Results: Patient with breast cancer and a somatic (tumour) AKT1 variant

A 58-year-old post-menopausal woman with metastatic oestrogen receptor (ER)-positive, human epidermal growth factor-2 (HER2)-negative breast cancer has been on a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor and letrozole for two years and has developed progressive liver metastases. A liver biopsy confirms that the cancer is still ER-positive and HER2-negative. The liver biopsy is submitted for massively parallel sequencing (sometimes called next-generation sequencing) of a large panel of cancer-related genes as a screening investigation for a clinical trial. A somatic (tumour) variant in the AKT1 gene is reported.

AKT 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 ER-positive, HER2-negative metastatic breast cancer; however, most patients will go on to develop treatment resistance.
• The AKT genes (AKT1, 2 and 3) encode the AKT serine-threonine protein kinases (also referred to as protein kinase B alpha, beta and gamma). These proteins are phosphorylated by phosphoinositide 3-kinase (PI3K), and are key components of the signalling pathways which control cell proliferation, survival, metabolism and angiogenesis in both normal and malignant cells.
• Overactivation of the PI3K-AKT-PTEN signalling pathway, as a result of an activating PIK3CA or AKT1 variant or an inactivating variant in PTEN, is found in about half of all ER-positive, HER2-negative breast cancers.
• Capivasertib is a first-in-class small-molecule inhibitor of AKT1, AKT2 and AKT3.
• The phase II randomised CAPItello-291 clinical trial compared treatment with capivasertib plus fulvestrant to placebo plus fulvestrant in patients with ER-positive, HER2-negative advanced breast cancer who had progressed during or after treatment with an aromatase inhibitor (with or without previous CDK4/6 inhibitor therapy). Progression-free survival (PFS) was increased with capivasertib in all patients. The greatest benefit was seen in patients who had a genomic variant in the AKT pathway (defined as activating alteration in PIK3CA or AKT1, or inactivation of PTEN), with a PFS of 7.3 months in the capivasertib-fulvestrant group compared to 3.1 months in the placebo-fulvestrant group (hazard ratio 0.50; 95% CI, 0.38 to 0.65; P<0.001).

Management of the current cancer

• Capivasertib, in combination with fulvestrant, has been approved by the US Food and Drug Administration for the treatment of adult patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer with one or more biomarker alterations (PIK3CA, AKT1 or PTEN). Eligibility requires progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.
• Capivasertib is not currently approved by the European Medicines Agency or the NHS.
• Access to novel endocrine therapies for metastatic breast cancer with AKT variants may be available in the context of clinical trials.
• AKT somatic (tumour) results do not have any implications for constitutional (germline) genomic testing of patients with breast cancer.

• 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, Oliveira M, Howell SJ and others for the CAPItello study group: ‘Capivasertib in hormone receptor-positive advanced breast cancer‘. The New England Journal of Medicine 2023: volume 388, issue 22, pages 2,058–2,070. DOI: 10.1056/NEJMoa2214131