Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 May 15;1(5):650-62.

Systematic review of pharmacogenetic testing for predicting clinical benefit to anti-EGFR therapy in metastatic colorectal cancer

Jennifer S Lin  1 , Elizabeth M Webber, Caitlyn A Senger, Rebecca S Holmes, Evelyn P Whitlock
Affiliations

Systematic review of pharmacogenetic testing for predicting clinical benefit to anti-EGFR therapy in metastatic colorectal cancer

Jennifer S Lin et al. Am J Cancer Res. .

Abstract

Pharmacogenetic testing can help identify patients with metastatic colorectal cancer more likely to respond to anti-EGFR therapy. We systematically reviewed the benefits and harms of EGFR-related pharmacogenetic testing of molecular targets downstream to KRAS in the treatment of metastatic colorectal cancer. We searched five electronic databases from January 2000 through November 2010, and conducted separate grey literature and conference abstracts searches. Two reviewers independently assessed all articles for relevance and quality. We identified 27 studies, primarily fair- to marginal-quality, small retrospective, and single-arm cohort studies with significant overlap in patient populations. We identified seven studies that studied BRAF in independent patient populations, one that studied NRAS, four that studied PIK3CA, eight that studied PTEN expression, and five that studied AKT expression. The best evidence for BRAF, NRAS, and PIK3CA comes from the largest retrospective study (n=649) of chemorefractory patients from seven European countries. In this study, BRAF mutation was present in 6.5% of KRAS wild-type tumors. Only 8.3% of persons with BRAF mutations, compared to 38% of persons without BRAF mutations (p=0.0012), responded to chemotherapy with cetuximab. Clinical sensitivity and the false positive fraction (1- specificity) were estimated at 9.8% (95% CI 6.3, 14.5) and 1.6% (95% CI 0.2, 5.6), respectively. BRAF mutation was also associated with worse median progression-free survival (absolute difference 18 weeks, p<0.0001), and overall survival (absolute difference 28 weeks, p<0.0001). In the only study comparing outcomes in persons who did (n=227) and did not (n=332) receive cetuximab with combination chemotherapy, those with BRAF mutation had worse survival outcomes regardless of whether or not they received cetuximab. Although NRAS and PIK3CA exon 20 mutations were also associated with worse outcomes compared to persons without these mutations, evidence is based on a small number of identified mutations. Evidence for protein expression of PTEN and AKT is more sparse and limited by variable methods for assessing protein expression. Low-quality evidence addressing clinical validity of pharmacogenetic testing in metastatic colorectal cancer patients suggests that BRAF mutations are associated with poorer treatment response and survival outcomes, although this association may be independent of treatment with EGFR inhibitors.

Keywords: AKT; BRAF; NRAS; PTEN; anti-EGFR monoclonal antibodies; cetuximab; metastatic colorectal cancer; pani-tumumab; pharmacogenetic test; systematic review.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Mutation frequencies and loss of protein expression in the EGFR signaling pathway.
Figure 2
Figure 2
Analytic framework for clinical benefit and harms of EGFR-related pharmacogenetic testing of molecular targets in the treatment of metastatic colorectal cancer.
Figure 3
Figure 3
Search result and article flow.
Figure 4
Figure 4
Included studies illustrating overlapping populations.
See this image and copyright information in PMC

References

    1. American Cancer Society. Cancer Facts & Figures 2009. 2009
    1. US Food and Drug Administration. FDA approves Erbitux for colorectal cancer. Www Fda Gov. 2004
    1. US Food and Drug Administration. FDA approves Vectibix (panitumumab) to treat metastatic colorectal carcinoma. Www Fda Gov. 2007
    1. Blue Cross Blue Shield Association. SO. Chicago IL: Blue Cross Blue Shield Association (BCBS); 2009. KRAS mutations and epidermal growth factor receptor inhibitor therapy in metastatic colorectal cancer. - PubMed
    1. Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, McAllister PK, Morton RF, Schilsky RL. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009;27(12):2091–2096. - PubMed

LinkOut - more resources