Subtyping of metastatic breast cancer based on plasma circulating tumor DNA alterations: An observational, multicentre platform study

Zhe-Yu Hu, Yu Tang, Liping Liu, Ning Xie, Can Tian, Binliang Liu, Lixin Zou, Wei Zhou, Yikai Wang, Xuefeng Xia, Quchang Ouyang, Zhe-Yu Hu, Yu Tang, Liping Liu, Ning Xie, Can Tian, Binliang Liu, Lixin Zou, Wei Zhou, Yikai Wang, Xuefeng Xia, Quchang Ouyang

Abstract

Background: After multiple lines of therapies, no guideline or consensus is currently available for the treatment of patients with metastatic breast cancer. This study aims to evaluate the efficacy of a novel re-subtyping and treatment strategy based on ctDNA alterations.

Methods: This observational, multicentre study recruited 223 patients with metastatic breast cancer intending to receive late-line therapy from Dec 1, 2016, to June 31, 2019. This study took place in Hunan Cancer Hospital, the Forth Hospital of Changsha and Zhuzhou Central Hospital in China. ctDNA alterations were assessed by next-generation sequencing (NGS). Patients with druggable ctDNA alterations were treated with corresponding targeted drugs which are clinically available. Other patients received physician-chosen treatment. This study was registered with ClinicalTrials.gov, NCT05079074.

Findings: The progression-free survival (hazard ratio: 0.45, 95% Confidence Interval (CI): 0.33-0.62, P < 0.0001) and disease control rate (89.4% vs. 65.9%, P < 0.0001) were significantly improved in patients who received druggable ctDNA alteration-guided therapy compared with those of patients who received physician-chosen treatment. ctDNA alterations with top rank and high clustering scores were classified into four subtypes based on their functions as follows: 1) extracellular function (ECF), 2) cell proliferation (CP), 3) nuclear function (NF), and 4) cascade signaling pathway (CSP). A significant benefit from ctDNA alteration-guided treatment was observed in patients with NF and CSP ctDNA alterations, with hazard ratios of 0.39 (95% CI: 0.24-0.65, P = 0.0003) and 0.14 (95% CI: 0.04-0.46, P < 0.0001), respectively.

Interpretation: After multiline traditional pathological HR/HER2 subtype-guided therapies, ctDNA testing could identify druggable ctDNA alterations to guide late-line therapy for patients with metastatic breast cancer.

Funding: This work was supported by Key Grants of Research and Development in Hunan Province (2018SK2124, 2018SK2120), Natural Science Foundation of Hunan (2019JJ50360), Hunan Provincial Health Commission Project (B2019085, B2019089 and C2019070), and Changsha Science and Technology Project (kq2004125 and kq2004137).

Keywords: Disease control rate (DCR); Druggable circulating tumor DNA alterations; Genetic alterations of functional pathways; Late-line therapy; Progression-free survival (PFS).

Conflict of interest statement

The authors declare that they have no conflicts of interest.

© 2022 The Authors.

Figures

Figure 1
Figure 1
Kaplan–Meier plot of progression-free survival. Dashes represent censored patients. HR=hazard ratio. Univariate Cox regression analysis was performed to calculate the hazard ratio (HR) with 95% confidence interval (CI) of progression in the ctDNA-guided LLT group versus the traditional group.
Figure 2
Figure 2
Kaplan–Meier plot of progression-free survival. Dashes represent censored patients. HR=hazard ratio. Univariate Cox regression analysis was performed to calculate the hazard ratio (HR) with 95% confidence interval (CI) of progression in the ctDNA-guided LLT group versus the group of the 58 patients with ctDNA alterations but for whom no drugs were available.
Figure 3
Figure 3
ctDNA alterations. A. Heatmaps of baseline ctDNA alteration profiles and the corresponding treatment strategies for patients with B. Circle plot of 442 ctDNA alterations among 420 samples from 223 patients. Genes were clustered by the ‘complete’ method of the hclust function in R. The colors indicate the cutree score, ranging from 1 (blue) to 60 (red). Nearly three-fourths of all ctDNA alterations had a low score (blue, left and bottom regions of the circle).
Figure 3
Figure 3
ctDNA alterations. A. Heatmaps of baseline ctDNA alteration profiles and the corresponding treatment strategies for patients with B. Circle plot of 442 ctDNA alterations among 420 samples from 223 patients. Genes were clustered by the ‘complete’ method of the hclust function in R. The colors indicate the cutree score, ranging from 1 (blue) to 60 (red). Nearly three-fourths of all ctDNA alterations had a low score (blue, left and bottom regions of the circle).
Figure 4
Figure 4
Subgroup analyses of hazard ratios for progression-free survival by ctDNA-based subtype.

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