Potential and mechanism of mebendazole for treatment and maintenance of ovarian cancer.

OBJECTIVE: Mebendazole and other anti-parasitic drugs are being used off-prescription based on social media and unofficial accounts of their anti-cancer activity. The purpose of this study was to conduct a controlled evaluation of mebendazole's therapeutic efficacy in cell culture and in vivo models of ovarian cancer. The majority of ovarian cancers harbor p53 null or missense mutations, therefore the effects of p53 mutations and a mutant p53 reactivator, PRIMA-1MET (APR246) on mebendazole activity were evaluated. METHODS: Mebendazole was evaluated in cisplatin-resistant high grade serous stage 3C ovarian cancer patient derived xenograft (PDX) models: PDX-0003 (p53 null) and PDX-0030 (p53 positive), and on ovarian cancer cell lines: MES-OV (p53 R282W), ES2 (p53 S241F), A2780 (p53 wild type), SKOV3 parental (p53 null) and isogenic sublines, SKOV3 R273H p53 and SKOV3 R248W p53. Drug synergy and mechanisms were evaluated in cell cultures using isobolograms, clonogenic assays and western blots. Prevention of tumor establishment was studied in a MES-OV orthotopic model. RESULTS: Mebendazole inhibited growth of ovarian cancer cell cultures at nanomolar concentrations and PDXs at doses up to 50 mg/kg, and reduced orthotopic tumor establishment at 50 mg/kg. The mechanism of mebendazole was associated with p53-independent induction of p21 and tubule depolymerization. PRIMA-1MET also inhibited tumor establishment and worked synergistically with mebendazole in cell culture to inhibit growth and induce intrinsic apoptosis through a p53- and tubule destabilization-independent mechanism. CONCLUSION: This work demonstrates the therapeutic potential of repurposing mebendazole and supports clinical development of mebendazole for ovarian cancer therapy and maintenance.

Extending the platinum-free interval: The impact of omitting 2nd line platinum chemotherapy in intermediate platinum-sensitive ovarian cancer.

OBJECTIVES: Patients with epithelial ovarian cancer (EOC) recurring between 6 and 12 months after primary platinum chemotherapy have worse prognosis than those recurring in >12 months. Artificially prolonging the platinum-free interval (PFI) with cytotoxic chemotherapy was tested in MITO-8 with poor outcomes. This study aimed to determine the impact of using non-platinum or targeted therapy in 2nd line treatment of EOC patients recurring 6-12 months after completion of primary platinum-based chemotherapy. METHODS: A multi-institutional retrospective review of 177 patients with recurrent EOC and PFI of 6-12 months following primary chemotherapy was performed comparing platinum versus non-platinum chemotherapy or targeted therapy for 2nd line treatment. PFI1 was defined as the date of last chemotherapy to date of recurrence. PFS2/3 were defined as start of 2nd or 3rd line chemotherapy to start of subsequent line. RESULTS: Of 177 patients, the majority of patients were Caucasian, had serous histology, and underwent primary cytoreductive surgery. Median PFI1 was 8.2 months (95% CI 8-9 months). Second line platinum was omitted in 28% of patients. Bevacizumab was used in 2nd line in 16% of patients; 19% received other targeted therapies. Median PFS2 for platinum chemotherapy was longer than non-platinum (7.1 vs 3 months, p = 0.0114). Median PFS2 was significantly longer for platinum vs. targeted therapy (7.1 vs. 3 months p = 0.0431). Median OS for platinum in 2nd line vs. no platinum was 43.6 vs. 37.6 months (p = 0.0174). CONCLUSIONS: Use of non-platinum chemotherapy and even targeted therapy to prolong PFI in patients with EOC recurring between 6 and 12 months leads to worse survival.

A phase 1b dose escalation study of ipafricept (OMP54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer.

