HER2⁺ Tumor Molecular Subtypes Predict Response to Dual HER2 Blockade

Dual HER2 blockade with trastuzumab and lapatinib has proven effective in patients with HER2⁺ breast cancer, and in a subset of patients may even eliminate the need for chemotherapy. However, biomarkers are needed to identify patients who will be especially sensitive to HER2 blockade. HER2⁺ breast tumors are divided into multiple intrinsic molecular subtypes—luminal A, luminal B, HER2-enriched, and basal-like—that can be identified based on gene expression patterns, as well as a normal-like subtype. Llombart-Cussac and colleagues hypothesized that the HER2-enriched subtype, which is estrogen-receptor and progesterone-receptor negative and HER2 positive, would have the highest EGFR–HER2 activation and that these patients would derive the most benefit from combined therapy with trastuzumab and lapatinib. Based on this hypothesis, 151 patients with previously untreated HER2⁺ stage I–IIIA invasive breast cancer were enrolled in an open-label phase II trial evaluating trastuzumab in combination with lapatinib prior to surgery, including 101 patients with the HER2-enriched subtype. The primary outcome was the ability of the HER2-enriched molecular subtype to predict pathologic complete response, and secondary outcomes included gene expression changes and the safety and tolerability of trastuzumab plus lapatinib. Overall, pathologic complete responses were achieved in 46 patients (30%). The highest complete response rate was observed in the HER2-enriched subtype, with 41 out of 101 patients (41%) achieving a complete response compared with 5 of 50 (10%) of patients with non–HER2-enriched subtypes. Further, HER2 blockade led to a greater reduction in residual tumor burden in patients with HER2-enriched tumors. Trastuzumab and lapatinib were well tolerated, with the majority of adverse events being grade 1–2. Collectively, these findings indicate that the HER2-enriched subset of HER2⁺ breast tumors are most sensitive to treatment with trastuzumab plus lapatinib, and dual HER2 blockade may eliminate the need for chemotherapy in these patients.

Llombart-Cussac A, Cortés J, Paré L, Galván P, Bermejo B, Martínez N, et al. HER2-enriched subtype as a predictor of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer (PAMELA): an open-label, single-group, multicentre, phase 2 trial. Lancet Oncol 2017 Feb 23 [Epub ahead of print].