Predictive and prognostic markers in colorectal cancer

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women in the United States, with an estimated 153,760 new cases predicted for 2007. Since the 1960s, 5-fluorouracil (5-FU) has remained the mainstay of therapeutic options in the treatment of advanced CRC, with response rates of 20% to 25%. The introduction of newer agents such as oxaliplatin and irinotecan in combination with 5-FU has increased response rates to 40% to 50% in advanced disease and improved overall survival. The development of monoclonal antibodies targeting the epidermal growth factor receptor or vascular endothelial growth factor has demonstrated additional clinical benefit for patients with metastatic disease. However, many patients succumb to their disease, and a significant proportion will experience severe chemotherapy-associated toxicities while deriving little or no benefit. To improve the treatment of CRC, efforts must be directed toward the identification of patients who are likely to respond to a specific therapy, those who will experience severe toxicities, and those who will benefit from chemotherapy in the adjuvant setting. However, the utility of individual markers of response, toxicity, and disease recurrence remains in question. Efforts are now under way to develop multimarker profiles that can more accurately predict disease response. In this review, we discuss both predictive and prognostic markers identified in the treatment of CRC in terms of their robustness and their ability to assist the clinician in developing the most efficacious and least toxic therapeutic strategy for each patient.

Figure 1. Mechanisms of action of 5-FU

Abbreviations: 5-FU = 5-fluorouracil; CH2THF = 5,10-methylenetetrahydrofolate; DPD = dihydropyrimidine dehydrogenase; dUTP = deoxyuridine triphosphate; dUTPase = dUTP pyrophosphatase; FdUDP = 5′-fluoro-2′-deoxyuridine-5′-diphosphate; FdUMP = 5′-fluoro-2′-deoxyuridine-5′-monophosphate; FUDR= 2′-deoxy-5-fluorouridine; FUMP= 5′-fluorouridine-5′-monophosphate; FUTP= 5′-fluorouridine-5′-triphosphate; LV = leucovorin; TP = thymidine phosphorylase; TS = thymidylate synthase

Figure 2. Schematic of the steps involved in the activation and metabolism of CPT-11 (irinotecan) as well as its proposed mechanisms of action and resistance

Abbreviations: β Gluc = beta-glucuronidase; BCRP = breast cancer resistance protein; CE = carboxylesterase; ds = double strand; MDR1 = multidrug resistance protein 1; Topo I= topoisomerase I; ss = single strand; UGT = uridine diphosphate glucuronosyltransferase

Figure 3. Schematic of the steps involved in the activation and metabolism of oxaliplatin as well as proposed mechanisms of action and resistance

Abbreviations: ERCC1 = excision repair cross complementing protein 1; XRCC1 = xray repair cross complementing 1; XPD = xeroderma pigmentosum group D; GSH = glutathione; GST = glutathione-S-transferase; MT = metallothionein molecules; Oxali = oxaliplatin; pt = platinum

Figure 4. Simplified diagram illustrating multiple pathways and downstream effects modulated by EGFR and VEGFR signaling in colorectal cancer

Abbreviations: EGF = epidermal growth factor; EGFR = epidermal growth factor receptor; MAPK = mitogen-activated protein kinase; PI3K = phosphoinositide 3- kinase; STAT = signal transducer and activator of transcription; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor