Faculty Bibliography

OBJECTIVES:To determine whether perioperative red blood cell transfusion (PRBCT) affects infection, thrombosis, or survival rates in epithelial ovarian cancer (EOC) patients undergoing neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS). METHODS:Demographics, operative characteristics, and outcome data were abstracted from records of stage IIIC-IV EOC patients managed with NACT-IDS from 01/2010-07/2015. Associations of PRBCT with morbidity and oncologic outcomes were evaluated. RESULTS:Of 270 patients, 136 (50.4%) received PRBCT. Patients with preoperative anemia and higher estimated blood loss (EBL) were more likely to undergo PRBCT (OR,95%CI 1.80, 1.02-3.17) and (OR,95%CI 1.00, 1.002-1.004), respectively. There were no significant differences in PRBCT based on patient age, Charlson Comorbidity Index, or stage. When compared to low complexity operations, patients with moderate and high complexity surgeries were more likely to receive PRBCT (OR,95%CI 1.81, 1.05-3.09) and (OR,95%CI 2.25, 1.13-4.50), respectively. On univariate analysis, PRBCT was associated with intraabdominal infection (OR,95%CI 8.31, 1.03-67.41), but not wound complications (OR,95%CI 1.57, 0.76-3.23) or venous thromboembolism/pulmonary embolism (VTE/PE) (OR,95%CI 2.02, 0.49-8.23). After adjusting for surgical complexity and preoperative anemia, PRBCT was not independently associated with intraabdominal infection (OR,95%CI 7.66, 0.92-63.66), wound complications (OR,95%CI 1.70, 0.80-3.64), or VTE/PE (OR,95%CI 2.15, 0.51-9.09). When comparing patients undergoing PRBCT versus those who did not, there were no significant differences in median progression-free survival (PFS) or median overall survival (OS) on univariate analysis after adjusting for age, stage and residual disease. CONCLUSIONS:Among patients undergoing NACT-IDS, intraabdominal infection, wound complication and VTE/PE rates are similar, regardless of PRBCT. PRBCT does not impact PFS or OS.

OBJECTIVE:A scoring system has been proposed to predict gross residual disease at primary debulking surgery (PDS) for advanced epithelial ovarian cancer. This scoring system has not been assessed in patients undergoing neoadjuvant chemotherapy (NACT). The aim of this study is to assess the reproducibility and prognostic significance of the scoring system when applied to women undergoing NACT followed by interval debulking surgery (IDS). METHODS:A retrospective cohort study was conducted of patients with advanced ovarian cancer who underwent NACT and IDS between 2005 and 2014. Change in tumor burden using computed tomography (CT) at diagnosis (T0) and after initiation of NACT but before IDS (T1) was independently assessed by two radiologists blinded to outcomes using two read criteria: a scoring system utilizing clinical and radiologic criteria and RECIST 1.1. Relationship between CT assessments to surgical outcome, progression free survival (PFS) and overall survival (OS) were evaluated. Reader agreement was measured using Fleiss's kappa (ĸ). RESULTS:76 patients were analyzed. Optimal surgical outcome was achieved in 69 (91%) of patients. Median progression free survival was 13.2 months and overall survival was 32.6 months, respectively. Predictive score change from T0 to T1 of >1 (denoting an improvement in disease burden) was associated with optimal cytoreduction (p = 0.02 and 0.01 for readers 1 and 2, respectively). Neither predictive score nor RECIST 1.1 assessment was predictive of OS or PFS. Reader agreement was substantial for predictive score (κ = 0.77) and moderate for RECIST (κ = 0.51) assessments. CONCLUSIONS:A change in score before and after neoadjuvant chemotherapy minimizes reader variability and predicts surgical outcome.

