Cell-free DNA as a molecular tool for monitoring disease progression and response to therapy in breast cancer patients

Liang, Diana H.; Ensor, Joe; Liu, Zhe Bin; Patel, Asmita; Patel, Tejal; Chang, Jenny C.; Rodriguez, Angel Augusto

doi:10.1007/s10549-015-3635-5

Cited by 54 publications

(49 citation statements)

References 35 publications

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“…Our findings build upon a single case report utilizing the same ctDNA assay of an EGFR T790M mutation detected at progression when repeat tissue biopsy was insufficient for NGS but responded to the third generation TKI osimertinib [52]. Another case series using the same ctDNA assay reported high response rates to targeted therapy of ERBB2 (HER2) amplifications in metastatic breast cancer patients [53]. Taken together, these findings suggest that plasma-based NGS of ctDNA is a reliable and accurate surrogate for tissue NGS not only for determining the presence of tumor-derived mutations, but also for predicting response to therapy.…”

Section: Discussionsupporting

confidence: 60%

Biopsy-free circulating tumor DNA assay identifies actionable mutations in lung cancer

et al. 2016

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IntroductionThe potential of oncogene-driven targeted therapy is perhaps most fully realized in non-small cell lung cancer (NSCLC), given the number of genomic targets and approved matched therapies. However, invasive tissue biopsy at the time of each disease progression may not be possible and is associated with high morbidity and cost. Use of newly available “liquid biopsies” can circumvent these issues.Results83% of subjects had at least one genomic alteration identified in plasma. Most commonly mutated genes were TP53, KRAS and EGFR. Subjects with no detectable ctDNA were more likely to have small volume disease, lepidic growth pattern, mucinous tumors or isolated leptomeningeal disease.MethodsSubjects were individuals with NSCLC undergoing analysis of cell-free circulating tumor DNA using a validated, commercially-available next-generation sequencing assay at a single institution. Demographic, clinicopathologic information and results from tissue and plasma-based genomic testing were reviewed for each subject.ConclusionsThis is the first clinic-based series of NSCLC patients assessing outcomes of targeted therapies using a commercially available ctDNA assay. Over 80% of patients had detectable ctDNA, concordance between paired tissue and blood for truncal oncogenic drivers was high and patients with biomarkers identified in plasma had PFS in the expected range. These data suggest that biopsy-free ctDNA analysis is a viable first choice when the diagnostic tissue biopsy is insufficient for genotyping or at the time of progression when a repeated invasive tissue biopsy is not possible/preferred.

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Section: Discussionsupporting

confidence: 60%

Biopsy-free circulating tumor DNA assay identifies actionable mutations in lung cancer

et al. 2016

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“…Another study reported sensitivity of 49.9% and a specificity of 99.8% for patients with advanced or metastatic solid tumors when examining 50 hotspot genes across tissue and ctDNA platforms (34). In breast cancer, high concordance between tissue and ctDNA for PIK3CA mutations and ERBB2 amplifications has been reported, but poor agreement for TP53 mutations and EGFR amplifications (35). Our study indicates the need for more comprehensive analysis of tissue and ctDNA NGS concordance beyond single genes and hotspot regions to determine utility and potential clinical applications of ctDNA biopsies.…”

Section: Discussionmentioning

confidence: 99%

Concordance of Genomic Alterations by Next-Generation Sequencing in Tumor Tissue versus Circulating Tumor DNA in Breast Cancer

Chae

Davis

Jain

et al. 2017

Molecular Cancer Therapeutics

119

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While identifying genomic alterations in tumor tissue is the current gold-standard technique for molecular profiling, circulating tumor DNA (ctDNA) represents a noninvasive method of assessing genomic alterations using peripheral blood. The concordance of genomic alterations between two commercially available ctDNA and tissue biopsies was compared in 45 patients with breast cancer using paired next-generation sequencing tissue and ctDNA biopsies. Across all genes, concordance between the two platforms was 91.0% to 94.2%. When only considering genomic alterations in either assay (e.g., excluding wild type/wild type genes), concordance was 10.8% to 15.1% with full plus partial concordance of 13.8% to 19.3%. Concordant mutations were associated with significantly higher variant allele frequency. Over half of mutations detected in either technique were not detected using the other biopsy technique. Including variants of unknown significance, the average number of alterations per patient was significantly higher for tissue (4.56) compared with ctDNA (2.16). When eliminating alterations not detectable in the ctDNA assay, mean number of alterations for tissue and ctDNA was similar (2.67 for tissue, 2.16 for ctDNA). Across five representative genes (TP53, PIK3CA, ERBB2, BRCA1, and BRCA2), sensitivity and specificity were 35.7% and 95.0%, respectively. Concordance when genomic alterations was detected in either tissue or ctDNA was low with each technique detecting a significant amount of nonoverlapping mutations. Potential explanations for the lack of concordance include tumor heterogeneity, different sequencing techniques, spatial and temporal factors, and potential germline DNA contamination. The study indicates that both tissue and blood-based NGS may be necessary to describe the complex biology of breast cancer.

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“…In order to observe more accurate concordance rates, the comparison of tissue and plasma results should include samples temporally concurrent and pre-treatment so that ctDNA is not suppressed to undetectable levels, and only the genetic footprint in common between the two tests can be compared. Several publications meet these study design criteria (two pan-cancer, one each in NSCLC, breast, colorectal, anaplastic thyroid and pancreatic cancer) and all show high diagnostic concordance for concurrent samples (99%, 86%, 100%, 100%, 100%, 72% and 98%, respectively) (17,27,29,31–34). Reasons that results might be positive in tissue but not in ctDNA include the following: suppression of ctDNA shedding by treatment; and the fact that not all tumors shed DNA into the bloodstream even pre-treatment or at progression.…”

Section: Discussionmentioning

confidence: 99%

Utility of Genomic Assessment of Blood-Derived Circulating Tumor DNA (ctDNA) in Patients with Advanced Lung Adenocarcinoma

Schwaederlé¹,

Patel²,

Husain³

et al. 2017

Clinical Cancer Research

135

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Background Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with non-small cell lung adenocarcinoma (NSCLC) were ascertained and correlated with clinical characteristics and therapeutic outcomes. Methods and Findings Comprehensive plasma ctDNA testing was performed in 88 consecutive patients; 34 also had tissue next generation sequencing; 29, other forms of genotyping; and 25 (28.4%) had no tissue molecular tests because of inadequate tissue or biopsy contraindications. Seventy-two patients (82%) had ≥ 1 ctDNA alteration(s); amongst these, 75% carried alteration(s) potentially actionable by FDA-approved (61.1%) or experimental drug(s) in clinical trials (additional 13.9%). The most frequent alterations were in TP53 (44.3% of patients), EGFR (27.3%), MET (14.8%), KRAS (13.6%), and ALK (6.8%) genes. The concordance rate for EGFR alterations was 80.8% (100% versus 61.5% (≤ 1 versus > 1 month between tests; P = 0.04)) for patients with any detectable ctDNA alterations. Twenty-five patients (28.4%) received therapy matching ≥ 1 ctDNA alteration(s); 72.3% (N=16/22) of the evaluable matched patients achieved stable disease ≥ 6 months (SD) or partial response (PR). Five patients with ctDNA-detected EGFR T790M were subsequently treated with a third generation EGFR inhibitor; all five achieved SD ≥ 6 months/PR. Patients with ≥ 1 alteration with ≥ 5% variant allele fraction (versus < 5%) had a significantly shorter median survival (P = 0.012). Conclusions ctDNA analysis detected alterations in the majority of patients, with potentially targetable aberrations found at expected frequencies. Therapy matched to ctDNA alterations demonstrated appreciable therapeutic efficacy, suggesting clinical utility that warrants future prospective studies.

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Cell-free DNA as a molecular tool for monitoring disease progression and response to therapy in breast cancer patients

Cited by 54 publications

References 35 publications

Biopsy-free circulating tumor DNA assay identifies actionable mutations in lung cancer

Biopsy-free circulating tumor DNA assay identifies actionable mutations in lung cancer

Concordance of Genomic Alterations by Next-Generation Sequencing in Tumor Tissue versus Circulating Tumor DNA in Breast Cancer

Utility of Genomic Assessment of Blood-Derived Circulating Tumor DNA (ctDNA) in Patients with Advanced Lung Adenocarcinoma

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