PIK3CA-mutated Metastatic Breast Cancer

An analysis from SAFIR02 trial results in better understanding of the characteristics of the MBC population harbouring PIK3CA mutations
31 Jan 2020

An analysis of outcomes and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer (MBC) from the SAFIR02 trial showed that patients with PIK3CA-mutated hormone receptor (HR)-positive/HER2-negative tumours have a poor outcome and resistance to chemotherapy. Patients with PIK3CA-mutated triple-negative breast cancer (TNBC) present a better overall survival (OS). This could be explained by an enrichment of PIK3CA mutations in luminal breast cancer which lost HR expression in the metastatic setting. The results were published online on 24 January 2020 in the Annals of Oncology.

The authors led by Prof. Fabrice André of the Gustave Roussy, Villejuif, France wrote in the study background that PIK3CA somatic mutations occur in around 20%–40% of early breast cancers (EBCs) and are more frequent in HR-positive disease. The clinical relevance of PIK3CA mutations has been evaluated in EBC; these studies suggested that PIK3CA mutations are associated with a good outcome in patients with HR-positive/HER2-negative EBC. Although data have been extensively reported in EBC, no study has focused on the molecular characterisation and clinical outcome of patients with PIK3CA-mutated MBC. Better understanding of the characteristics of the MBC population harbouring PIK3CA mutations will allow to better position PI3K inhibitors in the treatment landscape and to discover new populations for drug development.

A total of 649 patients with MBC from the SAFIR02 trial (NCT02299999), with available mutational profiles were selected for outcome analysis. PIK3CA mutations were prospectively determined by next-generation sequencing (NGS) in metastatic samples. The mutational landscape of PIK3CA-mutated MBC was assessed by whole-exome sequencing in 617 patients. The prognostic value of PIK3CA mutations during chemotherapy was assessed in plasma samples from 44 patients by NGS and digital PCR.

PIK3CA mutation was found in 28% of HR-positive/HER2-negative tumours and 10% of TNBC (p < 0.001). PIK3CA-mutated HR-positive/HER2-negative MBC was less sensitive to chemotherapy (adjusted odds ratio: 0.40; p = 0.002), and presented a worse OS compared with PIK3CA wild-type (adjusted hazard ratio: 1.44; p = 0.04). 

PIK3CA-mutated HR-positive/HER2-negative MBC was enriched in MAP3K1 mutations (15% versus 5%, p = 0.0005).

In metastatic TNBC, the median OS in patients with PIK3CA mutation was 24 versus 14 months for PIK3CA wild-type (p = 0.03). The study team further looked at the distribution of PIK3CA mutation in metastatic TNBC according to HR expression on the primary tumour. In total, 6% of patients without HR expression on the primary and 36% of patients with HR-positive primary tumours presented PIK3CA mutation (p < 0.001).

The level of residual PIK3CA mutations in plasma after one to three cycles of chemotherapy was associated with a poor OS (continuous variable, hazard ratio: 1.03, p = 0.007).

The authors pointed out to unmet medical needs in patients with PIK3CA-mutated HR-positive/HER2-negative MBC where new drugs are needed. In addition, there is a need to investigate the predictive value of MAP3K1 mutations and PIK3CA co-alterations for the sensitivity to PI3K inhibitors. In metastatic TNBC, the study findings suggest that there is an opportunity to develop PI3K inhibitors, especially in patients whose primary tumours express HR.

This work was supported by Fondation ARC Pour La Recherche Sur Le Cancer, Breast Cancer Research Foundation, Operation Parrain Chercheurs, and Transcan.

Reference

Mosele F, Stefanovska B, Lusque A, et al. Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Annals of Oncology; Published online 24 January 2020.  https://doi.org/10.1016/j.annonc.2019.11.006

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