Pang Hui, Zhang Guoqiang, Yan Na, Lang Jidong, Liang Yuebin, Xu Xinyuan, Cui Yaowen, Wu Xueya, Li Xianjun, Shan Ming, Wang Xiaoqin, Meng Xiangzhi, Liu Jiaxiang, Tian Geng, Cai Li, Yuan Dawei, Wang Xin
Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
Department of Science, Geneis (Beijing) Co., Ltd., Beijing, China.
Front Oncol. 2021 Nov 19;11:738222. doi: 10.3389/fonc.2021.738222. eCollection 2021.
Tamoxifen (TAM) is the most commonly used adjuvant endocrine drug for hormone receptor-positive (HR+) breast cancer patients. However, how to accurately evaluate the risk of breast cancer recurrence and metastasis after adjuvant TAM therapy is still a major concern. In recent years, many studies have shown that the clinical outcomes of TAM-treated breast cancer patients are influenced by the activity of some cytochrome P450 (CYP) enzymes that catalyze the formation of active TAM metabolites like endoxifen and 4-hydroxytamoxifen. In this study, we aimed to first develop and validate an algorithm combining polymorphisms in CYP genes and clinicopathological signatures to identify a subpopulation of breast cancer patients who might benefit most from TAM adjuvant therapy and meanwhile evaluate major risk factors related to TAM resistance. Specifically, a total of 256 patients with invasive breast cancer who received adjuvant endocrine therapy were selected. The genotypes at 10 loci from three TAM metabolism-related CYP genes were detected by time-of-flight mass spectrometry and multiplex long PCR. Combining the 10 loci with nine clinicopathological characteristics, we obtained 19 important features whose association with cancer recurrence was assessed by importance score random forests. After that, a logistic regression model was trained to calculate TAM risk-of-recurrence score (TAM RORs), which is adopted to assess a patient's risk of recurrence after TAM treatment. The sensitivity and specificity of the model in an independent test cohort were 86.67% and 64.56%, respectively. This study showed that breast cancer patients with high TAM RORs were less sensitive to TAM treatment and manifested more invasive characteristics, whereas those with low TAM RORs were highly sensitive to TAM treatment, and their conditions were stable during the follow-up period. There were some risk factors that had a significant effect on the efficacy of TAM. They were tissue classification (tumor Grade < 2 . Grade ≥ 2, = 2.2e-16), the number of lymph node metastases (Node-Negative . Node < 4, = 5.3e-07; Node < 4 . Node ≥ 4, = 0.003; Node-Negative . Node ≥ 4, = 7.2e-15), and the expression levels of estrogen receptor (ER) and progesterone receptor (PR) (ER < 50% . ER ≥ 50%, = 1.3e-12; PR < 50% . PR ≥ 50%, = 2.6e-08). The really remarkable thing is that different genotypes of show significant differences in prediction function (. , < 0.019; . , < 0.037). There are more than 50% Chinese who have CYP2D6*10 mutation. So the genotype of should be tested before TAM therapy.
他莫昔芬（TAM）是激素受体阳性（HR+）乳腺癌患者最常用的辅助内分泌药物。然而，如何准确评估辅助性TAM治疗后乳腺癌复发和转移的风险仍是一个主要问题。近年来，许多研究表明，接受TAM治疗的乳腺癌患者的临床结局受一些细胞色素P450（CYP）酶活性的影响，这些酶催化活性TAM代谢产物如内昔芬和4-羟基他莫昔芬的形成。在本研究中，我们旨在首先开发并验证一种结合CYP基因多态性和临床病理特征的算法，以识别可能从TAM辅助治疗中获益最大的乳腺癌患者亚群，同时评估与TAM耐药相关的主要风险因素。具体而言，共选择了256例接受辅助内分泌治疗的浸润性乳腺癌患者。通过飞行时间质谱和多重长PCR检测了来自三个与TAM代谢相关的CYP基因的10个位点的基因型。将这10个位点与九个临床病理特征相结合，我们获得了19个重要特征，通过重要性评分随机森林评估它们与癌症复发的关联。之后，训练了一个逻辑回归模型来计算TAM复发风险评分（TAM RORs），用于评估患者接受TAM治疗后的复发风险。该模型在独立测试队列中的敏感性和特异性分别为86.67%和64.56%。本研究表明，TAM RORs高的乳腺癌患者对TAM治疗不太敏感，表现出更具侵袭性的特征，而TAM RORs低的患者对TAM治疗高度敏感，且在随访期间病情稳定。有一些风险因素对TAM的疗效有显著影响。它们是组织分类（肿瘤分级<2.分级≥2，P = 2.2e - 16）、淋巴结转移数量（淋巴结阴性.淋巴结<4，P = 5.3e - 07；淋巴结<4.淋巴结≥4，P = 0.003；淋巴结阴性.淋巴结≥4，P = 7.2e - 15）以及雌激素受体（ER）和孕激素受体（PR）的表达水平（ER<50%.ER≥50%，P = 1.3e - 12；PR<50%.PR≥50%，P = 2.6e - 08）。真正值得注意的是，CYP2D6的不同基因型在预测功能上显示出显著差异（例如，P<0.019；例如，P<0.037）。超过50%的中国人有CYP2D6*10突变。因此，在TAM治疗前应检测CYP2D6的基因型。
