Results: Patient with breast cancer and a somatic (tumour) PIK3CA variant

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.

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.

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

• NHS England: National Genomic Test Directory
• NICE: Alpelisib with fulvestrant for treating hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer

References:

• André F, Ciruelos EM, Juric D and others. ‘Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: Final overall survival results from SOLAR-1‘. Annals of Oncology 2021: volume 32, issue 2, pages 208–217. DOI: 10.1016/j.annonc.2020.11.011
• Gennari A, André F, Barrios CH and others. ‘ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer‘. Annals of Oncology 2021: volume 32, issue 12, pages 1,475–1,495. DOI: 10.1016/j.annonc.2021.09.019

For patients

• Breast Cancer Now: Alpelisib (Piqray)