Scott McMeekin

Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma.

OBJECTIVE Patients with endometrial carcinoma who progress after first-line chemotherapy have a poor prognosis. Phosphoinositide 3-kinase (PI3K) inhibitors are investigational treatment options in this setting. This study evaluated the efficacy and safety of the PI3K inhibitor pilaralisib (SAR245408; XL147) in advanced or recurrent endometrial carcinoma. METHODS This Phase II, multicenter, single-arm, open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma, who had received one or two prior chemotherapy regimens. Patients received pilaralisib 600mg capsules or 400mg tablets once daily. Primary endpoints were objective response rate (ORR), proportion of patients with progression-free survival (PFS) >6months and safety. Molecular profiling in archival tumor tissue and circulating tumor DNA were performed to identify molecular markers associated with response or resistance to pilaralisib. RESULTS 67 patients were enrolled, of which 50 and 17 patients had received one or two prior regimens, respectively. Complete or partial tumor responses occurred in two patients each (ORR 6.0%); three had tumors with normal PTEN expression and PIK3R1 mutations and one had a tumor with PTEN protein deficiency. However, there was no association between molecular alterations and clinical activity. Rate of PFS>6months was 11.9%. The most commonly reported treatment-related adverse events (AEs) were rash (40.3%), diarrhea (37.3%) and fatigue (28.4%). The most commonly reported treatment-related grade ≥3 AEs were rash (9.0%), diarrhea (4.5%) and increased alanine aminotransferase (4.5%). CONCLUSIONS Pilaralisib was associated with a favorable safety profile and minimal antitumor activity in advanced or recurrent endometrial carcinoma.

Exosomes: A Role for Naturally Occurring Nanovesicles in Cancer Growth, Diagnosis and Treatment

Exosomes are 30-100 nm bodies secreted from almost all types of cells into the extracellular spaces. They enclose in their lumen active genetic information in the form of messenger RNA (mRNA), micro RNA (miRNA), DNA and active peptides that are representative of the parental cell and can be isolated from different body fluids. Exosomes can participate in inter-cellular communication by trafficking molecules to their target cells. Because they can stably carry cargo including miRNA, mRNA, and proteins and can pass through stringent biological barriers (e.g., blood brain barrier) without eliciting an immune response, they are considered as an ideal acellular vehicle for drug delivery. In this review, we describe the structure and biogenesis of exosomes and new directions related to their role in diagnosis and treatment of diseases, especially for cancer. We also discuss potential challenges associated with exosomes that should be addressed before exosome-based therapy can be applied to clinical settings.

Characteristics of 10-year survivors of high-grade serous ovarian carcinoma

OBJECTIVE High-grade serous carcinoma (HGSC) generally presents at an advanced stage with poor long-term (LT) survival. Here we describe clinical features found in women surviving HGSC for ten or more years. METHODS A multi-center research consortium was established between five participating academic centers. Patient selection criteria included high-grade serous ovarian, fallopian tube, or peritoneal carcinoma with at least ten years of follow up. Non-serous, borderline tumors and low-grade serous subtypes were excluded. RESULTS The 203 identified LT ten-year survivors with HGSC were diagnosed at a median age of 57years (range 37-84years). The majority of patients had stage IIIC (72.4%) disease at presentation. Of those who underwent primary cytoreductive surgery, optimal cytoreduction was achieved in 143 (85.6%) patients. After a median follow up of 144months, 88 (46.8%) patients did not develop recurrent disease after initial treatment. Unexpected findings from this survey of LT survivors includes 14% of patients having had suboptimal cytoreduction, 11% of patients having an initial platinum free interval of <12months, and nearly 53% of patients having recurrent disease, yet still surviving more than ten years after diagnosis. CONCLUSIONS LT survivors of HGSC of the ovary generally have favorable clinical features including optimal surgical cytoreduction and primary platinum sensitive disease. The majority of patients will develop recurrent disease, however many remained disease free for more than 10years. Future work will compare the clinical features of this unusual cohort of LT survivors with the characteristics of HGSC patients having less favorable outcomes.

Phase III randomized trial of second-line ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer

OBJECTIVE The purpose of this multicenter, open label, randomized phase III study was to determine whether ixabepilone resulted in improved overall survival (OS) compared with commonly used single-agent chemotherapy (doxorubicin or paclitaxel) in women with locally advanced, recurrent, or metastatic endometrial cancer with at least one failed prior platinum-based chemotherapeutic regimen. METHODS Patients were randomized 1:1 to ixabepilone (40mg/m(2)), or either paclitaxel (175mg/m(2)) or doxorubicin (60mg/m(2)), every 21days. Patients that had previously received an anthracycline were randomized to ixabepilone or paclitaxel; all other patients were randomized to ixabepilone or doxorubicin. An interim analysis of futility for OS was planned. RESULTS At the time of database lock, 496 patients were randomized to receive ixabepilone (n=248) or control (n=248); nine patients in the control arm were not treated. The interim analysis of futility for OS (219 events) favored the control chemotherapy arm (hazard ratio=1.3 [95% confidence interval: 1.0-1.7], stratified log rank test P=0.0397), indicating that the study would not meet its primary objective. The study was discontinued based on the interim OS results. The frequency of adverse events was comparable between the treatment arms. CONCLUSIONS The study did not meet its primary objective of improving OS in the ixabepilone arm compared to the control chemotherapy arm. A favorable risk/benefit ratio was not observed for ixabepilone versus control at the time of the interim analysis. The safety results were consistent with the known safety profiles of ixabepilone and control.

Phase III trial of induction gemcitabine or paclitaxel plus carboplatin followed by paclitaxel consolidation in ovarian cancer

OBJECTIVE The safety and efficacy of gemcitabine plus carboplatin (GC) or paclitaxel plus carboplatin (TC) induction regimens with or without paclitaxel consolidation therapy were assessed in ovarian cancer (OC). METHODS Patients with stage IC-IV OC were randomized to either GC (gemcitabine 1,000 mg/m(2), days 1 and 8, plus carboplatin area under the curve [AUC] 5, day 1) or TC (paclitaxel 175 mg/m(2) plus carboplatin AUC 6, day 1) every 21 days for up to six cycles. Patients with complete response (CR) were allowed optional consolidation with paclitaxel 135 mg/m(2) every 28 days for ≤ 12 months. Patients without CR received single-agent crossover therapy at induction doses/schedules until CR, disease progression (PD), or unacceptable toxicity. PD or death in 636 patients was required to compare induction arms with 80% statistical power for progression-free survival (PFS), the primary endpoint. RESULTS Randomized induction therapy was received by 820 of 919 patients enrolled; 352 patients with CR received paclitaxel consolidation whereas 155 patients without CR received single-agent crossover therapy. PFS was similar for GC and TC (median, 20.0 and 22.2 months, respectively; P=.199). Despite high censoring rates (>52%), overall survival was longer for TC (median, 57.3 versus 43.8 months for GC; P=.013). Controlling for patient characteristics including performance status, residual tumor size, and tumor stage, there was no statistical difference in a multivariate analysis (HR=1.22; 95% CI=0.99-1.52; P=.067). CONCLUSIONS GC does not improve PFS over TC as first-line induction chemotherapy in OC. Although favoring TC, overall survival analyses were limited by the study design and high censoring rates.

Early prediction of clinical benefit of treating ovarian cancer using quantitative CT image feature analysis.

Background In current clinical trials of treating ovarian cancer patients, how to accurately predict patients’ response to the chemotherapy at an early stage remains an important and unsolved challenge. Purpose To investigate feasibility of applying a new quantitative image analysis method for predicting early response of ovarian cancer patients to chemotherapy in clinical trials. Material and Methods A dataset of 30 patients was retrospectively selected in this study, among which 12 were responders with 6-month progression-free survival (PFS) and 18 were non-responders. A computer-aided detection scheme was developed to segment tumors depicted on two sets of CT images acquired pre-treatment and 4–6 weeks post treatment. The scheme computed changes of three image features related to the tumor volume, density, and density variance. We analyzed performance of using each image feature and applying a decision tree to predict patients’ 6-month PFS. The prediction accuracy of using quantitative image features was also compared with the clinical record based on the Response Evaluation Criteria in Solid Tumors (RECIST) guideline. Results The areas under receiver operating characteristic curve (AUC) were 0.773 ± 0.086, 0.680 ± 0.109, and 0.668 ± 0.101, when using each of three features, respectively. AUC value increased to 0.831 ± 0.078 when combining these features together. The decision-tree classifier achieved a higher predicting accuracy (76.7%) than using RECIST guideline (60.0%). Conclusion This study demonstrated the potential of using a quantitative image feature analysis method to improve accuracy of predicting early response of ovarian cancer patients to the chemotherapy in clinical trials.

MICU1 drives glycolysis and chemoresistance in ovarian cancer.

