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PIK3CA Mutation Analysis

Test code(s) 16897, 18902

Question 1. What is PIK3CA, and what is the significance of PIK3CA mutations?

PIK3CA is a gene that encodes a lipid kinase involved in multiple signaling pathways. These pathways influence cellular functions such as growth, death, and proliferation. PIK3CA mutations activate the PI3K-PTEN-AKT pathway, which is downstream from both the EGFR and the RAS-RAF-MAPK pathways. PIK3CA mutations may cause oncogenic transformation independent of RAS or RAF mutations.

PIK3CA mutations occur in about 15% to 30% of breast, endometrial, and colon cancers.1, 2 They occur less frequently in lung cancer and other types of cancer. Presence of PIK3CA mutations is associated with poor prognosis and lack of response to specific therapies in patients with breast, endometrial, or colon cancer. In lung cancers, PIK3CA mutations can identify prognostically relevant subgroups.

Question 2. What is the meaning of PIK3CA mutations in breast and colon cancer?

Breast Cancer

PIK3CA mutation predicts a lower pathologic complete response rate following anti-HER2 therapy in patients with HER2 amplification. PIK3CA mutations may also predict adverse outcome, independent of therapy, in certain breast cancer patient cohorts.

Colon Cancer

PIK3CA mutations predict a shorter disease-free and relapse-free survival. PIK3CA point mutations also forecast higher mortality rates in patients with wild-type KRAS tumors than in those with KRAS-mutated tumors.2 PIK3CA mutations have been associated with resistance to anti-EGFR therapy (eg, cetuximab and panitumumab) in some studies1,2 but not in others.2-4 The reasons for the discrepancy are not clear.

Question 3. What is the benefit of testing for mutations in multiple genes, including PIK3CA, in patients with colorectal cancer?

Mutations in multiple genes are associated with colorectal cancer prognosis and response to therapy. So testing mutiple genes provides more complete information. The Quest Diagnostics Colorectal Cancer Mutation Panel (test code 18902) includes testing for mutations in KRAS, NRAS, BRAF, and PIK3CA. Thus, it includes testing for mutations in both EGFR downstream signaling pathways. Testing for mutations in these 4 genes can identify oncogenic mutations that result in bypass of EGFR signaling in 65% to 70% of colorectal cancer cases.3 Presence of 1 or more mutations predicts diminished response to anti-EGFR therapy.

Question 4. Which PIK3CA mutations are detected and how are they interpreted?

Quest Diagnostics sequences exons 1, 9, and 20 of the PIK3CA gene. These exons harbor over 91% of all reported PIK3CA cancer-associated mutations.4 The most commonly encountered mutations, particularly those involving E542 and E545 in exon 9 and H1047 in exon 20, are associated with pathway activation, and their adverse effects are well supported by clinical data.5 The significance of less commonly observed PIK3CA mutations can sometimes be inferred based on structural and experimental studies.5-7

Question 5. How is the PIK3CA mutation analysis test performed, and what are the performance characteristics?

DNA is extracted from formalin-fixed, paraffin-embedded tissue. Using PCR, the DNA in the entire coding region of exons 1, 9, and 20 is amplified. PCR products are subsequently purified and sequenced. We perform a forward and reverse dye-terminator Sanger sequencing method and gel capillary electrophoresis on an automated platform.

Our validation studies indicate this test is precise, accurate, and sensitive. The analytical sensitivity is 20% tumor cells in the background of normal cells. Testing is performed on the portion of the specimen where tumor is enriched.

Question 6. Which specimens are acceptable for this test?

Acceptable specimens include formalin-fixed, paraffin-embedded tissue blocks or slides with at least 5% tumor present, though at least 20% is preferred. Tissue that is not paraffin-embedded may be tested after review by the laboratory director.

Question 7. What type of report will I receive after submitting a sample? How long will it take to obtain results?

The patient report will include a list of mutations resulting in an amino acid change. If a rare mutation with an unknown clinical significance is detected, the report will include an interpretive comment based on a review of the available literature.

Results are typically reported within 7 days of specimen submission.


  1. Huang CH, Mandelker D, Gabelli SB, et al. Insights into the oncogenic effects of PIK3CA mutations from the structure of p110alpha/p85alpha. Cell Cycle. 2008;7:1151-1156.
  2. Catasus L, Gallardo A, Cuatrecasas M, et al. PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are assoicated with adverse prognostic parameters. Mod Pathol. 2008;21:131-139.
  3. Tol J, Dijkstra JR, Klomp M, et al. Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab. Eur J Cancer. 2010;46:1997-2009.
  4. Bachman KE, Argani P, Pedram A, Samuels Y, et al. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther. 2004;3:772-775.
  5. Ogino S, Nosho K, Kirkner GJ, et al. PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol. 2009;27:1477-1484.
  6. DeRoock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations of the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: A retrospective consortium analysis. Lancet Oncol. 2010;11:753-762.
  7. Sartore-Bianchi A, Martini M, Molinari F, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009;69:1851-1857.
  8. Prenan H, DeSchutter J, Jacobs B, et al. PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res.2009;15:3184-3188.
  9. Vogt PK, Kang S, Elsliger MA, et al. Cancer-specific mutations in phosphatidylinositol 3-kinase. Trends Biochem Sci. 2007;32:342-349.
  10. COSMIC database of the Sanger Institute. http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=gene&ln=PIK3CA

    Additional References Supporting the Role of PIK3CA in Solid Tumors

    Breast Cancer

  11. Cizkova M, Dujaric ME, Lehmann-Che J, Scott V, et al. Outcome impact of PIK3CA mutations in HER2-positive breast cancer patients treated with trastuzumab. Br J Cancer. 2013;108:1807-1809.
  12. Razis E, Bobos M, Kotoula V, et al. Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast Cancer Res Treat. 2011;128:447-456.
  13. Lai YL, Mau BL, Cheng WH, et al. PIK3CA exon 20 mutation is independently associated with a poor prognosis in breast cancer patients. Ann Surg Oncol. 2008;15:1064-1069.
  14. Barbareschi M, Buttitta F, Felicioni L, et al. Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res. 2007;13:6064-6069.

    Colon Cancer

  15. Kato S, Iida S, Higuchi T, et al. PIK3CA mutation is predictive of poor survival in patients with colorectal cancer. Int J Cancer. 2007;121:1771-1778.
This FAQ is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.

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