Clinical Evidence of Circulating Tumor DNA Application in Aggressive Breast Cancer
Abstract
:1. Introduction
2. General Overview of Cell-Free DNA
3. The Importance of Testing for Circulating Tumor DNA
4. Analytical and Clinical Validity of Cfdna
5. Gene Analysis
5.1. BRCA1/2 Genes
5.2. ESR1 Gene
5.3. PIK3CA Gene
5.4. TP53 Gene
5.5. ERBB2 Gene
6. Conclusions
7. Perspectives
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene | Patient Cohort | Molecule Testing Technique | Main Findings | Clinical Significance | References |
---|---|---|---|---|---|
ESR1 | 541 postmenopausal women with a diagnosis of MBC. | Analyzed ESR1 mutations (Y537S and D538G) on cell-free DNA (cfDNA) using droplet digital polymerase chain reaction (ddPCR). | D538G (21.1%) Y537S (13.3%) 30 had both mutations. | These mutations were associated with shorter overall survival: - wild-type, 32.1 months - D538G, 25.99 months - Y537S, 19.98 months - Both mutations, 15.15 months. | [72] |
86 estrogen receptor-positive BC patients.185 plasma samples (151 plasma samples from 69 MBC patients, and 34 plasma samples from 17 primary BC (PBC) patients). | Multiplex droplet digital PCR assays in a snapshot and serially. | cfDNA ESR1 and PIK3CA mutations were found in 28.9% and 24.6% of MBC patients, respectively. | All patients with ESR1 mutations had resistance to prior AI (aromatase inhibitor) therapy. 85% of patients with ESR1 mutations had resistance to prior SERM (Selective estrogen receptor modulators) therapy. | [73] | |
BRCA1/2 | 828 patients with advanced breast, ovarian, prostate, or pancreatic cancer. (the study was conducted in accordance with the Declaration of Helsinki). | Plasma-based NGS assay. | Of 828 patients, 60 (7.2%) had at least one BRCA1/2 loss-of-function mutation, 42 patients with germline mutations and 18 (14 patients had breast cancer) with somatic mutations only. | NGS analysis of cfDNA identified high rates of therapeutically relevant mutations, including deleterious BRCA1/2 somatic mutations missed by germline testing. | [74] |
24 patients with proven BRCA1/2 germline mutations (19 ovarian cancer patients and 5 patients with MBC who received prior treatment with platinum-based chemotherapy and/or PARP inhibitors). | Targeted massively parallel sequencing of tumor DNA from ovarian cancer patients, cfDNA from ovarian and breast cancer patients, and their germline DNA. | Identification of BRCA1 or BRCA2 reversion mutations in the cfDNA of 4 ovarian cancer patients (21%) and 2 breast cancer patients (40%). | cfDNA sequencing can help identify putative BRCA1/2 reversion mutations which may facilitate patient selection for PARP inhibition therapy. | [75] | |
PIK3CA | Thirty patients with advanced BC (ABC); | PIK3CA mutation analysis was performed using ddPCR. | The presence of a PI3K mutation in liquid biopsy correlates with worse PFS in patients with ABC receiving CDK4/6i. | Integration of PI3K status assessment with other molecular information could improve the management of patients with aggressive breast cancer and better suggest the best therapeutic strategy. | [76] |
TP53 | 46 patients with nonmetastatic triple-negative breast cancer; | Characterization of TP53 gene mutations in tumor tissue through massively parallel sequencing (MPS). Monitoring of previously characterized mutations based on ctDNA analysis by ddPCR at four time points: pre-NCT, post-cycle, pre-surgery, and post-surgery. | Results show a marked decrease in ctDNA levels and positivity rate during chemotherapy cycles. | The high prevalence of TP53 mutations in TNBC is a potential biomarker for ctDNA monitoring during NCT, and therefore is a tool for TNBC management. | [77] |
113 lung and 18 breast cancer patients | NGS analysis of ctDNA: Panel for hot spot regions in 11 genes for lung cancer and 10 genes for breast cancer. | Variations in the TP53 gene were detected at a high frequency in both tumor types, followed by the PIK3CA gene in breast cancer. | Based on NGS and ddPCR techniques, liquid biopsy could be a very effective method for managing terminal cancer cases and monitoring treatment responses. | [78] | |
68 patients with metastatic breast cancer (MBC). | cfDNA and gDNA (Genomic DNA) analysis by next-generation sequencing (NGS) | TP53 mutations occurred in 10 (45.45%) TNBC patients, 9 (36.00%) HER2+ patients, and 7 (22.22%) HR+ patients. TP53 represents the gene with the highest number of somatic mutations. | Mutations in TP53 cDNA and PIK3CA genes likely limit survival and promote disease progression. | [79] | |
ERBB2 | 636 women with HER2 nonamplified MBC. | ctDNA analysis by NGS. | Results of this study indicate the efficacy of neratinib for HER2-mutated nonamplified breast cancer. | This study supports the potential use of ctDNA to identify patients with HER2-mutated breast cancer to establish a new standard of care. | [80] |
Multicohort, phase 2a, platform trial of ctDNA testing in 18 UK hospitals.1051 patients were registered in the study. | ddPCR and NGS are used to detect ctDNA mutations. Patients were recruited into four parallel treatment cohorts corresponding to the mutations identified in the ctDNA (ESR1; HER2; AKT1 and PTEN). | The findings of this study demonstrate the clinically relevant activity of targeted therapies against rare HER2 and AKT1 mutations. | The results of this research show that ctDNA analysis, with the technologies used in this study, is accurate enough to be routinely adopted into clinical practice. | [81] |
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El Hejjioui, B.; Bouguenouch, L.; Melhouf, M.A.; El Mouhi, H.; Bennis, S. Clinical Evidence of Circulating Tumor DNA Application in Aggressive Breast Cancer. Diagnostics 2023, 13, 470. https://doi.org/10.3390/diagnostics13030470
El Hejjioui B, Bouguenouch L, Melhouf MA, El Mouhi H, Bennis S. Clinical Evidence of Circulating Tumor DNA Application in Aggressive Breast Cancer. Diagnostics. 2023; 13(3):470. https://doi.org/10.3390/diagnostics13030470
Chicago/Turabian StyleEl Hejjioui, Brahim, Laila Bouguenouch, Moulay Abdelilah Melhouf, Hind El Mouhi, and Sanae Bennis. 2023. "Clinical Evidence of Circulating Tumor DNA Application in Aggressive Breast Cancer" Diagnostics 13, no. 3: 470. https://doi.org/10.3390/diagnostics13030470