Abstract PO2-01-06: Prognostic value of residual disease (RD) biology and gene expression changes during the neoadjuvant treatment in HER2+ early-breast cancer (EBC)
Authors: Fernandez-Martinez Aranzazu , Tanioka Maki , Ahn Sung Gwe , Zagami Paola , Pascual Tomás , Rediti Mattia , Tang Gong , Hoadley Katherine A , Venet David , Rashid Naim U. , Spears Patty , Bliss Judith , Huober Jens , Rastogi Priya , Islam Md N. , Cortés Javier , Llombart-Cussac Antonio , Swain Sandra , Sotiriou Christos , Prat Aleix , Perou Charles M , Carey Lisa 
Published: May 2024

Abstract
Title Prognostic value of residual disease (RD) biology and gene expression changes during the neoadjuvant treatment in HER2+ early-breast cancer (EBC). Background In HER2+ EBC, neoadjuvant trastuzumab-based therapy is the standard of care, with adjuvant therapy determined by whether residual disease (RD) is present. Patients (pts) with RD have significantly higher relapse rates than pts with pathologic complete response. Differences in tumor and immune biology between pre-treated and post-treated tumors after HER2-blockade have been described, but little is known about how these changes can affect long-term outcomes or can be leveraged to tailor adjuvant treatment. Here we evaluate the biology of RD using gene expression analyses of pre- and post-treated HER2+ tumors, and their prognostic value to predict event-free survival (EFS) in a pooled analysis of 4 neoadjuvant studies in which single-agent trastuzumab or combined with lapatinib was explored, with and without chemotherapy: CALGB 40601 (Alliance), PAMELA, NeoALTTO, and NSABP B-41. Methods Gene expression profiling by RNA sequencing was assessed on 497 pre-treated samples from pts with RD, and on pre-treated and RD in 171 tumor pairs. Intrinsic subtypes and 22 tumor and immune gene expression signatures (GESs) were evaluated. We studied and compared the association of gene expression biomarkers with EFS in different cohorts and time points, including when GESs were calculated at baseline (N=497), in the 171 paired baseline and RD samples, and the nature of biomarker changes during neoadjuvant therapy. Association between GESs and EFS was explored by uni- and multivariable Cox regression models adjusted by clinical parameters (i.e., study, treatment arm, hormone receptor status, clinical tumor size, and clinical node involvement), and the performance of the models was assessed by the c-index. Results In 497 baseline untreated samples from pts with RD after neoadjuvant therapy (N=497), intrinsic subtypes were significantly associated with EFS (log-rank [LR] P 0.007), with Luminal A showing the best prognosis and Basal-like the worst. Among 171 paired tumors, HER2-Enriched tumors were more common in baseline (50.3%) with change to Normal-like (49.7%) and Luminal A (18.7%) in RD (chi-square P &lt; 0.001). This luminal phenotypic change was also confirmed by a significant reduction in the correlation to the HER2-Enriched centroid and a significant increase in the correlation to the Luminal A centroid between pre- and post-treated samples; a significant decrease in ERBB2 gene expression and the HER2 amplicon gene expression signature was also observed (Wilcoxon P &lt; 0.001). At an immune GES level, we found a significant increase in B cell, CD8+ T cell, and NK cell signatures in RD specimens. In contrast, T reg GES was significantly downregulated (Wilcoxon P &lt; 0.05). In uni- and multivariable models, immune GESs provided more prognostic information when assessed in RD samples. In contrast, subtype-related biomarkers provided more prognostic information at baseline. From all the multivariable models, the best (c-index= 0.78) included the IgG signature assessed in RD (adjusted hazard ratio 0.46, 95% CI 0.30-0.70, adjusted P 0.005). IgG signature levels (tertiles) in RD could also stratify pts into different groups based on prognostic information (EFS at 7 years: 69% in IgG low vs. 91% in IgG high, LR P 0.02). Conclusions In pts with HER2+ EBC and RD after neoadjuvant treatment with HER2-blockade, tumor-related biomarkers seem to provide more prognostic information when calculated at baseline, whereas immune biomarkers in the RD perform better for EFS prognostication. This finding could be relevant for implementing RD biomarkers in the clinic to stratify pts into different prognostic groups and tailor the post-operative treatment strategy. Supported in part by U10 CA180821, U10 CA180882, R01-CA229409
https://acknowledgments.alliancefound.org
Citation Format: Aranzazu Fernandez-Martinez, Maki Tanioka, Sung Gwe Ahn, Paola Zagami, Tomás Pascual, Mattia Rediti, Gong Tang, Katherine A Hoadley, David Venet, Naim U. Rashid, Patty Spears, Judith Bliss, Jens Huober, Priya Rastogi, Md N. Islam, Javier Cortés, Antonio Llombart-Cussac, Sandra Swain, Christos Sotiriou, Aleix Prat, Charles M Perou, Lisa Carey. Prognostic value of residual disease (RD) biology and gene expression changes during the neoadjuvant treatment in HER2+ early-breast cancer (EBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-01-06.