OBJECTIVES: The WNT pathway is an important oncologic driver of epithelial ovarian cancer (EOC). The first-in-class recombinant fusion protein ipafricept (IPA) blocks Wnt signaling through binding of Wnt ligands. This phase Ib trial was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RPh2) for IPA in combination with taxane and platinum therapy (C/P). METHODS: Dose escalation started with a standard 3 + 3 design for IPA/C/P with q3w intravenous IPA on Day 1, in cycles 1 to 6 with C (AUC = 5 mg/ml·min) and P (175 mg/m2). For enhanced bone safety the trial was revised to 6-patient cohorts with a q3w regimen of IPA on Day 1 and C/P on Day 3 (IPA → C/P). RESULTS: 37 patients have been treated; 30 of whom were treated following protocol revision to q3w IPA(D1) → C/P(D3) (2 & 4 mg/kg). IPA-related TEAEs that occurred in ≥15% included: fatigue (40%); nausea (35%); diarrhea and decreased appetite (22%) each; dysgeusia (19%); and vomiting (16.2%). 22% reported ≥1 IPA related TEAE Grade ≥3 the most common of which was neutropenia at 16%. There were no DLTs; the MTD was not reached. The maximum administered dose based on bone safety was 6 mg/kg. The overall response rate (ORR) was 75.7%. Median PFS was 10.3 months (95% CI 8.5-14.2) and OS 33 months (95% CI 23.4-NR). CONCLUSIONS: IPA is well tolerated in combination with sequential C/P. ORR, PFS and OS are comparable to historical data but bone toxicity at efficacy doses of this particular Wnt inhibitor limit further development in EOC.

Update in the use and evaluation of poly (ADP-ribose) polymerase inhibitors in epithelial ovarian cancer: current and pending clinical research.

PURPOSE OF REVIEW: This review will provide an update of recently presented clinical data as well as discuss ongoing trials focused on the incorporation of poly (ADP-ribose) polymerase inhibitors (PARPi) into the treatment paradigm for ovarian cancer. RECENT FINDINGS: As of this publication, PARPi have indications in many parts of the globe as maintenance therapy following response to platinum-based chemotherapy in the setting of platinum-sensitive recurrence. In addition, in the United States, two PARPi have indications as monotherapy treatment for recurrent ovarian cancer in patients with a BRCA mutation and at least two prior lines of therapy. Exciting data was published in October 2018, demonstrating an unprecedented benefit to utilization of olaparib following response to front-line platinum-based chemotherapy among patients with a BRCA mutation and this data is expected to expand the indication for olaparib globally. SUMMARY: Ongoing studies will seek to expand the benefit of PARPi beyond the BRCA population in front-line therapy as well as to overcome inherent and acquired resistance to PARPi with studies of novel combinations with antiangiogenesis agents, immune-oncology agents and chemotherapy. These efforts may identify more settings and populations in which PARPi provide clinical benefit.

Management of the toxicities of common targeted therapeutics for gynecologic cancers.

As precision medicine has become a focus in oncology in recent years, many targeted and biologic agents are being used along with or in place of traditional cytotoxic chemotherapy. As these drugs have been developed and some have received FDA approval, we have gained substantial data about the adverse event profiles. However, the management and approach to the toxicities incurred and subsequent complications are often not well understood, especially for physicians who have a varied clinical practice. The purpose of this review is to provide an overview of the frequency and types of adverse events and appropriate management steps when prescribing modern targeted therapies for gynecologic cancers in the classes of anti-angiogenic agents, poly-ADP-ribose polymerase (PARP) inhibitors, and immunotherapy drugs.

A contemporary framework of health equity applied to gynecologic cancer care: A Society of Gynecologic Oncology evidenced-based review.

Health disparities are defined as the preventable difference in the burden of disease, injury, and violence, or opportunity to achieve optimal health that socially disadvantaged populations experience compared to the population as a whole. Disparities in incidence and cancer outcomes for women with gynecologic malignancies have been well described particularly for American women of Black race. The etiology of these disparities has been tied to socio-economics, cultural, educational and genetic factors. While access to high quality treatment has been primarily linked to survival from cervical and ovarian cancer, innate biologic distinctions have been principally cited as reasons for differences in incidence and mortality in cancers of the uterine corpus. This article will update the framework of disparities to incorporate a broader understanding of the social determinants of health and how they affect health equity by addressing the root causes of disparities within the health care system. Special populations are identified who are at risk for health inequities which include but are not limited to Black race, underserved racial and ethnic minorities (e.g. indigenous peoples, low English fluency), trans/gender nonconforming people and rural populations. Each of these populations at risk have unique structural barriers within the healthcare system impacting gynecologic cancer outcomes. The authors provide practical recommendations for practitioners aimed at eliminating cancer related outcome disparities.

Consideration of older patients for enrollment in phase 1 clinical trials: Exploring treatment related toxicities and outcomes.

OBJECTIVES: Age imposes a disparity in the treatment of and outcomes with gynecologic cancer. Older patients are underrepresented in primary treatment trials, but little is known about their ability to withstand trial-based treatment for recurrent or refractory disease. This study sought to examine treatment-related toxicities and outcomes of older versus younger patients participating in phase 1 clinical trials. METHODS: A retrospective analysis of patients enrolled in phase 1 clinical trials for gynecologic malignancies from 2010 to 2016 was performed. Demographic and clinic-pathologic data was abstracted. Toxicities were defined as either grade III or IV by CTCAE criteria. Best response was calculated using RECIST criteria. Associations between categorical variables were determined using Fisher's exact test and continuous variables using Wilcoxon rank sum test. Survival was estimated using the Kaplan-Meier method. RESULTS: 237 patients were included with 22% (n=51) comprising the older cohort (≥70years). The vast majority (98%) were treated for recurrent disease. Older patients incurred similar grade III/IV hematologic (21% vs 16%, p=0.38) and non-hematologic toxicities (26% vs 29%, p=0.64). Older patients discontinued treatment due to toxicity only 8% of the time. Median survival was 13.0 and 10.3months in the <70 and ≥70 groups, respectively (p=0.35). 63% of patients ≥70 achieved clinical benefit. CONCLUSIONS: Although historically older patients have not been routinely considered for enrollment in phase 1 trials, our data demonstrates similar toxicity profiles to that of younger patients and 63% clinical benefit rate. Thus, with careful selection, patients ≥70 should be considered when facing recurrent or refractory gynecologic cancer.

Factors influencing clinical trial enrollment among ovarian cancer patients.

OBJECTIVE: To characterize patients who did not enroll on a clinical trial and identify barriers that may limit enrollment among patients with advanced epithelial ovarian cancer (EOC) presenting for first-line chemotherapy. METHODS: We conducted a retrospective review of patients diagnosed with stage II-IV EOC from 10/2009-4/2013, a time period during which multiple trials were available to all EOC patients, including optimally debulked, suboptimally debulked, or undergoing neoadjuvant chemotherapy. Enrollment status, demographics, tumor characteristics, and treatment details were recorded. SAS version 9.3 was used for all analyses. RESULTS: 144 patients met study criteria; 67% were enrolled on a trial. Enrolled patients were significantly younger (median 61 vs 68years, p=0.002). Stage (p=0.30), race (p=0.75), and performance status (p=0.38) were similar between enrolled and non-enrolled patients. Distance did not impact enrollment, as nearly half of patients in both groups lived >50miles from the treatment center (39.0% vs 47.8%, p=0.36). Mode of chemotherapy administration significantly differed based on participation (all p<0.05). Despite similar residual disease status (p=1.00) and number of chemotherapy regimens received (p=0.59), patients treated on trial had a higher 3-year survival rate (70.7% vs 51.7%, p=0.031). The difference in median progression-free survival approached significance (20.2 vs 9.2months, p=0.091). CONCLUSION: In an institution where the culture is to offer clinical trials to all eligible patients, 33% of front-line EOC patients did not participate. Increasing age was associated with non-participation. Modifiable barriers must be overcome so that trial enrollment can better reflect true EOC demographics.

Three versus six cycles of adjuvant platinum-based chemotherapy in early stage clear cell ovarian carcinoma - A multi-institutional cohort.

OBJECTIVES: To determine if 6 versus 3cycles of adjuvant platinum-based chemotherapy with or without taxane impacts survival in early stage ovarian clear cell carcinoma (OCCC). METHODS: We retrospectively identified all cases of stage I and II OCCC treated at 5 institutions from January 1994 through December 2011. Patients were divided into 2 groups: those who received 3 versus 6cycles of adjuvant chemotherapy. Our cohort consisted of 210 patients with stage IA-II disease, 116 of whom underwent full surgical staging. Cox proportional hazards regression and Kaplan-Meier analyses were performed to evaluate progression-free (PFS) and overall survival (OS) between groups. RESULTS: Among 210 eligible patients, the median age was 53years (range 30-88). The majority of patients were Caucasian (83.8%). All patients received adjuvant chemotherapy with 90% receiving carboplatin and paclitaxel. Thirty-eight (18.1%) patients received 3cycles, and 172 (81.9%) patients received 6cycles of adjuvant treatment. Recurrence rate was comparable between groups (18.4% vs. 27.3% for 3 vs. 6cycles, p=0.4). There was no impact of 3 versus 6cycles of chemotherapy on PFS (hazard ratio [HR] 1.4; 95% confidence interval [CI] 0.63-3.12, p=0.4) or OS (HR 1.65; 95% CI 0.59-4.65, p=0.3) on univariate analysis. There was no benefit to more chemotherapy in stratified analysis by stage nor on multivariate analysis adjusting for the impact of stage. Subgroup analysis of surgically staged patients also showed no difference in survival between 3 versus 6cycles of chemotherapy. CONCLUSIONS: Three cycles of platinum with or without taxane adjuvant chemotherapy were comparable to 6cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort. CONDENSATION: Three cycles of platinum with or without taxane adjuvant chemotherapy are comparable to 6 cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort.

The pro-inflammatory effect of obesity on high grade serous ovarian cancer.

INTRODUCTION: Obesity is a known generator of chronic inflammation but has an uncertain role in ovarian carcinogenesis and survival. Pro-inflammatory cytokines have previously been associated with poor outcomes. Given the established links, we sought to determine whether obesity and pro-inflammatory cytokines affect platinum sensitivity. METHODS: A retrospective review was performed of patients undergoing primary debulking surgery (PDS) for high grade serous ovarian cancer (HGSC) who had available pre-operative serum. Oncologic and treatment characteristics were recorded and analyzed using SAS version 9.3. Bioplex reagent kit was used to measure serum cytokine concentrations. RESULTS: 86 patients met study criteria. Most were Caucasian (88%) and non-diabetic (92%). All patients had advanced stage (III/IV) disease and received chemotherapy after PDS. In univariate analysis, lower VEGF (p=0.013) was associated with longer overall survival (OS). Low IL-8 level (p=0.053) was marginally associated with platinum resistant disease. After adjusting for covariates including residual disease and maintenance therapy, IL-8 was no longer associated with platinum sensitive status (p=0.13), VEGF remained associated with OS (low vs. high HR 0.3, 95% CI 0.1-0.8, p=0.018), and higher IL-12 was associated with longer PFS (HR 0.4, 95% CI 0.2-0.9, p=0.031). CONCLUSION: In HGSC, pro-inflammatory cytokines are influenced by obesity, as differing inter-cytokine correlations were observed based on BMI, possibly due to dysregulation between cytokines in the setting of obesity. Differences in survival and platinum sensitivity were not noted. Future studies are warranted to determine whether obesity may be a modifiable risk factor for poorer outcomes due to differing immune response.

