液体活检在乳腺癌精准治疗中的应用进展及展望

doi:10.19401/j.cnki.1007-3639.2022.08.003

中国癌症杂志 ›› 2022, Vol. 32 ›› Issue (8): 688-697.doi: 10.19401/j.cnki.1007-3639.2022.08.003

液体活检在乳腺癌精准治疗中的应用进展及展望

张羽()(), 刘强()()

中山大学孙逸仙纪念医院乳腺肿瘤中心,广东广州 510000

收稿日期:2022-07-01 修回日期:2022-07-20 出版日期:2022-08-30 发布日期:2022-09-19
通信作者: 刘强 E-mail:zhangy583@mail2.sysu.edu.cn;victorlq@hotmail.com
作者简介:张羽（ORCID：0000-0002-1339-8367）,中山大学孙逸仙纪念医院乳腺肿瘤中心硕士研究生,E-mail: zhangy583@mail2.sysu.edu.cn
刘强,主任医师、研究员、教授、逸仙乳腺肿瘤医院执行副院长、中山大学孙逸仙纪念医院外科主任、乳腺肿瘤中心主任、乳腺外科主任。现任欧洲肿瘤学院国际年轻乳腺癌共识专家组成员,亚洲乳腺癌协作组成员,中国临床肿瘤学会乳腺癌专业委员会常务委员兼副秘书长,中国抗癌协会乳腺癌专业委员会常务委员,中国抗癌协会肿瘤分子医学专业委员会常务委员,广东省医学会乳腺病学分会主任委员,广东省抗癌协会乳腺癌专业委员会候任主任委员等。毕业于中南大学湘雅医学院和新加坡国立大学,先后任哈佛大学Dana Farber癌症中心博士后及讲师,2011年以中山大学“百人计划”引进回国。长期从事乳腺肿瘤临床及科研工作,擅长乳腺良恶性疾病的鉴别诊断、乳腺癌的手术和综合治疗,尤其高难度保乳手术和疑难乳腺癌的个体化精准治疗。先后主持多项国家级重大项目包括国家自然科学基金重点项目和973课题,在SCI收录的期刊上发表论文超过80篇。率先开展液体活检和免疫联合治疗在乳腺癌中的应用,发起和制定中国首部年轻乳腺癌专家共识,2020年获人民日报社主办的“国之名医·优秀风范”荣誉称号。

Advances of liquid biopsy in precision treatment of breast cancer

ZHANG Yu()(), LIU Qiang()()

Department of Breast Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China

Received:2022-07-01 Revised:2022-07-20 Published:2022-08-30 Online:2022-09-19
Contact: LIU Qiang E-mail:zhangy583@mail2.sysu.edu.cn;victorlq@hotmail.com

摘要/Abstract

摘要：

在全球范围内,乳腺癌是女性最常见的恶性肿瘤。近年来,迅速扩大的基因组学知识体系不仅揭示了恶性肿瘤的复杂性,也使得恶性肿瘤的治疗范式从以肿瘤类型为导向逐渐转向以基因为导向,根据生物标志物分析为患者进行个体化治疗。目前大量研究已证实从患者获得肿瘤分子图谱优化了癌症个性化治疗方案的选择,以及对治疗反应、耐药及肿瘤复发的监测。而液体活检,通过对体液中肿瘤衍生材料所包含的基因组等数据进行分析,可以获得关于个体患者肿瘤特征的详细信息,为基于精准医学的治疗开辟新思路。在乳腺癌精准治疗中,液体活检可以预测生存预后、检测微小残留疾病（minimal residual disease,MRD）、监测治疗效果,在（新）辅助治疗及解救治疗中发挥作用。虽然液体活检在乳腺癌精准治疗方面的研究取得了令人瞩目的进展,但是仍存在一些问题,还需要更多的工作来进一步改进技术。本文将就近年来液体活检在乳腺癌精准治疗中的应用研究进展进行综述,并对未来的发展趋势予以展望。

关键词: 乳腺癌, 精准治疗, 液体活检, 循环肿瘤细胞, 循环肿瘤DNA

Abstract:

Breast cancer is the most common malignant tumor in women worldwide. Recently, the complexity of malignant tumors has been revealed following the rapid expansion of the knowledge system of genomics, and the treatment of tumors has shifted from tumor type-oriented therapy to gene-oriented therapy, which is based on biomarker analysis. Great efforts have proved that tumor molecular profiles from patients are capable to improve the selection of personalized treatment options, as well as monitoring of treatment response, drug resistance and tumor recurrence. Liquid biopsy, a method to analyze the genome and other data contained in tumor-derived materials in body fluids, can obtain detailed information about the characteristics of individual patient's tumors, providing new ideas for precision treatment. In the precise treatment of breast cancer, liquid biopsy can predict survival prognosis, detect minimal residual disease (MRD), monitor treatment efficacy, and play a role in (neo)adjuvant treatment and rescue treatment. Although the research of liquid biopsy in the precise treatment of breast cancer has made remarkable progress, there are still some problems, and more work is needed to further improve the technology. In this paper, we reviewed the research progress of liquid biopsy in the precision therapy of breast cancer in recent years, and the future trend of liquid biopsy is forecasted.

Key words: Breast cancer, Precision therapy, Liquid biopsy, Circulating tumor cell, ctDNA

中图分类号:

R737.9

张羽, 刘强. 液体活检在乳腺癌精准治疗中的应用进展及展望[J]. 中国癌症杂志, 2022, 32(8): 688-697.

ZHANG Yu, LIU Qiang. Advances of liquid biopsy in precision treatment of breast cancer[J]. China Oncology, 2022, 32(8): 688-697.

