Abstract
PurposeAlthough association studies of genetic variations with the clinical outcomes of breast cancer patients treated with tamoxifen have been reported, genetic factors which could determine individual response to tamoxifen are not fully clarified. We performed a genome-wide association study (GWAS) to identify novel genetic markers for response to tamoxifen.Experimental designWe prospectively collected 347 blood samples from patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. We used Ki-67 response in breast cancer tissues after preoperative short-term tamoxifen therapy as a surrogate marker for response to tamoxifen. We performed GWAS and genotype imputation using 275 patients, and an independent set of 72 patients was used for replication study.ResultsThe combined result of GWAS and the replication study, and subsequent imputation analysis indicated possible association of three loci with Ki-67 response after tamoxifen therapy (rs17198973 on chromosome 4q34.3, rs4577773 on 6q12, and rs7087428 on 10p13, Pcombined = 5.69 x 10−6, 1.64 x 10−5, and 9.77 x 10−6, respectively). When patients were classified into three groups by the scoring system based on the genotypes of the three SNPs, patients with higher scores showed significantly higher after/before ratio of Ki-67 compared to those with lower scores (P = 1.8 x 10−12), suggesting the cumulative effect of the three SNPs.ConclusionWe identified three novel loci, which could be associated with clinical response to tamoxifen. These findings provide new insights into personalized hormonal therapy for the patients with breast cancer.
Highlights
The clinical benefit of the antiestrogen agent “tamoxifen” for the treatment of estrogen receptor (ER)-positive breast cancers is well-known [1]
We identified three novel loci, which could be associated with clinical response to tamoxifen
These findings provide new insights into personalized hormonal therapy for the patients with breast cancer
Summary
The clinical benefit of the antiestrogen agent “tamoxifen” for the treatment of estrogen receptor (ER)-positive breast cancers is well-known [1]. Inter-individual differences in response to tamoxifen therapy have been reported and 30–50% of patients with adjuvant tamoxifen therapy suffer a relapse and die of the disease [3, 4]. Many studies have suggested that metabolites of tamoxifen, 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen (endoxifen) are the active therapeutic moieties of tamoxifen. To clarify the clinical significance of CYP2D6 allele in tamoxifen therapy, we recently carried out the prospective CYP2D6-tamoxifen study and reported the positive association between CYP2D6 genotype and response to tamoxifen using Ki-67 change in breast cancer tissues after short-term preoperative tamoxifen therapy [21], which has been known as a promising surrogate marker for clinical response to tamoxifen [21,22,23,24]
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