中国好声音 马飞教授:基因分型指导乳腺癌内分泌治疗?!

文 / 良医汇
2017-12-07 18:59

中国好声音 马飞教授:基因分型指导乳腺癌内分泌治疗?!

作者:马飞 中国医学科学院肿瘤医院内科来源:肿瘤资讯

当地时间12月5日至9日,第40届圣安东尼奥乳腺癌研讨会(San Antonio Breast Cancer Symposium, SABCS)如期而至。本次大会吸引全球超过90个国家的乳腺癌专家学者参会,同时也有多项中国研究入选。

单中心回顾数据:绝经前乳腺癌患者的接受他莫昔芬的不良预后与的CYP2D6*10基因型相关,托瑞米芬不受影响

CYP2D6*10 genotype was associated with worse outcome of premenopausal breast cancer patients receiving adjuvant tamoxifen but not toremifene: a single institution expericence

1.Bo Lan, 2.Fei Ma, 3.Ying Fan, 4.Xiaoyu Zhai,5.Binghe XuNational Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China, 100021

Background:

Cytochrome P-450 (CYP450) enzyme, CYP2D6, is involved in the conversion of tamoxifen (TAM) to its main active metabolites. Variants of CYP2D6 gene may result in a decreased enzyme activity and lead to poor prognosis of the patients. Toremifene (TOR), another kind of SERM is not metabolited by CYP2D6 enzyme thus may not be influenced by its polymorphism. We conducted this study to validate the association between CYP2D6*10 (c.100C>T) genotype and the outcomes of patients receiving TAM and TOR respectively.

Methods:

A total of 276 patients with primary early-stage ER-positive breast cancer received adjuvant tamoxifen (n=169) or toremifene (n=107) therapy at Natinal Cancer Center from 2004-2012 were analyzed. All patients had received 5-year endocrine therapy after completion of surgery. TaqMan SNP genotyping assays was performed on CYP2D6*10 from blood samples. The association of CYP2D6 *10 genotype with disease free survival (DFS) and clinicopathological characteristics was analyzed in patients receiving tamoxifen and toremifen.

Results:

20.3% (56 of 276) of the patients were homozygous for variant T/T genotype. The frequency of CYP2D6 *10 allele in our study was 43.8%. Among 169 patients in tamoxifen group, 5-year DFS rate was considerably lower in patients with homozygous variant T/T genotype than the others (73.4% versus 83.2%, P=0.004). And the T/T genotype was found to be a significant prognostic marker for DFS in multivariate analysis (hazard ratio = 4.57; P<0.001). For the toremifene group, there was no difference of DFS between T/T genotype and the others (P=0.332). The 5-year DFS rate for tamoxifen and toremifene treatment group were similar (81.6% vs 83.2%, P=0.274). For all the 56 homozygous variant T/T genotype patients, patients receiving toremifene treatment had a much higher 5-year DFS rate than those receiving tamoxifen but the difference was not statistically significant (90.0% versus 73.4%, P=0.192).

Conclusions:

About one fifth of Chinese breast cancer patients had homozygous CYP2D6 *10 T/T genotype. They might get less benefit from TAM adjuvant treatment. Toremifene may be a better option for this group of patients.

中国医学科学院肿瘤医院徐兵河团队题为“单中心回顾数据:绝经前乳腺癌患者的接受他莫昔芬的不良预后与的CYP2D6*10基因型相关,托瑞米芬不受影响”研究成果入选大会壁报(摘要号:P3-12-09)。【肿瘤资讯】特邀马飞教授对这项研究进行了分析和点评。

随着基因组研究的深入,我们知道每个肿瘤患者都是不同的,需要“精准治疗”。激素受体阳性乳腺癌患者这个特殊的人群,其内分泌治疗的疗效经过多年的验证得到广大同道的认可。他莫昔芬(TAM)是一种选择性雌激素受体调节剂(SERM),是绝经前乳腺癌患者使用最广泛的辅助内分泌治疗药物。细胞色素P-450(CYP450)酶CYP2D6参与他莫昔芬在体内代谢为其活性产物Endoxifen。CYP2D6基因突变可能导致酶活性下降,导致患者预后不良。不同于白种人,中国女性中最常见的多态性是等位基因*10位点突变,主要是188 C突变为T,导致酶的活性降低。基于一些回顾性研究,他莫昔芬治疗的CYP2D6*10T/T基因型患者的临床预后较差。另外一类SERM托瑞米芬(TOR)不通过CYP2D6酶代谢,因此可能不受其多态性的影响。我们进行此项研究以验证CYP2D6*10基因型与接受TAM和TOR患者的结果之间的关联。

研究方法:

对2004—2012年在国家癌症中心接受辅助他莫昔芬(n = 169)或托瑞米芬(n = 107)治疗的276例原发性早期ER阳性乳腺癌患者进行分析。所有患者在完成手术后接受了5年的内分泌治疗。采用TaqMan SNP基因分型测定患者血液样品的CYP2D6*10基因型。在接受他莫昔芬和托瑞米芬治疗的患者中分析CYP2D6*10基因型与无疾病生存(DFS)和临床病理特征之间的关系。

研究结果:

32.6%(90/276)的患者是纯合子野生型的C/C基因型,47.1%(130/276)的患者是杂合子C/T基因型,20.3%(56/276)是纯合子突变型T/T基因型。本研究人群中CYP2D6*10等位基因突变频率为43.8%。他莫昔芬和托瑞米芬治疗组5年DFS率分别为81.6%和83.2%。两组间DFS差异无统计学意义(P = 0.274)。他莫昔芬组169例患者中,T/ T纯合突变型患者的5年DFS率显着低于野生型C / C或C / T基因型患者(73.4%比83.2%,P = 0.004)。T / T基因型在经上述患者特征调整后,在多因素分析中被发现是DFS的显著预后指标(风险比= 4.7; P <0.001)。托瑞米芬组T / T基因型与其他两组差异无统计学意义(P = 0.332)。对于所有56个纯合突变型T / T基因型患者,接受托瑞米芬治疗的患者5年DFS率远高于他莫昔芬,但无统计学意义(90.0%比73.4%,P = 0.192)。

研究结论:

约有1/5的中国人乳腺癌患者为T / T基因型纯合基因型,这类患者TAM辅助治疗效果可能不佳。托瑞米芬可能是这类患者更好的选择。需要进一步的大规模前瞻性临床研究来验证这个结论。

中国好声音 马飞教授:基因分型指导乳腺癌内分泌治疗?!

马飞教授

医学博士,中国医学科学院肿瘤医院内科副主任,主任医师,研究生导师

中国老年学会老年肿瘤分会总干事长

北京乳腺病防治学会健康管理专业委员会主任委员

中国抗癌协会乳腺癌青年委员会副主任委员

国家自然科学基金和教育部博士点基金评审专家

参考文献

Session: Poster Session 3: Treatment: Adjuvant endocrine Therapy (5:00 PM-7:00 PM)

Date/Time: Thursday, December 7, 2017 - 5:00 pm

Room: Hall 1

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中国好声音 马飞教授:基因分型指导乳腺癌内分泌治疗?!

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