Initiation of a formalized precision medicine program in gynecologic oncology.

OBJECTIVE: In an effort to better incorporate precision medicine into clinical practice, we initiated a pilot project to screen, discuss, and genetically characterize patients with metastatic or recurrent gynecologic malignancies for whom no curative standard of care exists. METHODS: In 7/2014, we initiated a multi-disciplinary Precision Medicine Board (PMB) whose purpose was to apply molecular profiling to select and prioritize early phase clinical trial enrollment for high-risk gynecologic malignancies. Additional objectives were to record outcomes and enable scientific discussions of mutations which may foster local translational research. FoundationOne was the preferred genomic platform; results were reviewed by a team comprised of disease site specialists, phase I trialists, and basic and translational scientists affiliated with the Gynecologic Cancer Program. A detailed database for each patient was created and is followed prospectively for treatment use and resultant outcomes. RESULTS: To date, we have presented 62 cases with interpretable FoundationOne testing on 60 tumor samples (31 ovarian, 18 uterine, 9 cervical, and 4 other female genital tract). Significant genomic alterations were commonly found in all tumor types (median: 3); TP53 (45%) and PIK3CA (27%) were the most frequently noted mutations; however, molecular profiling resulted in identification of few actionable mutations (6%). To date, we have matched 4 patients on therapies based on actionable mutations. CONCLUSIONS: The predominant function of our PMB is establishment of a forum to enhance research while providing clinical care for refractory malignancies. We have matched patients with specific mutations to ongoing trials and are developing investigator-initiated studies based on trends within genomic profiling results. Longer-term follow up will be required to determine the success of this strategy.

Primary and acquired platinum-resistance among women with high grade serous ovarian cancer.

OBJECTIVE: Women with primary platinum resistant (PPR) high grade serous ovarian cancer (HGSOC) are known to have a poor prognosis. Less is known regarding outcomes in patients with acquired platinum resistance (APR). The goal of this study was to evaluate survival in both PPR and APR patients. METHODS: A retrospective review of HGSOC patients diagnosed between 2000 and 2010 was performed. Descriptive statistics summarized clinical characteristics and demographics. The Kaplan-Meier method estimated progression free survival (PFS) and overall survival (OS). The association of OS and clinical factors was modeled using Cox proportional-hazards. RESULTS: Of the 330 patients identified, 81 (25%) had PPR. Of the remaining women, 55 (22%) developed APR. Median PFS of PPR patients was 4.2months and median OS was 17.8months. On multivariate analysis, the number of biologic agents received was the only predictor of OS. Patients with APR had a median PFS of 14.2months and a median OS of 56months. OS from the date of platinum resistance was 21.9months, though this was not different than PPR patients (p=0.19). Multivariate analysis found cancer stage and clinical trial participation to be associated with OS. CONCLUSIONS: Platinum resistance confers a poor prognosis in the APR and PPR setting. The number of biologic agents received is the strongest predictor of OS among women with PPR. Cancer stage and clinical trial participation predicts OS in patients with APR. Providing opportunities to participate in clinical trials, especially those involving targeted therapy, should be a priority in these populations.

Impact of histology and surgical approach on survival among women with early-stage, high-grade uterine cancer: An NRG Oncology/Gynecologic Oncology Group ancillary analysis.

