Advances of liquid biopsy in precision treatment of breast cancer

doi:10.19401/j.cnki.1007-3639.2022.08.003

Abstract

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

CLC Number:

R737.9

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

Figures/Tables 1

Tab. 1

Key studies of liquid biopsy analyses in patients with breast cancer"

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

Tab. 1

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