Brandon-Luke L. Seagle

Covariate-Adjusted Restricted Mean Survival Times and Curves

TO THE EDITOR: We applaud Trinquart et al for their recent article in Journal of Clinical Oncology, which was a structured metaanalysis comparing the use of hazard ratios (HRs) with restricted mean survival times (RMSTs). We write to expand on the merits of RMST estimates and to demonstrate their adjustment by covariates. Trinquart et al observed that use of RMSTs rather than HRs led to the same statistical conclusion in 53 of 54 trials, that use of the HRs resulted in systematically more optimistic estimated effects, and that there was evidence of nonproportionality of hazards in 24% of trials under study. Statisticians are comfortable noting that the HR is the log-difference in first derivative of the survival function, assuming proportional hazards (PHs) are constant over time. Analogous to the area under the survival curve, the RMST is an intuitive descriptive statistic because it reports treatment effects on the scale of months or years rather than relative hazard. We submit that methods for adjusting RMST for covariates can be performed using a workflow whereby RMST estimates are derived from a Cox regression model. An illustration follows using the R language package survival: the data set colon is a randomized trial of levamisole (Lev) versus Lev with fluorouracil (Lev 1 FU) for adjuvant treatment of colon cancer. The trial reported that the addition of fluorouracil significantly increased recurrence-free survival (log-rank test, P , .001). The Kaplan-Meier estimates show amedian 38.8 months versus NAmonths. The awkward term NA reflects a survival curve with too few events to observe the time at which 50% of subjects remain event free: 185 of 304 Lev 1 FU subjects (61%) were event free at the end of the study, hence the termNA. Under a PHmodel, the HRwas 0.61 (95%CI, 0.48 to 0.77). Truncating follow-up at 60 months, the RMST estimates were 36.0 and 43.7 months. RMSTestimates offer an advantage compared with the Kaplan-Meier–estimated medians (which cannot be estimated for the Lev1 FUarm) andHRs (which do not yield a time estimate of the survival benefit). To demonstrate covariate adjustment, we fitted an additive Cox model for treatment and age. The age effect is weakly supported by

Metastatic Uterine Leiomyosarcoma Involving Bilateral Ovarian Stroma without Capsular Involvement Implies a Local Route of Hematogenous Dissemination

Uterine sarcomas spread via lymphatic and hematogenous dissemination, direct extension, or transtubal transport. Distant metastasis often involves the lungs. Ovarian metastasis is uncommon. Here we present an unusual case of a large, high-grade uLMS with metastatic disease internal to both ovaries without capsular involvement or other abdominal diseases, and discovered in a patient with distant metastases to the lungs, suggesting likely hematogenous dissemination of uLMS to the ovaries in this case. Knowledge of usual uLMS metastases may influence surgical management in select cases.

Scholarship Support for Veterans Enrolling in MD, JD, and MBA Programs

Enrolling in MD, JD, and MBA Programs Military veterans may bring a distinct perspective to medicine, law, business, or other professions or occupations. The Post-9/11 GI Bill is a scholarship program that can be used for most accredited degree programs (including undergraduate and graduate programs, such as medical, law, or business school) and is available to all honorably discharged veterans who served on active duty. This program covers all tuition and fees for a veteran if attending an in-state public school. For private or out-of-state public schools, the GI Bill covers a portion of tuition and fees not to exceed the maximum allowed by law per academic year. To supplement the GI Bill’s support, an academic graduate program may elect to participate in the Yellow Ribbon scholarship program at the amount of its choosing to be matched by the Veterans Administration (VA). Total VA scholarship support is funds received from the GI Bill, the graduate program’s offered Yellow Ribbon award, and the matching VA Yellow Ribbon award. We examined VA scholarship support by MD programs, determined by participation in the Yellow Ribbon program, and compared it with juris doctorate (JD) and master of business administration (MBA) programs at the same institutions.

The Impact of a Hospital Based Doula Program on Cesarean Section Rate [28O]

