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

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.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).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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0883-9) contains supplementary material, which is available to authorized users.

PIK3CA mutations and their response to neoadjuvant treatment in early breast cancer: A systematic review and meta‐analysis

“…As shown in Table , 20 studies including 4392 patients were included in our meta‐analysis . Overall, PIK3CA mutation incidence in our meta‐analysis was 22.4% (range 7.7–39.0%).…”

“…pCR was 28% for PIK3CA MT and 38% for PIK3CA WT. Seven studies were conducted in the United States, nine in Europe, and four in Asia . Two studies included objective response rate, while the others reported pCR as the endpoint in WT versus MT PIK3CA tumors.…”

“…A total of 13 studies of unselected HER2+ patients were used for analysis (Table ) . In this study, unselected HER2+ patients are defined as the entire HER2+ population with no restriction to HR status or NAT regime.…”

The prognostic value of PI3K mutational status in breast cancer: A meta‐analysis

“…40 Interestingly, further results from the EMILIA trial showed that PFS was not affected by the PIK3CA mutational status in patients treated with TDM-1, while patients harbouring PIK3CA mutations, treated with standard HER2 therapy, had shorter PFS compared to PIK3CA wild-type patients (4.3 vs 6.4 months respectively). 41 More recently, Toomey et al 42 were the first to report that PI3KCA/ERBB mutations in patients receiving neoadjuvant docetaxel, carboplatin, trastuzumab and lapatinib may be more likely to experience pCR in comparison to patients with the wild-type gene. Of the overall patients 15% were HR-ERBB2−; 9% were HR-ERBB2+; 64% were HR+ ERBB2−; and 12% were HR+ ERBB2+.…”

Targeted lapatinib anti-HER2/ErbB2 therapy resistance in breast cancer: opportunities to overcome a difficult problem

“…Activation of pro-proliferative signaling pathways such as PI3K/Akt/mTOR, Src, or MAPK is also associated with a worse prognosis and resistance in HER2+ breast cancer patients. Combinatorial treatment with agents that target these pathways, such as everolimus, AZD0530, or dasatinib improve survival in lapatinib-and trastuzumab-refractory patients [68][69][70] . The development of marker or gene assays, to better predict treatment response tailored to specific genetic and genomic features of the breast cancer would be helpful to prevent anti-HER2 treatment resistance.…”