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

• Published in: Breast cancer research : BCR Vol. 19; no. 1; p. 87
• Main Authors: Toomey, Sinead, Eustace, Alexander J, Fay, Joanna, Sheehan, Katherine M, Carr, Aoife, Milewska, Malgorzata, Madden, Stephen F, Teiserskiene, Ausra, Kay, Elaine W, O'Donovan, Norma, Gallagher, William, Grogan, Liam, Breathnach, Oscar, Walshe, Janice, Kelly, Catherine, Moulton, Brian, Kennedy, M John, Gullo, Guiseppe, Hill, Arnold D, Power, Colm, Duke, Deirdre, Hambly, Niamh, Crown, John, Hennessy, Bryan T
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 27-07-2017; BioMed Central; BMC
• Subjects: 1-Phosphatidylinositol 3-kinase; Adjuvant chemotherapy; AKT protein; Biopsy; Breast cancer; Carboplatin; Care and treatment; Epidermal growth factor; Epidermal growth factor receptors; ErbB protein; ErbB-2 protein; ErbB-3 protein; Estrogen receptors; Gene mutation; Genetic aspects; Genomes; Genotyping; HER2; Immunohistochemistry; Immunotherapy; Kinases; Lapatinib; Mass spectroscopy; Monoclonal antibodies; Mutation; Physiological aspects; PI3K pathway; Polymerase chain reaction; Progesterone; Protein-tyrosine kinase receptors; PTEN protein; Signal transduction; Somatic mutations; Targeted cancer therapy; Tensin; Trastuzumab; Tumors; Ireland; PI3K pathway; Breast cancer; Lapatinib; Somatic mutations; HER2; Trastuzumab
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-017-0883-9

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.
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.
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).
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.
ClinicalTrials.gov, NCT01485926 . Registered on 2 December 2011.