INTRODUCTION: Previous studies have shown a positive association between continuous labor support and positive perinatal outcomes including a shortened duration of labor, increased rate of spontaneous vaginal delivery and a decreased use of interventions including oxytocin, analgesia, operative vaginal deliveries and cesarean sections. The purpose of this study was to compare labor and delivery outcomes between a cohort of patients who received hospital-sponsored doula continuous labor support and a matched cohort of patients who did not elect to receive doula services. METHODS: We analyzed the charts of all patients who delivered a single infant either by cesarean section or vaginal delivery between 1/1/2012 and 12/31/2013 at Danbury Hospital. Planned cesarean sections, multifetal gestations, fetal demises, urgent or emergent deliveries, and precipitous deliveries were excluded. The primary outcome was cesarean section rate. Secondary outcomes also calculated included labor augmentation rate, labor induction rate, VBAC rate, neonatal outcomes (Apgar score, weight). The results were adjusted for patient age and parity. RESULTS: After exclusions, the cohort of patients who received doula care included 275 women and the matched cohort included 2688 patients. The rate of cesarean section in the Doula group was 19.6% whereas the rate was 16.2% in the control group (P=.315). VBAC rate, augmentation and induction rate were not statistically different between the two groups. CONCLUSION: This study did not show a statistically significant decreased cesarean section rate among women who had continuous labor support. Limitations of this study include small sample size, limited data on socioeconomic factors between groups and possible confounding factors.

Abstract 4754: Overexpression of TSH and ERBB2 (HER2) receptors is associated with sharply decreased survival in high grade serous ovarian cancer

Objective. To test if hormone or growth factor receptor expression is associated with survival among patients with high grade serous ovarian cancer (HGS OvCa) we analyzed tumor mRNA expression microarray and clinical data from The Cancer Genome Atlas (TCGA). Methods. HGS OvCa patients were surgically staged prior to treatment with IP (n = 90) or IV-only (n = 398) chemotherapy. Multivariate Cox proportional-hazards regression tested associations of expression of 9 hormone or growth factor receptors with progression free survival (PFS) and overall survival (OS). Hazard ratios are hazard per each one standard deviation increase in gene expression. Expression was analyzed as a continuous variable by restricted mean survival analysis. Mean PFS or OS were compared between IP and IV groups by permutation testing stratified by expression. P-values were two-tailed. Results. Expression of ESR1, PGR, FSHR, LHCGR, MET, and EGFR were not associated with PFS or OS. TSHR expression was associated with decreased OS (HR 1.22 (1.06-1.41), p = 0.005) and PFS (HR 1.18 (1.05-1.33), p = 0.006) among IV-only treated patients. ERBB2 expression was associated with decreased OS (HR 1.48 (1.05-2.10), p = 0.027) among patients who received IP chemotherapy. Using multigene (ESR2, PGR, TSHR, and ERBB2) analysis, among the IP group, ERBB2 (HR 1.76 (1.11-2.79), p = 0.015) and ESR2 (HR 0.28 (0.08-0.93), p = 0.037) were associated with OS. Only TSHR expression was associated with decreased OS (HR 1.22 (1.06-1.41), p = 0.005) and decreased PFS (HR 1.18 (1.05-1.33), p = 0.007) on multigene analysis of IV-only treated patients. OS and PFS decreased steeply at high expression of TSHR and ERBB2. Among patients with upper 10th percentile TSHR expression, no significant difference in mean OS or PFS was observed between patients treated with IP versus IV-only chemotherapy. Patients with lower TSHR expression ( Conclusions. Among HGS OvCa patients treated with IV-only chemotherapy, increased tumor TSHR expression was associated with decreased OS and PFS. High TSHR expression characterized patients who did not benefit from IP chemotherapy. Citation Format: Brandon-Luke L. Seagle, Monica Dandapani, Chen Hui Luo, Claire Hoppenot, Robert Samuelson, Kevin H. Eng, Kunle Odunsi, Shohreh Shahabi. Overexpression of TSH and ERBB2 (HER2) receptors is associated with sharply decreased survival in high grade serous ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4754.

Abstract 4753: Ovarian cancer stem cell marker ALDH1A2 is a candidate biomarker for patient selection for intraperitoneal chemotherapy

