On July 27, 2020, the European Medicines Agency authorised marketing of alpelisib for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

The PIK3CA gene, encoding the catalytic subunit p110alfa of the PI3K enzyme, plays a key role in the neoplastic transformation. In fact, the PI3K pathway regulates different cellular functions, such as cellular proliferation, cellular migration and angiogenesis, and it is one of the signal transduction mechanisms most frequently activated in several types of solid tumours. PIK3CA mutations result in an abnormal form of the enzyme to be produced. This modified enzyme causes the constitutive activation of the PI3K pathway, which stimulates cancer cells to divide and grow in an uncontrolled fashion. PIK3CA is the most common mutated gene in breast cancer. About 40% of HR+/Her2- breast cancers (the most frequent breast cancer subtype) harbour PIK3CA activating mutations.
Alpelisib is a new generation PI3K inhibitor, specific for the catalytic subunit p110? and highly active against its mutated form.
About two months ago, the European Commission approved alpelisib in combination with fulvestrant for postmenopausal women, and men, with HR+/Her2-, locally advanced or metastatic breast cancer with a PIK3CA-mutation after disease progression following endocrine therapy as monotherapy.
FDA already approved alpelisib, with the same indications, on May 24, 2019.

Approval was based on SOLAR-1, a phase 3, randomised, double-blinded, placebo-controlled trial with 572 patients, among them 341 with PIK3CA mutations. In the cohort of patients with mutated PIK3CA, the combined alpelisib + fulvestrant therapy almost doubled the PFS compared with fulvestrant monotherapy (11 vs 5.7 months). Whereas no PFS benefit was observed in patients whose tumours did not have a PIK3CA mutation.

Only 11 PIK3CA mutations were considered for trial enrolment in SOLAR-1, but it is possible that other gene variants, described or presumed as pathogenic, and detected in more than 25% of HR+/Her2- breast cancers harbouring a PIK3CA mutation, can be predictive of response to alpelisib.

The mutational analysis of PIK3CA can be performed with different methods: Real Time PCR, Pyrosequencing, MassARRAY and NGS, which are all offered by Diatech Pharmacogenetics through its CE-IVD solutions.

More information at www.diatechpharmacogenetics.com


  1. Piqray (alpelisib) EPAR – Medicine overview. EMA 30/07/2020
  2. FDA approves alpelisib for metastatic breast cancer. FDA, 28/05/2019
  3. André et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor–Positive Advanced Breast Cancer. New Engl J Med. 2019; 380:1929-1940; doi: 10.1056/NEJMoa1813904
  4. Khoury et al. Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer. Front. Oncol. 31 August 2020; https://doi.org/10.3389/fonc.2020.01475