HER2DX and survival outcomes in early-stage HER2-positive breast cancer: an individual patient-level meta-analysis.

Abstract

HER2-positive breast cancer accounts for 15-20% of all breast cancers and is characterised by HER2 (also known as ERBB2) amplification. Although HER2-targeted therapies have markedly improved outcomes, current clinical-pathological variables and pathological complete response after neoadjuvant therapy are insufficient to fully capture biological heterogeneity and guide personalised treatment. HER2DX is a genomic test that integrates tumour biology and clinical data to stratify risk. Here, we conducted an individual patient-level meta-analysis to evaluate the association between the HER2DX risk score and survival outcomes in early-stage HER2-positive breast cancer. We conducted a systematic review and individual patient-level meta-analysis using data from studies of stage 1-3 HER2-positive breast cancer, incorporating HER2DX risk scores, clinical information, and survival outcomes. A systematic literature search was conducted in PubMed on Dec 15, 2024, and complemented by a review of in-house databases to identify eligible studies with HER2DX testing and patient-level data. Eligible studies were required to include more than 50 patients with HER2-positive early breast cancer treated with anti-HER2 therapy, with available survival outcomes, and HER2DX testing performed. Individual-level data were requested from study investigators or accessed through public repositories. HER2DX risk score was evaluated as continuous score and as a risk group using pre-established cutoffs (low vs high). The primary endpoint of the study was event-free survival, estimated using the Kaplan-Meier method. Univariable and multivariable stratified Cox models were used to estimate stratified hazard ratios (HRs). The study was registered in PROSPERO (CRD42025634137). 11 studies met the inclusion criteria (APT, ATEMPT, CALGB40601, DAPHNe, GOM-HGUGM-2018-05, NEOHER, SOLTI-PAMELA, PHERGain, HUAC, SCAN-B, and DFCI-14-409) and were selected for the meta-analysis. Of 3244 patients identified across the selected studies, 2518 were included in the analysis (those with available HER2DX clinical data and survival outcomes). The median follow-up was 6·1 years (95% CI 6·0-6·3). Of 2518 patients, 891 (35·4%) had stage 1 disease, 1133 (45·0%) stage 2 disease, and 494 (19·6%) stage 3 disease. Hormone receptor-positive disease was present in 1660 (65·9%) of 2518 patients and 1259 (50·0%) of 2518 patients had a high HER2DX risk score. In the multivariable analysis, HER2DX as a continuous variable was independently associated with event-free survival (stratified HR per 10-unit increment 1·25, 95% CI 1·14-1·38; p<0·0001). Patients classified as HER2DX low risk had a 6-year event-free survival rate of 93·6% (95% CI 92·0-95·2), compared with 82·9% (80·0-85·5) for the HER2DX high-risk group, representing a 10·7% absolute difference (stratified HR 2·72, 95% CI 1·97-3·76; p<0·0001). This association was consistent across subgroups, regardless of tumour stage, nodal stage, pathological complete response, or hormone receptor status. HER2DX provides clinically meaningful prognostic stratification in early-stage HER2-positive breast cancer, beyond standard clinical-pathological variables and pathological response. These results support its use in tailoring treatment intensity and guiding clinical decision making. Reveal Genomics.