Fernanda Musa

An analysis of patients with bulky advanced stage ovarian, tubal, and peritoneal carcinoma treated with primary debulking surgery (PDS) during an identical time period as the randomized EORTC-NCIC trial of PDS vs neoadjuvant chemotherapy (NACT)

OBJECTIVE The recent EORTC-NCIC randomized trial comparing primary debulking surgery (PDS) to neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian carcinoma (EOC) reported a median progression-free survival (PFS) of 12 months and overall survival (OS) of 30 months for both arms. Due to the equivalent survival and decreased morbidity with NACT, many now consider it the preferred approach. We analyzed the outcomes of patients treated with PDS at our institution during the same time period in which the EORTC-NCIC trial was conducted, using identical inclusion criteria. METHODS We identified all patients undergoing primary treatment for advanced EOC at our institution from 9/98-12/06. Study inclusion and exclusion criteria were identical to those of the EORTC-NCIC trial. Standard statistical tests were used. RESULTS Of 316 eligible patients, 285 (90%) underwent PDS and 31 (10%) received NACT due to extra-abdominal disease, medical comorbidities, and/or advanced age (>85 years). Of the 285 patients who underwent PDS, most had carcinoma of ovarian origin (248, 87%); stage IIIC disease (249, 87%); grade 3 tumors (237, 83%); and serous histology (249, 87%). Optimal cytoreduction (≤1 cm residual) was achieved in 203 patients (71%). Postoperative platinum-based chemotherapy was given to 281 of 285 patients (99%). The median PFS and OS were 17 and 50 months, respectively. CONCLUSION PDS should continue to be the preferred initial management for patients with bulky stages IIIC-IV ovarian carcinoma. NACT should be reserved for those who cannot tolerate PDS and/or for whom optimal cytoreduction is not feasible.

Mucinous histology is a risk factor for nodal metastases in endometrial cancer

OBJECTIVES Mucinous adenocarcinoma of the endometrium (MUC) is a rare histological variant of endometrial carcinoma accounting for 1-9% of endometrioid tumors. Few studies have characterized its clinical behavior. This is a case-control study at a single institution comparing the risk factors and clinical course of MUC relative to endometrioid adenocarcinoma. METHODS A case-control study was performed including patients treated for endometrial cancer between 1996 and 2006. 41 cases of mucinous adenocarcinoma were identified. Each case was matched with two controls of endometrioid histology by age and histological grade. Cases and controls were compared with regard to known risk factors for endometrial cancer and the extent of disease at diagnosis. Chi-square tests were used to compare proportions and Students t-tests for the comparison of means. Multivariate regression was used to identify the independent predictors of lymph node metastases. Overall survival was calculated using the Kaplan-Meier method and compared with the Log-rank test. p<.05 was considered significant for all tests. RESULTS Cases and controls were matched by age and FIGO grade and were found to be similar in regard to ethnicity, body mass index and medical history. No significant difference in myometrial invasion (MI)>50% or the presence of lymph-vascular space invasion was found between cases and controls, however, 17% of patients with MUC had lymph node metastases compared to 3% of controls (p=.01). Multivariate analysis controlling for both tumor grade and depth of MI identified mucinous histology as an independent predictor of lymph node metastasis (p=.02). There was no difference in adjuvant treatment, recurrence rate or survival between the two groups. CONCLUSION Mucinous differentiation was found to be an independent predictor of lymph node metastasis in the study population. Comprehensive surgical staging including retroperitoneal node dissection should be strongly considered in all endometrial cancer patients with predominantly mucinous histology.

