Relationship Between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer.
Purpose: HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprised of the cytotoxic agent DM1 linked to the HER2-targeted antibody trastuzumab, was correlated with expression of specific biomarkers in the phase III EMILIA study.
Methods: Tumors were evaluated for HER2 (n = 866), EGFR (n = 832), and HER3 (n = 860) mRNA expression by quantitative reverse transcriptase-PCR; for PTEN protein expression (n = 271) by immunohistochemistry; and for PIK3CA mutations (n = 259) using a mutation detection kit. Survival outcomes were analyzed by biomarker subgroups. T-DM1 was also tested on cell lines and in breast cancer xenograft models containing PIK3CA mutations.
Results: Longer progression-free and overall survival were observed with T-DM1 compared to capecitabine plus lapatinib in all biomarker subgroups. PIK3CA mutations were associated with shorter median progression-free survival (mutant vs. wild-type: 4.3 vs. 6.4 months) and overall survival (17.3 vs. 27.8 months) in capecitabine-plus-lapatinib-treated patients but not in T-DM1-treated patients (progression-free survival, 10.9 vs. 9.8 months; overall survival, not reached in mutant or wild-type). T-DM1 showed potent activity in cell lines and xenograft models with PIK3CA mutations.
Conclusion: While other standard HER2-directed therapies are less effective in tumors with PI3KCA mutations, T-DM1 appears to be effective in both PI3KCA-mutated and wild-type tumors.