Abstract P1-04-05: Independent validation of the HER2DX genomic test in HER2-positive breast cancer treated with neoadjuvant paclitaxel, trastuzumab and pertuzumab (THP): a correlative analysis from the DAPHNe phase II clinical trial
Authors: Waks Adrienne , Ogayo Esther R. , Paré Laia , Marín-Aguilera Mercedes , Brasó-Maristany Fara , Galván Patricia , Castillo Oleguer , Martínez-Sáez Olga , Vivancos Ana , Villagrasa Patricia , Tarantino Paolo , Desai Neelam , Guerriero Jennifer , Metzger Otto , Tung Nadine , Krop Ian , Parker Joel S , Perou Charles M. , Prat Aleix , Winer Eric , Tolaney Sara , Mittendorf Elizabeth A. 
Published: March 2023

Abstract
Background: HER2DX is a 27-gene prognostic (risk-score) and predictive (pathological complete response [pCR]-score) assay in early-stage HER2+ breast cancer (BC) based on clinical data and the expression of 4 gene signatures (immune, proliferation, luminal differentiation, and HER2 amplicon). Here we aim to evaluate, for the first time, the ability of HER2DX to predict pCR following neoadjuvant THP in HER2+ BC.
Methods: Standardized HER2DX was evaluated centrally on baseline pre-treatment FFPE tumor biopsies from the DAPHNe phase II trial (Waks et al. NPJ Breast 2022; NCT03716180), in which patients (pts) with newly diagnosed stage II-III HER2+ BC were treated with neoadjuvant weekly paclitaxel × 12 and HP every 3 weeks × 4. Primary aim was to test the ability of HER2DX pCR-score to predict pCR (ypT0/isN0). Secondary objectives were to test the ability of HER2DX pCR-score to predict pCR independent of clinical-pathological variables and PAM50 subtype (HER2-enriched vs not) and to evaluate the association of HER2DX pCR-score with HER2DX risk-score. Five patients who received additional neoadjuvant chemotherapy after THP were excluded from this analysis. Logistic regression and receiver-operator curve (ROC) analysis were assessed. Statistical analyses were performed in R code 4.0.5.
Results: HER2DX was evaluated in 80 of 97 pts (82.5%) enrolled in the DAPHNe trial who received study treatment. Clinical T2-4 disease represented 81.3% of cases (n=65), clinical node-negative disease (cN0) represented 65.0% of cases (n=52), and 70.0% of tumors (n=56) were hormone receptor-positive. The overall pCR rate was 60.0% (95% confidence interval [CI] 49.3-70.7): 87.0% (95% CI 79.6-94.4) in hormone receptor-negative disease and 48.2% (95% CI 37.2-59.1) in hormone receptor-positive disease. The proportion of HER2DX low-, medium- and high-pCR groups was 38.8%, 27.5% and 33.7%, respectively. HER2DX pCR-score (as a continuous variable from 0 to 100) was significantly associated with pCR (odds ratio [OR]=1.05, p&lt; 0.0001). In the overall population, the pCR rates in HER2DX pCR-high, pCR-med and pCR-low groups were 92.6%, 63.6% and 29.0% (pCR-high vs pCR-low OR=30.6, p&lt; 0.0001), respectively. The AUC ROC of HER2DX pCR score (as a continuous variable) and pCR status was 0.835. In the ER-negative population, the pCR rates in HER2DX pCR-high, pCR-med and pCR-low groups were 94.7%, 66.7%, and 0%, respectively (Table 1). HER2DX pCR-score was significantly associated with pCR independent of hormone receptor status, HER2 immunohistochemistry (IHC) score, clinical stage, and PAM50 HER2-enriched subtype. The correlation between HER2DX pCR-score and HER2DX risk-score was weak (Pearson coefficient=-0.12), as previously described (Prat et al. EBiomedicine 2022). 51.3% of patients were categorized as HER2DX low-risk.
Conclusion: The 27-gene HER2DX genomic test predicts pCR following neoadjuvant THP in newly diagnosed stage II-III HER2+ BC. Patients with HER2DX pCR-low score and HER2DX high-risk score, representing 22.5% of pts, warrant further attention in order to optimize therapeutic strategies in this subset. The combination of HER2DX pCR-score and risk-score might guide therapeutic decisions by identifying patients who are ideal candidates for de-escalated or escalated systemic and locoregional treatments.
Table 1
Citation Format: Adrienne Waks, Esther R. Ogayo, Laia Paré, Mercedes Marín-Aguilera, Fara Brasó-Maristany, Patricia Galván, Oleguer Castillo, Olga Martínez-Sáez, Ana Vivancos, Patricia Villagrasa, Paolo Tarantino, Neelam Desai, Jennifer Guerriero, Otto Metzger, Nadine Tung, Ian Krop, Joel S Parker, Charles M. Perou, Aleix Prat, Eric Winer, Sara Tolaney, Elizabeth A. Mittendorf. Independent validation of the HER2DX genomic test in HER2-positive breast cancer treated with neoadjuvant paclitaxel, trastuzumab and pertuzumab (THP): a correlative analysis from the DAPHNe phase II clinical trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-04-05.