Abstract A003: Global and TNBC-specific biomarkers of sensitivity and resistance in early stage breast cancer from the I-SPY2 biomarker data compendium
Authors: Bui Tam Binh V , Wolf Denise M , Gallagher Rosa I , Wulfkuhle Julia , Yau Christina , Brown-Swigart Lamorna , Rosenbluth Jennifer , Yee Douglas , Hirst Gillian L , Esserman Laura J , Petricoin Emanuel F , Van 't Veer Laura J 
Published: February 2024

Abstract
Introduction Diverse qualifying and exploratory sensitivity and resistance biomarkers were previously identified in the I-SPY2 trial. Notably, for TNBC patients, fewer predictive biomarkers were found compared with other receptor subgroups. Here we summarize and synthesize observations of biomarkers associated with sensitivity or resistance in the overall trial population and specifically in the TNBC population, to help further elucidate underlying biological mechanisms. Methods The I-SPY2 990 Data Compendium (PMID 35623341) contains pre-treatment full transcriptome expression data of 987 patients and quantitative expression data from 139 proteins/phosphoproteins from 736 patients across 10 treatment arms of the I-SPY2 trial. In this analysis, we re-organized and synthesized the pathologic complete response (pCR)-association results from previous analyses of these data to identify areas of overlap and discrepancies between global predictive biomarkers and TNBC-specific biomarkers, in all treatment arms together and in the control (chemotherapy) arm. Global biomarkers are defined as significantly associated with sensitivity or resistance in the overall trial population (all treatment arms, all receptor subtypes), while general control markers are receptor subtype-independent markers in the control arm. Results Global sensitivity biomarkers (n=42), where higher levels associate with pCR, included markers from mostly immune, HER2 and cell cycle/proliferation related pathways. In the TNBC population 13 sensitivity biomarkers were identified, which all overlapped with global sensitivity markers, e.g. immune gene signatures and EGFR protein. General control markers of sensitivity (n=15) included immune markers and cell cycle/proliferation signatures, amongst others, but were mainly distinct from sensitivity markers in the TNBC subgroup analysis of the control arm (n=6), with EGFR as the only overlapping biomarker. Remarkably, almost all general sensitivity markers in the control arm were also global sensitivity markers (n=13/15). Unlike sensitivity biomarkers, in TNBC only 2/11 biomarkers of resistance, where higher levels associate with non-pCR, overlapped with global resistance markers, which were cyclin D1 and p53. Global resistance markers (n=14) were mostly hormone receptor related biomarkers, while in TNBC resistance markers (n=11) included MEK1/2, FOXO1, CHK1 and CHK2, amongst others. Most significant general control markers of resistance were also global resistance markers (n=4/5), including IGF1R mRNA. Discussion This analysis shows that nearly all sensitivity and resistance biomarkers in the control arm overlap with global markers. We hypothesize that this is (partly) explained by the standard neoadjuvant chemotherapy backbone that is shared between all treatment arms. Interestingly, almost no resistance biomarkers in TNBC overlapped with global resistance markers, further supporting that resistance mechanisms in TNBC are receptor-subtype specific. Additional analysis of those markers could help further elucidate resistance biology in TNBC.
Citation Format: Tam Binh V Bui, Denise M Wolf, Rosa I Gallagher, Julia Wulfkuhle, Christina Yau, Lamorna Brown-Swigart, Jennifer Rosenbluth, Douglas Yee, Gillian L Hirst, Laura J Esserman, Emanuel F Petricoin, Laura J Van 't Veer. Global and TNBC-specific biomarkers of sensitivity and resistance in early stage breast cancer from the I-SPY2 biomarker data compendium [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A003.