High mutation burden of circulating cell‐free DNA in early‐stage breast cancer patients is associated with a poor relapse‐free survival

Abstract

Background High tumor mutation burden is shown to be associated with a poor clinical outcome. As the tumor‐derived fraction of circulating cell‐free DNA (cfDNA) is shown to reflect the genetic spectrum of the tumor, we examined whether the mutation burden of cfDNA could be used to predict the clinical outcomes of early‐stage breast cancer (BC) patients. Methods We selected a set of 79 Finnish early‐stage BC cases with a good prognosis based on traditional prognostic parameters but some of which still developed relapsed disease during follow‐up. cfDNA was isolated from the serum collected at the time of diagnosis, sequenced, and compared to matched primary tumors, clinical parameters, and survival data. Results High cfDNA mutation burden was associated with the poor relapse‐free survival (RFS) ( P = .016, HR = 2.23, 95% Cl 1.16‐4.27) when patients were divided into high and low mutation burden according to the median number of somatic variants. A high discordance was observed between the matched tumor and cfDNA samples, thus highlighting the challenges related to the liquid biopsy of early‐stage cancer cases. Despite the low number of detected tumor‐specific variants, the presence of tumor‐specific somatic variants in the cfDNA was associated with the poor RFS ( P = .009, HR = 2.31, 95% Cl 1.23‐4.31). Conclusions Our results confirm previously observed challenges about the accuracy of liquid biopsy‐based genotyping of early‐stage cancers and support the parallel sequencing of tumor and cfDNA while also demonstrating how the presence of tumor‐specific somatic variants and the high mutation burden in the cfDNA are both associated with the poor RFS, thus indicating the prognostic potential of liquid biopsy in the context of early‐stage cancers.

Clinical utility of liquid biopsy in breast cancer: A systematic review

“…However, ROC curve analysis indicated that the afore mentioned tumor-specific variants do not support prognostic ability for RFS (AUC 0.521, p = 0.748). 85 In another primary study, it was shown that the total number of somatic mutations and the mean frequency of allelic variants in ctDNA were significantly higher in patients with disease progression compared to patients with stable disease. 26 In another, it was verified that DFS was significantly worse in ctDNA positive patients (VAF > 0.1%) than in those with negative ctDNA (p < 0.001).…”

Liquid biopsy as an option for predictive testing and prognosis in patients with lung cancer

“…Despite the scattered results of cfDNA TMB, it may still be clinically useful since TMB has shown promising results for predicting response and prognosis of lung cancer patients treated with immunotherapy (Gandara et al 2018 ; Khagi et al 2017 ). Regarding other cancer types, one study on breast cancer patients treated with surgery and radiotherapy has shown an association between the number of cfDNA variants and relapse-free survival (Kujala et al 2020 ). Jaiswal et al ( 2014 ) found that the presence of a somatic mutation in peripheral blood cells was associated with an increase in all-cause mortality.…”

Liquid Biopsy as an Option for Predictive Testing and Prognosis in Patients with Lung Cancer

“…Despite the scattered results of cfDNA TMB, it may still be clinically useful since TMB has shown promising results for predicting response and prognosis of lung cancer patients treated with immunotherapy (Gandara et al 2018;Khagi et al 2017). Regarding other cancer types, one study on breast cancer patients treated with surgery and radiotherapy has shown an association between the number of cfDNA variants and relapse-free survival (Kujala et al 2020). Jaiswal et al (2014) found that the presence of a somatic mutation in peripheral blood cells was associated with an increase in all-cause mortality.…”