Genetic predictors of taxane-induced neurotoxicity in a SWOG phase III intergroup adjuvant breast cancer treatment trial (S0221)

Lara E. Sucheston, Hua Zhao, Song Yao, Gary Zirpoli, Song Liu, William E. Barlow, Halle C F Moore, G. Thomas Budd, Dawn L. Hershman, Warren Davis, Gregory L. Ciupak, James A. Stewart, Claudine Isaacs, Timothy J. Hobday, Muhammad Salim, Gabriel N. Hortobagyi, Julie R. Gralow, Robert B Livingston, Kathy S. Albain, Daniel F. HayesChristine B. Ambrosone

Research output: Contribution to journalArticle

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Abstract

Taxanes have resulted in improved survival for breast cancer patients, but often cause neurological toxicities. Identification of biomarkers related to toxicities could be important for dictating treatment regimen. We evaluated single nucleotide polymorphisms (SNPs) in the Fanconi Anemia (FA)/BRCA pathway in relation to grade 3/4 neurotoxicities in patients (n = 888) from SWOG0221, a phase III adjuvant trial for breast cancer of 4 dose/schedules of cyclophosphamide (C), doxorubicin (A), and paclitaxel (T). In a separate cohort, we measured the correlation of significant FANCD2 SNPs with corresponding gene expression. For FANCD2, permutation testing revealed that 4 (out of 20) SNPs were significantly associated with an almost two-fold increased risk of toxicity. Two FANCD2 haplotypes were also associated with neurological toxicity, with odds ratios (OR) in the overall population of 1.8 (95% confidence interval (CI) 1.3, 2.5) and 1.7 (95% CI, 1.2, 2.4). Although numbers were small, an African-American-specific haplotype was associated with an almost 3-fold increase in risk of neurologic toxicity (OR = 2.84, 95% CI = 1.2, 6.9). Expression analyses revealed that significant FANCD2 SNPs were associated with FANCD2 expression levels (P = 0.03). There were no associations between SNPs in BRCA1 and neurotoxicities. In this trial of CA+T for breast cancer, SNPs in FANCD2, but not in BRCA1, were associated with a 70-80% increase in the odds of grade 3/4 neurological toxicities and increased expression of the gene. If replicated, women with these genotypes should be closely monitored for toxicities and could be targeted for preventive measures or alternative therapeutic approaches.

Original languageEnglish (US)
Pages (from-to)993-1002
Number of pages10
JournalBreast Cancer Research and Treatment
Volume130
Issue number3
DOIs
StatePublished - Dec 2011

Fingerprint

Single Nucleotide Polymorphism
Breast Neoplasms
Confidence Intervals
Haplotypes
Therapeutics
Odds Ratio
Fanconi Anemia
Gene Expression
Taxoids
Paclitaxel
African Americans
Doxorubicin
Cyclophosphamide
Nervous System
taxane
Appointments and Schedules
Biomarkers
Genotype
Survival
Population

Keywords

  • DNA repair polymorphisms
  • FANCD2
  • Gene expression
  • Genetic variants
  • Neurotoxicity
  • Pharmacogenetics
  • Pharmacogenomics
  • Taxanes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Genetic predictors of taxane-induced neurotoxicity in a SWOG phase III intergroup adjuvant breast cancer treatment trial (S0221). / Sucheston, Lara E.; Zhao, Hua; Yao, Song; Zirpoli, Gary; Liu, Song; Barlow, William E.; Moore, Halle C F; Thomas Budd, G.; Hershman, Dawn L.; Davis, Warren; Ciupak, Gregory L.; Stewart, James A.; Isaacs, Claudine; Hobday, Timothy J.; Salim, Muhammad; Hortobagyi, Gabriel N.; Gralow, Julie R.; Livingston, Robert B; Albain, Kathy S.; Hayes, Daniel F.; Ambrosone, Christine B.

In: Breast Cancer Research and Treatment, Vol. 130, No. 3, 12.2011, p. 993-1002.

Research output: Contribution to journalArticle

Sucheston, LE, Zhao, H, Yao, S, Zirpoli, G, Liu, S, Barlow, WE, Moore, HCF, Thomas Budd, G, Hershman, DL, Davis, W, Ciupak, GL, Stewart, JA, Isaacs, C, Hobday, TJ, Salim, M, Hortobagyi, GN, Gralow, JR, Livingston, RB, Albain, KS, Hayes, DF & Ambrosone, CB 2011, 'Genetic predictors of taxane-induced neurotoxicity in a SWOG phase III intergroup adjuvant breast cancer treatment trial (S0221)', Breast Cancer Research and Treatment, vol. 130, no. 3, pp. 993-1002. https://doi.org/10.1007/s10549-011-1671-3
Sucheston, Lara E. ; Zhao, Hua ; Yao, Song ; Zirpoli, Gary ; Liu, Song ; Barlow, William E. ; Moore, Halle C F ; Thomas Budd, G. ; Hershman, Dawn L. ; Davis, Warren ; Ciupak, Gregory L. ; Stewart, James A. ; Isaacs, Claudine ; Hobday, Timothy J. ; Salim, Muhammad ; Hortobagyi, Gabriel N. ; Gralow, Julie R. ; Livingston, Robert B ; Albain, Kathy S. ; Hayes, Daniel F. ; Ambrosone, Christine B. / Genetic predictors of taxane-induced neurotoxicity in a SWOG phase III intergroup adjuvant breast cancer treatment trial (S0221). In: Breast Cancer Research and Treatment. 2011 ; Vol. 130, No. 3. pp. 993-1002.
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AU - Zirpoli, Gary

AU - Liu, Song

AU - Barlow, William E.

AU - Moore, Halle C F

AU - Thomas Budd, G.

AU - Hershman, Dawn L.

AU - Davis, Warren

AU - Ciupak, Gregory L.

AU - Stewart, James A.

AU - Isaacs, Claudine

AU - Hobday, Timothy J.

AU - Salim, Muhammad

AU - Hortobagyi, Gabriel N.

AU - Gralow, Julie R.

AU - Livingston, Robert B

AU - Albain, Kathy S.

AU - Hayes, Daniel F.

AU - Ambrosone, Christine B.

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