Concordance of Genomic Variants in Matched Primary Breast Cancer, Metastatic Tumor, and Circulating Tumor DNA: The MIRROR Study

Abstract

PURPOSE Genetic heterogeneity between primary tumors and their metastatic lesions has been documented in several breast cancer studies. However, the selection of therapy for patients with metastatic breast cancer and the search for biomarkers for targeted therapy are often based on findings from the primary tumor, mainly because of the difficulty of distant metastasis core biopsies. New methods for monitoring genomic changes in metastatic breast cancer are needed (ie, circulating tumor DNA [ctDNA] genomic analysis). The objectives of this study were to assess the concordance of genomic variants between primary and metastatic tumor tissues and the sensitivity of plasma ctDNA analysis to identify variants detected in tumor biopsies. PATIENTS AND METHODS Next-generation sequencing technology was used to assess the genomic mutation profile of a panel of 54 cancer genes in matched samples of primary tumor, metastatic tumor, and plasma from 40 patients with metastatic breast cancer. RESULTS Using Ion Torrent technology (ThermoFisher Scientific, Waltham, MA), we identified 110 variants that were common to the primary and metastatic tumors. ctDNA analysis had a sensitivity of 0.972 in detecting variants present in both primary and metastatic tissues. In addition, we identified 13 variants in metastatic tissue and ctDNA not present in primary tumor. CONCLUSION We identified genomic variants present in metastatic biopsies and plasma ctDNA that were not present in the primary tumor. Deep sequencing of plasma ctDNA detected most DNA variants previously identified in matched primary and metastatic tissues. ctDNA might aid in therapy selection and in the search for biomarkers for drug development in metastatic breast cancer.

Dynamics of genomic and immune responses during primary immunotherapy resistance in mismatch repair–deficient tumors

“…S10). Further, consistent with the notion of ctDNA providing a global view representing genomic changes from diverse metastatic sites (Moreno et al 2019), ctDNA also captured variants that were not detected in the tumor (58.6% of ctDNA variants were unique to ctDNA; n = 521). Third, the tumor transcriptome data generally supported reduced post-treatment JAK1 signaling, with the notable exception of STAT1 expression, which increased post-treatment (Fig.…”

Immunotherapy in Breast Cancer and the Potential Role of Liquid Biopsy

“…The primary goal of deep sequencing is to detect rare mutated DNA copies shed by tumors (ctDNA) and differentiate them from wildtype copies that are simultaneously released from normal hematopoietic cells undergoing apoptosis. Comparative sequencing studies have shown that specific mutations in ctDNA vs. matched primary tumor tissue are generally concordant (43,44), however, temporal spacing (e.g., timing of sample collection) and tumor heterogeneity could also lead to discrepancies (45). Overall, these data suggest that ctDNA can complement tissue sequencing to find actionable biomarkers.…”

“…Comparative sequencing studies have shown that specific mutations in ctDNA vs . matched primary tumor tissue are generally concordant ( 43 , 44 ), however, temporal spacing (e.g., timing of sample collection) and tumor heterogeneity could also lead to discrepancies ( 45 ). Overall, these data suggest that ctDNA can complement tissue sequencing to find actionable biomarkers.…”

Circulating Tumor DNA-Based Genomic Profiling Assays in Adult Solid Tumors for Precision Oncology: Recent Advancements and Future Challenges

“…In cases where biopsy samples are difficult to retrieve and the quality and quantity of tissue specimens are insufficient for tissue-based CGP, liquid biopsy should be considered the assay of choice. Furthermore, if patients present with multiple lesions or metastases, liquid biopsy should be preferred due to its ability to detect intertumoral heterogeneity, which could be missed by a single tissue testing [145][146][147]. The detection of spatial tumor heterogeneity was highlighted in a study that sequenced paired primary tumor, metastatic tissue, and plasma cfDNA of breast cancer patients [146].…”

“…Furthermore, if patients present with multiple lesions or metastases, liquid biopsy should be preferred due to its ability to detect intertumoral heterogeneity, which could be missed by a single tissue testing [145][146][147]. The detection of spatial tumor heterogeneity was highlighted in a study that sequenced paired primary tumor, metastatic tissue, and plasma cfDNA of breast cancer patients [146]. Plasma cfDNA detected up to 97% of alterations from primary and metastatic tissues, and 13 of the variants in metastatic tumors were exclusively detected from ctDNA, and not in the corresponding primary tumors [146].…”