Gene expression profiles of breast cancers before and after treatment with doxorubicin or docetaxel (CBX91). unidentified

Objective: Tumor gene expression signatures have been used to classify, prognosticate and predict chemotherapy sensitivity in breast cancer, although almost all efforts have been focused on the unchallenged baseline tumor. Most cancer patients receive systemic therapy, and exposure to drug may modify the tumor's short- and long-term outcomes. Drug-induced tumor gene signatures may thus be more predictive of treatment outcomes than the unperturbed tumor gene signatures. Methods: Using a set of 47 breast cancer patients, we obtained paired pre- and post chemotherapy tumor biopsies and developed gene panels of baseline tumor (T1), post-chemotherapy tumor (T2), and chemotherapy-induced relative change signatures (T??) to predict pathological response and progression-free survival (PFS). The signatures were validated in 2 independent test sets with paired pre- and post-chemotherapy tumor samples, comprising of 18-20 patients each. Results: T2 and Tdelta were superior to T1 signatures in predicting for PFS (AUC of ROC 0.770 and 0.660 vs 0.530) and pathological response (AUC of ROC 0.631 and 0.462 vs 0.446) in the validation sets. In multivariate analysis for PFS with other clinical predictors, T2 but not T1 signatures remained significant independent predictors. Conclusions: Post-chemotherapy tumor gene signatures outperformed baseline signatures and clinical predictors in predicting for pathological response and PFS, independent of clinical and pathological response to chemotherapy. Drug-induced tumor gene signatures may be more informative than unchallenged signatures in predicting treatment outcomes. These findings challenge the current practice of relying only on the baseline tumor to predict outcome, which overlooks the contributions of therapeutic interventions.