Objective. To evaluate ovarian cancer stem cells as predictors of survival we analyzed associations of cancer stem cell markers ALDH1, CD117 and CD133 with survival outcomes among patients with high grade serous ovarian cancer (HGS OvCa). Methods. Data from HGS OvCa patients who were surgically staged prior to treatment with IP (n = 90) or IV-only (n = 398) chemotherapy was obtained from The Cancer Genome Atlas. Multivariate Cox proportional-hazards regression tested associations of tumor mRNA expression of 5 cancer stem cell markers with progression free survival (PFS) and overall survival (OS). Expression was analyzed as a continuous variable by restricted mean survival (RMS) analysis. Mean PFS or OS were compared between IP and IV groups by permutation testing stratified by expression. P-values were two-tailed. Results. Increased tumor ALDH1A2 expression was associated with decreased OS among patients treated with IP chemotherapy, HR 2.36 (1.16-4.80), p = 0.017. IP treated patients with upper 20th percentile ALDH1A2 expression had decreased OS compared to bottom 20th percentile expression (30.4 versus 51.1 months, -20.7 months difference, p = 0.017). RMS curves for PFS and OS of IP versus IV treated patients crossed at high ALDH1A2 expression, indicating that IP treated patients had decreased survival compared to IV-only treated patients. Patients with upper 20th percentile ALDH1A2 expression treated with IP versus IV-only chemotherapy had no difference in mean PFS (21.3 versus 21.6 months, -0.3 months difference, p = 0.67) and decreased OS (30.4 versus 35.3 months, -4.9 months difference, p Conclusions. High primary tumor ALDH1A2 expression was independently associated with significantly decreased OS among patients treated with IP chemotherapy. High ALDH1A2 was associated with lack of benefit or decreased survival among patients treated with IP compared to IV-only adjuvant chemotherapy. Citation Format: Brandon-Luke L. Seagle, Monica Dandapani, Chen Hui Luo, Claire Hoppenot, Robert Samuelson, Kevin H. Eng, Kunle Odunsi, Shohreh Shahabi. Ovarian cancer stem cell marker ALDH1A2 is a candidate biomarker for patient selection for intraperitoneal chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4753.

Abstract 4442: TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizing agents in monoclonal cells and comparison of clinical outcomes from The Cancer Genome Atlas data

TP53 is mutated in 96% of high grade serous epithelial ovarian carcinomas (HGS EOC) sequenced by The Cancer Genome Atlas (TCGA). Missense mutations at hot spot codons R273, R248, and R175 are the most common oncogenic TP53 mutations among ovarian cancers. To evaluate if TP53 hot spot mutations confer selective resistance to microtubule stabilizing agents (MSAs), the effects of MSAs on hot spot TP53 mutant ovarian carcinoma cell lines were determined. HGS EOCs that expressed one of the three most common TP53 hot spot missense mutations were also identified and studied using TCGA datasets. The human TP53 wild-type ovarian carcinoma cell line A2780 was stably transfected with an empty vector pCMV-neo or a missense TP53 mutation at hot spot codon 175 (m175), 248 (m248), or 273 (m273). Doubling times and inhibitory concentrations of each cell line treated with the MSAs paclitaxel, epoB, and ixabepilone were determined. Effects of epoB on TP53 expression, phosphorylation, and acetylation, as well as TP53-regulated expression of p21 and mdm2, were examined by Western blot analysis. Expression of TP53 target genes p21, GADD45, BAX, PIDD, NF-kB2, PAI-1, and MDR1 was also measured by RT-PCR. Available TCGA genomic and clinical datasets of HGS EOCs were used to identify patients whose tumors expressed one of the three most common TP53 hot spot mutations. Progression free and overall survival outcomes, TP53 expression levels, and available disease and treatment parameters of patients with the hot spot mutations were compared. PARP cleavage, cell growth and cytotoxicity studies demonstrate that the TP53 mutant cell line m248 is resistant to epoB and is not acetylated during epoB treatment. p21 and PAI-1 were induced by epoB in A2780 cells. Expression of p21, GADD45 and PAI-1 in mutant cell lines was generally down regulated. The cell line m273 is 2-3-fold resistant to paclitaxel, possibly due to high expression of MDR1. Patients identified from available TCGA ovarian cancer datasets whose tumors expressed a TP53 missense mutation at codon R273 (n = 15), R248 (n = 11), or R175 (n = 15) demonstrated 10.8, 12.3 and 17.8 months (p = 0.54) median progression free survival and 84.1, 36.1, and 60.6 months (p = 0.23) median overall survival outcomes, respectively. Differences in TP53 expression level, debulking status, disease stage and grade, and age at presentation between cases grouped according to hot spot mutation were not significant. Monoclonal human ovarian cancer cells with different TP53 hot spot mutations were selectively resistant to MSAs paclitaxel and epoB. Patients with HGS EOC and a TP53 hot spot mutation had comparable charactertistics and outcomes. Mutational studies in monoclonal cell lines may offer limited insight regarding clinical disease in HGS EOC considering the established high genetic instability and heterogeneity of HGS EOC. Citation Format: Brandon-Luke L. Seagle, Gerda Hofstteter, Chia-Ping Yang, Kevin Eng, Oluwatosin Odunsi-Akanji, Kunle Odunsi, Shohreh Shahabi. TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizing agents in monoclonal cells and comparison of clinical outcomes from The Cancer Genome Atlas data. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4442. doi:10.1158/1538-7445.AM2015-4442