Authors :
Otene, S. A.; Gbaa, Z. L.; Omolabake, B. I.; Tsegha, L. J.; Onyewuchi, A. J.; Ojo, B. A.; Gbaa, A. F.; Labe, R.M.
Volume/Issue :
Volume 10 - 2025, Issue 10 - October
Google Scholar :
https://tinyurl.com/4cyyxae5
Scribd :
https://tinyurl.com/mry4u38k
DOI :
https://doi.org/10.38124/ijisrt/25oct1032
Note : A published paper may take 4-5 working days from the publication date to appear in PlumX Metrics, Semantic Scholar, and ResearchGate.
Note : Google Scholar may take 30 to 40 days to display the article.
Abstract :
Background
Early-stage breast cancer carries a significant risk of recurrence due to undetectable minimal residual disease (MRD).
Conventional surveillance lacks sensitivity for early relapse detection. Liquid biopsy, particularly circulating tumor DNA
(ctDNA), offers a promising non-invasive strategy to detect MRD and predict recurrence.
Methods
This review synthesizes recent evidence on liquid biopsy applications in early-stage breast cancer, with emphasis on MRD
detection and recurrence monitoring. We evaluate key assay platforms—including digital droplet PCR (ddPCR), next-
generation sequencing (NGS), and cancer personalized profiling by deep sequencing (CAPP-Seq)—and examine their clinical
integration.
Results
Liquid biopsy demonstrates high sensitivity and specificity in detecting ctDNA at subclinical levels, enabling earlier relapse
prediction compared to imaging or serum markers. ddPCR offers affordability and precision for targeted mutations, while NGS
and CAPP-Seq provide broader genomic coverage and adaptability. Integration into clinical pathways enables dynamic
monitoring from diagnosis through treatment and surveillance. However, challenges remain, including assay standardization,
cost, and validation across diverse populations.
Conclusion
Liquid biopsy represents a paradigm shift in early-stage breast cancer management, enabling proactive monitoring and
individualized treatment. Future priorities include global assay harmonization, large-scale validation trials, and in tegration of
multi-omic and AI-based approaches to enhance predictive accuracy and clinical adoption.
Keywords :
Blood To Bedside, Breast Cancer, Liquid Biopsy, Minimal Residual Disease, Recurrence Prediction.
References :
- Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. doi:10.3322/caac.21660.
- Waks AG, Winer EP. Breast cancer treatment: A review. JAMA. 2019;321(3):288–300. doi:10.1001/jama.2018.19323.
- Bidard FC, Jacot W, Kiavue N, Dureau S, Kadi A, Brain E, et al. Efficacy of circulating tumor cell count–driven therapy for metastatic breast cancer: The STIC CTC randomized clinical trial. JAMA Oncol. 2021;7(1):34–41. doi:10.1001/jamaoncol.2020.5210.
- Ma L, Guo H, Zhao Y, Liu Z, Wang C, Bu J, et al. Liquid biopsy in cancer: current status, challenges and future prospects. Signal Transduct Target Ther. 2024;9(1):336. doi:10.1038/s41392-024-02021-w.
- Agostinetto E, Nader-Marta G, Ignatiadis M. Circulating tumor DNA in breast cancer: a biomarker for patient selection. Curr Opin Oncol. 2023;35(5):426–35. doi:10.1097/CCO.0000000000000964.
- Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, et al. Liquid biopsies come of age: Towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017;17(4):223–38. doi:10.1038/nrc.2017.7.
- Garcia-Murillas I, Schiavon G, Weigelt B, Ng C, Hrebien S, Cutts RJ, et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med. 2015;7(302):302ra133. doi:10.1126/scitranslmed. aab0021.
- Coombes RC, Page K, Salari R, Hastings RK, Armstrong A, Ahmed S, et al. Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence. Clin Cancer Res. 2019;25(14):4255–63. doi: 10.1158/1078-0432.CCR-18-3663.
- Reinert T, Henriksen TV, Christensen E, Sharma S, Salari R, Sethi H, et al. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol. 2019;5(8):1124–31. doi:10.1001/jamaoncol.2019.0528.
- Magbanua MJM, Swigart LB, Wu HT, Hirst G, Yau C, Wolf DM, et al. Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and predicts outcome. Sci Transl Med. 2021;13(604): eabc9220. doi:10.1126/scitranslmed.abc9220.
- Parsons HA, Rhoades JN, Reed SC, Gydush G, Ram P, Exman P, et al. Sensitive detection of minimal residual disease in patients treated for early-stage breast cancer. Clin Cancer Res. 2020;26(11):2556–64. doi: 10.1158/1078-0432.CCR-19-3303.
- O’Leary B, Hrebien S, Beaney M, Fribbens C, Garcia-Murillas I, Jiang J, et al. Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. Nat Commun. 2018; 9:896. doi:10.1038/s41467-018-03215-x.
- Rothé F, Laes JF, Lambrechts D, Smeets D, Vincent D, Maetens M, et al. Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer. Ann Oncol. 2014;25(10):1959–65. doi:10.1093/annonc/mdu288.
- Turner NC, Swift C, Jenkins B, Kilburn L, Coakley M, Beaney M, et al. Results of the c-TRAK TN trial: ctDNA mutation tracking to detect molecular residual disease in early-stage triple-negative breast cancer. Ann Oncol. 2023;34(2):200–11. doi: 10.1016/j.annonc.2022.11.005.
- Siravegna G, Mussolin B, Venesio T, Marsoni S, Seoane J, Dive C, et al. How liquid biopsies can change clinical practice in oncology. Ann Oncol. 2019;30(10):1580–90. doi:10.1093/annonc/mdz227.
- Scherer F, Kurtz DM, Newman AM, Stehr H, Craig AF, Esfahani MS, et al. Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA. Sci Transl Med. 2016;8(364):364ra155. doi:10.1126/scitranslmed. aai8545.
- Olsson E, Winter C, George A, Chen Y, Howlin J, Tang MH, et al. Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med. 2015;7(8):1034–47. doi:10.15252/emmm.201404913.
- Riva F, Bidard FC, Houy A, Saliou A, Madic J, Cottu P, et al. Patient-specific circulating tumor DNA detection during neoadjuvant chemotherapy in triple-negative breast cancer. Clin Chem. 2017;63(3):691–9. doi:10.1373/clinchem.2016.264757.
- Rack B, Schindlbeck C, Jückstock J, Andergassen U, Hepp P, Zwingers T, et al. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst. 2014; 106(5): dju066. doi:10.1093/jnci/dju066.
- Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Pan H, Gray R, Braybrooke J, Davies C, Taylor C, et al. 20-Year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377(19):1836–46. doi:10.1056/NEJMoa1701830.
- Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thürlimann B, et al. Personalizing the treatment of women with early breast cancer: Highlights of the St Gallen International Expert Consensus. Ann Oncol. 2013;24(9):2206–23. doi:10.1093/annonc/mdt303.
- Bidard FC, Weigelt B, Reis-Filho JS. Going with the flow: From circulating tumor cells to DNA. Sci Transl Med. 2013;5(207):207ps14. doi:10.1126/scitranslmed.3005275.
- Garcia-Murillas I, Chopra N, Comino-Méndez I, Beaney M, Tovey H, Cutts RJ, et al. Assessment of molecular relapse detection in early-stage breast cancer. JAMA Oncol. 2019;5(10):1473–8. doi:10.1001/jamaoncol.2019.1473.
- Turner NC, Kingston B, Kilburn LS, Kernaghan S, Wardley AM, Macpherson IR, et al. Circulating tumor DNA detection and therapy response in early breast cancer: Results from the c-TRAK TN trial. Nat Med. 2020;26(10):1534–40. doi:10.1038/s41591-020-1005-3.
- Parsons HA, Rhoades J, Reed SC, Gydush G, Ram P, Exman P, et al. Sensitive detection of minimal residual disease in patients treated for early-stage breast cancer. Clin Cancer Res. 2020;26(11):2556–64. doi: 10.1158/1078-0432.CCR-19-3303.
- Newman AM, Bratman SV, To J, Wynne JF, Eclov NCW, Modlin LA, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20(5):548–54. doi:10.1038/nm.3519.
- Kinde I, Wu J, Papadopoulos N, Kinzler KW, Vogelstein B. Detection and quantification of rare mutations with massively parallel sequencing. Proc Natl Acad Sci U S A. 2011;108(23):9530–5. doi:10.1073/pnas.1019545108.
- Shen SY, Singhania R, Fehringer G, Chakravarthy A, Roehrl MHA, Chadwick D, et al. Sensitive tumour detection and classification using plasma cell-free DNA methylomes. Nature. 2018;563(7732):579–83. doi:10.1038/s41586-018-0703-0.
- Mouliere F, Chandrananda D, Piskorz AM, Moore EK, Morris J, Ahlborn LB, et al. Enhanced detection of circulating tumor DNA by fragment size analysis. Sci Transl Med. 2018;10(466): eaat4921. doi:10.1126/scitranslmed. aat4921.
- Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477–87. doi:10.1056/NEJMoa1408617.
- Merker JD, Oxnard GR, Compton C, Diehn M, Hurley P, Lazar AJ, et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists joint review. J Clin Oncol. 2018;36(16):1631–41. doi:10.1200/JCO.2017.76.8671.
- Newman AM, Lovejoy AF, Klass DM, Kurtz DM, Chabon JJ, Scherer F, et al. Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol. 2016; 34(5):547–55. doi:10.1038/nbt.3520.
- Siravegna G, Marsoni S, Siena S, Bardelli A. Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol. 2017;14(9):531–48. doi:10.1038/nrclinonc.2017.14.
- Pantel K, Alix-Panabières C. Liquid biopsy and minimal residual disease — latest advances and implications for cure. Nat Rev Clin Oncol. 2019;16(7):409–24. doi:10.1038/s41571-019-0187-3.
- Khatcheressian JL, Hurley P, Bantug E, Esserman LJ, Grunfeld E, Halberg F, et al. Breast cancer follow-up and management after primary treatment: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(7):961–5. doi:10.1200/JCO.2012.45.9859.
- Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, et al. Liquid biopsies come of age: Towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017;17(4):223–38. doi:10.1038/nrc.2017.7.
- Garcia-Murillas I, Chopra N, Comino-Méndez I, Beaney M, Tovey H, Cutts RJ, et al. Assessment of molecular relapse detection in early-stage breast cancer. JAMA Oncol. 2019;5(10):1473–8. doi:10.1001/jamaoncol.2019.1473.
- Parsons HA, Rhoades J, Reed SC, Gydush G, Ram P, Exman P, et al. Sensitive detection of minimal residual disease in patients treated for early-stage breast cancer. Clin Cancer Res. 2020;26(11):2556–64. doi: 10.1158/1078-0432.CCR-19-3303.
- Newman AM, Lovejoy AF, Klass DM, Kurtz DM, Chabon JJ, Scherer F, et al. Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol. 2016;34(5):547–55. doi:10.1038/nbt.3520.
- O’Leary B, Cutts RJ, Liu Y, Hrebien S, Huang X, Fenwick K, et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 2018;8(11):1390–403. doi:10.1158/2159-8290.CD-18-0822.
- Newman AM, Bratman SV, To J, Wynne JF, Eclov NC, Modlin LA, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20(5):548–54. doi:10.1038/nm.3519.
- Merker JD, Oxnard GR, Compton C, Diehn M, Hurley P, Lazar AJ, et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists joint review. J Clin Oncol. 2018;36(16):1631–41. doi:10.1200/JCO.2017.76.8671.
- Bronkhorst AJ, Ungerer V, Holdenrieder S. The emerging role of cell-free DNA as a molecular marker for cancer management. Biomol Detect Quantif. 2019; 17:100087. doi: 10.1016/j.bdq.2019.100087.
- Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, et al. Liquid biopsies come of age: Towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017;17(4):223–38. doi:10.1038/nrc.2017.7.
- Coombes RC, Page K, Salari R, Hastings RK, Armstrong A, Ahmed S, et al. Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence. Clin Cancer Res. 2019;25(14):4255–63. doi: 10.1158/1078-0432.CCR-18-3663.
- Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477–87. doi:10.1056/NEJMoa1408617.
- Turner NC, Kingston B, Kilburn LS, Kernaghan S, Wardley AM, Macpherson IR, et al. Circulating tumor DNA detection and therapy response in early breast cancer: Results from the c-TRAK TN trial. Nat Med. 2020;26(10):1534–40. doi:10.1038/s41591-020-1005-3.
- Wan JCM, Heider K, Gale D, Murphy S, Fisher E, Mouliere F, et al. ctDNA monitoring using patient-specific sequencing and integration of variant reads. Sci Transl Med. 2020;12(548): eaaz8084. doi:10.1126/scitranslmed. aaz8084.
- Chan HT, Chin YM, Nakamura Y, Low SK. Clonal hematopoiesis in liquid biopsy: From biological noise to valuable clinical insights. Clin Transl Med. 2020;10(8): e206. doi:10.1002/ctm2.206.
- Siravegna G, Mussolin B, Venesio T, Marsoni S, Seoane J, Dive C, et al. How liquid biopsies can change clinical practice in oncology. Ann Oncol. 2019;30(10):1580–90. doi:10.1093/annonc/mdz227.
- Parikh AR, Van Seventer EE, Siravegna G, Hartwig AV, Jaimovich A, He Y, et al. Minimal residual disease detection using a plasma-only circulating tumor DNA assay in colorectal cancer patients. Clin Cancer Res. 2021;27(20):5586–94.
- Reinert T, Henriksen TV, Christensen E, Sharma S, Salari R, Sethi H, et al. Analysis of plasma cell-free DNA by ultradeep sequencing in patients with stages I to III colorectal cancer. JAMA Oncol. 2019;5(8):1124–31.
- Chen G, Peng J, Xiao Q, Wu HX, Wu X, Wang F, et al. Postoperative circulating tumor DNA as markers of recurrence risk in stages II to III colorectal cancer. J Hematol Oncol. 2021;14(1):80.
- Liu MC, Oxnard GR, Klein EA, Swanton C, Seiden MV, CCGA Consortium. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. 2020; 31(6):745–59.
