title: Molecular determinants of irinotecan efficacy.
abstract: Molecular markers predicting the efficacy of CPT-11 based chemotherapies in patients with colorectal cancer (CRC) are unknown. Therefore, we investigated whether mRNA levels of drug targets (Topoisomerase I, TS), enzymes involved in 5-FU metabolism (DPD), in angiogenesis (EGFR, IL-8, VEGF) and in DNA-repair/drug detoxification (ERCC1, GST-P1) are associated with the clinical outcome of patients with CRC treated with first-line CPT-11 based chemotherapy. Thirty three patients with metastatic CRC were included in the study. Intratumoral gene expression levels were assessed from paraffin-embedded tissue samples, using laser capture microdissection and quantitative Real-Time PCR. Complete response was observed in 1 patient, partial response in 12 patients, stable disease in 13 patients and progressive disease in 6 patients. Response was inevaluable for 1 patient. Patients with complete response or partial response were classified as responders, while patients with stable disease or progressive disease were classified as nonresponders. High intratumoral mRNA levels of EGFR, ERCC1 and GSPT-P1 were each significantly associated with response to CPT-11 based chemotherapy. Recursive partitioning analysis showed that mRNA levels of EGFR and ERCC1 are primarily responsible for delineating responders from nonresponders. Also, the combination of high intratumoral gene expression levels of both EGFR and ERCC1 was significantly associated with progression-free survival. The mRNA levels of EGFR had a significant correlation with expression levels of ERCC1, GST-P1 and VEGF. This small retrospective study suggests that gene expression levels of EGFR, ERCC1 and GST-P1 may be useful in predicting the clinical outcome of patients with metastatic CRC treated with first-line CPT-11 based chemotherapy.
authors.affiliation: Divison of Medical Oncology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, 90033, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Vallböhmer
authors.forename: Syma
authors.initials: S
authors.lastname: Iqbal
authors.forename: Dong Yun
authors.initials: DY
authors.lastname: Yang
authors.forename: Katrin E
authors.initials: KE
authors.lastname: Rhodes
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Gordon
authors.forename: William
authors.initials: W
authors.lastname: Fazzone
authors.forename: Anne M
authors.initials: AM
authors.lastname: Schultheis
authors.forename: Andy E
authors.initials: AE
authors.lastname: Sherrod
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Danenberg
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D018572:Disease-Free Survival; D004720:Endonucleases / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D010454:Peptide Termination Factors / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D016209:Interleukin-8; D010454:Peptide Termination Factors; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C087971:peptide-chain-release factor 3; D000077146:Irinotecan; D066246:ErbB Receptors; C071447:ERCC1 protein, human; D004720:Endonucleases; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin