Pharmacogenomics is the study of the role of inherited and acquired genetic variation in drug response.1 A focus of research in recent years on genome-wide association studies ultimately may help identify patient- and/or cancer-specific biomarkers that will facilitate optimization of drug therapy including guiding drug selection, dose, and treatment duration.2 The identification of the role of KRASmutations in select patients with colorectal cancer (CRC) who are candidates for epidermal growth factor receptor (EGFR) in hibitors is one example of the clinical application of the advances in pharmacogenomics.
The current management of a patient with metastatic CRC may include surgery, local therapy with radiofrequency ablation, or transarterial chemoembolization, but the primary treatment remains pharmacotherapy with chemotherapy. Chemotherapy has been shown to improve disease-related symptoms and overall quality of life in patients with metastatic disease, downsize lesions in patients with potentially resectable disease, and ultimately prolong survival.3 The number of active chemotherapy agents is few, however, with treatment consisting of the combination of or single-agent therapy with fluorouracil, capecitabine, oxaliplatin, and/or irinotecan. One of the most significant advances in drug therapy for metastatic CRC in the past decade has been the addition of targeted therapy to chemo therapy. Cetuximab and panitumumab target EGFR, whereas bevacizumab targets angiogenesis. These agents have been shown to play a role in treatment of metastatic CRC but, unfortunately, not all patients benefit equally from them.
Inhibition of the EGFR is one strategy for management of select malignancies. Cetuximab, a chimeric monoclonal antibody, and panitumumab, a fully humanized monoclonal antibody, target the external binding sites of the EGFR.4,5 Although the EGFR is expressed on many nonmalignant human cells, higher levels are expressed in certain cancers, such as CRC. The binding of the EGFR to the extracellular binding site of EGFR activates several signal transduction pathways, causing downstream changes in gene expression and ultimately cell growth and proliferation.
Randomized trials with cetuximab and panitumumab, alone and combined with chemotherapy, have shown these drugs to benefit individuals with metastatic CRC, as measured by prolonged progression-free survival and increased time to disease progression.6-8 Single-agent cetuximab has been shown to improve overall survival in patients with metastatic CRC when compared with best supportive care.6,9 Despite the benefits seen with these agents, they are not without challenges. The cost of therapy is significant and may be prohibitive for some patients. In addition, these drugs have side effects, such as rash, and potentially serious infusion-related reactions.6-10 As with any drug therapy, there is interest in reserving these agents for those patients likely to benefit from treatment and avoiding the costs and risks in those unlikely to benefit from treatment.
KRAS Status and EGFR Inhibition
Mutations in KRAS have been identified, and select mutations appear to impact the activity of EGFR inhibitors in patients with malignancies such as CRC.11 Although these mutations have been evaluated in several tumors, the largest body of evidence for the implications of KRAS mutations, as well as the most significant effect on the treatment continuum, has occurred with metastatic CRC. Approximately 35% to 45% of patients with metastatic CRC will have mutations in the pathways downstream from the EGFR, which effectively provide an escape mechanism that allows the tumors to overcome the pharmacologic blockade induced by anti-EGFR molecules.11 This promotes a permanently active state where cells can evade apoptosis. KRAS is a protooncogene that is the most commonly mutated gene in this pathway. There are only a few mutations in the KRAS gene, and more than 90% involve 3 codons: 12, 13, and 61.11 If KRAS remains unmutated, it is referred to as KRAS wild type (WT). Because the number of mutations is low and testing for the mutations is relatively easy, tumor DNA testing has become an area of interest in predicting response to therapy and prognosis.12
There is a growing body of evidence addressing the relationship between KRAS mutation and response to anti-EGFR monoclonal antibodies. Initial studies for cetuximab and panitumumab did not evaluate KRAS mutation status, but retrospective analyses have been completed since, and both singlearm and randomized trials provide comparisons of efficacy between KRAS WT and KRAS-mutated patients. Individually, these trials are difficult to compare, but a recent meta-analysis and retrospective consortium analysis summarize the data clearly.13,14 Individuals who are KRAS WT who have received anti-EGFR monoclonal antibody therapy have significantly improved overall survival compared with KRAS-mutated patients. In addition, KRAS WT patients had significantly longer progression-free survival and time to progression with anti-EGFR monoclonal therapy. Further, KRAS-mutated patients had significantly higher treatment failure rates with anti-EGFR monoclonal therapy.13-15
Anti-EGFR Therapy and CRC
The unequivocal benefit seen in KRAS WT patients when compared with KRAS-mutant patients with metastatic CRC has led to additional studies attempting to replicate the findings in other solid tumors. Cetuximab is used in both non-small cell lung cancer and head and neck cancer, and it will be important to determine the role of KRAS mutation on the efficacy of cetuximab in these cancers. Thus far, trials comparing cetuximab plus chemotherapy with chemotherapy alone in non-small cell lung cancer have not shown differences in outcomes for patients with KRAS mutations. Further study is warranted.
Other areas for continued research include further investigating components downstream of KRAS, identifying whether mutations in codon 12 or 13 are more predictive of response, and integrating additional molecular biomarkers, such as BRAF, PTEN, or PIK3CA aberrations. Finally, there are mixed results in the prognostic value of KRAS mutations, and further study is necessary before this information can be of use.
Overall, the evidence to date illustrates that patients with CRC and KRAS mutations are virtually insensitive to anti-EGFR therapy. The data are so compelling that the prescribing information for both cetuximab and panitumumab have been modified to indicate that these agents are only to be used in KRAS WT patients. Further, the National Comprehensive Cancer Network has issued guidelines that strongly recommend KRAS genotyping of tumor tissue (either primary tumor or metastatic disease) in all patients at the time of diagnosis of metastatic CRC.16 Although patients with mutations at codon 12 or 13 should not receive cetuximab or panitumumab, patients without mutations who receive these agents alone or in combination with other anticancer agents may derive significant benefit, including improved response rate, progression-free survival, and overall survival with the administration of cetuximab or panitumumab. With further study, we will continue, hopefully, to better identify subgroups of patients who will most benefit from targeted therapy and improve clinical outcomes for patients with metastatic CRC.
- Weinshilboum RM, Wang L. Pharmacogenetics and pharmacogenomics: development, science, and translation. Ann Rev Genomics Hum Genet. 2006;7:223-245.
- Wang L, McLeod HL, Weinshilboum RM. Genomics and drug response. N Engl J Med. 2011;364:1144-1153.
- Cunningham D, Atkin W, Lenze HJ, et al. Colorectal cancer. Lancet. 2010;375:1030-1047.
- Vectabix (panitumumab) [package insert]. Thousand Oaks, CA: Amgen Inc; 2011.
- Erbitux (cetuximab) [package insert]. Branchburg, NJ: ImClone Systems Inc; 2011.
- Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337-345.
- Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658-1664.
- Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663-671.
- Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040-2048.
- Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26: 2311-2319.
- Rizzo S, Bronte F, Fanale D, et al. Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti- EGFR therapy? Cancer Treat Rev. 2010;36S3:S56-S61.
- Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Review Cancer. 2003;3:459-465.
- Dahabreh IJ, Terasawa T, Castaldi PJ, Trikalinos TA. Systematic review: anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med. 2011;154:37-49.
- DeRoock 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;11:753-762.
- Allegra CJ, Jessup JM, Somerfield MR, et al. 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;27:2091-2096.
- National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Colon Cancer. V.3.2011. www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed June 1, 2011.