What is PIK3CA?

PIK3CA is a gene that encodes one piece (a subunit) of an enzyme called phosphatidylinositol 3-kinase. PIK3CA plays a role in the way cell growth, cell survival, and cell migration are controlled. Mutations in the PIK3CA gene can lead to uncontrolled cell growth and may cause cancer as well as some rare diseases of abnormal growth. Genes, like PIK3CA, that can cause normal cells to become tumor (tumour) cells are called oncogenes. The PIK3CA mutations associated with colorectal cancer are not hereditary, which means they are not passed on from parents to children.

PIK3CA mutations are found in 20-25% of colon cancers and 10% of rectal cancers. The majority of PIK3CA mutations (80%) are found in exon 9 and exon 20. An exon is a sub-segment of a gene containing the DNA instructions for the cell to make RNA and protein. Exon 9 mutations are more common than exon 20 mutations. Only 3% of colorectal cancers have the PIK3CA exon 20 mutation.  

In addition to colorectal cancer, PIK3CA oncogene mutations are involved in several human cancers including breast cancer, ovarian cancer, and non-small cell lung cancer (NSCLC).

PIK3CA is both a prognostic biomarker and a predictive biomarker. It gives information about the likely course of the disease (prognosis), and it predicts which treatments will be effective in a particular colorectal cancer.

PIK3CA mutation is more common in right-sided (proximal) colon cancers than in left-sided (distal) colon cancers and rectal cancers. PIK3CA mutations are also associated with higher tumor mutational burden (TMB). PIK3CA exon 9 mutations are associated with a higher likelihood of KRAS mutations, but a lower rate of BRAF mutation and microsatellite instability (MSI-High). Mutations in exon 20 of PIK3CA are associated with a higher rate of KRAS mutations and BRAF mutations, as well as microsatellite instability (MSI-High).

How is PIK3CA tested?

PIK3CA mutation status is tested in a biopsy sample of your cancer cells. PIK3CA testing is usually done by next-generation sequencing (NGS) in a multi-gene panel. PIK3CA mutation status does not always correlate between primary tumor and metastasis, so both tumors may be tested.  

What do my PIK3CA test results mean?

If your colorectal cancer has no PIK3CA mutation, your results will be reported as “PIK3CA wild-type (WT)”. If your colorectal tumor has a PIK3CA gene mutation, your results will be reported as “PIK3CA mutant” and may name a specific mutation, like “mutant exon 9” or “mutant exon 20”.

How do my PIK3CA test results impact my treatment?

If your PIK3CA result is wild-type (WT)  

• PIK3CA wild-type is associated with a better overall prognosis
• Your treatment options include traditional chemotherapy, targeted therapy, and immunotherapy as indicated by the results of your other biomarker testing, for example RAS mutation status, BRAF mutation status, or tumor mutational burden (TMB).

If your PIK3CA result is mutant exon 9 or mutant exon 20

• EGFR inhibitors like cetuximab and panitumumab are less effective in colorectal cancer with PIK3CA exon 20 mutations.
• PIK3CA gene mutation may predict a good response to aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs).
• Aspirin or other NSAIDs may be used as neoadjuvant therapy (treatment before surgery) and adjuvant therapy (treatment after surgery), as well as in prevention of colorectal cancer recurrence after treatment is completed.
• There are ongoing clinical trials for cancer treatments that directly target mutant PIK3CA in metastatic colorectal cancer (mCRC). There is already a targeted therapy drug (alpelisib) approved for the treatment of metastatic breast cancer with PIK3CA mutation. Talk to your medical team about whether you could benefit from a clinical trial.  

Who should be tested for PIK3CA mutations?

There are no standardized recommendations for PIK3CA testing. Most PIK3CA testing is done as part of a multi-gene sequencing panel in patients with metastatic colorectal cancer (mCRC) or in the setting of a clinical trial. Talk to your oncology team about whether PIK3CA testing could be useful for you.