Cancer cells actively promote aerobic glycolysis to sustain their metabolic requirements through mechanisms not always clear. Here, we demonstrate that the gatekeeper of mitochondrial Ca2+ uptake, Mitochondrial Calcium Uptake 1 (MICU1/CBARA1) drives aerobic glycolysis in ovarian cancer. We show that MICU1 is overexpressed in a panel of ovarian cancer cell lines and that MICU1 overexpression correlates with poor overall survival (OS). Silencing MICU1 in vitro increases oxygen consumption, decreases lactate production, inhibits clonal growth, migration and invasion of ovarian cancer cells, whereas silencing in vivo inhibits tumour growth, increases cisplatin efficacy and OS. Mechanistically, silencing MICU1 activates pyruvate dehydrogenase (PDH) by stimulating the PDPhosphatase-phosphoPDH-PDH axis. Forced-expression of MICU1 in normal cells phenocopies the metabolic aberrations of malignant cells. Consistent with the in vitro and in vivo findings we observe a significant correlation between MICU1 and pPDH (inactive form of PDH) expression with poor prognosis. Thus, MICU1 could serve as an important therapeutic target to normalize metabolic aberrations responsible for poor prognosis in ovarian cancer.

Panniculectomy with simultaneous gynecologic oncology surgery

From July 1996 to May 2000, obese patients scheduled to undergo gynecologic oncologic procedures at Froiedtert Memorial Hospital or Waukesha Memorial Hospital in Milwaukee, Wisconsin, were offered a panniculectomy when warranted. To evaluate the benefits and risks associated with this procedure, the authors conducted a retrospective study of the 41 patients who underwent paniculectomy. The average age of the women was 55 years. Their average weight was 126 kg (range, 80-196) with a mean body mass index (BMI) of 48 kg/m2.-Three-fourths of the patients had class III obesity (N = 30). Seventy-eight percent were hypertensive, and 29% had diabetes. Prior abdominal surgery had been performed in 63%. Early postoperative complications included fever of unknown etiology (N = 6; 15%) and oliguric acute renal failure that improved by the time of discharge (N = 2). One woman developed deep venous thrombosis, which was successfully treated with low-molecular-weight heparin. Two patients had wound infections while in the hospital. One was a cellulitis, and the other was a drain site infection. In addition, three women developed wound infections later in the postoperative period, including two cases of cellulitis and one seroma. Two patients died of complications related tosurgery. One woman with a BMI of 44.3 kg/m2 had a suspected myocardial infarction while undergoing a total abdominal hysterectomy with pelvic lymphadenectomy. She died on the third postoperative day. A second patient underwent total abdominal hysterectomy with pelvic and para-aortic lymph node dissection. She experienced no problems postoperatively but had a massive pulmonary embolism just as she was leaving the hospital on postoperative day 5. She died after 3 days in the intensive care unit. A univariate analysis of possible risk factors for complications found that diabetes was significantly associated with early postoperative complications (P = .05). Increasing patient age led to a significantly greater risk for late postoperative complications (P = .05), and a higher BMI increased the risk of wound infection (P = .06).

Abstract C44: Endometrial carcinoma recurrence in black and white women in the NRG Oncology/Gynecologic Oncology Group 210 trial

BACKGROUND: Black women diagnosed with endometrial carcinoma have a higher risk of recurrence compared with white women. Higher recurrence risk among black women is due, in part, to a greater frequency of aggressive tumor characteristics including non-endometrioid histologies and advanced stage tumors. The risk of recurrence for black and white women within distinct tumor groupings has not been well-examined due to low numbers of black women and under-representation of aggressive histologic subtypes in single institution studies. Therefore, we examined the association between self-reported race and recurrence risk stratified by histologic subtype in the NRG Oncology/Gynecology Oncology Group (GOG) 210, a prospective observational study that enrolled 6,124 newly diagnosed endometrial carcinoma patients between 2003 and 2011. METHODS: We restricted this analysis to 618 black and 4,316 white women with endometrial carcinoma. At study enrollment, women completed a questionnaire that assessed risk factors for gynecologic cancers. Recurrence, defined as evidence of disease following complete response to primary therapy, was abstracted from medical records. Tumor characteristics were available from surgical pathology reports and a centralized review by pathologists with expertise in gynecologic cancers. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between race (black vs. white) and recurrence risk in models stratified by histologic subtype (low-grade endometrioid, high-grade endometrioid, serous, mixed epithelial, carcinosarcoma, clear cell) and adjusted for stage (I, II, III, IV), age at diagnosis (continuous), and adjuvant therapy (none, chemotherapy, radiation, chemotherapy and radiation, unknown). We also examined income (

Evaluation of chemotherapy response in ovarian cancer treatment using quantitative CT image biomarkers: A preliminary study

20,000-