OBJECTIVES: We sought to analyze the clinicopathologic features, recurrence patterns and survival outcomes of women with high-grade uterine cancer (UC) enrolled on The Gynecologic Oncology Group (GOG) LAP2 trial. METHODS: This is a post-hoc analysis of LAP-2 patients with grade 3 endometrioid adenocarcinoma (ENDO), uterine serous (USC), clear cell (CC) and carcinosarcoma (CS). Demographics, clinicopathologic features, and recurrence patterns, were compared by histology and surgical approach. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: Of the 2600 patients enrolled in LAP-2, 753 patients had high-grade UC: 350 had ENDO, 289 had USC, 42 had CC and 72 had CS. Compared with the ENDO cohort, those with other high-grade subtypes were older (p<0.001) and were more likely to have positive peritoneal cytology (p<0.001), positive lymph nodes (p=0.05) and higher disease stage on final pathology (p<0.001). With a median follow-up time of 60months, compared to patients with ENDO, those with USC, CCC and CS subtypes had higher recurrence rates (p<0.001), extra-pelvic recurrences (p<0.001) and poorer PFS (p<0.001) and OS (p<0.001). Those diagnosed with USC and CS experienced the worst survival outcomes (p=0.003). Patterns of recurrence and survival were not different in those staged with LSC vs LAP. On multivariable analysis, age, stage, pelvic washings and Type II histology were independently and adversely associated with survival. CONCLUSIONS: Women with apparent early-stage, USC and CS histologies have poorer outcomes than women with grade 3 endometrioid adenocarcinoma. Patterns of recurrence and survival were not impacted by surgical approach.

Post-intensive care unit syndrome in gynecologic oncology patients.

PURPOSE: The purposes of the present study are to describe the demographic and treatment characteristics of women on the gynecologic oncology service who required intensive care and assess prevalence of risk factors for post-intensive care syndrome (PICS). METHODS: A retrospective chart review was performed encompassing patients requiring admission to the intensive care unit (ICU) on the gynecology oncology service between 1/2008 and 12/2012. Descriptive statistics were computed using SAS version 9.3. RESULTS: One hundred eleven patients met study criteria. Most were Caucasian (85 %), were married (50 %), and had stage III/IV disease (82 %). Risk factors for PICS were as follows: 9 % had baseline anxiety, 20 % had baseline depression, 21 % were taking an SSRI prior to admission, and 18 % took other psychiatric medications. Most ICU admissions (47 %) were for planned post-operative management. Thirty-seven percent required mechanical ventilation for a median of 1 day (range, 1-24). Twenty percent required new scheduled psychiatric medications while in the ICU, and 8.1 % of patients were discharged with a newly prescribed antidepressant. Of patients, 15.3 % had consultations with psychiatry or social work. Six percent of patients expired, and 18 % had a nontraditional discharge disposition. Overall, 60 % of the patients had at least one recognized risk factor for PICS. CONCLUSIONS: Given the preponderance of psychiatric disorders and mechanical ventilation during post-operative ICU care in patients with gynecologic cancer, prospective evaluation of risk factors and utility of risk-reducing interventions for PICS is warranted. Long-term cognitive or physical disability is known to hasten mortality; thus, preventative strategies may increase the survival and quality of life for this patient population.

Intimate Partner Violence and Barriers to Cervical Cancer Screening: A Gynecologic Oncology Fellow Research Network Study.

OBJECTIVES: The aims of the study were to examine barriers to cervical cancer screening among women who have experienced intimate partner violence (IPV) and accessed domestic violence shelters, to compare barriers among those up-to-date (UTD) and not UTD on screening, and to evaluate acceptability of human papillomavirus self-sampling. MATERIALS AND METHODS: This is a cross-sectional survey in which domestic violence shelters in Ohio were identified and women completed an anonymous survey assessing UTD screening status, barriers related to screening, history of IPV, intention to follow up on abnormal screening, and acceptability of self-sampling. Characteristics of UTD and not UTD women were compared using Mann-Whitney U tests. RESULTS: A total of 142 women from 11 shelters completed the survey. Twenty-three percent of women were not UTD. Women who were not UTD reported more access-related barriers (mean = 2.2 vs 1.8; p = .006). There was no difference in reported IPV-related barriers between women who were not UTD and those who are UTD (mean = 2.51 in not UTD vs 2.24 in UTD; p = .13). Regarding future screening, of the women who expressed a preference, more women not UTD preferred self-sampling than UTD women (32% vs 14%; p = .05). CONCLUSIONS: In this study, access-related barriers were more commonly reported among women not UTD with screening. Addressing these barriers at domestic violence shelters may improve screening among not UTD women. Self-sampling may also be one feasible approach to support screening in this population.

Central nervous system metastasis in gynecologic cancer: symptom management, prognosis and palliative management strategies.

INTRODUCTION: CNS metastasis (CNSmet) with gynecologic malignancy (GM) is associated with poor prognosis and symptom burden. Two prognostic indices, the recursive partitioning analysis (RPA) and graded prognostic assessment (GPA), used in other solid tumors to guide intervention options were evaluated among GM patients. METHODS: Retrospective chart review was performed to identify patients with primary GM diagnosed with CNSmet from 2005-2014. RPA and GPA were applied and evaluated for goodness of fit. Long-term survivors (LTS) were those with survival time from CNSmet ≥9 months. RESULTS: 35 patients were identified with median age of 62 years (range, 41-78). The majority had ovarian cancer (54%). Median survival was 4.5 months (0.1-25.9), and median time from initial diagnosis was 2.6 years (0-19.6). Presenting symptoms varied but headache (57%) and altered mental status (23%) were most common. 37% had a solitary CNS lesion, 31% had 2-8, and 31% >8. 57% were treated with WBRT, 14% with stereotactic radiosurgery (SRS), and 20% with combinations of treatments, and 2 elected for hospice. 27% (9/33) of the patients were LTS. The GPA was not significantly associated with patient outcome (p=0.46). The RPA predicted time to death (p=.0010). CONCLUSION: Prognostic indices used to guide therapeutic interventions perform poorly in GM. Detection and aggressive symptom management are critical in maintaining QOL. Multidisciplinary consultation is critical to optimize outcomes and symptom control.

Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer.

Olaparib (Lynparza™; AZD2281) is a potent PARP-1 and PARP-2 inhibitor with biologic activity in ovarian cancer as well as other solid tumors. It has been tested in Phase I and II trials and has single-agent activity in both germline BRCA mutated and sporadic ovarian cancer. Phase III trials assessing the efficacy of olaparib in the maintenance setting following first line and platinum-sensitive recurrence are underway for patients with a germline BRCA mutation, given the inherent molecular compatibility with the drug's mechanism of action.

The impact of obesity on surgical staging, complications, and survival with uterine cancer: a Gynecologic Oncology Group LAP2 ancillary data study.

OBJECTIVE: To determine the association of body mass index (BMI) on complications, recurrence, and survival in GOG LAP2, a randomized comparison of laparoscopic versus open staging in clinically early stage uterine cancer (EC). METHODS: An ancillary data analysis of GOG LAP2 was performed. Categorical variables were compared using Pearson chi-square test and continuous variables using the Wilcoxon-Mann-Whitney and Kruskal-Wallis tests by BMI group. Survival was estimated using the Kaplan-Meier method. Cox proportional hazards model was used to evaluate independent prognostic factors on survival. Statistical tests were two-tailed with α=0.05, except where noted. Statistical analyses utilized R programming language. RESULTS: 2596 women were included. BMI (kg/m(2)) groups were <25 (29.5%), 25-30 (28.2%), 30-35 (21%), 35-40 (10.9%), and ≥40 (10.4%). Stage (p=0.021), grade (p<0.001), and histology (p=0.005) differed by BMI. Obese women were less likely to have high risk (HR) disease (+lymph nodes/ovaries/cytology) or tumor features that met GOG99 high intermediate risk (HIR) criteria (p<0.001). Adjuvant therapy (p=0.151) and recurrence (p=0.46) did not vary by BMI. Hospitalization >2days, antibiotic use, wound infection, and venous thrombophlebitis were higher with BMI ≥40. BMI (p=0.016), age (p<0.0001), race (p=0.033), and risk group (p<0.0001) predicted all-cause mortality. BMI was not predictive of disease-specific survival (p=0.79), but age (p=0.032) and risk group (p<0.0001) were significant factors. CONCLUSION: Obese women have greater surgical risk and lower risk of metastatic disease. BMI is associated with all-cause but not disease-specific mortality, emphasizing the detrimental effect of obesity (independent of EC), which deserves particular attention.

Pathologic features associated with resolution of complex atypical hyperplasia and grade 1 endometrial adenocarcinoma after progestin therapy.

OBJECTIVE: To determine the response of complex atypical hyperplasia (CAH) and well differentiated endometrioid adenocarcinoma of the uterus (WDC) to progestin therapy and whether pre-treatment estrogen and progesterone receptor status predicts outcome. METHODS: We performed a retrospective review encompassing women treated with progestin therapy for CAH or WDC at two institutions. Clinicopathologic, treatment, and recurrence data were recorded. Pre/post-treatment pathologic evaluation was performed. SAS 9.2 was used for statistical analyses. RESULTS: Forty-six patients were included. The median age was 35, and median BMI was 36.9. Thirty-seven percent were diagnosed with CAH and 63% had WDC. Megestrol acetate was the most commonly used agent (89%); 24% received multiple progestin therapies. Median treatment length was 6 months (range, 1-84); 36% of the patients underwent eventual hysterectomy, and 17.4% had carcinoma in their uterine specimens (8 primary endometrial, 1 primary ovarian). After a median follow-up of 35 months (range, 2-162), 65% experienced a complete response (CR), 28% had persistent or progressive disease, and 23% had a CR followed by recurrence. On univariate analysis, decreased post-treatment glandular cellularity (p = 0.0006), absence of post-treatment mitotic figures (p = 0.0008), and use of multiple progestin agents (p = 0.025) were associated with CR; however, only decreased glandular cellularity was significant on multivariate analysis (p = 0.007). Estrogen and progesterone receptor expression was not associated with treatment response. CONCLUSION: In women with CAH or WDC, the overall response rate to progestin therapy was 65%; pre-treatment estrogen/progesterone receptor status did not predict response to treatment.

The survival detriment of venous thromboembolism with epithelial ovarian cancer.

OBJECTIVE: The aim of this study is to evaluate the effect of venous thromboembolism (VTE) chronology with respect to surgery on survival with epithelial ovarian cancer (EOC). METHODS: An IRB approved, retrospective review was performed of patients treated for Stage I-IV EOC from 1996 to 2011. Cox proportional hazards model was used to assess associations between VTE and the primary outcomes of progression free survival (PFS) and overall survival (OS). SAS 9.3 was used for statistical analyses. RESULTS: 586 patients met study criteria. Median age was 63 years (range, 17-94); median BMI was 27.1 kg/m(2) (range, 13.7-67.0). Most tumors were high grade serous (68.3%) and advanced stage (III/IV, 75.4%). 3.7% had a preoperative VTE; 13.2% had a postoperative VTE. Upon multivariate analysis adjusting for age, stage, histology, performance status, and residual disease, preoperative VTE was predictive of OS (HR 3.1, 95% CI: 1.6-6.1, p=0.001) but not PFS (p=0.55). Postoperative VTE was associated with shorter PFS (HR 1.45, 95% CI: 1.04-2.02, p=0.03) and OS (HR 1.8, 95% CI: 1.3-2.6, p=0.001). When VTE timing was modeled, preoperative VTE (HR 3.5, 95% CI: 1.8-6.9, p<0.001) and postoperative VTE after primary therapy (HR 2.3, 95% CI: 1.4-3.6, p=0.001) were predictive of OS. CONCLUSION: Preoperative and postoperative VTE appear to have a detrimental effect on OS with EOC. When modeled as a binary variable, postoperative VTE attenuated PFS; however, when VTE timing was modeled, postoperative VTE was not associated with PFS. It is unclear whether VTE is an inherent poor prognostic marker or if improved VTE prophylaxis and treatment may enable similar survival to patients without these events.