Dual mTORC1/2 inhibition in a preclinical xenograft tumor model of endometrial cancer☆

OBJECTIVES Up to 70% of endometrioid endometrial cancers carry PTEN gene deletions that can upregulate mTOR activity. Investigational mTOR kinase inhibitors may provide a novel therapeutic approach for these tumors. Using a xenograft tumor model of endometrial cancer, we assessed the activity of mTOR and downstream effector proteins in the mTOR translational control pathway after treatment with a dual mTOR complex 1 and 2 (mTORC1/2) catalytic inhibitor (PP242) compared to that of an allosteric mTOR complex 1 (mTORC1) inhibitor (everolimus, RAD001). METHODS Grade 3 endometrioid endometrial cancer cells (AN3CA) were xenografted into nude mice. Animals were treated with PP242, PP242 and carboplatin, carboplatin, RAD001, and RAD001 and carboplatin. Mean tumor volume was compared across groups by ANOVA. Immunoblot analysis was performed to assess mTORC1/2 activity using P-Akt, P-S6 and P-4E-BP1. RESULTS The mean tumor volume of PP242+carboplatin was significantly lower than in all other treatment groups, P < 0.001 (89% smaller). The RAD001+carboplatin group was also smaller, but this did not reach statistical significance (P = 0.097). Immunoblot analysis of tumor lysates treated with PP242 demonstrated inhibition of activated P-Akt. CONCLUSIONS Catalytic mTORC1/2 inhibition demonstrates clear efficacy in tumor growth control that is enhanced by the addition of a DNA damage agent, carboplatin. Targeting mTORC1/2 leads to inhibition of Akt activation and strong downregulation of effectors of mTORC1, resulting in downregulation of protein synthesis. Based on this study, mTORC1/2 kinase inhibitors warrant further investigation as a potential treatment for endometrial cancer.

Does the presence of adenomyosis and lymphovascular space invasion affect lymph node status in patients with endometrioid adenocarcinoma of the endometrium

OBJECTIVE We sought to determine the prevalence of adenomyosis and assess its effect on lymph node status in endometrioid adenocarcinoma of the endometrium (EAC). STUDY DESIGN Hysterectomy specimens from a single institution were reviewed for the presence of adenomyosis, lymphovascular space invasion (LVSI), tumor grade, histology, and lymph node status. Standard statistical analysis was used to compare variables. RESULTS Adenomyosis was present in 42% of total and 66% of malignant hysterectomy specimens (P = .009). Adenomyosis was most commonly associated with EAC histology (P = .023). LVSI was found to be an independent predictor of lymph node metastasis in EAC patients without adenomyosis, but not in those with coexisting adenomyosis (odds ratio, 58.7; P = .03; and odds ratio, 4.98; P = .15; respectively). CONCLUSION Adenomyosis was associated with a lower risk of lymph node metastasis in EAC patients with LVSI. Further studies are needed to investigate the role of adenomyosis in lymphatic tumor infiltration.

Postoperative Bowel Herniation in a 5-mm Nonbladed Trocar Site

The possibility of a strangulated hernia involving a 5-mm port site warrants consideration under the appropriate clinical scenario.

Phase II study of irinotecan in combination with bevacizumab in recurrent ovarian cancer

OBJECTIVES To evaluate the efficacy and safety of irinotecan and bevacizumab in recurrent ovarian cancer. The primary objective was to estimate the progression free survival (PFS) rate at 6months. Secondary objectives included estimation of overall survival (OS), objective response rate (ORR), duration of response, and an evaluation of toxicity. METHODS Recurrent ovarian cancer patients with no limit on prior treatments were eligible. Irinotecan 250mg/m2 (amended to 175mg/m2 after toxicity assessment in first 6 patients) and bevacizumab 15mg/kg were administered every 3weeks until progression or toxicity. Response was assessed by RECIST or CA-125 criteria every 2cycles. RESULTS Twenty nine patients enrolled (10 were platinum-sensitive and 19 were platinum-resistant). The median number of prior regimens was 5 (range 1-12); 13 patients had prior bevacizumab and 11 prior topotecan. The PFS rate at 6months was 55.2% (95% CI: 40%-77%). The median number of study cycles given was 7 (range 1-34). Median PFS was 6.8months (95% CI: 5.1-12.1months); median OS was 15.4months (95% CI: 11.9-20.4months). In this study, no complete response (CR) was observed. The objective response rate (ORR; PR or CR) for all patients entered was 27.6% (95% CI: 12.7%-47.2%) and the clinical benefit rate (CR+PR+SD) was 72.4% (95% CI: 52.8%-87.3%); twelve patients experienced duration of response longer than 6months. In the 24 patients with measurable disease, a partial response (PR) was documented in 8 (30%) patients; 13 patients maintained stable disease (SD) at first assessment. The most common grade 3/4 toxicity was diarrhea. No treatment-related deaths were observed. CONCLUSIONS Irinotecan and bevacizumab has activity in heavily pre-treated patients with recurrent ovarian cancer, including those with prior bevacizumab and topoisomerase inhibitor use.

