Abstract B077: Subtype-specific signaling dynamics during treatment in non-responding breast cancer patients in the neoadjuvant I-SPY2 TRIAL: are there clues on how to overcome resistance?
Authors: Wolf Denise M. , Yau Christina , Magbanua Mark Jesus M. , Sayaman Rosalyn , Wulfkhule Julia , Gallagher Rosa I. , Brown-Swigart Lamorna , Campbell Michael J. , Basu Amrita , Hirst Gillian L. , Perlmutter Jane , DeMichele Angela , Yee Doug , Pusztai Lajos , Pohlmann Paula R. , Clark Amy S. , Rugo Hope S. , Petricoin Emanuel F. , Esserman Laura J. , van ‘t Veer Laura 
Published: February 2024

Abstract
Background: Despite ever-improving treatments (Tx) for early-stage aggressive breast cancer – e.g., neoadjuvant platinum and immune agents (IO) for TN and dual-anti-HER2 for HER2+ - many patients don’t respond, and insight into resistance mechanisms and how to overcome them are lacking. To look for clues, we performed serial gene expression profiling of non-responding patients to assess which tumor features change during treatment, and to identify dynamics most associated with distant recurrence. Methods: Non-response was defined as moderate or extensive residual cancer burden after Tx. 167 non-responders [76 HR+HER2-, 72 TN, 19 HER2+] with mRNA at one or more on-treatment time points (148 pretreatment (T0), 122 on-treatment (T1), and 120 surgical (T3)) were considered. Normalized data were scored for 112 published signatures representing immune, proliferation, ER/PR, HER2-related, ECM, and development; and for 50 Cancer Hallmarks (MSigDB). Signatures were assessed for early (T1-T0), late (T3-T1) and overall (T3-T0) changes during Tx using Wilcoxon tests, adjusted using the Benjamini-Hochberg method (BH p&lt;0.05). 110/167 (66%) pts have distant recurrence free survival (DRFS) data, with median follow-up of ~4.5yr. Associations with DRFS were assessed using Cox Proportional Hazards modeling, also adjusted (BH log rank test p&lt;0.05). Results: Signaling dynamics during Tx differed by receptor subtype. Within HR+HER2-, in addition to a decrease in ESR1_PGR, early decreases in proliferation and interferon (but not T/B-cell) signatures were observed; along with late increases in TGFB, IL8 and IL2, and Mast-cell. In TN, late decreases in T/B-cell, and Tumor-Immune signaling were observed, including those predicting IO sensitivity (STAT1_sig, DendriticCell and Chemokine12). Among the few signaling changes in common between subtypes were early increases in xenobiotic metabolism and late increases in hypoxia. Associations with DRFS were subtype-specific as well. In HR+HER2-, high levels of proliferation at T3 associate with decreased DRFS, and late increases in macrophage and Th1-related immune signatures associated with improved DRFS. Paradoxically, though high Mast-cell at T0 were previously shown to associate with non-pCR, high levels at T3 and increases late in Tx associate with improved DRFS. In TN, there were few significant associations with DRFS. Finally, we assessed the overlap between signatures that change during treatment and those that associate with DRFS, and to our surprise found no significant association. Conclusion: We observed subtype-specific changes in signatures over Tx in non-responders, however these changes do not generally predict an association with DRFS. Early targeting of xenobiosis; or TGFB, IL2 or IL8 in HR+HER2-, may be promising for overcoming resistance; but likely not a Mast-cell inhibitor, where high levels predict both resistance and survival.
Citation Format: Denise M. Wolf, Christina Yau, Mark Jesus M. Magbanua, Rosalyn Sayaman, Julia Wulfkhule, Rosa I. Gallagher, Lamorna Brown-Swigart, Michael J. Campbell, Amrita Basu, Gillian L. Hirst, Jane Perlmutter, Angela DeMichele, Doug Yee, Lajos Pusztai, Paula R. Pohlmann, Amy S. Clark, Hope S. Rugo, Emanuel F. Petricoin, Laura J. Esserman, Laura van ‘t Veer. Subtype-specific signaling dynamics during treatment in non-responding breast cancer patients in the neoadjuvant I-SPY2 TRIAL: are there clues on how to overcome resistance? [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 B077.