Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer

Abstract

The 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.

Figure 1

Overview of interlinked cellular signaling pathways involved in the proliferation and progression of colorectal cancer. Agents targeting signaling proteins that have been evaluated or are currently being evaluated in phase II, III, or IV clinical trials for colorectal cancer are shown. The epidermal growth factor receptor (EGFR)–related family of receptor tyrosine kinases includes human epidermal growth factor receptor (HER1), EGFR, or c-erbB1; HER2 or c-erbB2; HER3 or c-erbB3; and HER4 or c-erbB4. C-MET = mesenchymal–epithelial transition factor; EGF = epidermal growth factor; HDAC = histone deacetylases; HGF = hepatocyte growth factor; IGF-1 = insulin-like growth factor-I; IGF-1R = insulin-like growth factor-I receptor; IR = insulin receptor; VEGF = vascular endothelial growth factor; VEGF-R = vascular endothelial growth factor receptor.

Figure 2

Progression-free interval and KRAS mutation status of tumor in patients with metastatic colorectal cancer who were randomly assigned to treatment with best supportive care (BSC) alone or panitumumab (Panit) plus BSC in a phase III study (27). A) Tumors with mutant KRAS status. B) Tumors with wild-type KRAS status (27) (with permission from the American Society of Clinical Oncology). CI = confidence interval; HR = hazard ratio.

Figure 3

Progression-free interval by response to panitumumab in a subgroup of patients with metastatic colorectal cancer whose tumors carry wild-type KRAS. Data are from a phase III study (27,61).

Figure 4

Probability of survival by worst grade of skin toxicity in patients with metastatic colorectal cancer who were treated with EGFR-targeted monoclonal antibodies in two randomized phase III studies. A) Patients treated with panitumumab. Data are from a landmark analysis that was limited to patients with progression-free interval of at least 28 days (13) (with permission from the American Society of Clinical Oncology. B) Patients treated with cetuximab (12). Reproduced with permission from the New England Journal of Medicine. Copyright 2007 Massachusetts Medical Society. All rights reserved. CI = confidence interval; HR = hazard ratio.