- Wan N, Weinberg D, Liu TY, Niehaus K, Ariazi EA, Delubac D, et al. Machine learning enables detection of early-stage colorectal cancer by whole-genome sequencing of plasma cell-free DNA. BMC Cancer. 2019;19(1):832.
- Cohen JD, Li L, Wang Y, Thoburn C, Afsari B, Danilova L, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018;359(6378):926–30.
- Chen M, Zhao H. Next-generation sequencing in liquid biopsy: cancer screening and early detection. Hum Genomics. 2019;13(1):34.
- Wan JCM, Heider K, Gale D, Murphy S, Fisher E, Mouliere F, et al. ctDNA monitoring using patient-specific sequencing and integration of variant reads. Sci Transl Med. 2020;12(548):eaaz8084.
- Tie J, Wang Y, Cohen JD, Li L, Christie M, Simons K, et al. Circulating tumor DNA analyses as markers of recurrence risk and benefit of adjuvant therapy for stage III colon cancer. JAMA Oncol. 2019;5(12):1710–7.
- Wan N, Weinberg D, Liu TY, Niehaus K, Ahsanuddin S, Ariazi EA, et al. Whole-genome circulating tumor DNA methylation landscape for biomarker discovery in colorectal cancer. Nat Commun. 2020; 11(1):5252.
- Riva F, Bidard FC, Houy A, Saliou A, Madic J, Rampanou A, et al. Patient-specific circulating tumor DNA detection during neoadjuvant chemotherapy in triple-negative breast cancer. Clin Chem. 2017; 63(3):691–9. doi:10.1373/clinchem.2016.263897.
- Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10(8):472–84. doi:10.1038/nrclinonc.2013.110.
- Chae YK, Oh MS. Detection of minimal residual disease using ctDNA in breast cancer: current evidence and future directions. J Clin Med. 2020; 9(9):2879. doi:10.3390/jcm9092879.
- De Mattos-Arruda L, Weigelt B, Cortes J, Won HH, Ng CKY, Nuciforo P, et al. Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-principle. Ann Oncol. 2014;25(9):1729–35. doi:10.1093/annonc/mdu239.
- Olsson E, Winter C, George A, Chen Y, Howlin J, Tang MH, et al. Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med. 2015;7(8):1034–47. doi:10.15252/emmm.201404913.
- Wang Y, Springer S, Zhang M, McMahon KW, Kinde I, Dobbyn L, et al. Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord. Proc Natl Acad Sci U S A. 2015;112(31):9704–9. doi:10.1073/pnas.1511694112.
- O’Leary B, Hrebien S, Beaney M, Fribbens C, Garcia-Murillas I, Jiang J, et al. Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. Nat Commun. 2018; 9(1):896. Doi: 10.1038/s41467-018-03215-x.
- Garcia-Murillas I, Turner NC. Assessing tumor dynamics and resistance mechanisms using circulating tumor DNA in breast cancer. Genome Med. 2016; 8:45. doi:10.1186/s13073-016-0304-y.
- Phallen J, Sausen M, Adleff V, Leal A, Hruban C, White J, et al. Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med. 2017;9(403): eaan2415. doi:10.1126/scitranslmed. aan2415.
Background
Early-stage breast cancer carries a significant risk of recurrence due to undetectable minimal residual disease (MRD).
Conventional surveillance lacks sensitivity for early relapse detection. Liquid biopsy, particularly circulating tumor DNA
(ctDNA), offers a promising non-invasive strategy to detect MRD and predict recurrence.
Methods
This review synthesizes recent evidence on liquid biopsy applications in early-stage breast cancer, with emphasis on MRD
detection and recurrence monitoring. We evaluate key assay platforms—including digital droplet PCR (ddPCR), next-
generation sequencing (NGS), and cancer personalized profiling by deep sequencing (CAPP-Seq)—and examine their clinical
integration.
Results
Liquid biopsy demonstrates high sensitivity and specificity in detecting ctDNA at subclinical levels, enabling earlier relapse
prediction compared to imaging or serum markers. ddPCR offers affordability and precision for targeted mutations, while NGS
and CAPP-Seq provide broader genomic coverage and adaptability. Integration into clinical pathways enables dynamic
monitoring from diagnosis through treatment and surveillance. However, challenges remain, including assay standardization,
cost, and validation across diverse populations.
Conclusion
Liquid biopsy represents a paradigm shift in early-stage breast cancer management, enabling proactive monitoring and
individualized treatment. Future priorities include global assay harmonization, large-scale validation trials, and in tegration of
multi-omic and AI-based approaches to enhance predictive accuracy and clinical adoption.
Keywords :
Blood To Bedside, Breast Cancer, Liquid Biopsy, Minimal Residual Disease, Recurrence Prediction.