title: DNA copy number profiles correlate with outcome in colorectal cancer patients treated with fluoropyrimidine/antifolate-based regimens.
abstract: For decades 5-fluorouracil (5-FU) has remained the treatment of choice in the adjuvant and palliative setting of colorectal cancer (CRC). The combinations of 5-FU or its oral prodrug capecitabine with irinotecan/oxaliplatin and the novel agents bevacizumab/cetuximab increased responses. However, the overall prognosis is poor, and predictive biomarkers of cytotoxic drugs activity are missing. Pharmacogenetic studies focused on candidate determinants of drug activity/metabolism, such as thymidylate synthase or dihydropyrimidine dehydrogenase, but reported controversial results. Given the heterogeneous and complex nature of CRC, it is likely that many aberrations underlying its progression can also affect therapeutic response. Therefore, high-throughput arrays for genome-wide-DNA aberrations play a pivotal role for new markers discovery by moving from hypothesis-driven, targeted-research to unbiased screening of the whole genetic spectrum. Chromosomal aberrations are critical events in tumorigenesis, and genomic regions harbouring DNA gains/losses have been identified in 85% of CRC patients. These aberrations change the expression of many genes, which might explain the differential effects of specific chemotherapeutic agents. In particular, recent studies reported correlations between DNA copy-number profiles and response to fluoropyrimidine-based regimens, such as leucovorin-modulated-5-FU+irinotecan (FOLFIRI), capecitabine+irinotecan (CAPIRI) and pemetrexed+irinotecan (ALIRI). Genome-wide profiling by oligonucleotide-based array-comparative-genomic-hybridization (aCGH) revealed genomic loci, of which the copy-number status may serve as marker for outcome after FOLFIRI and CAPIRI. Larger randomized and prospective trials of these aCGH platforms in CRC patients treated with fluoropyrimidine-based regimens are ongoing, and will ultimately demonstrate whether these findings can be of actual value to predict clinical outcome and direct the choice of therapy.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam - CCA 1.52, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Leticia G
authors.initials: LG
authors.lastname: Leon
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.forename: Kees
authors.initials: K
authors.lastname: Smid
authors.forename: Bart P P
authors.initials: BP
authors.lastname: van Houte
authors.forename: Axel R
authors.initials: AR
authors.lastname: Hanauske
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D056915:DNA Copy Number Variations; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000627:therapeutic use; D005493:Folic Acid Antagonists / Q000008:administration & dosage; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D000068437:Pemetrexed; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D005971:Glutamates; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin