In the literature: February 2020

Abstract

The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathways is one of the most frequently deregulated pathways in human cancers. This pathway controls multiple cellular processes, including metabolism, motility, proliferation, growth and survival. It can be aberrantly activated through multiple mechanisms, including diverse genomic alterations involving oncogenes and tumour suppressor genes.1 These alterations offer opportunities for therapeutic targeting of the pathway. PI3Kα protein complex is composed of regulatory (p85α) and catalytic (p110α) subunits. Pik3ca codes for p110α, which is the most frequently mutated oncogene across different cancers. Many distinct mutations have been identified, including hotspot single-amino acid substitutions in the helical (E542K and E545K) or kinase (H1047R) domains. These mutations are present in 40% of patients with luminal breast cancer (BC) and are a target for cancer therapy. In fact, several PI3K inhibitors have been developed in clinical trials. Recently, alpelisib (an oral α-specific PI3K inhibitor that selectively inhibits p110α) has been approved in combination with fulvestrant as it improved progression-free survival and overall response rate among patients with P ik 3 ca mutant luminal metastatic BC.2 In early clinical trials with alpelisib, the authors observed that double Pik3ca mutations could be a biomarker candidate. For this reason, the authors undertake a deep analysis of the prevalence of double mutations and their potential biological meaning. The prevalence of double Pik3ca mutations in different public datasets across different tumours types was between 12% and 13%. Indeed, breast, uterine and colorectal cancers had the greatest number of multiple P ik 3 ca -mutant tumours. Double mutations were enriched in luminal BCs compared with HER2+ or triple-negative BCs (15.4% vs 5.4%, p=0.004), and occur at similar frequencies in therapy-naive primary tumours and metastatic tumours (11.6% vs 15.7%, p=0.130). Interestingly, distinct patterns of comutation were observed. Thus, in BC, …