The benefit of adjuvant pertuzumab and trastuzumab according to estrogen receptor and HER2 expression: a subanalysis of the APHINITY trial

Agostinetto, E; Gentile, G; Samy, F; Di Cosimo, S; Aftimos, P; Pond&#233;, N; Eiger, D; Lambertini, M; Cameron, D; Kiermaier, A; Bailey, A; Viale, G; Loi, S; Piccart, M; de Azambuja, E

Author(s): Agostinetto, E; Gentile, G; Samy, F; Di Cosimo, S; Aftimos, P; Pondé, N; Eiger, D; Lambertini, M; Cameron, D; Kiermaier, A; Bailey, A; Viale, G; Loi, S; Piccart, M; de Azambuja, E;
Details: Publication Year 2026-08-01,Volume 118,Issue #8,Page 1504-1513
Journal Title: Journal of the National Cancer Institute
Publication Type: Research article
Abstract: BACKGROUND: Responses to anti-HER2 therapy can vary based on estrogen receptor expression and HER2 gene amplification. This study assessed the magnitude of benefit by adding pertuzumab to trastuzumab and chemotherapy by estrogen receptor and HER2 levels in the APHINITY trial. METHODS: APHINITY (ClinicalTrials.gov identifier NCT01358877; BIG 4-11) was a randomized, double-blind, phase 3 trial comparing pertuzumab with placebo added to adjuvant trastuzumab and chemotherapy in 4804 patients with HER2-positive early breast cancer. The primary endpoint of this exploratory analysis was invasive disease-free survival (IDFS). Subgroup analyses used Cox models across 4 groups defined by HER2 fluorescence in situ hybridization (FISH) ratio and estrogen receptor status, adjusted for treatment arm, chemotherapy regimen, and a combined variable of nodal status and protocol version. Tumors with a FISH ratio below 2 were excluded, leaving 4782 evaluable cases. The HER2 FISH ratio was classified as low (2 to <5) or high (≥5) and estrogen receptor expression by immunohistochemistry as negative or positive using 1% and 10% cutoffs. IDFS, HER2 FISH ratio, and estrogen receptor expression were also analyzed by intrinsic molecular subtype. RESULTS: All subgroups benefited from pertuzumab, with the largest benefit in HER2 FISH-low/estrogen receptor-positive tumors (hazard ratio = 0.70, 95% CI = 0.51 to 0.95). Other subgroups showed smaller benefits, with HER2 FISH-high/estrogen receptor-negative tumors having the least numerical improvement (hazard ratio = 0.85, 95% CI = 0.59 to 1.25). No statistically significant IDFS differences were observed between HER2-enriched and non-HER2-enriched tumors. CONCLUSIONS: Pertuzumab improved IDFS in all subgroups, with the greatest improvement in HER2 FISH-low/estrogen receptor-positive tumors. These exploratory findings are hypothesis generating and support prospective validation of biomarker-guided strategies. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01358877.
Publisher: Oxford University Press
Keywords: Humans; Female; Antibodies, Monoclonal, Humanized/administration & dosage; *Erb-b2 Receptor Tyrosine Kinases/metabolism/genetics; *Breast Neoplasms/drug therapy/pathology/metabolism/chemistry; *Trastuzumab/administration & dosage; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use; *Receptors, Estrogen/metabolism; Chemotherapy, Adjuvant; Double-Blind Method; Middle Aged; In Situ Hybridization, Fluorescence; Adult; Disease-Free Survival; Aged; Biomarkers, Tumor
Department(s): Laboratory Research; Medical Oncology
Publisher's Version: https://doi.org/10.1093/jnci/djag095
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-04-14 03:18:13

Last Modified: 2026-09-03 12:44:07