Part 01 Background

Colorectal cancer (CRC) is the third most prevalent malignancy worldwide and the second leading cause of cancer death. It is estimated that more than 1.9 million new cases of colorectal cancer (including anal cancer) and 904,000 deaths will occur in 2022, accounting for nearly one-tenth of cancer cases and deaths ^[1]. Colorectal cancer ranks third in morbidity but second in mortality.

Part 02. Mutations in the PIK3CA gene

PIK3CA gene, as a key gene in PI3K-AKT pathway, is essentially a proto-onco gene, located on chromosome 3, with a total of 20 exons, which is responsible for encoding p110α protein of PI3K. Among them, exon 9 encodes the helical domain of p110α, exon 20 encodes the kinase domain of p110α, and about 80% of PIK3CA gene mutations occur in exon 9 and exon 20. The three most common hot spot mutations are H1047R in exon 20 and E542K and E545K in exon 9. In particular, the E545K mutation disrupted inhibition between the SH2 domains in p110 and p85, and the exon 20 mutation caused a change in activity of the p110a kinase domain H5-17. The mutation causes the abnormal enhancement of PI3K chemotaxis activity and promotes the cell to become cancerous ^[2].

Part 03. Mutation of PIK3CA gene & colorectal cancer

PIK3CA gene mutation has been found in glioblastoma, endometrial cancer, bladder cancer, gastric cancer, breast cancer, colorectal cancer and other cancers, among which, according to reports, the mutation rate of PIK3CA gene in CRC is 3.5%–24.7%. The PIK3CA mutation has a significant molecular effect on the location of CRC: tumors located in the proximal colon have a higher mutation rate of PIK3CA than those in the distal colon and rectum ^[3].

Part 04 PIK3CA gene and drug use

The PIK3CA mutation rate in the China population is approximately 3.5%, which together with the RAS signaling pathway constitutes two parallel pathways downstream of EGFR.

According to some existing research results ^[4], PIK3CA mutation may be an effective prediction marker for aspirin treatment, but there is still a lack of good consistency between the various studies.

Study of PIK3CA mutation in colorectal cancer

In individuals with exon 20, the relative risk for objective response in patients with PIK3CA mutations was 0.25 [95% confidence interval] (CI) 0.05–1.19 relative to that in wild-type PIK3CA patients; P = 0.082。

The results suggest that our patient had a poor prognosis with exon 20 mutations. The objective response was not statistically superior to that in PIK3CA wild-type patients, partly due to the small sample size. It is concluded that the mutation in exon 9 of PIK3CA does not affect the results of anti-EGFR targeted therapy, while the mutation in exon 20 may lead to worse effects of anti-EGFR targeted therapy ^[5].

Part 05. Summary

PIK3CA gene is closely related to colorectal cancer, and its high mutation rate is a gene that cannot be ignored in colorectal cancer. However, at present, because the correlation between PIK3CA mutation and anti-EGFR monoclonal antibody efficacy cannot be completely determined, the level of detection evidence for PIK3CA will be lower. In the high-throughput sequencing China Experts Consensus on Molecular Detection of colorectal Cancer, PIK3CA is an optional molecular detection marker.

Part 06. Testing Product

Detection contents:

KRAS: 26 somatic mutations in exons 2, 3 and 4

NRAS: 3 somatic mutations in exons 2 and 3

PIK3CA: H1047R mutation and H1047R mutation in exon 20

BRAF: E542K and E545K mutations in exon 9 and the V600E mutation in exon 15

References

[1] CA Cancer J Clin. 2024; 1–35.

[2] Significance of PIK3CA gene in colorectal cancer

[3] Significance of PIK3CA gene mutation in non-metastatic colorectal cancer

[4] N Engl J Med. 2012;Oct 25; 367(17):1596-606.

[5] Ann Oncol. 2012; 23(6):1518-1525.

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