The ?triple negative breast cancer? (TNBC), refers to a heterogeneous collection of the tumors that lack expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 amplification. Unlike, ER- positive and HER2-amplified breast cancers; the lack of high frequency oncogenic driver mutations in TNBC has limited treatment options for women with the disease. However, TNBCs have higher rates of clinical response to pre-surgical (neo-adjuvant) chemotherapy, despite the lack of targeted therapy. Despite better responses to chemotherapy, TNBC patients still have a higher rate of distant recurrence and a poorer prognosis than women with other breast cancer subtypes. TNBC patients who experience a pathologic complete response (pCR) to neoadjuvant chemotherapy have significant improvements in both disease-free and overall survival compared with patients with residual invasive disease. In contrast, those patients with residual disease have a much poorer prognosis and are 6 times more likely to have recurrence and 12 times more likely to die. While 30% of patients with TNBC benefit from neoadjuvant chemotherapy, currently there is no effective way to identify those TNBC patients that would benefit most. TNBC's heterogeneous response to chemotherapy suggests that different TNBC subtypes may exist and are associated drug responses. We recently developed a novel gene expression signature with 2188 genes based on a new algorithm to classify TNBCs into six subtypes and implemented the algorithm in the software ?TNBCtype?. Our study showed that each TNBC subtype displays a unique biology. Furthermore, we identified representative TNBC cell line models for these subtypes that display differential sensitivity to targeted and chemotherapy. Therefore, to translate our pre-clinical results, there is a critical need to develop new strategies to develop a refined, reproducible, robust and clinically useful subtyping tool to identify TNBC patients most likely to benefit from neoadjuvant chemotherapy, and discover the new biomarkers for targeted treatments in patients that are resistant to chemotherapy. We propose the following specific aims to address these challenges: (1) develop and validate a robust TNBC subtyping model; (2) identify TNBC subtype specific chemotherapy response gene signatures; (3) discover TNBC chemotherapy resistant biomarkers by integrative genomic approach.
The overall goal of this proposal is to achieve direct impact on the personalized treatment for triple negative breast cancer (TNBC) patients. The TNBC subtyping model and subtype-specific chemotherapy response gene signature will guide differential use of already FDA-approved chemotherapy-based regimens for TNBC patients. The novel biomarker finding will help lead to new therapeutic targets for chemoresistant patients in each TNBC subtype.
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