Faculty Bibliography

PURPOSE:Despite the tissue-agnostic approval of pembrolizumab in mismatch repair deficient (MMRD) solid tumors, important unanswered questions remain about the role of immune checkpoint blockade in mismatch repair-proficient (MMRP) and -deficient endometrial cancer (EC). METHODS:; and (2) MMRP cohort with normal IHC expression of all MMR proteins. Coprimary end points were objective response (OR) and progression-free survival at 6 months (PFS6). Avelumab 10 mg/kg intravenously was administered every 2 weeks until progression or unacceptable toxicity. RESULTS:-mutated. The MMRP cohort was closed at the first stage because of futility: Only one of 16 patients exhibited both OR and PFS6 responses. The MMRD cohort met the predefined primary end point of four ORs after accrual of only 17 patients; of 15 patients who initiated avelumab, four exhibited OR (one complete response, three partial responses; OR rate, 26.7%; 95% CI, 7.8% to 55.1%) and six (including all four ORs) PFS6 responses (PFS6, 40.0%; 95% CI, 16.3% to 66.7%), four of which are ongoing as of data cutoff date. Responses were observed in the absence of PD-L1 expression. IHC captured all cases of MMRD subsequently determined by polymerase chain reaction or genomically via targeted sequencing. CONCLUSION:mutated ECs was low.

OBJECTIVE:To examine the association between ovarian conservation and oncologic outcome in surgically-treated young women with early-stage, low-grade endometrial cancer. METHODS:This multicenter retrospective study examined women aged <50 with stage I grade 1-2 endometrioid endometrial cancer who underwent primary surgery with hysterectomy from 2000 to 2014 (US cohort n = 1196, and Japan cohort n = 495). Recurrence patterns, survival, and the presence of a metachronous secondary malignancy were assessed based on ovarian conservation versus oophorectomy. RESULTS:During the study period, the ovarian conservation rate significantly increased in the US cohort from 5.4% to 16.4% (P = 0.020) whereas the rate was unchanged in the Japan cohort (6.3-8.7%, P = 0.787). In the US cohort, ovarian conservation was not associated with disease-free survival (hazard ratio [HR] 0.829, 95% confidence interval [CI] 0.188-3.663, P = 0.805), overall survival (HR not estimated, P = 0.981), or metachronous secondary malignancy (HR 1.787, 95% CI 0.603-5.295, P = 0.295). In the Japan cohort, ovarian conservation was associated with decreased disease-free survival (HR 5.214, 95% CI 1.557-17.464, P = 0.007) and an increased risk of a metachronous secondary malignancy, particularly ovarian cancer (HR 7.119, 95% CI 1.349-37.554, P = 0.021), but was not associated with overall survival (HR not estimated, P = 0.987). Ovarian recurrence or metachronous secondary ovarian cancer occurred after a median time of 5.9 years, and all cases were salvaged. CONCLUSION:Our study suggests that adoption of ovarian conservation in young women with early-stage low-grade endometrial cancer varies by population. Ovarian conservation for young women with early-stage, low-grade endometrial cancer may be potentially associated with increased risks of ovarian recurrence or metachronous secondary ovarian cancer in certain populations; nevertheless, ovarian conservation did not negatively impact overall survival.

BACKGROUND:Complete surgical resection affords the best prognosis at the time of interval debulking surgery. When complete surgical resection is unachievable, optimal residual disease is considered the next best alternative. Despite contradicting evidence on the survival benefit of interval debulking surgery if macroscopic residual disease remains, the current definition of "optimal" in patients undergoing interval debulking surgery is defined as largest diameter of disease measuring ≤1.0 cm, independent of the total volume of disease. OBJECTIVE:To examine the relationship between volume and anatomic distribution of residual disease and oncologic outcomes among patients with advanced-stage epithelial ovarian/fallopian tube/primary peritoneal carcinoma undergoing neoadjuvant chemotherapy then interval debulking surgery. For patients who did not undergo a complete surgical resection, a surrogate for volume of residual disease was used to assess oncologic outcomes. STUDY DESIGN:Patient demographics, operative characteristics, anatomic site of residual disease, and outcome data were collected from medical records of patients with International Federation of Gynecology and Obstetrics stage IIIC and IV epithelial ovarian cancer undergoing interval debulking surgery from January 2010 to July 2015. Among patients who did not undergo complete surgical resection but had ≤1 cm of residual disease, the number of anatomic sites (single location vs multiple locations) with residual disease was used as a surrogate for volume of residual disease. The effect of residual disease volume on progression-free survival and overall survival was evaluated. RESULTS:Of 270 patients undergoing interval debulking surgery, 173 (64.1%) had complete surgical resection, 34 (12.6%) had ≤1 cm of residual disease in a single anatomic location, 47 (17.4%) had ≤1 cm of residual disease in multiple anatomic locations, and 16 (5.9%) were suboptimally debulked. Median progression-free survival for each group was 14, 12, 10, and 6 months, respectively (P<.001). Median overall survival for each group was: 58, 37, 26, and 33 months, respectively (P<.001). CONCLUSION:Following interval debulking surgery, patients with complete surgical resection have the best prognosis, followed by patients with ≤1 cm single-anatomic location disease. In contrast, despite being considered "optimally debulked," patients with ≤1 cm multiple-anatomic location disease have a survival similar to suboptimally debulked patients.

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.