Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer.
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Di Nicolantonio, Federica
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CitationJ. Natl. Cancer Inst. 2009, 101 (19):1308-24
AbstractThe monoclonal antibodies panitumumab and cetuximab that target the epidermal growth factor receptor (EGFR) have expanded the range of treatment options for metastatic colorectal cancer. Initial evaluation of these agents as monotherapy in patients with EGFR-expressing chemotherapy-refractory tumors yielded response rates of approximately 10%. The realization that detection of positive EGFR expression by immunostaining does not reliably predict clinical outcome of EGFR-targeted treatment has led to an intense search for alternative predictive biomarkers. Oncogenic activation of signaling pathways downstream of the EGFR, such as mutation of KRAS, BRAF, or PIK3CA oncogenes, or inactivation of the PTEN tumor suppressor gene is central to the progression of colorectal cancer. Tumor KRAS mutations, which may be present in 35%-45% of patients with colorectal cancer, have emerged as an important predictive marker of resistance to panitumumab or cetuximab treatment. In addition, among colorectal tumors carrying wild-type KRAS, mutation of BRAF or PIK3CA or loss of PTEN expression may be associated with resistance to EGFR-targeted monoclonal antibody treatment, although these additional biomarkers require further validation before incorporation into clinical practice. Additional knowledge of the molecular basis for sensitivity or resistance to EGFR-targeted monoclonal antibodies will allow the development of new treatment algorithms to identify patients who are most likely to respond to treatment and could also provide rationale for combining therapies to overcome primary resistance. The use of KRAS mutations as a selection biomarker for anti-EGFR monoclonal antibody (eg, panitumumab or cetuximab) treatment is the first major step toward individualized treatment for patients with metastatic colorectal cancer.
- 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?
- Authors: Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group.
- Issue date: 2013 Jul
- The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis.
- Authors: Therkildsen C, Bergmann TK, Henrichsen-Schnack T, Ladelund S, Nilbert M
- Issue date: 2014 Jul
- [Molecular predictive markers of EGFR-targeted therapy in metastatic colorectal cancer].
- Authors: Fabian P, Berkovcová J
- Issue date: 2011 Oct
- PTEN gene expression and mutations in the PIK3CA gene as predictors of clinical benefit to anti-epidermal growth factor receptor antibody therapy in patients with KRAS wild-type metastatic colorectal cancer.
- Authors: Sood A, McClain D, Maitra R, Basu-Mallick A, Seetharam R, Kaubisch A, Rajdev L, Mariadason JM, Tanaka K, Goel S
- Issue date: 2012 Jun
- Clinical usefulness of KRAS, BRAF, and PIK3CA mutations as predictive markers of cetuximab efficacy in irinotecan- and oxaliplatin-refractory Japanese patients with metastatic colorectal cancer.
- Authors: Soeda H, Shimodaira H, Watanabe M, Suzuki T, Gamoh M, Mori T, Komine K, Iwama N, Kato S, Ishioka C
- Issue date: 2013 Aug