A genome-wide association study identifies three novel genetic markers for response to tamoxifen: A prospective multicenter study.

PURPOSE: Although 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 DESIGN: We 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. RESULTS: The 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. CONCLUSION: 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.

Significant Effect of Polymorphisms in CYP2D6 on Response to Tamoxifen Therapy for Breast Cancer: A Prospective Multicenter Study.

Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, "endoxifen." There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy.Experimental Design: We enrolled 279 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. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes.Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor-positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele).Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. Clin Cancer Res; 23(8); 2019-26. ©2016 AACR.

Clinical application of the one-step nucleic acid amplification method to detect sentinel lymph node metastasis in breast cancer.

BACKGROUND: The one-step nucleic acid amplification (OSNA) method can assess the expression level of cytokeratin 19 mRNA in sentinel lymph nodes in breast cancer. We compared the time required for diagnosis and concordance of results between the OSNA method and conventional intraoperative pathological examination. We then examined the relationship between the frequency of non-sentinel lymph node metastasis and (1) the expression level of CK19 mRNA in the sentinel lymph nodes and (2) clinico-pathological features of the primary tumor. METHODS: In the comparison study, pairs of sentinel lymph node sections from 53 consecutive patients were examined: one section by hematoxylin-eosin staining and the other by OSNA assay. The latter involved reverse-transcription loop-mediated isothermal amplification of cytokeratin 19 mRNA, assessed quantitatively. In the second phase, 306 sentinel lymph nodes were removed from 248 consecutive patients, and whole sentinel lymph nodes were examined by OSNA assay alone. RESULTS: OSNA assay was a little more time-consuming than conventional pathological diagnosis (34-45 vs. 22-25 min, p < 0.0001). Concordance between the two methods was 93%. The frequency of non-sentinel lymph node metastasis (p < 0.0001) and the total number of lymph node metastases (p < 0.0001) increased with the amount of cytokeratin 19 mRNA on OSNA assay. We found no significant relationship between the amount of cytokeratin 19 mRNA in sentinel lymph nodes and breast cancer immunohistochemical subtype. CONCLUSIONS: The OSNA method is suitable to detect sentinel lymph node metastasis and to predict the possibility of non-sentinel metastasis. This semi-automated quantitative analysis system reduces the burden on pathologists.

[A patient with of metastatic breast cancer with a well-controlled quality of life using S-1 therapy as first-line chemotherapy].

We experienced a case of endocrine therapy-resistant recurrent breast cancer with liver and bone metastases, treated with S-1 as first-line chemotherapy and maintaining a good quality of life. The patient was a 31-year-old premenopausal woman. She was diagnosed with cancer of the left breast(T1(18mm), N0, M(-))and underwent breast-conserving surgery, sentinel lymph node biopsy, and radiation therapy in August 2002. As there was hormone sensitivity, she was treated with LHRH analog for 3 years and tamoxifen for 5 years as adjuvant therapy. After her first childbirth, she had a recurrence of liver and bone metastases. After treatment with endocrine therapy failed, an oral administration of S-1 was initiated as first-line chemotherapy considering her QOL. She received 8 months of S-1 therapy with no severe adverse reactions and maintained a high quality of life. Treatment with S-1 is thought to be useful for first-line chemotherapy if the treatment demonstrates a therapeutic equivalence with taxane on patients' overall survival.