Liquid Biopsy in Breast CancerArticle in several languages: English | deutsch
In recent years, the blood-based analysis of circulating tumour cells (CTCs) and nucleic acids (DNA/RNA), otherwise known as liquid biopsy, has become increasingly important in breast cancer. Numerous trials have already underscored the high prognostic significance of CTC detection in both early and metastatic stages. Moreover, the changes in CTC levels and circulating tumour DNA (ctDNA) during the course of the disease correlate with the response to treatment. Research currently focuses on liquid-biopsy based therapeutic interventions in metastatic breast cancer. In this context, alpelisib, a PI3K inhibitor, was the first agent to be approved by FDA and EMA.
Key wordsliquid biopsy - breast cancer - circulating tumour DNA - circulating tumour cell - targeted therapy
Received: 29 June 2020
Accepted after revision: 02 August 2020
06 November 2020 (online)
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- 1 Fisher B, Ravdin RG, Ausman RK. et al. Surgical adjuvant chemotherapy in cancer of the breast: results of a decade of cooperative investigation. Ann Surg 1968; 168: 337-356
- 2 Banys M, Hahn M, Gruber I. et al. Detection and clinical relevance of hematogenous tumor cell dissemination in patients with ductal carcinoma in situ. Breast Cancer Res Treat 2014; 144: 531-538
- 3 Luzzi KJ, MacDonald IC, Schmidt EE. et al. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 1998; 153: 865-873
- 4 Mehes G, Witt A, Kubista E. et al. Circulating breast cancer cells are frequently apoptotic. Am J Pathol 2001; 159: 17-20
- 5 Meng S, Tripathy D, Frenkel EP. et al. Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 2004; 10: 8152-8162
- 6 Krawczyk N, Meier-Stiegen F, Banys M. et al. Expression of stem cell and epithelial-mesenchymal transition markers in circulating tumor cells of breast cancer patients. Biomed Res Int 2014; 2014: 415721
- 7 Mani SA, Guo W, Liao MJ. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704-715
- 8 Brabletz T. EMT and MET in metastasis: where are the cancer stem cells?. Cancer Cell 2012; 22: 699-701
- 9 Schwarzenbach H, Pantel K, Kemper B. et al. Comparative evaluation of cell-free tumor DNA in blood and disseminated tumor cells in bone marrow of patients with primary breast cancer. Breast Cancer Res 2009; 11: R71
- 10 Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 2011; 11: 426-437
- 11 Ignatiadis M, Riethdorf S, Bidard FC. et al. International study on inter-reader variability for circulating tumor cells in breast cancer. Breast Cancer Res 2014; 16: R43
- 12 Allard WJ, Matera J, Miller MC. et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 2004; 10: 6897-6904
- 13 Fehm T, Braun S, Muller V. et al. A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation. Cancer 2006; 107: 885-892
- 14 Fehm TN, Meier-Stiegen F, Driemel C. et al. Diagnostic leukapheresis for CTC analysis in breast cancer patients: CTC frequency, clinical experiences and recommendations for standardized reporting. Cytometry A 2018; 93: 1213-1219
- 15 Alix-Panabieres C, Pantel K. Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy. Cancer Discov 2016; 6: 479-491
- 16 [Anonym] Colloquium Senologie 2019/2020. München: LUKON Verlagsgesellschaft mbH; 2019
- 17 Jung A, Kirchner T. Liquid Biopsy in Tumor Genetic Diagnosis. Dtsch Arztebl Int 2018; 115: 169-174
- 18 Husemann Y, Geigl JB, Schubert F. et al. Systemic spread is an early step in breast cancer. Cancer Cell 2008; 13: 58-68
- 19 Janni WJ, Rack B, Terstappen LW. et al. Pooled Analysis of the Prognostic Relevance of Circulating Tumor Cells in Primary Breast Cancer. Clin Cancer Res 2016; 22: 2583-2593
- 20 Cristofanilli M, Pierga JY, Reuben J. et al. The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper. Crit Rev Oncol Hematol 2019; 134: 39-45
- 21 Bidard FC, Michiels S, Riethdorf S. et al. Circulating Tumor Cells in Breast Cancer Patients Treated by Neoadjuvant Chemotherapy: A Meta-analysis. J Natl Cancer Inst 2018; 110: 560-567
- 22 Tan G, Chu C, Gui X. et al. The prognostic value of circulating cell-free DNA in breast cancer: A meta-analysis. Medicine (Baltimore) 2018; 97: e0197
- 23 Fujita N, Nakayama T, Yamamoto N. et al. Methylated DNA and total DNA in serum detected by one-step methylation-specific PCR is predictive of poor prognosis for breast cancer patients. Oncology 2012; 83: 273-282
- 24 Fernandez-Garcia D, Hills A, Page K. et al. Plasma cell-free DNA (cfDNA) as a predictive and prognostic marker in patients with metastatic breast cancer. Breast Cancer Res 2019; 21: 149
- 25 Radovich M, Jiang G, Chitambar C. et al. Detection of circulating tumor DNA (ctDNA) after neoadjuvant chemotherapy is significantly associated with disease recurrence in early-stage triple-negative breast cancer (TNBC): Preplanned correlative results from clinical trial BRE12-158. San Antonio Breast Cancer Symposium 2019; Abstr. GS5-02.
- 26 Garcia JM, Garcia V, Silva J. et al. Extracellular tumor DNA in plasma and overall survival in breast cancer patients. Genes Chromosomes Cancer 2006; 45: 692-701
- 27 Fujita N, Kagara N, Yamamoto N. et al. Methylated DNA and high total DNA levels in the serum of patients with breast cancer following neoadjuvant chemotherapy are predictive of a poor prognosis. Oncol Lett 2014; 8: 397-403
- 28 Shaw JA, Guttery DS, Hills A. et al. