Genomic correlates of response to adjuvant trastuzumab (H) and pertuzumab (P) in HER2+ breast cancer (BC): Biomarker analysis of the APHINITY trial.

Abstract

1012 Background: We conducted a comprehensive genomic and immune-marker based analysis to identify prognostic and predictive biomarkers beyond clinical parameters (eg nodal status) in the setting of HP-based therapy. Methods: APHINITY, a phase III study, randomized 4805 pt with HER2+ BC to adjuvant chemo/H, plus P or placebo. Tumor Infiltrating Lymphocytes (TILs) were analysed using published methods. A nested case-control design with 1023 pt samples (3 controls matched to 1 distant relapse) underwent DNA (targeted) and RNA sequencing. Inverse probability weighting with Kaplan-Meier estimator weights, and models adjusted for treatment, hormone receptor, nodal status, age and chemotherapy type were used. Results are reported descriptively with 95% CIs. Interaction p-values are unadjusted for multiplicity. Results: DNA-seq, RNA-seq and TIL analyses were successful in 940/1023 (92%), 974/1023 (95%), and 4313/4804 (90%) samples, respectively. Prognosis (arms pooled): PI3K/PTEN/AKT alterations (HR 1.35; CI 1.01-1.79), MYC (HR 1.61; CI 1.16-2.23) or ZNF703 amplification (HR 1.62; CI 1.07-2.47) suggest poorer prognosis while TOP2A amplification (HR 0.49; CI, 0.32-0.74) suggests better prognosis independent of anthracycline use. Higher mRNA expression of an immune signature (IFNG, PD-L1, CXCL9 (HR 0.68; CI 0.52-0.89)) and TILs (HR 0.91; CI 0.86-0.96) also suggest better outcomes. Predictive effects: Table shows the HR for H+P benefit versus H for selected markers. PAM50 subtype did not predict benefit. Conclusions: In this comprehensive biomarker analysis, higher levels of immune markers and HER2 appeared to be associated with better prognosis and greater H+P benefit. Clinical trial information: NCT01358877. [Table: see text]