combined colon and endometrial cancer screening is a patient-centered approach that is feasible, acceptable, and may improve adherence to Lynch syndrome screening recommendations.

Lymphovascular space invasion portends poor prognosis in low-risk endometrial cancer

Objective The prognostic significance of lymphovascular space invasion (LVSI) in patients with early-stage endometrial cancer is not established. We sought to determine if LVSI status in patients with early-stage low-risk endometrial cancer correlates with recurrence and survival. Methods The records of all women who underwent hysterectomy for primary treatment of endometrial cancer from January 2006 through January 2011 at 1 academic institution were reviewed. Patients with grade 1 or 2 endometrioid histology, myometrial invasion less than 50%, and disease confined to the uterus (clinical International Federation of Obstetrics and Gynecology stage IA) were analyzed. Fisher exact test and the Wilcoxon rank-sum test were applied to compare patients with and without LVSI. Recurrence-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results Two hundred forty patients met the inclusion criteria. Forty (16.7%) had LVSI. Ninety-one patients (37.9%) underwent lymphadenectomy. Median tumor size was 30 mm in patients with and 26 mm in patients without LVSI (P = 0.150). Thirty patients (12.5%) received adjuvant therapy. Site of recurrence did not differ between patients with and without LVSI. Patients with LVSI were more likely to have myometrial invasion (P < 0.001), postoperative pathologic grade 2 disease (P < 0.001), to undergo lymphadenectomy (P = 0.049) and receive adjuvant therapy (P < 0.001). The 5-year cumulative incidence of recurrence was 3.8% in the no-LVSI group and 14.2% in the LVSI group (P = 0.053). The presence of LVSI was significantly associated with worse RFS (P = 0.002) and OS (P = 0.013). Conclusions Patients with low-risk endometrial cancer and LVSI have worse RFS and OS despite being more likely to undergo lymphadenectomy and adjuvant therapy.

Challenges in the diagnosis and management of cervical neuroendocrine carcinoma

Neuroendocrine carcinoma represents about 1% all cervical cancers accounting for 100–200 diagnoses annually in the USA. Although it is uncommon, it is an aggressive histologic subtype of this otherwise favorable disease. To date, there are no prospective studies or randomized trials specific to this disease to guide standard of care management. Published literature consists of small case series mostly describing single-institution experiences. The Society of Gynecologic Oncology and Gynecologic Cancer InterGroup have issued consensus guidelines about the treatment of this disease based on the existing retrospective literature and expert opinion. Ongoing research is focused on further clarifying the best treatment regimen and defining molecular alterations of these tumors that can be exploited by novel treatment mechanisms. The objective of this manuscript is to describe this entity, review the literature, summarize current treatment recommendations, and propose possible research efforts for women with neuroendocrine cervical cancer.

Relaxin Signaling in Uterine Fibroids

Uterine fibroid is the most common tumor of female reproductive organs. The role of relaxin signaling in leiomyoma development was analyzed. We used 23 matched pairs of leiomyoma and normal myometrium samples to compare the expression of relaxin family peptide receptors RXFP1 and RXFP2, caveolin 1, desmin, and steroid receptors and their cofactors, NCOR1 and NCOR2. The expression of RXFP1, evaluated by quantitative reverse transcription‐PCR, was downregulated in fibroid tissues. Relaxin or insulin‐like peptide 3 treatment suppressed transforming growth factor β‐induced phosphorylation of SMAD2 in rat leiomyoma ELT‐3 cells in vitro, suggesting a possible involvement of relaxins in the etiology of leiomyoma.

Combination therapy with topotecan, paclitaxel, and bevacizumab improves progression-free survival in recurrent small cell neuroendocrine carcinoma of the cervix

OBJECTIVES To assess if the combination of topotecan, paclitaxel, and bevacizumab (TPB) was active in recurrent SCCC and to compare the survival of patients with SCCC who received TPB to a group of women with SCCC who did not receive this regimen. METHODS We retrospectively analyzed women with recurrent SCCC who received chemotherapy as primary therapy. Women treated with TPB for first recurrence were compared to women treated with non-TPB chemotherapy. RESULTS Thirteen patients received TPB, and 21 received non-TPB chemotherapy, most commonly platinum with or without a taxane. Median progression-free survival (PFS) was 7.8months for TPB and 4.0months for non-TPB regimens (hazard ratio [HR] 0.21, 95% CI 0.09-0.54, P=0.001). Median overall survival (OS) was 9.7months for TPB and 9.4months for non-TPB regimens (HR 0.53, 95% CI 0.23-1.22, P=0.13). Eight women (62%) who received TPB versus four (19%) who received non-TPB regimens were on treatment for >6months (P=0.02), and four patients (31%) in the TPB group versus two (10%) in the non-TPB group were on treatment for >12months (P=0.17). In the TPB group, three patients (23%) had complete response, two (15%) had complete response outside the brain with progression in the brain, 3 (23%) had a partial response, 2 (15%) had stable disease, and 3 (23%) had progressive disease. CONCLUSIONS These findings indicate that TPB for recurrent SCCC significantly improved PFS over non-TPB regimens, and trends towards improved OS. Furthermore, a significant number of patients had a durable clinical benefit.