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 (PFS) advantage in patients with PIK3CA-mutated metastatic breast cancer receiving alpelesib and fulvestrant compared to those treated with placebo plus fulvestrant.
• Capiversatib is an oral AKT inhibitor. AKT is a key protein in the PI3K–AKT–PTEN biological pathway. In the CAPIitello-291 randomised phase III trial patients with ER-positive, HER2-negative breast cancer patients who had progressed on first-line endocrine therapy and had alterations in AKT, PTEN or PIK3CA had a significantly improved progression free survival with the addition of capiversatib to the control intervention of fulvestrant.
• Inavolisib is a novel PI3K degrader that was investigated in the the INAVO120 trial along with palbociclib and fulvestrant. The drug was used in patients with locally advanced or metastatic PIK3CA-mutated breast cancerwho experienced disease progression during or within 12 months of completing adjuvant endocrine therapy, and without prior exposure to systemic therapy for metastatic disease. This trial demonstrated a significantly longer progression free survival (PFS) with this combination compared with palbociclib, fulvestrant and placebo.

Management of the current cancer

• Alpelisib combined with fulvestrant is recommended by NICE as an option for treating patients with ER-positive, HER2-negative, PIK3CA-mutated advanced breast cancer who have progressed after treatment with a CDK4/6 inhibitor and an aromatase inhibitor.
• Capivasertib plus fulvestrant is recommended by NICE as an option for treating ER-positive HER2‑negative advanced breast cancer that has:
  • one or more PIK3CA, AKT1 or PTEN gene alterations; and
  • recurred or progressed after treatment with a CDK 4/6 inhibitor plus an aromatase inhibitor.
• Both alpelisib and capiversatib are available via the Cancer Drugs Fund.
• Inavolisib has been approved by the FDA for treatment of endocrine resistant PIK3CA-mutated ER-positive HER2-negative advanced breast cancer in conjunction with palbociclib and fulvestrant. Review by the EMA is in progress. This drug is not currently available in the NHS.
• Testing for somatic (tumour) PIK3CA variants is available through the National Genomic Test Directory for cancer via test code M3.6.
• Alternatively, testing for PIK3CA variants in advanced ER-positive HER2-negative breast cancer can be performed via a ctDNA test (liquid biopsy). This in included in the National Genomic Test Directory as test code M3.13. Details of the ctDNA testing pathway in your local area can be obtained from your Genomic Laboratory Hub.
• For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

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

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
• Turner NC, Im SA, Saura C and others. ‘Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer‘. The New England Journal of Medicine 2024: volume 391, issue 17, pages 1584–1596. DOI: 10.1056/NEJMoa2404625
• Turner NC, Oliveira M, Howell, SJ et al. Capivasertib in Hormone Receptor–Positive Advanced Breast Cancer | New England Journal of Medicine 2023. N Engl J Med 2023;388:2058-2070 DOI: 10.1056/NEJMoa221413

For patients

• Breast Cancer Now: Alpelisib (Piqray)
• Breast Cancer Now: Capivasertib (Truqap)