Abstract PS09-04: The benefit of adjuvant pertuzumab and trastuzumab according to estrogen receptor and HER2 expression: sub-analysis of the APHINITY trial

Abstract Background: Some studies suggest that response to HER2-targeting agents may differ according to estrogen receptor (ER) and HER2 expression levels. This study aimed to investigate the magnitude of benefit from the addition of pertuzumab to trastuzumab and chemotherapy according to ER and HER2 expression levels in the APHINITY trial. Methods: APHINITY (NCT01358877; BIG 4-11) was a randomized, double-blind, phase III study comparing the addition of pertuzumab or placebo to adjuvant trastuzumab and chemotherapy in an ITT population of 4804 patients with HER2-positive early breast cancer. The primary objective of this exploratory, unplanned analysis was to compare whether the addition of pertuzumab to trastuzumab had an impact in invasive disease-free survival (IDFS) within different subgroups defined by HER2 FISH amplification ratio and/or ER percentage of positivity on immunohistochemistry (IHC) (centrally assessed). Patients with a FISH ratio less than 2 were excluded from this analysis, leaving 4782 patients. IDFS was defined as the time from randomization until the date of the first occurrence of an IDFS event. HER2 FISH amplification ratio was categorized as low (2≤ FISH ratio < 5) vs. high (FISH ratio ≥5). ER expression on IHC was categorized as negative ( < 1%) vs. positive (≥1%). A subgroup analysis using Cox proportional hazards regression models was used to model IDFS, assessing four categories formed by cross classifying the FISH ratio and ER groups. The model was adjusted for randomized arm, adjuvant chemotherapy regimen received, and a combined variable of nodal status and protocol version. Results: The 4782 patients had a median age of 51 years old (IQR 44-59), with a median follow up time of 73.6 months (IQR 63.0-75.2). Most patients received an anthracycline-based chemotherapy (n=3712, 77.6%). ER expression was positive in 3047 patients (63.7%). HER2 FISH amplification ratio was high in 2479 patients (51.8%). All FISH ratio/ER subgroups seem to derive IDFS benefit from the addition of pertuzumab (HR < 1) (Table 1). The HER2 FISH ratio-low/ER positive subgroup had the largest reduction in risk of an IDFS event, 30% for the pertuzumab arm (HR=0.70, 95% CI 0.51-0.95) versus placebo. Smaller differences in IDFS events were observed between the treatment arms in the other subgroups. The subgroup of tumors with HER2 FISH ratio-high/ER-negative expression showed the numerically smallest benefit in IDFS events with the addition of pertuzumab (HR 0.85, 95% CI 0.59-1.25), see Table 1. Conclusions: In this APHINITY sub-analysis, patients treated with pertuzumab/trastuzumab derive similar benefit regardless of ER and HER2 expression levels. More research is needed to find predictive biomarkers to escalate or de-escalate treatments. Table 1. Abbreviations: FISH: fluorescence in situ hybridization, ER: estrogen receptor; IDFS: invasive disease-free survival; CI: confidence interval; HR: hazard ratio Citation Format: Evandro de Azambuja, Elisa Agostinetto, Faye Samy, Serena Di Cosimo, Philippe Aftimos, Noam Pondé, Daniel Eiger, Matteo Lambertini, David Cameron, Astrid Kiermaier, Andrew Bailey, Giuseppe Viale, Sherene Loi, Martine Piccart. The benefit of adjuvant pertuzumab and trastuzumab according to estrogen receptor and HER2 expression: sub-analysis of the APHINITY trial [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 PS09-04.