UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan

Leslie E. Carlini, Neal J. Meropol, John Bever, Michael L. Andria, Todd Hill, Philip Gold, Andre Rogatko, Hao Wang, Rebecca L. Blanchard

Research output: Contribution to journalArticle

Abstract

Purpose: Capecitabine and irinotecan are commonly used in the treatment of metastatic colorectal cancer (CRC). We hypothesized that germline polymorphisms within genes related to drug target (thymidylate synthase) or metabolizing enzymes (UDP-glucuronosyltransferase, UGT) would impact response and toxicity to the combination of capecitabine plus irinotecan (CPT-11). Experimental Design: Sixty-seven patients with measurable CRC were treated with irinotecan i.v. (100 or 125 mg/m2) on days 1 and 8 and capecitabine orally (900 or 1,000 mg/m2, twice daily) on days 2 through 15 of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using Pyrosequencing, GeneScan, and direct sequencing (Big Dye terminator) technologies. Results: The overall objective response rate was 45% with 21 patients (31%) exhibiting grade 3 or 4 diarrhea and 3 patients (4.5%) demonstrating grade 3 or 4 neutropenia in the first two cycles. Low enzyme activity UGT1A7 genotypes, UGT1A7*2/*2 (six patients) and UGT1A7*3/*3 (seven patients), were significantly associated with antitumor response (p = 0.013) and lack of severe gastrointestinal toxicity (p = 0.003). In addition, the UGT1A9 -118 (dT)9/9 genotype was significantly associated with reduced toxicity (p = 0.002) and increased response (p = 0.047). There were no statistically significant associations between UGT1A1, UGT1A6, or thymidylate synthase genotypes and toxicity or tumor response. Conclusions: These data strongly suggest that UGT1A7 and/or UGT1A9 genotypes may be predictors of response and toxicity in CRC patients treated with capecitabine plus irinotecan. Specifically, patients with genotypes conferring low UGT1A7 activity and/or the UGT1A9 (dT)9/9 genotype may be particularly likely to exhibit greater antitumor response with little toxicity.

Original languageEnglish (US)
Pages (from-to)1226-1236
Number of pages11
JournalClinical Cancer Research
Volume11
Issue number3
StatePublished - Feb 1 2005
Externally publishedYes

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irinotecan
Colorectal Neoplasms
Genotype
Thymidylate Synthase
Glucuronosyltransferase
Enzymes
Capecitabine
Neutropenia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Carlini, L. E., Meropol, N. J., Bever, J., Andria, M. L., Hill, T., Gold, P., ... Blanchard, R. L. (2005). UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clinical Cancer Research, 11(3), 1226-1236.

UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. / Carlini, Leslie E.; Meropol, Neal J.; Bever, John; Andria, Michael L.; Hill, Todd; Gold, Philip; Rogatko, Andre; Wang, Hao; Blanchard, Rebecca L.

In: Clinical Cancer Research, Vol. 11, No. 3, 01.02.2005, p. 1226-1236.

Research output: Contribution to journalArticle

Carlini, LE, Meropol, NJ, Bever, J, Andria, ML, Hill, T, Gold, P, Rogatko, A, Wang, H & Blanchard, RL 2005, 'UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan', Clinical Cancer Research, vol. 11, no. 3, pp. 1226-1236.
Carlini, Leslie E. ; Meropol, Neal J. ; Bever, John ; Andria, Michael L. ; Hill, Todd ; Gold, Philip ; Rogatko, Andre ; Wang, Hao ; Blanchard, Rebecca L. / UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 3. pp. 1226-1236.
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abstract = "Purpose: Capecitabine and irinotecan are commonly used in the treatment of metastatic colorectal cancer (CRC). We hypothesized that germline polymorphisms within genes related to drug target (thymidylate synthase) or metabolizing enzymes (UDP-glucuronosyltransferase, UGT) would impact response and toxicity to the combination of capecitabine plus irinotecan (CPT-11). Experimental Design: Sixty-seven patients with measurable CRC were treated with irinotecan i.v. (100 or 125 mg/m2) on days 1 and 8 and capecitabine orally (900 or 1,000 mg/m2, twice daily) on days 2 through 15 of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using Pyrosequencing, GeneScan, and direct sequencing (Big Dye terminator) technologies. Results: The overall objective response rate was 45{\%} with 21 patients (31{\%}) exhibiting grade 3 or 4 diarrhea and 3 patients (4.5{\%}) demonstrating grade 3 or 4 neutropenia in the first two cycles. Low enzyme activity UGT1A7 genotypes, UGT1A7*2/*2 (six patients) and UGT1A7*3/*3 (seven patients), were significantly associated with antitumor response (p = 0.013) and lack of severe gastrointestinal toxicity (p = 0.003). In addition, the UGT1A9 -118 (dT)9/9 genotype was significantly associated with reduced toxicity (p = 0.002) and increased response (p = 0.047). There were no statistically significant associations between UGT1A1, UGT1A6, or thymidylate synthase genotypes and toxicity or tumor response. Conclusions: These data strongly suggest that UGT1A7 and/or UGT1A9 genotypes may be predictors of response and toxicity in CRC patients treated with capecitabine plus irinotecan. Specifically, patients with genotypes conferring low UGT1A7 activity and/or the UGT1A9 (dT)9/9 genotype may be particularly likely to exhibit greater antitumor response with little toxicity.",
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T1 - UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan

AU - Carlini, Leslie E.

AU - Meropol, Neal J.

AU - Bever, John

AU - Andria, Michael L.

AU - Hill, Todd

AU - Gold, Philip

AU - Rogatko, Andre

AU - Wang, Hao

AU - Blanchard, Rebecca L.

PY - 2005/2/1

Y1 - 2005/2/1

N2 - Purpose: Capecitabine and irinotecan are commonly used in the treatment of metastatic colorectal cancer (CRC). We hypothesized that germline polymorphisms within genes related to drug target (thymidylate synthase) or metabolizing enzymes (UDP-glucuronosyltransferase, UGT) would impact response and toxicity to the combination of capecitabine plus irinotecan (CPT-11). Experimental Design: Sixty-seven patients with measurable CRC were treated with irinotecan i.v. (100 or 125 mg/m2) on days 1 and 8 and capecitabine orally (900 or 1,000 mg/m2, twice daily) on days 2 through 15 of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using Pyrosequencing, GeneScan, and direct sequencing (Big Dye terminator) technologies. Results: The overall objective response rate was 45% with 21 patients (31%) exhibiting grade 3 or 4 diarrhea and 3 patients (4.5%) demonstrating grade 3 or 4 neutropenia in the first two cycles. Low enzyme activity UGT1A7 genotypes, UGT1A7*2/*2 (six patients) and UGT1A7*3/*3 (seven patients), were significantly associated with antitumor response (p = 0.013) and lack of severe gastrointestinal toxicity (p = 0.003). In addition, the UGT1A9 -118 (dT)9/9 genotype was significantly associated with reduced toxicity (p = 0.002) and increased response (p = 0.047). There were no statistically significant associations between UGT1A1, UGT1A6, or thymidylate synthase genotypes and toxicity or tumor response. Conclusions: These data strongly suggest that UGT1A7 and/or UGT1A9 genotypes may be predictors of response and toxicity in CRC patients treated with capecitabine plus irinotecan. Specifically, patients with genotypes conferring low UGT1A7 activity and/or the UGT1A9 (dT)9/9 genotype may be particularly likely to exhibit greater antitumor response with little toxicity.

AB - Purpose: Capecitabine and irinotecan are commonly used in the treatment of metastatic colorectal cancer (CRC). We hypothesized that germline polymorphisms within genes related to drug target (thymidylate synthase) or metabolizing enzymes (UDP-glucuronosyltransferase, UGT) would impact response and toxicity to the combination of capecitabine plus irinotecan (CPT-11). Experimental Design: Sixty-seven patients with measurable CRC were treated with irinotecan i.v. (100 or 125 mg/m2) on days 1 and 8 and capecitabine orally (900 or 1,000 mg/m2, twice daily) on days 2 through 15 of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using Pyrosequencing, GeneScan, and direct sequencing (Big Dye terminator) technologies. Results: The overall objective response rate was 45% with 21 patients (31%) exhibiting grade 3 or 4 diarrhea and 3 patients (4.5%) demonstrating grade 3 or 4 neutropenia in the first two cycles. Low enzyme activity UGT1A7 genotypes, UGT1A7*2/*2 (six patients) and UGT1A7*3/*3 (seven patients), were significantly associated with antitumor response (p = 0.013) and lack of severe gastrointestinal toxicity (p = 0.003). In addition, the UGT1A9 -118 (dT)9/9 genotype was significantly associated with reduced toxicity (p = 0.002) and increased response (p = 0.047). There were no statistically significant associations between UGT1A1, UGT1A6, or thymidylate synthase genotypes and toxicity or tumor response. Conclusions: These data strongly suggest that UGT1A7 and/or UGT1A9 genotypes may be predictors of response and toxicity in CRC patients treated with capecitabine plus irinotecan. Specifically, patients with genotypes conferring low UGT1A7 activity and/or the UGT1A9 (dT)9/9 genotype may be particularly likely to exhibit greater antitumor response with little toxicity.

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