Genomic characteristics of trastuzumab-resistant Her2-positive metastatic breast cancer

PURPOSE: Resistance to trastuzumab therapy is linked to phosphoinositol 3-kinase (PI3K) pathway activation. One key downstream effector and regulator of this pathway is the mechanistic target of rapamycin (mTOR). In 2011, a phase I/II study evaluated the combination of trastuzumab and everolimus (a mTOR inhibitor) for treatment of Her2-positive metastatic breast cancer (MBC) for patients who had progressed on trastuzumab-based therapy. METHODS: We retrospectively analyzed GeneChip microarray data from 22 of 47 patients included in the study. RESULTS: Using an unbiased approach, we found that mutations in BRAF, EGFR and KIT are significantly more common in this heavily treated population when compared with the cohort of invasive breast carcinoma patients in The Cancer Genome Atlas (TCGA). Furthermore, 10 out of 22 patients had PIK3CA mutations (45.4%) but PI3KCA status was not predictive of PFS in our cohort. Finally, the use of OncoScan(tm) has allowed us to detected mutations in five genes that have not been shown to be mutated in TCGA subset of Her-2 overexpressing breast cancer: CTNNB1, HRAS, KRAS, NF2 and SMARCB1. CONCLUSION: Mutational burden in heavily treated trastuzumab-resistant Her2-positive metastatic breast cancer is highly variable and not directly correlated with outcome. Activation of the MAPK/ERK pathway through mutations in EGFR, BRAF or KIT may mediate resistance to trastuzumab.