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

Background: Responses to anti-human epidermal growth factor receptor 2 (HER2) therapy can vary based on estrogen receptor (ER) expression and HER2 gene amplification. This study assessed the magnitude of benefit by adding pertuzumab to trastuzumab and chemotherapy by ER and HER2 levels in the APHINITY trial. Methods: APHINITY (NCT01358877; BIG 4 to 11) was a randomized, double-blind, phase III trial comparing pertuzumab vs placebo added to adjuvant trastuzumab and chemotherapy in 4804 HER2-positive early breast cancer patients. The primary endpoint of this exploratory analysis was invasive disease-free survival (IDFS). Subgroup analyses used Cox models across four groups defined by HER2 FISH ratio and ER status, adjusted for treatment arm, chemotherapy regimen, and nodal status or protocol version. Tumors with FISH ratio <2 were excluded, leaving 4782 evaluable cases. HER2 FISH ratio was classified as low (2 ≤ ratio <5) or high (≥5), and ER expression by IHC as negative or positive using 1% and 10% cut-offs. IDFS, HER2 FISH ratio, and ER expression were also analyzed by intrinsic molecular subtype. Results: All subgroups benefited from pertuzumab, with the largest reduction in HER2 FISH-low/ER-positive tumors (HR 0.70, 95% CI 0.51 to 0.95). Other subgroups showed smaller benefits, with HER2 FISH-high/ER-negative tumors having the least numerical improvement (HR 0.85, 95% CI 0.59 to 1.25). No significant IDFS differences were observed between HER2-enriched and non-HER2-enriched tumors. Conclusions: Pertuzumab numerically improved IDFS in all subgroups, greatest in HER2 FISH-low/ER-positive tumors. These exploratory findings are hypothesis-generating and support prospective validation of biomarker-guided strategies. Trial registration: clinicaltrials.gov Identifier NCT01358877.