Cell Rep Med
Published online 2023:101312

Protein signaling and drug target activation signatures to guide therapy prioritization: Therapeutic resistance and sensitivity in the I-SPY 2 Trial

Gallagher RI, Wulfkuhle J, Wolf DM, Brown-Swigart L, Yau C, O’Grady N, Basu A, Lu R, Campbell MJ, Magbanua MJ, Coppé JP, Investigators IS 2, Asare SM, Sit L, Matthews JB, Perlmutter J, Hylton N, Liu MC, Symmans WF, Rugo HS, Isaacs C, DeMichele AM, Yee D, Pohlmann PR, Hirst GL, Esserman LJ, Veer LJ van ‘t, Petricoin EF

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.

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