126MO HER2DX and pathological complete response in HER2-positive breast cancer: A combined analysis of 4 neoadjuvant studies

The optimal neoadjuvant therapy for HER2-positive breast cancer patients is subject to ongoing debate and the use of biomarkers can help to personalise treatment decision. The 27-gene HER2DX test predicts pathological complete response (pCR) following neoadjuvant trastuzumab-based chemotherapy. Here, we evaluated the value of HER2DX to predict increases in pCR rate when 1) a second anti-HER2 agent is added to trastuzumab and chemotherapy, and 2) multi-agent chemotherapy is used instead of a single agent taxane in the context of dual HER2 blockade. We conducted a combined analysis of four neoadjuvant cohorts with HER2DX and clinical data (i.e., DAPHNe, GOM-HGUGM-2018-05, CALGB-40601 and ISPY-2). All patients were treated with neoadjuvant trastuzumab (n=568) in combination with multi-agent chemotherapy (n=282), a single taxane (n=286), pertuzumab (n=264), lapatinib (n=103) or without a second anti-HER2 drug (n=201). Interaction tests were performed to evaluate the predictive capacity of HER2DX to identify patients who benefit most from each treatment approach. HER2DX pCR as continuous score was significantly associated with pCR in all patients (odds-ratio [OR]=1.62, 95% CI 1.43-1.85; AUC=0.75), in patients treated with trastuzumab and chemotherapy (OR=1.48, 1.18-1.86) and in patients treated with dual HER2 blockade and chemotherapy (OR=1.69, 1.50-1.91). A statistically significant increase in pCR rate due to dual HER2 blockade over trastuzumab-only was observed in HER2DX pCR-high tumors treated with chemotherapy (OR=4.10, 1.85-9.07; interaction test p=0.03). A statistically significant increase in pCR rate due to multi-agent chemotherapy over a single taxane was observed in HER2DX pCR-medium tumors treated with dual HER2 blockade (OR=2.52, 1.18-5.52; interaction test p=0.01). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of type of treatment. HER2DX might help identify patients with HER2-positive breast cancer who benefit from neoadjuvant dual HER2 blockade in combination with a single taxane.