Abstract
Molecular subtyping of breast cancer is based mostly on HR/HER2 and gene expression-based immune, DNA repair deficiency, and luminal signatures. We extend this description via functional protein pathway activation mapping using pre-treatment, quantitative expression data from 139 proteins/phosphoproteins from 736 patients across 8 treatment arms of the I-SPY 2 Trial (ClinicalTrials.gov: NCT01042379). We identify predictive fit-for-purpose, mechanism-of-action-based signatures and individual predictive protein biomarker candidates by evaluating associations with pathologic complete response. Elevated levels of cyclin D1, estrogen receptor alpha, and androgen receptor S650 associate with non-response and are biomarkers for global resistance. We uncover protein/phosphoprotein-based signatures that can be utilized both for molecularly rationalized therapeutic selection and for response prediction. We introduce a dichotomous HER2 activation response predictive signature for stratifying triple-negative breast cancer patients to either HER2 or immune checkpoint therapy response as a model for how protein activation signatures provide a different lens to view the molecular landscape of breast cancer and synergize with transcriptomic-defined signatures.
Original language | English (US) |
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Article number | 101312 |
Journal | Cell Reports Medicine |
Volume | 4 |
Issue number | 12 |
DOIs | |
State | Published - Dec 19 2023 |
Keywords
- LCM
- RPPA
- biomarker
- breast cancer
- clinical trial
- drug target
- neoadjuvant
- phosphoprotein
- protein
- resistance
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology