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Background  The Cancer Genome Atlas analysis revealed that somatic  EGFR , receptor tyrosine-protein kinase erbB-2 ( ERBB2 ), Erb-B2 receptor tyrosine kinase 3 ( ERBB3 ) and Erb-B2 receptor tyrosine kinase 4 ( ERBB4 ) gene mutations (ERBB family mutations) occur alone or co-occur with somatic mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit ( PIK3CA ) in 19% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Because  ERBB  family mutations can activate the PI3K/AKT pathway and likely have similar canonical signalling effects to PI3K pathway mutations, we investigated their combined impact on response to neoadjuvant HER2-targeted therapies.    Methods  Baseline tumour biopsies were available from 74 patients with HER2-positive breast cancer who were enrolled in the phase II TCHL neoadjuvant study (ICORG 10-05) assessing TCH (docetaxel, carboplatin, trastuzumab) ( n  = 38) versus TCL (docetaxel, carboplatin, lapatinib) ( n  = 10) versus TCHL (docetaxel, carboplatin, trastuzumab, lapatinib) ( n  = 40), each for six cycles. Activating mutations in  PIK3CA  and  ERBB  family genes were identified using mass spectrometry-based genotyping. Phosphatase and tensin homolog (PTEN) expression was assessed by immunohistochemistry.    Results    PIK3CA  and/or  ERBB  family mutations were detected in 23 (31.1%) tumour samples tested, whereas PTEN expression was low in 31.1% of cases tested. Mutation frequency was similar in each treatment arm (31.3% in TCH arm, 30% in TCL arm and 31.3% in TCHL arm) and was not influenced by oestrogen receptor (ER) status (27.6% in ER-negative patients, 33.3% in ER-positive patients) or progesterone receptor (PR) status (32.6% in PR-negative patients, 29% in PR-positive patients). There was no significant difference in pathological complete response (pCR) rates between 47 patients with wild-type (WT) tumours and 22 patients whose tumours carried mutations (in either  PIK3CA  or  ERBB  family genes) (42.5% vs. 54.5%;  p  = 0.439). Similarly, there was no significant difference in pCR rates between patients with  PIK3CA/ERBB  family mutated/PTEN-low (i.e., PI3K-activated) tumours and patients without PI3K activation (50% vs. 44%;  p  = 0.769). However, in the TCHL (but not the TCH) group, the pCR rate was higher for 9 patients with  PIK3CA/ERBB  family mutated tumours than for 20 patients with  PIK3CA/ERBB  family WT tumours (77.8% vs. 35%;  p  = 0.05).    Conclusions  Our results indicate that patients who receive neoadjuvant TCHL and have  PIK3CA/ERBB  family mutated tumours may be more likely to have a pCR than patients with WT tumours.    Trial registration  ClinicalTrials.gov,  NCT01485926 . Registered on 2 December 2011.    Electronic supplementary material  The online version of this article (doi:10.1186/s13058-017-0883-9) contains supplementary material, which is available to authorized users.

breast cancer research

Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies