Ir primary chemotherapy. We then compared overall survival (OS) and progression-free survival (PFS) benefits between the COXEN-matched and unmatched groups among 274 patients treated with one of the three drugs in their primary and subsequent chemotherapies with follow-up survival information (Figure 3). These survival benefits were evaluated for all 274 patients as well as separately for platinum-sensitive and platinum-resistant patients as the two subgroups show quite different survival outcomes (excluding 34 patients too early to define their platinum response). The median overall survival time of the COXEN-matched group was 57.6 months, which was significantly longer than the 43.8 months for the unmatched group (log-rank test p-value = 0.042, Figure 3 A and Figure S8); the median OS times were 81.6 months vs. 56.4 months for the matched and unmatched patients within the platinum-sensitive patient subgroup and 35.4 months vs. 34.2 months within the platinum-resistant subgroup. Similarly, the median PFS time of the matched group was 20.3 months compared with 15.6 months for the unmatched group (log-rank test P-value = 0.033, Figure 3 B and Figure S9); the medianPFS times were 26.4 months vs. 20.1 months for the matched and unmatched patients within the platinum-sensitive patient subgroup and 8.9 months vs. 9.4 months within the platinum-resistant subgroup. We also examined the survival outcomes for the patients treated with one of the three drugs after their recurrent disease. Of 107 recurrent patients treated with one of the three drugs, 25 patients were treated with COXEN-matched drugs and 82 patients with other drugs. Median overall survival times were 65.9 and 44.2 months for the matched and unmatched groups, respectively (log-rank test p-value = 0.002, Figure 3 C and Figure S10); the median OS times were 118.8 months vs. 51.9 months of the matched and unmatched patients within the platinum-sensitive patient subgroup and 48.7 months vs. 35.4 months within the platinum-resistant subgroup. Therefore, the recurrent EOC patients in the matched group survived 21 months longer than the patients in the unmatched group. Also, the platinum-response subgroup analyses 6-MethoxybaicaleinMedChemExpress 6-Methoxybaicalein showed that survival improvement was greater for platinum-sensitive patients if they were treated with the predicted most beneficial drugs than platinumresistant patients.DiscussionDespite the VER-52296 clinical trials availability of multiple standard chemotherapy drugs and the recent advent of targeted therapeutic agents, the overall therapeutic response and survival of advanced EOC patients has not improved much over the last two decades. Advanced EOC patients are highly heterogeneous in their therapeutic responses, so only a small fraction of the patient population responds to each standard therapeutic option. Consequently, if existing and novel drugs are unselectively administered to individual patients, overall therapeutic outcome of advanced EOC is difficult to improve. In this study, we have obtained the single-drug COXEN predictors by integrating each drug’s in vitro drug activity data and patient therapeutic outcome information for three standard chemotherapy drugs used in treating advanced EOC: paclitaxel, cyclophosphamide, and topotecan, for which multiple independent patient data sets were available for our stringent statistical modeling, evaluation, and external testing. In particular, our initial biomarker discovery step from in vitro singledrug sensitivity data enabled us to identify gen.Ir primary chemotherapy. We then compared overall survival (OS) and progression-free survival (PFS) benefits between the COXEN-matched and unmatched groups among 274 patients treated with one of the three drugs in their primary and subsequent chemotherapies with follow-up survival information (Figure 3). These survival benefits were evaluated for all 274 patients as well as separately for platinum-sensitive and platinum-resistant patients as the two subgroups show quite different survival outcomes (excluding 34 patients too early to define their platinum response). The median overall survival time of the COXEN-matched group was 57.6 months, which was significantly longer than the 43.8 months for the unmatched group (log-rank test p-value = 0.042, Figure 3 A and Figure S8); the median OS times were 81.6 months vs. 56.4 months for the matched and unmatched patients within the platinum-sensitive patient subgroup and 35.4 months vs. 34.2 months within the platinum-resistant subgroup. Similarly, the median PFS time of the matched group was 20.3 months compared with 15.6 months for the unmatched group (log-rank test P-value = 0.033, Figure 3 B and Figure S9); the medianPFS times were 26.4 months vs. 20.1 months for the matched and unmatched patients within the platinum-sensitive patient subgroup and 8.9 months vs. 9.4 months within the platinum-resistant subgroup. We also examined the survival outcomes for the patients treated with one of the three drugs after their recurrent disease. Of 107 recurrent patients treated with one of the three drugs, 25 patients were treated with COXEN-matched drugs and 82 patients with other drugs. Median overall survival times were 65.9 and 44.2 months for the matched and unmatched groups, respectively (log-rank test p-value = 0.002, Figure 3 C and Figure S10); the median OS times were 118.8 months vs. 51.9 months of the matched and unmatched patients within the platinum-sensitive patient subgroup and 48.7 months vs. 35.4 months within the platinum-resistant subgroup. Therefore, the recurrent EOC patients in the matched group survived 21 months longer than the patients in the unmatched group. Also, the platinum-response subgroup analyses showed that survival improvement was greater for platinum-sensitive patients if they were treated with the predicted most beneficial drugs than platinumresistant patients.DiscussionDespite the availability of multiple standard chemotherapy drugs and the recent advent of targeted therapeutic agents, the overall therapeutic response and survival of advanced EOC patients has not improved much over the last two decades. Advanced EOC patients are highly heterogeneous in their therapeutic responses, so only a small fraction of the patient population responds to each standard therapeutic option. Consequently, if existing and novel drugs are unselectively administered to individual patients, overall therapeutic outcome of advanced EOC is difficult to improve. In this study, we have obtained the single-drug COXEN predictors by integrating each drug’s in vitro drug activity data and patient therapeutic outcome information for three standard chemotherapy drugs used in treating advanced EOC: paclitaxel, cyclophosphamide, and topotecan, for which multiple independent patient data sets were available for our stringent statistical modeling, evaluation, and external testing. In particular, our initial biomarker discovery step from in vitro singledrug sensitivity data enabled us to identify gen.
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