Reply to Genetic polymorphisms of CYP2D6*10 and CYP2C19*2,*3 are not associated with prognosis, endometrial thickness, or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen

Abstract

We are grateful to Dr. Goetz et al for their queries, which we consider both important and useful for a better understanding of our study. Our responses to these questions are set out below. Unfortunately, the exact percentage of patients who refused to give their consent for the blood collection during the study period is unknown; however, the estimated refusal rate was very low (a few percentage points). Blood collection was performed before surgery from all patients who had provided consent. Patients who had estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive breast cancers received adjuvant tamoxifen, so that all ER-negative tumors were PR-positive tumors. We included patients who had received adjuvant tamoxifen and chemotherapy and/or lutenizing hormone-releasing hormone agonist, because it has been proven that tamoxifen significantly improves recurrence-free survival rates even in conjunction with these concomitant treatments. Postoperative surveillance consisted of a physical examination every 3 to 6 months for 2 years, every 6 months for 2 to 5 years, and once a year thereafter and was combined with a blood test and chest x-ray (mammography every year). Nine patients were lost to follow-up, 20 patients developed recurrences, and none of the patients without recurrence died. Our study was underpowered, as pointed out by Goetz et al. Therefore, for our study,1 we conducted an exploratory meta-analysis of the studies reported to date.2, 3 That analysis indicated that there was no statistically significant impact of the cytochrome p450 (CYP) genotype CYP2D6*10/*10 on prognosis. The salient point of our report is that we studied the impact of this polymorphism on the effects of tamoxifen on its target organs, such as uterus, bone, and liver, on the assumption that this polymorphism, if it really does influence the effect of tamoxifen, affects these organs more markedly than tumors, because it is believed that the response to tamoxifen essentially is homogeneous for normal tissues (target organs) but heterogeneous for tumors. We were able to demonstrate that the CYP2D6*10/*10 genotype essentially has no impact on the effects of tamoxifen on these target organs, suggesting that changes in tamoxifen metabolite levels detected in the CYP2D6*10/*10 genotype are not clinically important enough to influence the effects of tamoxifen on these organs. Thus, it has been speculated that the CYP2D6*10/*10 genotype also has no significant impact on the effects of tamoxifen on prognosis. However, as clearly pointed out by Goetz et al, future studies that include a larger number of patients are needed to reach a definitive conclusion regarding the impact of the CYP2D6*10/*10 genotype on prognosis. Shinzaburo Noguchi MD*, Masatsugu Okishiro MD*, * Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.