Dual mTORC1/2 Inhibition as a Novel Strategy for the Resensitization and Treatment of Platinum-Resistant Ovarian Cancer.

There is considerable interest in the clinical development of inhibitors of mTOR complexes mTORC1 and 2. Because mTORC1 and its downstream mRNA translation effectors may protect against genotoxic DNA damage, we investigated the inhibition of mTORC1 and mTORC1/2 in the ability to reverse platinum resistance in tissue culture and in animal tumor models of serous ovarian cancer. Cell survival, tumor growth, PI3K–AKT–mTOR pathway signaling, DNA damage and repair response (DDR) gene expression, and translational control were all investigated. We show that platinum-resistant OVCAR-3 ovarian cancer cells are resensitized to low levels of carboplatin in culture by mTOR inhibition, demonstrating reduced survival after treatment with either mTORC1 inhibitor everolimus or mTORC1/2 inhibitor PP242. Platinum resistance is shown to be associated with activating phosphorylation of AKT and CHK1, inactivating phosphorylation of 4E-BP1, the negative regulator of eIF4E, which promotes increased cap-dependent mRNA translation and increased levels of CHK1 and BRCA1 proteins. Animals with platinum-resistant OVCAR-3 tumors treated with carboplatin plus mTORC1/2 inhibition had significantly longer median survival and strikingly reduced metastasis compared with animals treated with carboplatin plus everolimus, which inhibits only mTORC1. Reduced tumor growth, metastasis, and increased survival by mTORC1/2 inhibition with carboplatin treatment was associated with reduced AKT-activating phosphorylation and increased 4E-BP1 hypophosphorylation (activation). We conclude that mTORC1/2 inhibition is superior to mTORC1 inhibition in reversing platinum resistance in tumors and strongly impairs AKT activation, DNA repair responses, and translation, promoting improved survival in the background of platinum resistance. Mol Cancer Ther; 15(7); 1557–67. ©2016 AACR.

Targeting the PI3K/AKT/mTOR pathway in ovarian cancer

Ovarian cancer is the most common cause of mortality in U.S. women with gynecologic cancers. Without a successful screening strategy, most women present with advanced disease associated with a poor overall survival (OS) at 5 years despite high response rates to first line chemotherapy. Preclinical data points to the importance of PI3K/AKT/mTOR pathway activation in ovarian cancer tumorigenesis. Strategies to inhibit specific kinases in this pathway have been successful in laboratory studies and preliminary clinical trials. This review highlights the rationale behind the use of PI3K/AKT/mTOR inhibitors in clinical trials and thoroughly reviews the available therapeutic compounds and registered clinical trials to date. It outlines the importance of targeted clinical trials and the populations most likely to benefit from this strategy. It is with great anticipation that we await the results of the upcoming registered clinical trials and the opportunity to offer this novel therapeutic strategy to our patients with ovarian cancer.

Cross-Sectional Study of the Impact of a Natural Disaster on the Delivery of Gynecologic Oncology Care

OBJECTIVE We aimed to compare access to gynecologic oncology care at a private and a city hospital, both of which closed for a period of time because of Hurricane Sandy. METHODS This was a cross-sectional study of gynecologic oncology chemotherapy, radiotherapy, and surgical patients from October 29, 2012 (the eve of the storm), to February 7, 2013 (the reopening of the city hospital). New referrals during this time were excluded. Delays in chemotherapy, radiotherapy, and surgery were compared. RESULTS Analysis included 113 patients: 59 private patients (52.2%) and 54 city patients (47.8%). Of the private patients, 33/59 received chemotherapy (55.9%), 1/59 received radiotherapy (1.7%), and 28/59 had planned surgery (47.5%). Of the city patients, 40/54 received chemotherapy (74.1%), 7/54 received radiotherapy (12.3%), and 18/54 had planned surgery (33.3%). The mean delay in chemotherapy was 7.6 days at the private hospital and 21.7 days at the city hospital (P=0.0004). The mean delay in scheduled surgery was 14.2 days at the private hospital and 22.7 days at the city hospital (P=0.3979). The mean delay in radiotherapy was 0.0 days at the private hospital and 25.0 days at the city hospital (P=0.0046). Loss to follow-up rates were 3/59 of the private patients (5.1%) and 3/54 of the city patients (5.6%). CONCLUSIONS Gynecologic oncology care was maintained during a natural disaster despite temporary closure and relocation of services. Disparity in care was in access to chemotherapy.

Abstract 4525: mTOR complex inhibition as a novel therapeutic strategy in high-grade papillary serous ovarian cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Objectives: To compare mTOR complex 1 inhibition (RAD001) vs. mTOR complex 1/2 inhibition (PP242) as single agents and with Carboplatin (CPP) in a preclinical model of serous ovarian cancer (OVCA). Methods: In vitro: OVCAR3 and SKOV3 cell lines were exposed to the following treatment conditions: RAD001 or PP242 as single agents, vehicle, CPP alone, and RAD001 or PP242 followed by CPP. Colony forming assays (CFAs) were performed and quantified. mRNA levels of AKT, downstream targets of mTOR and the DNA repair response (ATR, ATM, BRCA1/2) were quantified by qRTPCR. Immunoblots characterized the protein expression of key components of mTOR and DNA repair pathways. Non-parametric analyses were used to compare results across groups on SPSS. In vivo: OVCAR3 cells expressing F-Luciferase were injected IP into SCID-BG mice. 15 wks post-injection, mice were exposed to the treatment conditions described above for 4 weeks. Tumor growth and response to treatment were assessed using bioluminescence imaging (IVIS). Results were analyzed on Living Image and Prism6. Results: In vitro: OVCAR3 and SKOV3 cells are highly sensitive to mTOR inhibition. CFAs showed significantly decreased colony counts and diameter in groups exposed to either PP242 or RAD001 vs. control, an effect that was potentiated by CPP (Fig 1). qRTPCR revealed a significant decrease in 4EBP1 mRNA with mTOR inhibition (p<0.0001), but no change in other biomarkers. Although treatment with both mTOR inhibitors resulted in decreased expression of p-S6 by immunoblots, treatment with the dual inhibitor (PP242) caused a decrease in p-AKT, p-4EBP1, total and p-CHK1, and total and p-BRCA1. The levels of these proteins were not changed by addition of CPP despite the significant effect observed in the functional assay (CFA). In vivo: Treatment with CPP + PP242 was associated with a longer median survival than other treatment groups (Table 1). A decrease in tumor burden was seen on IVIS and tumor flux (photons/sec) at the end of treatment was significantly lower in mice treated with CPP+PP242 compared to other groups (p<0.0001). Conclusions: Our preclinical model supports the concurrent use of dual mTOR inhibitors and platinum chemotherapy in the treatment of OVCA. mTOR complex 1/2 inhibition impairs the DNA repair response and correlates with improved survival in a murine model. Citation Format: Fernanda Musa, Amandine Alard, Gizelka David-West, Iulia Giuroiu, Stephanie Blank, Bhavana Pothuri, John P. Curtin, Robert Schneider. mTOR complex inhibition as a novel therapeutic strategy in high-grade papillary serous ovarian cancer. [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 4525. doi:10.1158/1538-7445.AM2014-4525