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Example clinical scenario

A 64-year-old woman with metastatic ER-positive, HER2-negative breast cancer has been on a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor and letrozole for three years when she develops progressive disease in her liver. A liver biopsy is taken and massively parallel sequencing (sometimes called next-generation sequencing) is performed on the tissue. The biopsy result shows that the tumour is still ER-positive, HER2-negative, and that there is a pathogenic PIK3CA variant.

Impact of the genomic result

PIK3CA variants in ER-positive, HER2-negative breast cancer

  • Endocrine therapy, with or without the use of a CDK4/6 inhibitor, is the standard treatment for patients with HR-positive, HER2-negative advanced breast cancer. However, most patients will go on to develop treatment resistance.
  • Approximately 40% of patients with HR-positive, HER2-negative breast cancer have activating variants in the gene PIK3CA, inducing hyperactivation of the alpha isoform (p110α) of phosphatidylinositol 3-kinase (PI3K).
  • This hyperactivation can lead to increased proliferation, cell survival and therefore oncogenesis. For this reason, PIK3CA variants are a negative prognostic factor in ER-positive, HER2-negative metastatic breast cancer.
  • Alpelisib is a small molecule inhibitor of alpha isoform (p110α) of phosphatidylinositol 3-kinase (PI3K).
  • The SOLAR-1 trial investigated the addition of alpelisib to fulvestrant in ER-positive, HER2-negative breast cancer patients who had progressed on first-line endocrine therapy. The trial showed a progression-free survival advantage in patients with PIK3CA-mutated metastatic breast cancer receiving alpelesib and fulvestrant compared to those treated with placebo plus fulvestrant.

What do you need to do?

Management of the current cancer

  • Alpelisib combined with fulvestrant is recommended for treating patients with ER-positive, HER2-negative, PIK3CA-mutated advanced breast cancer who have progressed after treatment with a CDK4/6 inhibitor and letrozole.
  • Testing for somatic (tumour) PIK3CA variants is available through the National Genomic Test Directory for cancer via test code M3.6.
  • Hyperglycaemia and skin rash are the most common adverse effects of the treatment according to the SOLAR-1 trial. It should therefore be used cautiously in patients with diabetes mellitus.
  • Glucose and HBA1C levels should be monitored throughout.

For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.


For clinicians


For patients

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  • Last reviewed: 08/10/2023
  • Next review due: 08/10/2024
  • Authors: Dr Amal Singh
  • Reviewers: Dr Ellen Copson, Dr Terri McVeigh