Gene polymorphisms in cyclophosphamide metabolism pathway, treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer

Song Yao, William E. Barlow, Kathy S. Albain, Ji Yeob Choi, Hua Zhao, Robert B. Livingston, Warren Davis, James M. Rae, I. Tien Yeh, Laura F. Hutchins, Peter M. Ravdin, Silvana Martino, Alan P. Lyss, C. Kent Osborne, Martin Abeloff, Gabriel N. Hortobagyi, Daniel F. Hayes, Christine B. Ambrosone

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Abstract

Purpose: There are no established genetic markers for prediction of outcomes after cyclophosphamide (CP)-containing adjuvant therapy for breast cancer. In an ancillary study to a SWOG (Southwest Oncology Group) trial (S8897), we investigated functional polymorphisms in 4 genes in CP pharmacokinetic pathways in relation to hematologic toxicity and disease-free survival (DFS). Experimental Design: Germline DNA was available from 458 women who were at high risk of relapse and was randomized to CAF (CP, intravenous doxorubicin, and 5-fluorouracil) versus CMF (CP, intravenous methotrexate, and 5-fluorouracil) ± tamoxifen, and from 874 women who had a presumed favorable prognosis and did not receive adjuvant therapy. Odds ratios for grade 3 and 4 hematologic toxicity in the treated group and hazard ratios for DFS associated with selected functional polymorphisms in CYP2B6, CYP3A4, GSTA1, and GSTP1 were estimated by logistic regression and Cox proportional hazard regression. Results: Compared with women with AA genotypes, those with at least 1 GSTP1 variant G allele had reduced risk of grade 3 and 4 neutropenia [odds ratios (OR) = 0.63, 95% CI = 0.41-0.97] and leucopenia (OR = 0.59, 95% CI = 0.39-0.89). No other associations between single nucleotide polymorphisms and toxicity or survival were found in the treated or untreated group. Conclusion: Known genetic variants in genes involved in CP pharmacokinetics may not have major effects on DFS in breast cancer patients. The lower risk of developing high-grade hematologic toxicity among women with variant GSTP1 alleles suggests that genetic markers in combination with clinical factors may be useful in defining a subgroup of women who are less susceptible to adverse hematologic toxicities with CP-containing therapies.

Original languageEnglish
Pages (from-to)6169-6176
Number of pages8
JournalClinical Cancer Research
Volume16
Issue number24
DOIs
StatePublished - 15 Dec 2010

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Cyclophosphamide
Disease-Free Survival
Clinical Trials
Breast Neoplasms
Genes
Odds Ratio
Genetic Markers
Fluorouracil
Therapeutics
Pharmacokinetics
Alleles
Cytochrome P-450 CYP3A
Hematologic Diseases
Leukopenia
Tamoxifen
Neutropenia
Methotrexate
Doxorubicin
Single Nucleotide Polymorphism
Research Design

Cite this

Yao, Song ; Barlow, William E. ; Albain, Kathy S. ; Choi, Ji Yeob ; Zhao, Hua ; Livingston, Robert B. ; Davis, Warren ; Rae, James M. ; Yeh, I. Tien ; Hutchins, Laura F. ; Ravdin, Peter M. ; Martino, Silvana ; Lyss, Alan P. ; Osborne, C. Kent ; Abeloff, Martin ; Hortobagyi, Gabriel N. ; Hayes, Daniel F. ; Ambrosone, Christine B. / Gene polymorphisms in cyclophosphamide metabolism pathway, treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 24. pp. 6169-6176.
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title = "Gene polymorphisms in cyclophosphamide metabolism pathway, treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer",
abstract = "Purpose: There are no established genetic markers for prediction of outcomes after cyclophosphamide (CP)-containing adjuvant therapy for breast cancer. In an ancillary study to a SWOG (Southwest Oncology Group) trial (S8897), we investigated functional polymorphisms in 4 genes in CP pharmacokinetic pathways in relation to hematologic toxicity and disease-free survival (DFS). Experimental Design: Germline DNA was available from 458 women who were at high risk of relapse and was randomized to CAF (CP, intravenous doxorubicin, and 5-fluorouracil) versus CMF (CP, intravenous methotrexate, and 5-fluorouracil) ± tamoxifen, and from 874 women who had a presumed favorable prognosis and did not receive adjuvant therapy. Odds ratios for grade 3 and 4 hematologic toxicity in the treated group and hazard ratios for DFS associated with selected functional polymorphisms in CYP2B6, CYP3A4, GSTA1, and GSTP1 were estimated by logistic regression and Cox proportional hazard regression. Results: Compared with women with AA genotypes, those with at least 1 GSTP1 variant G allele had reduced risk of grade 3 and 4 neutropenia [odds ratios (OR) = 0.63, 95{\%} CI = 0.41-0.97] and leucopenia (OR = 0.59, 95{\%} CI = 0.39-0.89). No other associations between single nucleotide polymorphisms and toxicity or survival were found in the treated or untreated group. Conclusion: Known genetic variants in genes involved in CP pharmacokinetics may not have major effects on DFS in breast cancer patients. The lower risk of developing high-grade hematologic toxicity among women with variant GSTP1 alleles suggests that genetic markers in combination with clinical factors may be useful in defining a subgroup of women who are less susceptible to adverse hematologic toxicities with CP-containing therapies.",
author = "Song Yao and Barlow, {William E.} and Albain, {Kathy S.} and Choi, {Ji Yeob} and Hua Zhao and Livingston, {Robert B.} and Warren Davis and Rae, {James M.} and Yeh, {I. Tien} and Hutchins, {Laura F.} and Ravdin, {Peter M.} and Silvana Martino and Lyss, {Alan P.} and Osborne, {C. Kent} and Martin Abeloff and Hortobagyi, {Gabriel N.} and Hayes, {Daniel F.} and Ambrosone, {Christine B.}",
year = "2010",
month = "12",
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doi = "10.1158/1078-0432.CCR-10-0281",
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Yao, S, Barlow, WE, Albain, KS, Choi, JY, Zhao, H, Livingston, RB, Davis, W, Rae, JM, Yeh, IT, Hutchins, LF, Ravdin, PM, Martino, S, Lyss, AP, Osborne, CK, Abeloff, M, Hortobagyi, GN, Hayes, DF & Ambrosone, CB 2010, 'Gene polymorphisms in cyclophosphamide metabolism pathway, treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer', Clinical Cancer Research, vol. 16, no. 24, pp. 6169-6176. https://doi.org/10.1158/1078-0432.CCR-10-0281

Gene polymorphisms in cyclophosphamide metabolism pathway, treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer. / Yao, Song; Barlow, William E.; Albain, Kathy S.; Choi, Ji Yeob; Zhao, Hua; Livingston, Robert B.; Davis, Warren; Rae, James M.; Yeh, I. Tien; Hutchins, Laura F.; Ravdin, Peter M.; Martino, Silvana; Lyss, Alan P.; Osborne, C. Kent; Abeloff, Martin; Hortobagyi, Gabriel N.; Hayes, Daniel F.; Ambrosone, Christine B.

In: Clinical Cancer Research, Vol. 16, No. 24, 15.12.2010, p. 6169-6176.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Gene polymorphisms in cyclophosphamide metabolism pathway, treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer

AU - Yao, Song

AU - Barlow, William E.

AU - Albain, Kathy S.

AU - Choi, Ji Yeob

AU - Zhao, Hua

AU - Livingston, Robert B.

AU - Davis, Warren

AU - Rae, James M.

AU - Yeh, I. Tien

AU - Hutchins, Laura F.

AU - Ravdin, Peter M.

AU - Martino, Silvana

AU - Lyss, Alan P.

AU - Osborne, C. Kent

AU - Abeloff, Martin

AU - Hortobagyi, Gabriel N.

AU - Hayes, Daniel F.

AU - Ambrosone, Christine B.

PY - 2010/12/15

Y1 - 2010/12/15

N2 - Purpose: There are no established genetic markers for prediction of outcomes after cyclophosphamide (CP)-containing adjuvant therapy for breast cancer. In an ancillary study to a SWOG (Southwest Oncology Group) trial (S8897), we investigated functional polymorphisms in 4 genes in CP pharmacokinetic pathways in relation to hematologic toxicity and disease-free survival (DFS). Experimental Design: Germline DNA was available from 458 women who were at high risk of relapse and was randomized to CAF (CP, intravenous doxorubicin, and 5-fluorouracil) versus CMF (CP, intravenous methotrexate, and 5-fluorouracil) ± tamoxifen, and from 874 women who had a presumed favorable prognosis and did not receive adjuvant therapy. Odds ratios for grade 3 and 4 hematologic toxicity in the treated group and hazard ratios for DFS associated with selected functional polymorphisms in CYP2B6, CYP3A4, GSTA1, and GSTP1 were estimated by logistic regression and Cox proportional hazard regression. Results: Compared with women with AA genotypes, those with at least 1 GSTP1 variant G allele had reduced risk of grade 3 and 4 neutropenia [odds ratios (OR) = 0.63, 95% CI = 0.41-0.97] and leucopenia (OR = 0.59, 95% CI = 0.39-0.89). No other associations between single nucleotide polymorphisms and toxicity or survival were found in the treated or untreated group. Conclusion: Known genetic variants in genes involved in CP pharmacokinetics may not have major effects on DFS in breast cancer patients. The lower risk of developing high-grade hematologic toxicity among women with variant GSTP1 alleles suggests that genetic markers in combination with clinical factors may be useful in defining a subgroup of women who are less susceptible to adverse hematologic toxicities with CP-containing therapies.

AB - Purpose: There are no established genetic markers for prediction of outcomes after cyclophosphamide (CP)-containing adjuvant therapy for breast cancer. In an ancillary study to a SWOG (Southwest Oncology Group) trial (S8897), we investigated functional polymorphisms in 4 genes in CP pharmacokinetic pathways in relation to hematologic toxicity and disease-free survival (DFS). Experimental Design: Germline DNA was available from 458 women who were at high risk of relapse and was randomized to CAF (CP, intravenous doxorubicin, and 5-fluorouracil) versus CMF (CP, intravenous methotrexate, and 5-fluorouracil) ± tamoxifen, and from 874 women who had a presumed favorable prognosis and did not receive adjuvant therapy. Odds ratios for grade 3 and 4 hematologic toxicity in the treated group and hazard ratios for DFS associated with selected functional polymorphisms in CYP2B6, CYP3A4, GSTA1, and GSTP1 were estimated by logistic regression and Cox proportional hazard regression. Results: Compared with women with AA genotypes, those with at least 1 GSTP1 variant G allele had reduced risk of grade 3 and 4 neutropenia [odds ratios (OR) = 0.63, 95% CI = 0.41-0.97] and leucopenia (OR = 0.59, 95% CI = 0.39-0.89). No other associations between single nucleotide polymorphisms and toxicity or survival were found in the treated or untreated group. Conclusion: Known genetic variants in genes involved in CP pharmacokinetics may not have major effects on DFS in breast cancer patients. The lower risk of developing high-grade hematologic toxicity among women with variant GSTP1 alleles suggests that genetic markers in combination with clinical factors may be useful in defining a subgroup of women who are less susceptible to adverse hematologic toxicities with CP-containing therapies.

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U2 - 10.1158/1078-0432.CCR-10-0281

DO - 10.1158/1078-0432.CCR-10-0281

M3 - Article

VL - 16

SP - 6169

EP - 6176

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 24

ER -