Am J Cancer Res 2011;1(5):650-662

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

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

Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon; 3800 North Interstate Avenue, Portland, OR
97227, USA.

Received April 4, 2011; accepted May 1, 2011; Epub May 6, 2011; published May 15, 2011

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, 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. (AJCR0000057).

Keywords: BRAF, NRAS, PTEN, AKT, metastatic colorectal cancer, anti-EGFR monoclonal antibodies, cetuximab, panitumumab,
pharmacogenetic test, systematic review

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Address all correspondence to:
Jennifer S. Lin, MD, MCR
Center for Health Research
Kaiser Permanente Northwest
Portland, Oregon
, USA.
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American Journal of Cancer Research
ISSN: 2156-6976