Longitudinal Shifts of Solid Tumor and Liquid Biopsy Sequencing Concordance in Metastatic Breast Cancer

Abstract

PURPOSE Tissue-based next-generation sequencing (NGS) in metastatic breast cancer (mBC) is limited by the inability to noninvasively track tumor evolution. Cell-free DNA (cfDNA) NGS has made sequential testing feasible; however, the relationship between cfDNA and tissue-based testing in mBC is not well understood. Here, we evaluate concordance between tissue and cfDNA NGS relative to cfDNA sampling frequency in a large, clinically annotated mBC data set. METHODS Tempus LENS was used to analyze deidentified records of mBC cases with Tempus xT (tissue) and xF (cfDNA) sequencing results. Then, various metrics of concordance were assessed within overlapping probe regions of the tissue and cfDNA assays (104 genes), focusing on pathogenic variants. Variant allele frequencies of discordant and concordant pathogenic variants were also compared. Analyses were stratified by mBC subtype and time between tests. RESULTS Records from 300 paired tissue and liquid biopsies were analyzed. Median time between tissue and blood collection was 78.5 days (standard deviation = 642.99). The median number of pathogenic variants/patient was one for cfDNA and two for tissue. Across the cohort, 77.8% of pathogenic tissue variants were found in cfDNA and 75.7% of pathogenic cfDNA variants were found in tissue when tests were ≤ 7 days apart, which decreased to 50.3% and 51.8%, respectively, for > 365 days. Furthermore, the median patient-level variant concordance was 67% when tests were ≤7 days apart and 30%-37% when > 30 days. The median variant allele frequencies of discordant variants were generally lower than those of concordant variants within the same time frame. CONCLUSION We observed high concordances between tissue and cfDNA results that generally decreased with longer durations between tests. Thus, cfDNA NGS reliably measures tissue genomics and is likely beneficial for longitudinal monitoring of molecular changes in mBC.

Circulating tumour DNA testing in metastatic breast cancer: Integration with tissue testing

“…They observed that 77.8% of pathogenic tissue variants were detected in cfDNA, and similarly, 75.7% of pathogenic cfDNA variants were identified in tissue when the tests were conducted within a 7‐day interval. However, these percentages decreased to 50.3% and 51.8%, respectively, when the time gap between tests exceeded 365 days 85 . These findings underscore the potential of ctDNA as a non‐invasive alternative approach, particularly in situations where tissue availability is limited.…”

“…However, these percentages decreased to 50.3% and 51.8%, respectively, when the time gap between tests exceeded 365 days. 85 These findings underscore the potential of ctDNA as a non-invasive alternative approach, particularly in situations where tissue availability is limited. Moreover, the study highlights the importance of considering the time interval between tests, as the decrease in concordance over time points out the necessity of timely samplings.…”

“…11,84 A study by Liu et al analysed 300 MBCpaired tissues and liquid biopsies from MBC patients using NGS and found significant concordance between tissue and cfDNA. 85 They observed that 77.8% of pathogenic tissue variants were detected in cfDNA, and similarly, 75.7% of pathogenic cfDNA variants were identified in tissue when the tests were conducted within a 7-day interval. However, these percentages decreased to 50.3% and 51.8%, respectively, when the time gap between tests exceeded 365 days.…”

“…In such cases, repeat blood sampling over time for ctDNA testing can facilitate longitudinal monitoring of molecular changes in MBC 11,84 . A study by Liu et al analysed 300 MBC‐paired tissues and liquid biopsies from MBC patients using NGS and found significant concordance between tissue and cfDNA 85 . They observed that 77.8% of pathogenic tissue variants were detected in cfDNA, and similarly, 75.7% of pathogenic cfDNA variants were identified in tissue when the tests were conducted within a 7‐day interval.…”

Recent Advances in Blood-Based Liquid Biopsy Approaches in Prostate Cancer

“…17 The reasons for the observed high, but imperfect concordance, also seen in other cancer types, can be varied. They likely include time between the tissue and liquid biopsies (reflecting tumor evolution, especially in late, heavily treated disease 12,25,73 ), intrapatient heterogeneity more likely to be fully captured in ctDNA than in tissue, 14,25 and a deeper analysis of the specific region of the lesion biopsied in tissue because of higher tumor fraction versus broader, lower tumor fraction analysis in ctDNA.…”