Bradley R. Corr

Immunotherapy in ovarian cancer

Ovarian cancer is the most deadly gynecologic malignancy, with more than 15,000 deaths anticipated in 2012.1 While approximately 80% of patients will respond to frontline chemotherapy, more than 60% of patients will experience disease recurrence and only 44% will be alive at 5 years.1,2 Host anti-tumor immune responses are associated with a significant improvement in overall survival for women with ovarian cancer.3,4 By bolstering these responses, it may therefore be possible to significantly influence the prognosis of women with this lethal disease. In this review, we will focus on innovative immune-based strategies which are currently being investigated in the treatment of ovarian cancer.

Effectiveness and safety of expanded perioperative thromboprophylaxis in complex gynecologic surgery

OBJECTIVE To determine the effectiveness and safety of an expanded perioperative venous thromboembolism (VTE) prophylaxis strategy in women undergoing complex gynecologic surgery. METHODS We performed a cohort study of 527 patients undergoing major surgery at a single institution over a thirty-month interval during which the gynecologic oncology service implemented an expanded approach to VTE prophylaxis. We compared rates of VTE pre- and post-intervention as well as bleeding and infectious complications. RESULTS Prior to the intervention, there were 23 VTE events in 345 patients (rate of 6.67%): 8 deep vein thromboses (DVTs) and 15 pulmonary emboli (PEs). Post-intervention, there were 5 VTE events in 182 patients (2.7%): 3 DVTs and 2 PEs (RR=0.4, p=0.056). Time-to-event analysis showed a significantly higher incidence of VTE events in the pre-intervention time frame compared to the post-intervention period (p=0.049). There were no significant differences in bleeding or infection complications between groups. CONCLUSIONS Implementation of a perioperative VTE prophylaxis protocol was safe, feasible and resulted in a clinically significant reduction in symptomatic VTE. Preoperative single-dose unfractionated heparin for all patients, combined with two weeks of thromboprophylaxis in gynecologic cancer patients, may decrease VTE events without increasing bleeding or infection.

Bevacizumab induced hypertension in gynecologic cancer: Does it resolve after completion of therapy?

Hypertension (HTN) induced by bevacizumab is a side effect that is often thought to resolve after treatment. However, there are currently no reports on rates of resolution. We assess the incidence and timing of the resolution of bevacizumab induced HTN. We evaluated all patients treated with bevacizumab for gynecologic malignancies at a single institution from 2012 through 2014. HTN was retrospectively diagnosed and staged by CTCAE v4.0 criteria. Resolution of HTN was defined as ≥ 2 values return to baseline blood pressure and/or discontinuation/decrease of blood pressure medications. We identified 104 patients; 35 were excluded due to receiving bevacizumab at time of analysis. Grade 2 or higher induced HTN was identified in 34/69 (49.3%) patients, of which 26/69 (37.7%) had grade 2 HTN and 8/69 (11.6%) had grade 3/4 HTN. Onset of HTN occurred at a median of 67 (14–791) days. Resolution of HTN occurred in 28/34 (82.4%) patients with a median time to resolution of 87 (3–236) days. BMI, history of HTN, blood pressure medications, prior bevacizumab treatment, number of bevacizumab cycles, CA-125 and albumin at initiation of treatment were not independent risk factors associated with developing HTN in multivariate analysis. Median PFS for those with HTN was 12.5 (1.9–45.8) months vs 11.0 (2.1–44.7) for those without (p = 0.17). Hypertension induced by bevacizumab resolved in 82% of patients in a median of 87 days. There were no identifiable risk factors associated with induced HTN and HTN was not a biomarker for improved prognosis in our cohort.

Cytokeratin 5-Positive Cells Represent a Therapy Resistant subpopulation in Epithelial Ovarian Cancer.

