Purpose: We sought to determine whether dysregulation of the RB tumor suppressor pathway was associated with improved response to neoadjuvant chemotherapy in breast cancer. Experimental Design: An RB-loss signature was used to analyze the association between pathway status and pathological complete response in gene expression datasets encompassing three different neoadjuvant regimens. Parallel immunohistochemical analysis of the RB-pathway was performed on pretreatment biopsies to determine the association with pathological response to neoadjuvant chemotherapy. Results: An RB loss gene expression signature was asssociated with increased pathological complete response in datasets from breast cancer patients treated neoadjuvant therapy encompasssing approximately 1,000 patients. The association with improved response to neoadjuvant chemotherapy was true in both ER-positive and ER-negative breast cancer. Elevated expression of p16ink4a is associated with the RB-loss of signature (R=0.493-0.5982), and p16ink4a mRNA levels were strongly associated with pathological complete response. In an independent cohort, immunohistochemical analyses of RB and p16ink4a revealed an association of RB loss (p=0.0018) or elevated p16ink4a (p=0.0253) with pathological complete response. Additionally, by Miller-Payne and Clinical-Pathologic Scoring (CPS) analyses, RB-deficient tumors experienced an overall improved response to neoadjuvant chemotherapy. Conclusion: Disruption of the RB-pathway as measured by several independent methods was associated with improved response to neoadjuvant chemotherapy. The RB-pathway status was relevant for pathological response in both ER-positive and ER-negative breast cancer with similar results observed with multiple chemotherapy regimens. Combined, these data indicate that RB-status is associated with the response to neoadjuvant chemotherapy in breast cancer and could be employed to inform treatment.
- Received March 20, 2012.
- Revision received July 2, 2012.
- Accepted July 3, 2012.
- Copyright © 2012, American Association for Cancer Research.