Protein-Level Analysis of Differential Response to Chemotherapy in Triple-Negative Breast Cancer Identifies CYP1B1 as a Biomarker for Chemotherapy Resistance.

Resistance to chemotherapy is a critical challenge in triple-negative breast cancer (TNBC). In this study, the proteomes of pretreatment core biopsy samples from 16 patients with TNBC with differential response to neoadjuvant chemotherapy (NAC) were analyzed by nanoLC/MS-MS to identify biomarkers of intrinsic chemotherapy resistance. This led to the identification of cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) and 71 additional proteins as significantly more abundant in chemoresistant than chemosensitive TNBC. IHC analysis of 80 TNBC samples confirmed an association between elevated tumor cell CYP1B1 and residual cancer burden class 2/3 disease after NAC in T cell-excluded (TCE) TNBC (P < 0.01) but not in T cell-infiltrated (TCI) TNBC. The frequency of complete pathologic response in TCE-TNBC with elevated CYP1B1 was 18% versus 56% in TCE-TNBC with low CYP1B1 and 75% in TCI-TNBC. Retrospective review of the chemotherapy regimens suggested that TCE-TNBC with elevated CYP1B1 was particularly resistant to doxorubicin/cyclophosphamide. This study is the first to associate resistance to NAC in TNBC with elevated CYP1B1. SIGNIFICANCE: This retrospective analysis of pretreatment TNBC core biopsies found that elevation of CYP1B1, a drug-metabolizing enzyme in tumor cells, was associated with resistance to NAC in patients with TNBC treated initially with doxorubicin. If confirmed, this pattern of chemotherapy resistance could guide future clinical trials.