Objective Cytokeratin 5 (CK5) is an epithelial cell marker implicated in stem and progenitor cell activity in glandular reproductive tissues and endocrine and chemotherapy resistance in estrogen receptor (ER)+ breast cancer. The goal of this study was to determine the prevalence of CK5 expression in ovarian cancer and the response of CK5+ cell populations to cisplatin therapy. Materials and Methods Cytokeratin 5 expression was evaluated in 2 ovarian tissue microarrays, representing 137 neoplasms, and 6 ovarian cancer cell lines. Cell lines were treated with IC50 (half-maximal inhibitory concentration) cisplatin, and the prevalence of CK5+ cells pretreatment and posttreatment was determined. Proliferation of CK5+ versus CK5− cell populations was determined using 5-bromo-2′-deoxyuridine incorporation. Chemotherapy-induced apoptosis in CK5+ versus CK5− cells was measured using immunohistochemical staining for cleaved caspase-3. Results Cytokeratin 5 was expressed in 39.3% (42 of 107) of epithelial ovarian cancers with a range of 1% to 80% positive cells. Serous and endometrioid histologic subtypes had the highest percentage of CK5+ specimens. Cytokeratin 5 expression correlated with ER positivity (38 of 42 CK5+ tumors were also ER+). Cytokeratin 5 was expressed in 5 of 6 overall and 4 of 4 ER+ epithelial ovarian cancer cell lines ranging from 2.4% to 52.7% positive cells. Cytokeratin 5+ compared with CK5− cells were slower proliferating. The prevalence of CK5+ cells increased after 48-hour cisplatin treatment in 4 of 5 cell lines tested. Cytokeratin 5+ ovarian cancer cells compared with CK5− ovarian cancer cells were more resistant to cisplatin-induced apoptosis. Conclusions Cytokeratin 5 is expressed in a significant proportion of epithelial ovarian cancers and represents a slower proliferating chemoresistant subpopulation that may warrant cotargeting in combination therapy.

Gynecologic biopsy for molecular profiling: a review for the interventional radiologist.

The interventional radiologist is often asked to obtain multiple biopsies of gynecological malignancies for genetic profiling. This article reviews the current indications for gynecological biopsy as well as how the information gained contributes to a personalized medicine plan for the individual patient. The specific focus of this review is the current knowledge and practice of molecular profiling for gynecological malignancies.

Metastatic cholangiocarcinoma to the ovary: a case series.

Metastases to the ovary can be a challenging diagnostic dilemma as they often present similarly to a primary ovarian cancer, and there are many potential sites of origin. We present a case series of 5 patients with known cholangiocarcinoma recurrent in the ovary after completion of initial multimodality therapy including surgical resection of the primary tumor followed by adjuvant chemotherapy.

Abstract A083: A phase Ib study of the combination of MLN0128 (dual TORC1/2 inhibitor) and MLN8237 (Aurora A inhibitor, alisertib) in patients with advanced solid tumors

Background: MLN0128 is an oral inhibitor of mTOR kinase and mTORC1/2 signaling. Alisertib is an oral inhibitor of Aurora A kinase. Senescence and upregulation of genes in the PI3K/AKT/mTor pathway have been observed in triple-negative breast cancer (TNBC) patient-derived xenograft models treated with alisertib, with greater tumor growth inhibition demonstrated in combination with MLN0128 as compared to each agent alone. An investigator-initiated trial was developed to evaluate the combination of MLN0128 and alisertib in patients with advanced solid tumors, followed by an expansion cohort in metastatic TNBC and other selected cancers. The goals of this ongoing study are to evaluate safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of the combination. Results of dose escalation are presented here. Methods: Patients with advanced solid tumors refractory to standard therapy were treated orally at escalating doses with the combination of MLN0128 daily on a continuous schedule and alisertib twice daily (BID) on days 1-7 of a 21-day cycle. Dose escalation was conducted according to a standard 3+3 design. Key eligibility criteria included HgbA1c max was 24.7 (± 13.6) ng/mL for MLN0128 and 1049 (±363) ng/mL for alisertib at combination MTD doses. MLN0128 AUC was 128.2 (±72.7) ng/mLxhr and alisertib AUC 0-8 was 6119 (±2331) ng/mlxhr at these doses. Conclusions: MLN0128 2mg daily on a continuous schedule and alisertib 30mg BID days 1-7 of a 21-day cycle is the MTD of the drug combination. An expansion cohort in patients with TNBC and other selected cancers is currently enrolling at this dose. Functional imaging and serial tumor biopsies are being integrated into this cohort to assess the pharmacodynamic interactions of the combination. Citation Format: S. Lindsey Davis, Elaine T. Lam, Bradley R. Corr, Cindy L. O9Bryant, Ashley Glode, Nichole Adler, Todd M. Pitts, John J. Tentler, Anna Capasso, Kyrie Dailey, Natalie J. Serkova, Colin D. Weekes, Daniel L. Gustafson, Christopher H. Lieu, Wells A. Messersmith, Stephen Leong, S. Gail Eckhardt, Jennifer R. Diamond. A phase Ib study of the combination of MLN0128 (dual TORC1/2 inhibitor) and MLN8237 (Aurora A inhibitor, alisertib) in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A083.

Minority Race Predicts Treatment by Non-gynecologic Oncologists in Women with Gynecologic Cancer

BackgroundOutcomes of women with gynecologic cancer are superior when treated by gynecologic oncologists. The National Surgical Quality Improvement Program (NSQIP) began identifying gynecologic surgeon subspecialty in 2014. We sought to identify characteristics and outcomes of women treated by general gynecologists in comparison with women treated by gynecologic oncologists.Patients and MethodsPatients undergoing hysterectomy for gynecologic malignancy in 2014 and 2015 were abstracted from the NSQIP database. Patient characteristics, morbidities, surgeon specialty, and operative outcomes were captured.Results7271 hysterectomies were performed for malignant disease, and 669 were performed by generalists. In comparison with generalists, gynecologic oncologists operated on patients who were older (P < 0.001), more likely to be White [odds ratio (OR) 2.1, P < 0.001], had disseminated cancer (OR 3.1, P < 0.001), had ascites (OR 2.6, P < 0.001), and were classified as American Society of Anesthesiologists (ASA) class ≥ 3 (OR 1.7, P < 0.001). Gynecologic oncologists were also more likely to have hospital readmissions (OR 1.7, P = 0.004) and perform lymph node dissections for endometrial cancer (OR 2.2, P < 0.001). On multivariable analysis, older age [adjusted OR (aOR) 1.0, P = 0.021], White race (aOR 2.0, P < 0.001), presence of disseminated cancer (aOR 2.5, P < 0.001), presence of ascites (aOR 1.8, P = 0.036), and ASA class ≥ 3 (aOR 1.6, P < 0.001) remained independent predictive factors for having a gynecologic oncology surgeon.ConclusionsThe majority of gynecologic cancer cases are performed by gynecologic oncologists. Generalists are more likely to operate on minority patients and patients with fewer comorbidities. Further efforts to ensure access to specialized cancer care for all patients are needed.

Evaluation of Preoperative Chest Imaging in Low-Risk Endometrial Cancer Patients.

Objective Current national guidelines recommend preoperative thoracic imaging for all patients undergoing surgery for endometrial cancer. The objective of this project was to report the incidence of pulmonary metastasis in endometrial cancer patients and describe tumor and patient characteristics to better identify a low-risk population for thoracic involvement. We evaluated the ideal modality of preoperative imaging for both low-risk and high-risk populations based on the risk of pulmonary involvement. Methods A retrospective cross-sectional study of patients undergoing surgical evaluation for endometrial cancer at a single institution from 2010 to 2014 was performed. Low-risk patients were defined as having a preoperative pathology sample showing grade 1 or 2 endometrioid endometrial cancer and a physical examination not concerning for extrauterine disease spread. Results A total of 352 patients were evaluated, of which 327 (92.9%) had preoperative thoracic imaging. Twenty-six patients had benign pathology or no preoperative sampling, leaving 301 patients for analysis. There were 228 (75.7%) of 301 patients classified as low-risk by our criteria. There were 20 (8.8%) of 228 low-risk patients with initial imaging concerning for pulmonary metastasis, but follow-up showed no evidence of disease. No low-risk patients (0/228; 95% confidence interval [CI], 0%–0.02%) had pulmonary metastasis. There were 4 (1.3%) of 301 (95% CI, 0%–0.04%) patients diagnosed with pulmonary metastasis based on preoperative imaging, and 4 (1.3%) of 301 (95% CI, 0.01%–0.04%) patients with recurrent pulmonary disease. Median time to pulmonary recurrence was 20 months. Conclusions The incidence of pulmonary metastasis found on preoperative imaging is exceptionally low in our defined low-risk population. All of the patients with pulmonary involvement either initially or upon recurrence had high-risk features. Given our findings, we would recommend that providers consider chest x-ray as the appropriate screening modality for the low-risk population and chest computed tomography for the high-risk population.