Abstract 5213: Evaluation of HER2DX risk-score in residual disease (RD) from HER2-positive (HER2+) early breast cancer (EBC) patients (pts) following neoadjuvant trastuzumab and pertuzumab (HP)-based therapy: An exploratory analysis from the PHERGain trial
Authors: Pérez-García José Manuel , Brasó-Maristany Fara , Martínez-García Elena , Gallardo Carmen Mora , Shimizu Eileen , Sánchez Olga Boix , Rodríguez-Morató Jose , Mancino Mario , Paré Laia , Villacampa Guillermo , Marín-Aguilera Mercedes , Galván Patricia , Vivancos Ana , Villagrasa Patricia , Parker Joel , Perou Charles M. , Llombart-Cussac Antonio , Cortés Javier , Prat Aleix 
Published: March 2024

Abstract
Introduction:
HER2DX is a prognostic (risk-score) and predictive (pathological complete response-score) genomic assay validated in baseline (BL) tumor samples from HER2+ EBC pts. RD after neoadjuvant anti-HER2-based therapy is associated with worse outcomes. Whether HER2DX risk-score analyzed in RD provides additional prognostic information is unknown.
Methods:
This retrospective analysis included 14 pts from group B of the PHERGain trial (NCT03161353): 6 who developed distant recurrences and 8 matched controls with HER2DX high-risk score at BL who did not. Group B pts had centrally confirmed, stage I-IIIA, HER2+ EBC and were treated with HP (± endocrine therapy), with chemotherapy added for pts without PET response after 2 treatment cycles or pathological complete response (Perez-Garcia et al, Lancet Oncol 2021).HER2DX was evaluated on tumor samples collected at BL and surgery. The primary objective was to determine the association of HER2DX risk-score in RD with the development of distant recurrences. Secondary objectives were to assess gene expression and the HER2DX signatures in BL vs RD and their association with distant recurrences. Cox regression models evaluated the association of variables with distant recurrence. Paired SAM with a false discovery rate &lt;5% identified differences in gene expression between BL and RD samples.
Results:
Median follow-up was 4.04 years. Five (83.3%) of 6 pts with distant recurrences had HER2DX high-risk scores at BL. The 8 control pts had HER2DX high-risk scores at BL but no relapse. In RD, all 6 pts (100%) who relapsed had a HER2DX high-risk score, while 4 (50%) of 8 pts without distant recurrence presented a HER2DX downstaging. Pts with HER2DX low-risk in RD had better 3-year distant disease-free survival than high-risk pts (100% vs 50%; hazard ratio = 4.34 [1.03-18.23], p=0.045). In RD, high expression of the proliferation signature and 15 genes, including proliferation genes, and low expression of 38 genes, including immune and luminal-related genes, were associated with poor prognosis. In paired analyses of BL and RD samples, 118 genes (63.8%) were differentially expressed in pts that did not relapse, while only 3 genes (1.6%) were differentially expressed in pts that relapsed.
Conclusions:
These data suggest that HER2DX risk-score in RD provides additional information on the likelihood of developing distant recurrences. In RD, high expression of immune and luminal genes was associated with a reduced risk, while high expression of proliferation genes was associated with a higher risk. Molecular changes after anti-HER2 therapy were mainly observed in RD of pts that did not relapse. Prognostic impact of HER2DX downstaging merits further evaluation.
Citation Format: José Manuel Pérez-García, Fara Brasó-Maristany, Elena Martínez-García, Carmen Mora Gallardo, Eileen Shimizu, Olga Boix Sánchez, Jose Rodríguez-Morató, Mario Mancino, Laia Paré, Guillermo Villacampa, Mercedes Marín-Aguilera, Patricia Galván, Ana Vivancos, Patricia Villagrasa, Joel Parker, Charles M. Perou, Antonio Llombart-Cussac, Javier Cortés, Aleix Prat. Evaluation of HER2DX risk-score in residual disease (RD) from HER2-positive (HER2+) early breast cancer (EBC) patients (pts) following neoadjuvant trastuzumab and pertuzumab (HP)-based therapy: An exploratory analysis from the PHERGain trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5213.