Dynamic analysis of circulating tumor DNA to predict the prognosis and monitor the treatment response of patients with metastatic triple-negative breast cancer: A prospective study
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eLife assessment
This prospective study advances our understanding of the predictive role of circulating tumor DNA (ctDNA) in the prognosis and of patients with mTNBC as well as other cancers. The evidence supporting the conclusions is convincing with rigorous analysis of the association between ctDNA (ctDNA-positive or not) with the progression-free survival (PFS) of patients. However, there are a few areas in which the article may be improved through further analysis of the clinical outcome and elaboration of the prospective study (i.e., the inclusion and exclusion criteria of the patients). The work will be of broad interest to clinicians, medical researchers and scientists working in cancers.
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Abstract
Limited data are available on applying circulating tumor DNA (ctDNA) in metastatic triple-negative breast cancer (mTNBC) patients. Here, we investigated the value of ctDNA for predicting the prognosis and monitoring the treatment response in mTNBC patients.
Methods:
We prospectively enrolled 70 Chinese patients with mTNBC who had progressed after ≤2 lines of chemotherapy and collected blood samples to extract ctDNA for 457-gene targeted panel sequencing.
Results:
Patients with ctDNA+, defined by 12 prognosis-relevant mutated genes, had a shorter progression-free survival (PFS) than ctDNA− patients (5.16 months vs . 9.05 months, p=0.001), and ctDNA+ was independently associated with a shorter PFS (HR, 95% CI: 2.67, 1.2–5.96; p=0.016) by multivariable analyses. Patients with a higher mutant-allele tumor heterogeneity (MATH) score (≥6.316) or a higher ctDNA fraction (ctDNA%≥0.05) had a significantly shorter PFS than patients with a lower MATH score (5.67 months vs .11.27 months, p=0.007) and patients with a lower ctDNA% (5.45 months vs . 12.17 months, p<0.001), respectively. Positive correlations with treatment response were observed for MATH score ( R =0.24, p=0.014) and ctDNA% ( R =0.3, p=0.002), but not the CEA, CA125, or CA153. Moreover, patients who remained ctDNA+ during dynamic monitoring tended to have a shorter PFS than those who did not (3.90 months vs . 6.10 months, p=0.135).
Conclusions:
ctDNA profiling provides insight into the mutational landscape of mTNBC and may reliably predict the prognosis and treatment response of mTNBC patients.
Funding:
This work was supported by the National Natural Science Foundation of China (Grant No. 81902713), Natural Science Foundation of Shandong Province (Grant No. ZR2019LZL018), Breast Disease Research Fund of Shandong Provincial Medical Association (Grant No. YXH2020ZX066), the Start-up Fund of Shandong Cancer Hospital (Grant No. 2020-PYB10), Beijing Science and Technology Innovation Fund (Grant No. KC2021-ZZ-0010-1).
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eLife assessment
This prospective study advances our understanding of the predictive role of circulating tumor DNA (ctDNA) in the prognosis and of patients with mTNBC as well as other cancers. The evidence supporting the conclusions is convincing with rigorous analysis of the association between ctDNA (ctDNA-positive or not) with the progression-free survival (PFS) of patients. However, there are a few areas in which the article may be improved through further analysis of the clinical outcome and elaboration of the prospective study (i.e., the inclusion and exclusion criteria of the patients). The work will be of broad interest to clinicians, medical researchers and scientists working in cancers.
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Reviewer #1 (Public Review):
In this study, Chi et al. present a study on ctDNA profiling to predict the prognosis and treatment response of mTNBC patients. The authors report that ctDNA+ status and baseline ctDNA-related markers (MATH score and ctDNA%) are associated with the survival and treatment response. The data are well presented. However, some questions related to the association between ctDNA and clinical outcomes, and a lack of an external cohort to validate the predictive value of ctDNA need to be addressed. The Methods section also needs to be detailed.
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Reviewer #2 (Public Review):
The manuscript by Chi, et al., mainly investigated the mutational characteristics of ctDNA, ctDNA-related markers in metastasis triple-negative breast cancer (mTNBC). They evaluated the translational value of ctDNA in predicting the prognosis and monitoring the treatment response of patients with mTNBC. Overall, this study is interesting and decent with great clinical significance.
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Reviewer #3 (Public Review):
The manuscript by Chi et al investigated the value of ctDNA for predicting the prognosis and monitoring the treatment response in mTNBC patients. They found that patients with ctDNA+, had a shorter progression-free survival (PFS) than ctDNA− patients (5.16 months vs. 9.05 months, P = 0.001) and ctDNA+ was independently associated with a shorter PFS (HR, 95%CI: 2.67, 1.2-5.96; P = 0.016) by multivariable analyses. This study provides novel insight into the mutational landscape of mTNBC and may reliably predict the prognosis and treatment response of mTNBC patients. Overall, this study is interesting and important.
Strengths
This study is well designed and novel.Weaknesses
This is a single-center study. Future studies may further validate the findings in other centers. -
