Medical Policy

 

Subject: Analysis of PIK3CA Status in Tumor Cells
Document #: GENE.00044 Publish Date:    12/27/2017
Status: Reviewed Last Review Date:    11/02/2017

Description/Scope

This document addresses DNA testing used to determine the PIK3CA status in individuals with cancer.

Mutations in the phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene has been implicated in the pathogenesis of several cancers, including but not limited to colon cancer, gliomas, gastric cancer, breast cancer, endometrial cancer, and lung cancer.  Researchers are exploring the role of PIK3CA mutations in the initiation and progression of various cancers.

Other names for PIK3CA include but are not limited to:

Note: For related documents see:

Position Statement

Investigational and Not Medically Necessary:

Analysis of PIK3CA status is considered investigational and not medically necessary for all indications.  

Rationale

PIK3CA gene mutations can be accurately and reliably detected.  PIK3CA mutations are reported to be found in approximately 10-20% of colorectal cancer (CRC) cases, with most of the mutations occurring on exons 9 (60-65%) or 20 (20-25%).  PIK3CA mutations are reported in approximately 26% of invasive breast cancer and 3% of lung cancer cases.  The analytic validity (sensitivity and specificity) of testing for PIK3CA mutation are reported at 99%.  Direct sequencing and real-time polymerase chain reaction (real-time PCR) are frequently used techniques for PIK3CA mutation analysis.  This testing is generally performed by CLIA certified laboratories.

Colorectal Cancer

The epidermal growth factor receptor (EGFR) and its downstream signaling pathways regulate key cellular events that direct the progression of many neoplasms.  EGFR is expressed in a variety of human tumors, including but not limited to carcinomas of the lung, colon, pancreas, breast, ovary, bladder, and kidney.  Mutations, gene amplification, and protein overexpression of various elements of this pathway not only contribute to carcinogenesis, but also influence prognosis and afford specific targets for therapeutic intervention.  The phosphatidylinositol 3-kinase- (PI3K-) protein kinase B (AKT) is one of the main intracellular pathways activated by EGFR.  This pathway leads to the activation of various transcription factors that influence cellular responses such as proliferation, differentiation, migration and apoptosis.  Disruptions in the signaling pathways can contribute to malignant transformation and tumor progression as a result of increased cell proliferation, prolonged survival, angiogenesis, antiapoptosis, invasion, and metastasis (Krasinskas, 2011).

Deregulation of the PI3K-AKT pathway can be created by several factors: activating mutations in the PIK3CA gene (p110 subunit); inactivation of the phosphatase and tensin homolog (PTEN) gene; or by activation of AKT.  The PIK3CA gene encodes phosphatidylinositol 3-kinase (PI3K), a key signal transducer in the PI3K-AKT pathway.  PIK3CA mutations have been estimated to occur in 10-20% of colon cancers, with most of the mutations involving hotspots on exons 9 and 20.  There is also a strong association between PIK3CA exon 9 mutations and KRAS mutations in that, as a prognostic marker, PIK3CA mutations are associated with shorter cancer-specific survival, but some research suggests this effect may be limited to individuals with KRAS wild-type (WT) tumors (de Roock, 2010; Hynes, 2005; Krasinskas, 2011; Ogino, 2009).

Although PIK3CA mutations account for approximately 10-20% of CRC, their effect on patient outcome has not been clearly established.  Capuzzo and colleagues (2008) analyzed KRAS, BRAF, PI3KCA, MET, and IGF1R in 85 individuals with metastatic colorectal cancer (mCRC) treated with cetuximab-based therapy in which EGFR status was known.  PIK3CA mutation was identified in 17.7% (14/85) of cetuximab-treated mCRC participants, but the overall response rate (ORR), time-to-progression and overall survival (OS) did not differ between mutated and non-mutated participants.  The authors also concluded that “combination of multiple mutation tests (KRAS or BRAF ± PI3KCA) did not provide additional information over a single mutation test (data not shown).”

Ogino and colleagues (2009) investigated the association of PIK3CA mutation with poor prognosis among individuals with curatively resected colon cancer.  Researchers examined the tumor tissue of 450 subjects with resected stage I-III colon cancer from two independent prospective cohort studies.  Cox proportional hazards models were used to calculate hazard ratios (HRs) of colon cancer-specific and overall mortalities, adjusted for patient characteristics and tumoral molecular features, including the CpG island methylation phenotype, microsatellite instability (MSI), LINE-1 hypomethylation, and mutations in p53, CIMP, KRAS, and BRAF.  A total of 82 participants (18%) had PIK3CA mutations in exons 9 and 20.  The authors concluded that PIK3CA mutation increases cancer-specific mortality in individuals with KRAS-WT tumors (HR=3.80; 95% confidence interval [CI], 1.56-9.27), but did not appear to have a significant effect on mortality in individuals with KRAS mutations (HR=1.25; 95% CI, 0.585-2.96). 

Tol and colleagues (2010) assessed the predictive value of potential relevant markers involved in the EGFR signaling pathways for response to cetuximab-based treatment.  In this randomized controlled, multicenter trial, formalin-fixed paraffin-embedded CRC tissue of the primary tumor was acquired from 559 individuals with mCRC that were treated with chemotherapy and bevacizumab with or without cetuximab (phase III CAIRO2 study).  DNA mutation analysis was conducted for BRAF (V600E), KRAS (codon 12 and 13) and PIK3CA (exon 9 and 20).  Tissue microarrays were constructed for the assessment of EGFR and human epidermal growth factor receptor 2 (HER2) gene copy number and EGFR and PTEN protein expression.  The results of these markers, individually or in combination, were correlated with OS and progression-free survival (PFS) in the subgroup of participants with a KRAS-WT tumor treated in the cetuximab arm.  The control group was comprised of KRAS-WT participants treated without cetuximab.  The authors found that the PIK3CA mutation was unrelated to outcome in KRAS-WT tumors treated in the cetuximab arm of the CAIRO 2 study.  The 5-year survival rate was 90% in PIK3CA-WT and 82% in PIK3CA mutants (log-rank p=0.075).

Sartore-Bianchi and colleagues (2009) presented the mutational analysis of PIK3CA and KRAS and evaluation of the PTEN protein status in a cohort of 110 subjects with mCRC treated with panitumumab or cetuximab.  A total of 15 individuals (13.6%) had PIK3CA mutations, and none of them responded to treatment with the anti-EGFR monoclonal antibodies (mAbs) panitumumab or cetuximab (p=0.038).  The statistical correlation was stronger when only KRAS-WT tumors were analyzed (p=0.016).  The participants with PIK3CA mutations displayed a worse clinical outcome also in terms of progression-free survival (p=0.035).  The researchers concluded that PIK3CA mutations could help to distinguish potential non-responders to anti-EGFR mAbs within the KRAS-WT subpopulation.

Contrary to the findings of Sartore-Bianchi above, in a similar study, Prenen and colleagues (2009) conducted a randomized controlled trial (RCT) which analyzed the PIK3CA and KRAS mutation status in 200 individuals with chemorefractory metastatic colorectal cancers treated with cetuximab in monotherapy or in combination with irinotecan, and correlated the mutation status with outcome.  The authors did not find a link between PIK3CA and anti-EGFR mAb resistance.  A total of 13% (5/39) of the participants with PIK3CA mutations responded to cetuximab, and 11% (18/160) did not (p=0.78).

In an attempt to further explore why most individuals with KRAS-WT tumors still did not respond to anti-EGFRs, De Roock and colleagues (2010) conducted a multicenter retrospective analysis of the effect of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab in individuals with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era.  A total of 1022 tumor DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from individuals treated with cetuximab between 2001 and 2008 were gathered from 11 centers in 7 European countries.  There were 773 primary tumor samples with sufficient quality DNA to be included in the mutation frequency analyses.  The researchers analyzed objective response (OR), PFS and OS in molecularly defined subgroups of the 649 chemotherapy-refractory subjects treated with cetuximab plus chemotherapy.  According to the analyses, 14.5% of samples harbored PIK3CA mutations and a lower response rate to cetuximab was associated with PIK3CA exon 20 mutations, but not to those with mutations in exon 9. 

It has been suggested that the results of the De Roock study may provide an explanation of the discrepancies between the Prenen (2009) and Sartore-Bianchi (2009) studies.  With regards to the percentage of PIK3CA mutations found, the Sartore-Bianchi et al group contained more exon 20 mutations (73%) than exon 9 mutations (27%), whereas the Prenen et al group contained fewer mutations in exon 20 (13%) than in exon 9 (78%).  These findings suggest that as a predictive marker, PIK3CA exon 20 mutations appear to be associated with less favorable outcomes after cetuximab (de Stefano, 2014).    

Ogino and colleagues (2013) examined the prognostic and predictive roles of PIK3CA mutation in subjects with stage III colon cancer enrolled in the National Cancer Institute–sponsored randomized clinical trial comparing postoperative adjuvant 5-fluorouracil (FU)/leucovorin (LV) with irinotecan/FU/LV (IFL) (CALGB 89803 [Alliance]).  The analysis represents correlative research based on a subset of participants within the trial and was limited to 627 subjects for whom archived formalin-fixed paraffin-embedded tumor tissue and PIK3CA sequencing data were available.  The study endpoints were: (1) recurrence-free survival (RFS), defined as the time from the study enrollment to tumor recurrence or occurrence of a new primary colon cancer; (2) disease-free survival (DFS), defined as time from the study enrollment to cancer recurrence, occurrence of a new primary colon cancer, or death from any cause; and (3) OS, defined as the time from the study enrollment to death from any cause.  For RFS, participants who died without known cancer recurrence were censored at last documented evaluation by a treating provider.  The authors found that compared with PIK3CA-WT cases, overall status of PIK3CA mutation positivity or the presence of PIK3CA mutation in either exon 9 or 20 alone was not statistically significantly associated with RFS, DFS or OS (log-rank p>0.70; p>0.40 in multivariable regression models).  There was no statistically significant interaction between PIK3CA and KRAS (or BRAF) mutation status in survival analysis (interaction p>0.18).  PIK3CA mutation status was not a predictor of better or worse response to IFL therapy compared with FU/LV therapy (interaction p>0.16).

In a more recent study, researchers examined the predictive and prognostic significance of additional biomarkers (BRAF, PIK3CA, and PTEN) in individuals with KRAS-WT advanced colorectal cancer.  Available colorectal tumor samples were analyzed from the CO.17 study (a phase III clinical trial conducted by the National Cancer Institute of Canada Clinical Trials Group [NCIC CTG] and the Australasian Gastrointestinal Trials Group [AGITG], which included individuals with chemotherapy refractory colorectal cancer who were randomized to receive cetuximab plus best supportive care [BSC] or BSC alone).  PIK3CA mutations were identified using a high-resolution melting screen with confirmation by sequencing.  For each biomarker, prognostic and predictive effects were examined using a Cox model with tests for treatment-biomarker interaction.  A total of 572 subjects with pretreated colorectal cancer were randomly assigned to receive cetuximab or BSC.  Of the 407 individuals assessed for PIK3CA status, 61 (15%) had mutations.  PIK3CA was not prognostic for overall or PFS in the BSC arm.  Neither was it predictive of benefit from cetuximab, either in the whole study population or the KRAS-WT subset.  In the KRAS-WT subgroup, the OS adjusted HR according to PIK3CA mutation status was 0.79 (interaction p=0.63).  The authors concluded that:  “In chemotherapy-refractory colorectal cancer, neither PIK3CA mutation status nor PTEN expression was prognostic, nor were they predictive of benefit from cetuximab” (Karapetis, 2014).

In 2013, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) issued recommendations regarding the testing of tumor tissue for mutations in the EGFR pathway downstream effector genes in individuals with metastatic colon cancer.  The authors specifically addressed the analytical validity, clinical validity and clinical utility of the use of selected pharmacogenomic tests (for codon 12 and 13 mutations in KRAS, the BRAF V600E mutation, variants in NRAS, and in PIK3CA, and loss of PTEN and AKT protein expression) in individuals with mCRC who are being considered for treatment with cetuximab or panitumumab.  With regards to the analytic validity of testing for PIK3CA mutations, the EWG found sufficient evidence demonstrating that PIK3CA mutations can be accurately and reliably detected.  With regards to the clinical validity, the EWG found insufficient evidence for association of results of testing for mutations in PIK3CA with treatment response to anti-EGFR therapy.  The members of the EWG also found “no evidence to support improved health outcomes associated with testing results” for PIK3CA variants.  The EGAPP recommendations also indicate the following:

In the absence of supporting evidence, and with consideration of other contextual issues, the EWG discourages the use of these tests in guiding decisions on initiating anti-EGFR therapy with cetuximab or panitumumab unless further evidence supports improved clinical outcomes (EGAPP, 2013).

