Circulating Tumor DNA Profiling From Breast Cancer Screening Through to Metastatic Disease

Abstract

PURPOSE We investigated the utility of the Oncomine Breast cfDNA Assay for detecting circulating tumor DNA (ctDNA) in women from a breast screening population, including healthy women with no abnormality detected by mammogram, and women on follow-up through to advanced breast cancer. MATERIALS AND METHODS Blood samples were taken from 373 women (127 healthy controls recruited through breast screening, 28 ductal carcinoma in situ, 60 primary breast cancers, 47 primary breast cancer on follow-up, and 111 metastatic breast cancers [MBC]) to recover plasma and germline DNA for analysis with the Oncomine Breast cfDNA Assay on the Ion S5 platform. RESULTS One hundred sixteen of 373 plasma samples had one or more somatic variants detected across eight of the 10 genes and were called ctDNA-positive; MBC had the highest proportion of ctDNA-positive samples (61; 55%) and healthy controls the lowest (20; 15.7%). ESR1, TP53, and PIK3CA mutations account for 93% of all variants detected and predict poor overall survival in MBC (hazard ratio = 3.461; 95% CI, 1.866 to 6.42; P = .001). Patients with MBC had higher plasma cell-free DNA levels, higher variant allele frequencies, and more polyclonal variants, notably in ESR1 than in all other groups. Only 15 individuals had evidence of potential clonal hematopoiesis of indeterminate potential mutations. CONCLUSION We were able detect ctDNA across the breast cancer spectrum, notably in MBC where variants in ESR1, TP53, and PIK3CA predicted poor overall survival. The assay could be used to monitor emergence of resistance mutations such as in ESR1 that herald resistance to aromatase inhibitors to tailor adjuvant therapies. However, we suggest caution is needed when interpreting results from a single plasma sample as variants were also detected in a small proportion of HCs.

The biomarkers related to immune infiltration to predict distant metastasis in breast cancer patients

“…Nowadays multiple biomarkers, such as circulating miRNA (Baldasici et al, 2022), circulating tumor DNA (Page et al, 2021) and circulating tumor cell (Ring et al, 2022), can be used to detect metastasis of BC. What's more, several serum biomarkers related to metastasis, including soluble POSTN (Jia et al, 2022), PTHrP (Washam et al, 2013), S100P (Peng et al, 2016), have been found.…”

The biomarkers related to immune infiltration to predict distant metastasis in patients with breast cancer

“…Nowadays multiple biomarkers, such as circulating miRNA 30 , circulating tumor DNA 31 and circulating tumor cell 32 , can be used to detect metastasis of breast cancer. What's more, several serum biomarkers related to metastasis,including soluble POSTN 33 , PTHrP 34 , S100P 35 ,have been found.…”

The Clinical Utility of Droplet Digital PCR for Profiling Circulating Tumor DNA in Breast Cancer Patients

“…In serial monitoring of variants detected, changes in the allele frequency of PIK3CA and TP53 mutations were reflective of response to chemotherapy [ 54 ]. In a report with 373 women including healthy controls (N = 127), ductal carcinoma in situ (N = 28), primary breast cancers (N = 60), primary breast cancer on follow-up (N = 47), and metastatic breast cancers (N = 111) using the Oncomine Breast Cancer cfDNA assay, ESR1 , TP53 , and PIK3CA mutations accounted for 93% of all variants detected and predicted poor overall survival (OS) in mBCa [ 55 ].…”