HER2 amplification is uncommon BRCA1/2 mutated breast cancer. We aimed to assess the relevance of both BRCA mutations and the expression of insulin-like growth factor receptor-1ß (IGF-R1ß) in patients with HER2-positive BC who met clinical criteria for BRCA testing treated with Trastuzumab for early/metastatic disease. Furthermore, we investigated by pathway reconstruction analysis the relationship among HER2 overexpression, BRCA and IGF-1R expression.
We analyzed data from 35 patients treated with adjuvant/neoadj Trastuzumab (82.9%) or after development of metastasis (17.1%). We performed immunochemistry for HER2, ER/PR, Ki67 and IGF-R1ß. Bioinformatic analysis was carried out to identify any correlation among HER2 overexpression, BRCA mutations and IGF-1Rß expression.
19 tumors (54%) presented BRCA mutations: 11(57.9%) were pathogenic. Median IGF-1Rß IHC score was 80 (range 0-285). IGF1Rß IHC score above median was found in 78.6% (10/14) of BRCA mutated and 26.7% (4/15) of BRCA not-mutated patients (p = 0.027). mPFS was 15.1 months in the overall population and 9.7months in patients harboring BRCA mutations. mDFS was 60.3 months in HER2+ BRCA mutated tumors, whilst was not reached in HER2+ BRCA not-mutated ones (p = 0.018). Interestingly, a trend toward a longer DFS was noted in HER2+ BRCA2 vs BRCA1 mutated patients. As for IGF-R1ß score, mDFS was 92.4 months in patients with IGF-R1ß+ tumors treated with adjuvant and/or neoadjuvant Trastuzumab and was not reached those with IGF-R1ß− tumors (p = 0.234). Reconstructed pathway showed that BRCA1 mutations lead to IGF-1R overexpression and to increased phosphorylation of AKT and, as a consequence, of the transcription factor Y box binding protein 1. YB-1 translocates into the nucleus to bind HER2 promoter, leading to HER2 overexpression, and increases the expression of EGFR.
Our results support that sensitivity to Trastuzumab seems to be associated with BRCA mutational status and to IGF-1R expression in a subset of HER2 positive BC patients.
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All authors have declared no conflicts of interest.