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

Sinéad Toomey ,Norma O’Donovan,Janice Walshe,Arnold D Hill,Deirdre Duke,Niamh Hambly,Katherine M Sheehan,Aoife Carr,Alex J Eustace ,Stephen F Madden,G Gullo ,Elaine W Kay,Liam Grogan,William M Gallagher ,Małgorzata Milewska ,Brian Moulton,Oscar S Breathnach ,Michael J Kennedy ,John Crown,Colm Power,Joanna Fay,Ausra Teiserskiene,Catherine M Kelly ,Bryan T Hennessy

doi:10.1186/s13058-017-0883-9

Abstract

BackgroundThe 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.MethodsBaseline 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.ResultsPIK3CA 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).ConclusionsOur 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 registrationClinicalTrials.gov, NCT01485926. Registered on 2 December 2011.

Highlights

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
There was no significant difference in pathological complete response rates between 47 patients with wild-type (WT) tumours and 22 patients whose tumours carried mutations (42.5% vs. 54.5%; p = 0.439)
Our results indicate that patients who receive neoadjuvant TCHL and have PIK3CA/ERBB family mutated tumours may be more likely to have a pathological complete response (pCR) than patients with WT tumours

Summary

Introduction

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. 20% of primary breast cancers have an alteration, usually amplification, of the human epidermal growth factor receptor 2 (HER2) gene. The addition of trastuzumab to conventional chemotherapy has significantly improved the outcomes for patients with both early-stage and metastatic HER2-altered breast cancer, with significantly improved survival in both settings [2]. A small minority of patients with HER2-positive metastatic disease achieve durable complete remissions, approximately 80% to 90% develop progressive cancer. Addition of trastuzumab to pre-operative chemotherapy results in 30% to 50% of patients achieving a pathological complete response (pCR) [2]. Approximately 20% of patients with HER2-positive early-stage disease and 90% of patients with metastatic disease will die from disease which is resistant to trastuzumab. Newer targeted antiHER2 agents have been studied in an attempt to overcome trastuzumab resistance [3,4,5]

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