中美晚期乳腺癌血液基因突变比较
原发性乳腺癌一旦发生远处转移即为晚期，转移性乳腺癌与原发性乳腺癌相比，基因组复杂性增加，并且与已知的体细胞基因突变相关，不同亚型乳腺癌的这些基因突变存在差异。血液活检与组织活检相比，可动态、微创检测全身血液循环的细胞游离DNA、循环肿瘤DNA、细胞游离RNA、循环肿瘤细胞、外泌体和蛋白质，已经成为确定预后、基因组特征和治疗效果的临床分析方法，尤其对于已经发生远处转移的晚期乳腺癌。虽然晚期乳腺癌患者的诊断和治疗已经取得巨大进步，但是中国与西方国家相比，乳腺癌的发病、管理和临床结局存在巨大差异。例如，中国乳腺癌的中位诊断年龄比美国和欧盟年轻近10岁，中国与美国乳腺癌患者的基因组分析结果也相互矛盾。因此，对不同种族的基因突变谱进行有意义的比较需要采用标准化平台技术。
2021年9月1日，施普林格自然旗下《乳腺癌研究与治疗》在线发表北京大学肿瘤医院刘笑然、桂欣钰、陈祎霏、李惠平、美国芝加哥西北大学费恩伯格医学院罗伯特卢里综合癌症中心马西莫·克里斯托法尼利、圣路易斯华盛顿大学医学院安德鲁·戴维斯、慧渡医疗虞建军、贾士东、杜攀等学者的研究报告，采用统一血液活检细胞游离DNA大规模并行测序分析，对中国与美国的激素受体阳性HER2阴性晚期乳腺癌一线治疗患者基因组特征进行了比较。激素受体阳性HER2阴性乳腺癌占全部乳腺癌病例七成以上。
该研究采用经美国临床实验室改进修正法案认证的慧渡医疗152基因血液活检分析，对27例美国患者和65例中国患者的血液循环肿瘤DNA进行测序，通过生存时间曲线分析基因组变异与无进展生存之间的相关性，并通过对数秩检验计算P值。
结果发现，中国患者与美国患者相比：
化疗和/或激素治疗：100%比11.1%
激素治疗＋CDK4/6抑制剂：0%比85.2%
基因变异：83%比85%
AKT1基因变异：1.5%比18.5%（P=0.008）
CDH1基因变异：3.1%比18.5%（P=0.021）
FGFR1基因扩增：24.6%比7.4%（P=0.048）
对于中国患者：
PTEN缺失与未缺失相比：无进展生存显著较短（中位5.7比13.2个月，P=0.03）
ESR1变异与未变异相比：无进展生存显著较短（中位9.0比13.2个月，P=0.02）
PTEN缺失、ESR1变异对美国患者无进展生存的影响不显著。有趣的是，对于接受CDK4/6抑制剂治疗的患者，PTEN缺失与无进展生存的相关性减少。
因此，该研究结果表明，中国与美国的激素受体阳性HER2阴性晚期乳腺癌患者循环肿瘤DNA改变（例如FGFR1、AKT1和CDH1）发生率显著不同。此外，PTEN缺失、ESR1变异对无进展生存的影响可见于中国患者而未见于美国患者。两个种族之间的基因组特征差异可能反映生物学差异，具有临床意义。
Breast Cancer Res Treat. 2021 Sep 1. Online ahead of print.
Cell-free DNA comparative analysis of the genomic landscape of first-line hormone receptor-positive metastatic breast cancer from the US and China.
Xiaoran Liu, Andrew A. Davis, Feng Xie, Xinyu Gui, Yifei Chen, Qiang Zhang, Lorenzo Gerratana, Youbin Zhang, Ami N. Shah, Amir Behdad, Firas Wehbe, Yong Huang, Jianjun Yu, Pan Du, Shidong Jia, Huiping Li, Massimo Cristofanilli.
Peking University Cancer Hospital & Institute, Beijing, China; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Washington University School of Medicine in St. Louis, St. Louis, MO, USA; Huidu (Shanghai) Medical Sciences, Ltd., Shanghai, China; Predicine, Inc., Hayward, CA, USA.
PURPOSE: Meaningful comparison of mutational landscapes across ethnic groups requires the use of standardized platform technology. We have used a harmonized NGS-based liquid biopsy assay to explore the differential genomic landscape of patients with initially hormone receptor-positive (HR+), HER2-negative MBC of first line metastasis or primary Stage IV at diagnosis from the United States (US) and China (CN).
METHODS: Plasma circulating tumor DNA (ctDNA) from 27 US patients and 65 CN patients was sequenced using the harmonized CLIA-certified, 152-gene PredicineCare liquid biopsy assay. Kaplan-Meier survival analysis was performed to analyze the correlation between genomic alterations and progression-free survival (PFS), and p-values were calculated using the log-rank test.
RESULTS: All patients in the CN cohort received chemotherapy and/or hormonal therapy, while 85.2% (23/27) patients in the US cohort received hormonal therapy plus CDK4/6 inhibitors. Mutations were detected in 23 of 27 (85%) US patients and 54 of 65 (83%) CN patients. The prevalence of AKT1 (P=0.008) and CDH1 (P=0.021) alterations were both higher in the US vs. CN cohort. In addition, FGFR1 amplification were more frequent in the CN vs. US cohort (P=0.048). PTEN deletions (P=0.03) and ESR1 alterations (P=0.02) were associated with shorter PFS in the CN cohort, neither of these associations were observed in the US cohort. Interestingly, a reduced association between PTEN deletion and PFS was observed in patients receiving CDK4/6 inhibitor treatment.
CONCLUSION: The differential prevalence of ctDNA-based alterations such as FGFR1, AKT1, and CDH1 was observed in initially HR+/HER2- MBC patients in the US vs. CN. In addition, the association of PTEN deletions with shorter PFS was found in the CN but not the US cohort. The differential genomic landscapes across the two ethnic groups may reflect biologic differences and clinical implications.
KEYWORDS: HR-positive advanced breast cancer; Circulating tumor DNA; Next-generation sequencing
DOI: 10.1007/s10549-021-06370-w