PARP inhibitors (PARPi) are FDA-approved monotherapy agents for the treatment of recurrent ovarian cancer in patients with and without a BRCA mutation. Despite promising response rates, not all patients derive benefit, and the majority develop resistance. PARPi treatment in vitro and in vivo induced an enrichment of CD133⁺ and CD117⁺ ovarian cancer stem cells (CSC). This effect was not affected by BRCA mutation status. In the CSC fractions, PARPi induced cell-cycle arrest in G₂-M with a consequent accumulation of γH2AX, RAD51, and uniquely DMC1 foci. DNA damage and repair monitoring assays demonstrated that CSCs display more efficient DNA repair due, in part, to activation of embryonic repair mechanisms which involved the RAD51 homologue, DMC1 recombinase. Preserved and induced homologous repair (HR) could be a mechanism of an inherent resistance of CSCs to the synthetic lethality of PARPi that likely promotes disease recurrence. IMPLICATIONS: Treatment with PARPi fails to significantly affect ovarian cancer CSC populations, likely contributing to recurrent disease. Ovarian cancer CSCs stabilize genomic integrity after PARPi treatment, due to a more efficient inherent DNA repair capacity. PARPi-induced DMC1 recombinase and HR proficiency provide CSCs the opportunity to repair DNA damage more efficiently.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/2/431/F1.large.jpg.

OBJECTIVE:This study aims to understand the treatment patterns and clinical outcomes of older women with cervical cancer compared to younger women. METHODS:Women undergoing care for cervical cancer between 2000 and 2013 at two academic institutions were identified. The cohort of older patients was defined as >65 years old at diagnosis. Patient charts were retrospectively reviewed, and clinical variables were extracted. Fisher's exact tests, logistic regression, and Kaplan-Meier analyses were performed. RESULTS:From 2000 to 2013 1119 women with cervical cancer were identified. Of these, 191 (17.0%) were >65 years old at the time of diagnosis. Older women were more likely to present with higher stage disease (p < 0.001). Controlling for stage, older women were less likely to undergo surgery during their treatment course (38% versus 70%, p < 0.001) and more likely to undergo radiation (77% versus 52%, p < 0.001), but no more likely to receive chemotherapy (p = 0.34). If they did undergo surgery, older women were less likely to have a pelvic lymph node dissection performed (41% versus 61%, p = 0.04), though the rate of positive pelvic lymph nodes was not different (p = 0.80). Overall survival was decreased in the older cohort (p < 0.001). A multivariate model identified age > 65 (HR 1.76, 95%CI 1.30-2.40), stage (HR 2.77, 95%CI 2.40-3.21), and ever undergoing surgery (HR 0.60, 95%CI 0.44-0.82) as independently associated with overall survival. CONCLUSIONS:Women over age 65 with cervical cancer are less likely to undergo surgical management and were observed to have a decreased overall survival, even when controlling for use of surgery and stage of disease.

OBJECTIVES:To examine the relationship between volume of residual disease and oncologic outcomes among patients with advanced-stage epithelial ovarian/fallopian tube/primary peritoneal carcinoma undergoing primary debulking surgery (PDS). For patients that did not undergo a complete surgical resection (CSR), a surrogate for volume of residual disease was used to assess oncologic outcomes. METHODS:Medical records of patients with FIGO stage IIIC and IV epithelial ovarian/fallopian tube/primary peritoneal carcinoma undergoing PDS between January 2010 and November 2014 were reviewed. Patient demographics, operative characteristics, residual disease, anatomic site of residual disease and outcome data were collected. Among patients who did not undergo CSR, but had ≤1 cm of residual disease, the number of anatomic sites (single location vs. multiple locations) with residual disease was utilized as a surrogate for volume of residual disease. The effect of residual disease volume on progression-free survival (PFS) and overall survival (OS) was evaluated. RESULTS:Of 240 patients undergoing PDS, 94 (39.2%) had CSR, 41 (17.1%) had ≤1 cm of residual disease confined to a single anatomic location (≤1 cm-SL), 67 (27.9%) had ≤1 cm of residual disease in multiple anatomic locations (≤1 cm-ML) and 38 (15.8%) were sub-optimally (SO) debulked. Median PFS for CSR, ≤1 cm-SL, ≤1 cm-ML and SO-debulked were: 23, 19, 13 and 10 months, respectively (p < 0.001). Median OS for CSR, ≤1 cm-SL, ≤1 cm-ML and SO-debulked were: Not yet reached, 64, 50 and 49 months, respectively (p = 0.001). CONCLUSIONS:Following PDS, CSR and ≤ 1 cm-SL patients have the best prognosis. In contrast, despite being considered "optimally debulked", ≤1 cm-ML patients have survival similar to those SO-debulked.

Recurrent ovarian cancer (OvCa) is thought to result in part from the inability to eliminate rare quiescent cancer stem cells (CSCs) that survive cytotoxic chemotherapy and drive tumor resurgence. The Sialyl-Thomsen-nouveau antigen (STn) is a carbohydrate moiety present on protein markers of CSCs in pancreatic, colon, and gastric malignancies. We have demonstrated that human OvCa cell lines contain varying levels of cells that independently express either STn or the ovarian CSC marker CD133. Here we determine co-expression of STn and CD133 in a subset of human OvCa cell lines. Analyses of colony and sphere forming capacity and of response to standard-of-care cytotoxic therapy suggest a subset of OvCa STn⁺ cells display some CSC features. The effect of the anti-STn antibody-drug conjugates (ADCs) S3F-CL-MMAE and 2G12-2B2-CL-MMAE on OvCa cell viability in vitro and in vivo was also assessed. Treatment with S3F-CL-MMAE reduced the viability of two of three OvCa cell lines in vitro and exposure to either S3F-CL-MMAE or 2G12-2B2-CL-MMAE reduced OVCAR3-derived xenograft volume in vivo, depleting STn⁺ tumor cells. In summary, STn⁺ cells demonstrate some stem-like properties and specific therapeutic targeting of STn in ovarian tumors may be an effective clinical strategy to eliminate both STn⁺ CSC and STn⁺ non-CSC populations.

BACKGROUND:The American Society of Clinical Oncology recommends that patients with advanced cancer receive dedicated palliative care services early in their disease course. This investigation serves to understand how palliative care services are utilized for ovarian cancer patients in a tertiary referral center. METHODS:We conducted a retrospective review of women treated for ovarian cancer at our institution from 2010 through 2015. Clinical variables included presence and timing of palliative care referral. Data were correlated utilizing univariable and multivariable parametric and non-parametric testing, and survivals were analyzed using the Kaplan-Meier method and cox-proportional hazard models. RESULTS:We identified 391 women treated for ovarian cancer, of whom 68% were diagnosed with stage III or IV disease. Palliative care referral was utilized in 28% in the outpatient (42%) and inpatient (58%) settings. Earlier use of referral was observed in those who never underwent surgical cytoreduction or had interval cytoreductive surgery (p < 0.001). Palliative care referral was independently associated with advanced stage (OR 1.7, p = 0.02), recurrence (OR 2.0, p = 0.002) and hospice referral (OR 6.0, p < 0.001). In 38% of women referral occurred within 30 days of death, and 17% within one week of death. Outpatient initial consultation was associated with an unadjusted 1 year overall survival benefit (p < 0.01) compared to inpatient consultation. CONCLUSIONS:The outcomes in this study suggest a late use of palliative care that is reactionary to patient needs and not a routine component of ovarian cancer care as national guidelines recommend.

BACKGROUND:The objective of this investigation was to characterize the expression landscape of immune regulatory molecules programmed death-ligand-1 (PD-L1, B7-H1) and B7-H4 in a cohort of endometrial tumors across the spectrum of grade and histology. MATERIALS AND METHODS:With institutional review board approval, 70 endometrial tumors from patients with known clinical outcomes were identified representing a spectrum of grade and histology. Immunohistochemistry (IHC) was performed for PD-L1 and B7-H4 and scored. Microsatellite instability (MSI) status was assessed for endometrioid tumors using the institutional IHC assay for expression of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2. RNA sequencing data from the Cancer Genome Atlas was queried for expression levels of CD274 (PD-L1 protein) and VTCN1 (B7-H4) across molecular subtypes of endometrial carcinoma and were correlated with a T cell infiltration index. RESULTS:We identified 40 low grade endometrioid tumors and a cohort of 30 high grade tumors. PD-L1 expression was observed in both high and low grade endometrial tumors (56% vs 35%, p=0.07). In the low grade tumors, PD-L1 expression was associated with MSI status (p<0.01). The high grade cohort had similar rates of PD-L1 expression compared to low grade MSI tumor (56% and 62% respectively), and both were distinct from low grade MSS tumors (22%, p<0.05). High (3+) B7-H4 positive cells were observed in both high and low grade carcinomas (33% and 31% respectively). RNA profiling data from confirmed highest CD274 expression in POLE and MSI tumors that was linearly correlated with T cell infiltration, while VTCN1 expression appeared consistent across molecular subtypes. CONCLUSIONS:While PD-L1 expression correlated with MSI and high grade tumors, B7-H4 expression was independent of grade, histology and immune cell infiltration. The development and testing of multi-agent therapeutics targeting PD-L1 and B7-H4 may be a novel strategy for endometrial tumors.

OBJECTIVE:To compare 3-year survival, length of hospitalization, perioperative mortality, risk of readmission, and residual disease associated with laparoscopic and laparotomic interval debulking surgery among women with epithelial ovarian cancer. METHODS:We used the National Cancer Database to identify a cohort of patients diagnosed with stage IIIC and IV epithelial ovarian cancer between 2010 and 2012 who underwent neoadjuvant chemotherapy and interval debulking surgery. We compared 3-year overall survival, duration of postoperative hospitalization, 90-day postoperative mortality, and residual disease status between women who underwent interval debulking by laparoscopy and by laparotomy. We used the Kaplan-Meier method and Cox regression models in survival analyses. At a significance of .05, this study had 80% power to detect an 8% difference in 3-year survival. The main analysis was intention to treat. RESULTS:We identified 3,071 women meeting inclusion criteria, of whom 450 (15%) underwent surgery initiated laparoscopically. There was no difference in 3-year survival between patients undergoing laparoscopy [47.5%; 95% confidence interval (CI) 41.4-53.5] and laparotomy (52.6%; 95% CI 50.3-55.0; P=.12). Survival did not differ after adjustment for demographic characteristics, facility type, presence of comorbidities, and stage (adjusted hazard ratio, 1.09; 95% CI 0.93-1.28; P=.26). Postoperative hospitalization was slightly shorter in the laparoscopy group (median 4 compared with 5 days, P<.001). Frequency of readmission (5.3% compared with 3.7%; P=.26), death within 90 days of surgery (2.8% compared with 2.9%, P=.93), and suboptimal debulking (20.6% compared with 22.6%, P=.29) did not differ between patients undergoing laparoscopy and laparotomy. CONCLUSION:Ovarian cancer patients selected for laparoscopic interval debulking surgery after neoadjuvant chemotherapy have 3-year survival rates similar to women who undergo interval debulking by laparotomy. Laparoscopy is associated with a modestly shorter postoperative hospitalization, whereas readmission rates and risk of perioperative death are similar for the surgeries.

STUDY OBJECTIVE:To assess outcomes of women with cervical cancer undergoing upfront radical hysterectomy (RH) via a minimally invasive surgery (MIS) or a traditional laparotomy (XL) approach at 2 large US academic institutions to determine whether the mode of surgery affects patient outcomes. DESIGN:Retrospective cohort study (Canadian Task Force classification II-1). SETTING:Two academic medical institutions in the United States. PATIENTS:Women undergoing upfront RH for cervical cancer between 2000 and 2013. INTERVENTION:Minimally invasive techniques (laparoscopic and robotic) for RH compared with XL. MEASUREMENTS AND MAIN RESULTS:) and a higher rate of perioperative blood transfusion (3.0% vs 26.2%; p < .001). Length of perioperative hospital stay was significantly shorter in the MIS group (1.9 days vs 4.9 days; p < .001). CONCLUSION:MIS RH does not compromise patient outcomes, including overall survival, rate of recurrence, and the frequency of pelvic lymph node dissection or positivity. Morbidity was decreased in the MIS group, including decreased EBL, fewer blood transfusions, and shorter hospital stay.