Breast Cancer

Researchers are also exploring the role of PIK3CA mutations in breast cancer disease.  In a single center retrospective cohort analysis of 590 participants, Kalinsky and colleagues (2009) explored the prognostic implications of PIK3CA mutations in breast cancer.  Archival formalin-fixed paraffin-embedded primary breast tumors from 590 participants selected for known vital status with a median follow-up of 12.8 years and a tumor > 1 cm, were genotyped for PIK3CA mutations.  Mutation rates and associations between mutation site and clinicopathologic characteristics were evaluated.  PFS, OS, and breast cancer-specific survival were examined using Kaplan-Meier or competing risk methodology.  PIK3CA mutation was identified in 32.5% of breast cancers and demonstrated a significant association with older age at diagnosis, hormone receptor positivity, HER2 negativity, lower tumor grade and stage, and lymph node negativity.  PIK3CA mutations were associated with significantly better clinical outcomes as demonstrated by significant improvement in OS (p=0.03) and breast cancer-specific survival (p=0.004).

Ellis and colleagues (2010) conducted a retrospective pooled analysis of four neoadjuvant endocrine therapy breast cancer trials involving 278 women.  The researchers found that PIK3CA mutations were not associated with endocrine therapy resistance.

Research has also explored the association between the PI3K signaling pathway and trastuzumab and/or lapatinib resistance.  Razis and colleagues (2011) evaluated the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer.  Formalin-fixed paraffin-embedded tumor tissue samples were collected from 256 individuals with trastuzumab-treated metastatic breast cancer (MBC).  Clinical information was collected retrospectively from the subjects' medical records.  Central review of HER2 status by fluorescent in situ hybridization (FISH) and/or immunohistochemistry (IHC) showed that of the 227 eligible participants only 139 (61%) were truly HER2-positive.  PIK3CA mutations were identified with single nucleotide polymorphism (SNP) genotyping.  PIK3CA mutations and/or PTEN loss status were evaluated together as a single parameter, to estimate the impact of activation of the PI3K/AKT molecular pathway, and it was significantly associated with both decreased time to progression (TTP) (p=0.003 in the total population, p=0.004 in HER2-positive subjects) and survival (survival, p=0.011 in total, p=0.006 in HER2-positive).  In the trastuzumab-treated breast cancer population, PIK3CA activating mutations were associated with shorter TTP and PTEN loss with decreased survival.  The activation of the PI3K/AKT pathway from either defect was associated with both TTP and survival, indicating the adverse effect of this pathway's status on trastuzumab efficacy.

Loi and colleagues (2013) evaluated PIK3CA genotype from 687 tumor samples from participants enrolled in the FinHER prospective, phase III, randomized clinical trial.  The FinHER involved 1010 women.  Individuals with HER2-positive breast cancer were further randomized to 9 weeks of trastuzumab or no trastuzumab.  A total of 705 of 1010 tumors had sufficient DNA for genotyping.  Distant disease-free survival (DDFS), OS, and interactions with trastuzumab were explored with Kaplan-Meier and Cox regression analyses.  All statistical tests were two-sided.  Median follow-up was 62 months.  Of the 705 tumors, 687 were successfully genotyped.  PIK3CA mutations (exons 1, 2, 4, 9, 13, 18, and 20) were present in 25.3% (174 of 687).  PIK3CA mutant participants compared with WT participants were observed to have a better prognosis during the first 3 years; however, this effect disappeared after 3 years.

At the time of this review, no consensus or evidence based practice guidelines from relevant professional societies was identified which addresses the use of PIK3CA mutation analysis as a predictive tumor biomarker in individuals with breast cancer.

Non-small cell lung cancer (NSCLC)

PIK3CA mutations have been identified in various types of human cancer, including, but not limited to non-small cell lung cancer (NSCLC).  Several EGFR tyrosine kinase inhibitors, for example, erlotinib [Tarceva®], gefitinib [Iressa®], or afatinib [Gilotrif®]), are currently used for the treatment of individuals with advanced-stage NSCLC.  In addition to exploring the role of PIK3CA mutations on the prognosis of individuals with NSCLC, researchers are investigating the influence of PIK3CA mutation on the clinical outcome of individuals being treated with therapeutic agents.

Dearden and colleagues (2013) performed meta-analyses to characterize patterns of mutation incidence in NSCLC.  A total of nine genes (TP53, EGFR, KRAS, LKB1, EML4-ALK, PTEN, BRAF, PIK3CA, and ErbB2) were evaluated.  One meta-analysis generated a ‘mutMap’ to visually represent mutation coincidence by ethnicity (Western or Asian) and histology (adenocarcinoma [ADC] or squamous cell carcinoma [SCC]).  Another meta-analysis assessed the incidence of individual mutations.  Extended analyses were used to explore the incidence of EGFR and KRAS mutations by ethnicity, histology, and smoking status.  PIK3CA was mutated in 1.3%, 1.4%, 1.7% and 6.5% in the Western ADC, Western SCC, Asian ADC and Asian SCC subgroups respectively.  The authors reminded the readers that “caution is advised when using these data to infer mutation incidence in different populations, since the meta-analyses depended on the available published data, which represent a small sample size with intrinsic limitations.” 

Fiala and colleagues (2013) reported on a retrospective analysis of subjects with squamous cell NSCLC who underwent EGFR, KRAS, and PIK3CA mutation testing.  Of the 208 individuals tested for PIK3CA mutations, 8 (3.8%) were positive for the mutation.  The existence of PIK3CA mutations was not in significant correlation with smoking status (6 out of 182 current or former-smokers vs. 2 out of 19 never-smokers; p=0.168) nor gender (5 out of 167 males vs. 3 out of 41 females; p=0.193).  Overall, 170 tested subjects were treated with EGFR-TKI.  The authors did not find any significant difference in survival between the participants harboring PIK3CA mutation and those harboring the WT PIK3CA gene (PFS=4.4 vs. 1.9 months, p=0.197; OS=8.8 vs. 7.6 months, p=0.687).

At the time of this review, no consensus or evidence based practice guidelines from relevant professional societies was identified which addresses the use of PIK3CA mutation analysis as a predictive tumor biomarker in individuals with lung cancer.

Summary

PIK3CA mutations occur relatively frequently in some cancers, including but not limited to colon and rectal cancers and have been implicated in the initiation and progression of various cancers.  PIK3CA gene mutations can be accurately and reliably detected and this testing is generally performed by CLIA certified laboratories.  PIK3CA mutations appear to be a promising predictive biomarker; however, additional studies are needed to conclusively define the impact of somatic mutations in the PIK3CA gene for the management of individuals with cancer.  Further data are needed which demonstrate the ability of genetic testing for PIK3CA gene mutations to guide clinical management (for instance to predict non-responsiveness to anti-EGFR therapy or to predict EGFR-TKI treatment efficacy) in individuals with cancer.  Well-designed and adequately powered studies are needed, which demonstrate that changes in the clinical management of individuals with cancer based on the findings of PIK3CA mutation testing (for example, withholding a chemotherapeutic agent) result in improved health outcomes (for example, improved PFS, improved OS or the avoidance of side effects of chemotherapeutic agents).

Background/Overview

PIK3CA mutations have been associated with the formation of tumors including but not limited to breast, ovarian, endometrial, and colorectal cancers.  Researchers are attempting to understand the role of PIK3CA in the development of malignant tumors and their role in guiding clinical decisions in individuals with cancer.

Definitions

Colorectal cancer: A type of cancer originating in the colon (the longest part of the large intestine) or the rectum (the last several inches of the large intestine before the anus).

Epidermal growth factor receptor (EGFR): A cell receptor that is associated with regulation of cell growth.

Malignant: Cancerous: Malignant cells can invade and destroy nearby tissue and spread to other parts of the body.

Metastatic: The spread of cancer from one part of the body to another; a metastatic tumor contains cells that are like those in the original (primary) tumor and have spread; also referred to as stage IV cancer.

Monoclonal antibody: A form of biologic therapy that acts specifically against a particular antigen.

Mutation: A permanent, transmissible change in genetic material.

Refractory disease: Illness or disease that does not respond to treatment.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT

 

81404

Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)  [when specified as the following]:

  • PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) (eg, colorectal cancer) targeted sequence analysis (eg, exon 9 and 20)

 

 

ICD-10 Diagnosis

 

C00.0-C96.9

Malignant neoplasms

Z15.01-Z15.09

Genetic susceptibility to malignant neoplasm

Z80.0-Z80.9

Family history of primary malignant neoplasm

Z85.00-Z85.9

Personal history of malignant neoplasm

References

Peer Reviewed Publications:

  1. Cappuzzo F, Varella-Garcia M, Finocchiaro G, et al. Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer. 2008; 99(1):83-89.
  2. Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol. 2013; 24(9):2371-2376.
  3. De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010; 11(8):753-762.
  4. De Stefano A, Carlomagno C. Beyond KRAS: Predictive factors of the efficacy of anti-EGFR monoclonal antibodies in the treatment of metastatic colorectal cancer. World J Gastroenterol. 2014; 20(29):9732-9743.
  5. Ellis MJ, Lin L, Crowder R, et al. Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat. 2010; 119(2):379-390.
  6. Fiala O, Pesek M, Finek J, et al. Gene mutations in squamous cell NSCLC: insignificance of EGFR, KRAS and PIK3CA mutations in prediction of EGFR-TKI treatment efficacy. Anticancer Res. 2013; 33(4):1705-1711.
  7. Henry NL, Schott AF, Hayes DF. Assessment of PIK3CA mutations in human epidermal growth factor receptor 2–positive breast cancer: clinical validity but not utility. J Clin Oncol. 2014; 32(29):3207-3209.
  8. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005; 5(5):341-354.
  9. Kalinsky K, Jacks LM, Heguy A, et al. PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res. 2009; 15(16):5049-5059.
  10. Karapetis CS, et al. PIK3CA, BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer- results from NCIC CTG/AGITG CO. 17. Clin Cancer Res. 2014; 20(3):744-53.
  11. Kawano O, Sasaki H, Endo K, et al. PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer. 2006; 54(2):209-215.
  12. Krasinskas AM. EGFR Signaling in Colorectal Carcinoma. Patholog Res Int. Pathology Research International, vol. 2011, Article ID 932932, 6 pages, 2011.
  13. Lin JS, Webber EM, Senger CA, et al. Systematic review of pharmacogenetic testing for predicting clinical benefit to anti-EGFR therapy in metastatic colorectal cancer. Am J Cancer Res. 2011; 1(5):650-662.
  14. Loi S, Michiels S, Lambrechts D, et al. Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer. J Natl Cancer Inst. 2013, 105(13):960-967.
  15. Mao C, Yang ZY, Hu XF, et al. PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. Ann Oncol. 2012; 23(6):1518-1525.
  16. Normanno N, Rachiglio AM, Lambiase M, ET AL. Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial. Ann Oncol. 2015; 26(8):1710-1714.
  17. Ogino S, Liao X, Imamura Y, et al. Predictive and prognostic analysis of PIK3CA mutation in stage III colon cancer intergroup trial. J Natl Cancer Inst. 2013; 105(23):1789-1798.
  18. 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(9):1477-1484.
  19. Papaxoinis G, Kotoula V, Alexopoulou Z, ET AL. Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study. PLoS One. 2015; 10(10):e0140293.  
  20. Prenen H, De Schutter J, Jacobs B, et al. PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res. 2009; 15(9):3184-3188.
  21. 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(2):447-456.
  22. 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(5):1851-1857.
  23. 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(11):1997-2009.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy? Genet Med. 2013; 15(7):517-527.
  2. National Center for Biotechnology Information (NCBI). GTR: Genetic Testing Registry. PIK3CA Mutation by Sequencing. Last updated May 31, 2016. Available at: http://www.ncbi.nlm.nih.gov/gtr/tests/514565/performance-characteristics/. Accessed on September 7, 2017.
Websites for Additional Information
  1. National Center for Biotechnology Information (NCBI). Genetic Testing Registry (GTR). Genetic tests for PIK3CA. Available at: http://ghr.nlm.nih.gov/gene/PIK3CA/show/Genetic+Testing+Registry. Last updated: 05/31/2016. Published August 23, 2016. Accessed on September 7, 2017.
Index

Catalytic subunit alpha polypeptide gene (PIK3CA)
PIK3CA
PI3K
PI3KCA
PI3K-alpha
PI3-kinase p110 subunit alpha

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Reviewed

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review.

Reviewed

11/01/2017

Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date”. Updated Review date, References and History sections. 

Reviewed

11/03/2016

MPTAC review.

Reviewed

11/02/2016

Hematology/Oncology Subcommittee review. Updated Review date, Description/Scope, Rationale, References, History and Index sections. 

Reviewed

11/05/2015

MPTAC review.

Reviewed

11/04/2015

Hematology/Oncology Subcommittee review. Updated Review date, Rationale, References and History sections.  Removed ICD-9 codes from Coding section.

Reviewed

05/07/2015

MPTAC review.

Reviewed

05/06/2015

Hematology/Oncology Subcommittee review. Title changed to “Analysis of PIK3CA Status in Tumor Cells”

New

11/13/2014

MPTAC review.

New

11/12/2014

Hematology/Oncology Subcommittee review. Initial document development.