图/表 1

表1

乳腺癌患者液体活检分析的关键研究"

Study (year)	Inclusion criteria	Detection method	Findings
Studies on CTCs
Trapp E, et al^[54] (2019)	Lymph node positive and high risk lymph node negative breast cancer (n=1 087)	CellSearch System	The presence of CTCs 2 years after chemotherapy was associated with decreased OS (HR=3.91, 95% CI: 2.04-7.52, P<0.001) and DFS (HR=2.31, 95% CI: 1.50-3.55, P<0.001)
Sparano J, et al^[55] (2018)	Lymph node positive and high risk lymph node negative breast cancer (n=547)	CellSearch System	Positive CTC assay result was associated with a 13.1-fold higher risk of recurrence (HR=13.1, 95% CI: 4.7-36.3)
Janni W J, et al^[29](2016)	Nonmetastatic breast cancer (various subtypes) (n=3 173)	CellSearch System	The presence of CTCs at the time of primary diagnosis was an independent prognostic factor for DFS (HR=1.82, 95% CI: 1.47-2.26), DDFS (HR=1.89, 95% CI: 1.49-2.40), BCSS (HR=2.04, 95% CI: 1.52-2.75), and overall survival (HR=1.97, 95% CI: 1.51-2.59)
Bidard, et al^[41](2014)	Metastatic breast cancer (various subtypes) (n=1 944)	CellSearch System	CTC count improves the prognostication of metastatic breast cancer when added to full clinicopathological predictive models (PFS LR=38.4, 95% CI: 21.9-60.3, P<0.000 1; OS LR=64.9, 95% CI: 41.3-93.4, P<0.000 1)
Studies on ctDNA
Kim M H, et al^[33](2022)	Stage Ⅱ-Ⅲ TNBC (n=465)	Low-pass whole genome sequencing (LP-WGS)	The baseline ctDNA CNA burden on LP-WGS before neoadjuvant chemotherapy robustly predicts recurrence risk in stage Ⅱ-Ⅲ TNBC patients. The ctDNAⅠ-score showed prognostic value independently from pCR status, suggesting ctDNAⅠ-score can serve as a useful clinical determinant for escalating or de-escalating (neo)adjuvant strategy in TNBC patients
Zhou Q, et al^[59](2022)	Early breast cancer who underwent NAC (various subtypes) (n=187)	Targeted NGS of 93 frequently mutated genes in breast cancer	ctDNA detection at metastasis was significantly associated with higher RCB (OR=0.062, 95% CI: 0.01-0.48, P=0.007 7). Of the 31 patients with detectable ctDNA at metastasis, 30 patients (96.8%) were non-responders (RCB Ⅱ, n=8; RCB Ⅲ, n=22) and only one patient responded to the treatment (RCBⅠ)
Shaw J, et al^[58](2022)	Primary breast cancer underwent surgery and adjuvant therapy (various subtypes) (n=188)	mPCR-NGS	Patients with a positive ctDNA test had poorer RFS (HR=47.5, 95% CI: 18.5-161.4, P<0.001) from surgery; OS was also significantly reduced for patients who were ctDNA positive (HR=84.15, 95% CI: 16.43-1 538.00, P <0.001)
Magbanua M J M, et al ^[35] (2021)	High-risk early breast cancer (various subtypes) (n=84)	Ultra-deep sequencing	Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence (non-pCR OR=4.33, P=0.012), while clearance was associated with improved survival even in patients who did not achieve pCR
Li S, et al^[32](2020)	Early breast cancer who underwent NAC (various subtypes) (n=52)	NGS of 1 021 cancer- related genes	ctDNA tracking during NAC outperformed imaging in predicting the overall response to NAC; Positive baseline ctDNA was significantly associated with worse DFS (P=0.011) and OS (P=0.004) in patients with early breast cancer, especially in estrogen receptor-negative patients
Garcia-Murillas I, et al^[56] (2019)	Early-stage breast cancer (various subtypes) (n=101)	dPCR	Detection of ctDNA during follow-up was associated with a high risk of future relapse of early-stage breast cancer (HR=25.2, 95% CI: 6.7-95.6, P<0.001)
Allouchery V, et al^[66] (2018)	Early breast cancer patients who completed at least 2 years of AI adjuvant treatment and experienced a documented relapse after the end of their treatment (various subtypes) (n=42)	ddPCR	No circulating ESR1 mutation was detectable at the end of AI adjuvant therapy. At first relapse, 5.3% of the patients (2 of 38) had a detectable circulating ESR1 mutation. At time of progression on first-line metastatic treatment, 33% of the patients (7 of 21) under AI had a detectable circulating ESR1 mutation compared with none of the patients under chemotherapy (0 of 10)
Stover D G, et al^[43] (2018)	Metastatic TNBC (n=164)	Low-coverage genome-wide sequencing	Evaluation of cfDNA tumor fraction was feasible for nearly all patients, and tumor fraction≥10% was associated with significantly worse survival (HR=2.14, 95% CI: 1.4 to 3.8, P<0.001)
Dawson S J, et al^[64] (2013)	Metastatic breast cancer who were receiving systemic therapy (various subtypes) (n=30)	ddPCR, tagged-amplicon deep sequencing, ADVIA Centaur immunoassay, CellSearch	ctDNA was successfully detected in 29 of the 30 women studied (97%); CA15-3 and CTCs were detected in 21 of 27 (78%) and 26 of 30 women (87%), respectively. ctDNA levels showed a greater correlation with changes in tumor burden than did CA15-3 or CTCs. ctDNA provided the earliest measure of treatment response in 10 of 19 women (53%), with an average lead time of 5 months before imaging

表1

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液体活检在乳腺癌精准治疗中的应用进展及展望

Advances of liquid biopsy in precision treatment of breast cancer

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