So obtained from the National Cancer Institute (http://discover.nci.nih.gov). Microarray gene expression data for frozen tissue samples obtained at the time of primary cytoreductive surgery from two large human ovarian cancer cohorts were used for the development and independent evaluation of our drug-response predictors. Clinical follow-up information after surgery and chemotherapy were fully available for these cohorts. The first cohort of 185 EOC patients treated with adjuvant chemotherapy, Bonome-185, was originally obtained for identifying prognostic molecular signatures of survival [11]. Of 185 patients, 112 (67 ) showed complete response (CR), 41 (25 ) partial response (PR), 14 (8 ) progression of disease (PD), and 18 had unrecorded APTO-253 site responses to the primary chemotherapy (Table 1). The best response to chemotherapy was determined according to RECIST or WHO criteria at the completion of adjuvant chemotherapy [12,13]. The second set of 448 epithelial ovarian cancer patients whose Affymetrix gene expression profiling and clinical follow-up data were available, TCGA-448, was obtained from The Cancer Genome Atlas (TCGA) consortium (http://tcga-data.nci.nih.gov) [14]. These EOC patients from .10 diverse clinical BLU-554 site centers had received primary platinum-based chemotherapy after surgery. The primary chemotherapy responses of this cohort were comprised of 272 (60.71 ) patients with CR, 54 with PR, 25 with stable disease (SD), and 36 with PD. However, a majority of the patients experienced recurrence or progression of disease and so were subsequently treated with additional chemotherapy drugs such as cyclophosphamide and topotecan. In particular, of 100 recurrent patients treated with topotecan, 47 patients were from the University of Washington (TCGA-UW) and the remainingPLOS ONE | www.plosone.orgSurvival Improvement by Personalized ChemotherapyTable 1. Epithelial ovarian cancer (EOC) patient cohorts for the development and validation of integrated predictors for patient response to standard chemotherapy drugs.Historical patient cohorts Characteristic Median Age(range) Stage I II III IV Others Histology Serous Clear Cell Others Surgical Outcome Optimal (,1 cm) Sub-optimal (. = 1 cm) Others (missing) Response to Initial Therapy CR PR SD PD Others Recurrence/ Disease Free Deaths Survival (month) Median PFS Median OS .5.83 44.2 16.7 44.8 12.42 50.4 112 (60.5 ) 41 (22.2 ) ?14 (7.6 ) 18 (9.7 ) ?145 (78.4 ) 272 (60.7 ) 54 (12 ) 25 (5.6 ) 36 (12.1 ) 61 (13.6 ) 332 (74.1 ) 238 (53.1 ) 28 (54.9 ) 22 (43.1 ) ?1 (2 ) ?44 (58 ) 31 (60.8 ) 92 (49.7 ) 93 (50.3 ) ?291 (65 ) 111 (24.8 ) 46 (10.3 ) 21 (41.2 ) 28 (54.9 ) 2 (3.9 ) 166 (89.7 ) ?19 (10.3 ) 448 (100 ) ??42 (82.4 ) 5 (9.8 ) 4 (7.8 ) 41 (41.4 ) 8 (8.1 ) 50 (50.5 ) ??144 (77.8 ) 41 (22.2 ) ??24 (5.4 ) 354 (79 ) 68 (15.2 ) 2 (0.4 ) ??46 (90.2 ) 5 (9.8 ) ?35 (35.4 ) 11 (11.1 ) 44 (44.4 ) 9 (9.1 ) ?Bonome185 63.6(26?5) TCGA-448 59 (27?7) UVA-51 62 (44?4) Wu-For each predictor, an external validation was conducted to confirm its objective predictability for the chemotherapy response and survival of EOC patients. For this external validation, the final predictors of the three drugs were independently applied to EOC cohorts, which were not used for our model development in any manner. Performance of these predictors was first evaluated by testing for a significant difference in the prediction scores between complete response (CR) and other (non-response; NR) patients using a non-parametric Wilcoxon rank-su.So obtained from the National Cancer Institute (http://discover.nci.nih.gov). Microarray gene expression data for frozen tissue samples obtained at the time of primary cytoreductive surgery from two large human ovarian cancer cohorts were used for the development and independent evaluation of our drug-response predictors. Clinical follow-up information after surgery and chemotherapy were fully available for these cohorts. The first cohort of 185 EOC patients treated with adjuvant chemotherapy, Bonome-185, was originally obtained for identifying prognostic molecular signatures of survival [11]. Of 185 patients, 112 (67 ) showed complete response (CR), 41 (25 ) partial response (PR), 14 (8 ) progression of disease (PD), and 18 had unrecorded responses to the primary chemotherapy (Table 1). The best response to chemotherapy was determined according to RECIST or WHO criteria at the completion of adjuvant chemotherapy [12,13]. The second set of 448 epithelial ovarian cancer patients whose Affymetrix gene expression profiling and clinical follow-up data were available, TCGA-448, was obtained from The Cancer Genome Atlas (TCGA) consortium (http://tcga-data.nci.nih.gov) [14]. These EOC patients from .10 diverse clinical centers had received primary platinum-based chemotherapy after surgery. The primary chemotherapy responses of this cohort were comprised of 272 (60.71 ) patients with CR, 54 with PR, 25 with stable disease (SD), and 36 with PD. However, a majority of the patients experienced recurrence or progression of disease and so were subsequently treated with additional chemotherapy drugs such as cyclophosphamide and topotecan. In particular, of 100 recurrent patients treated with topotecan, 47 patients were from the University of Washington (TCGA-UW) and the remainingPLOS ONE | www.plosone.orgSurvival Improvement by Personalized ChemotherapyTable 1. Epithelial ovarian cancer (EOC) patient cohorts for the development and validation of integrated predictors for patient response to standard chemotherapy drugs.Historical patient cohorts Characteristic Median Age(range) Stage I II III IV Others Histology Serous Clear Cell Others Surgical Outcome Optimal (,1 cm) Sub-optimal (. = 1 cm) Others (missing) Response to Initial Therapy CR PR SD PD Others Recurrence/ Disease Free Deaths Survival (month) Median PFS Median OS .5.83 44.2 16.7 44.8 12.42 50.4 112 (60.5 ) 41 (22.2 ) ?14 (7.6 ) 18 (9.7 ) ?145 (78.4 ) 272 (60.7 ) 54 (12 ) 25 (5.6 ) 36 (12.1 ) 61 (13.6 ) 332 (74.1 ) 238 (53.1 ) 28 (54.9 ) 22 (43.1 ) ?1 (2 ) ?44 (58 ) 31 (60.8 ) 92 (49.7 ) 93 (50.3 ) ?291 (65 ) 111 (24.8 ) 46 (10.3 ) 21 (41.2 ) 28 (54.9 ) 2 (3.9 ) 166 (89.7 ) ?19 (10.3 ) 448 (100 ) ??42 (82.4 ) 5 (9.8 ) 4 (7.8 ) 41 (41.4 ) 8 (8.1 ) 50 (50.5 ) ??144 (77.8 ) 41 (22.2 ) ??24 (5.4 ) 354 (79 ) 68 (15.2 ) 2 (0.4 ) ??46 (90.2 ) 5 (9.8 ) ?35 (35.4 ) 11 (11.1 ) 44 (44.4 ) 9 (9.1 ) ?Bonome185 63.6(26?5) TCGA-448 59 (27?7) UVA-51 62 (44?4) Wu-For each predictor, an external validation was conducted to confirm its objective predictability for the chemotherapy response and survival of EOC patients. For this external validation, the final predictors of the three drugs were independently applied to EOC cohorts, which were not used for our model development in any manner. Performance of these predictors was first evaluated by testing for a significant difference in the prediction scores between complete response (CR) and other (non-response; NR) patients using a non-parametric Wilcoxon rank-su.
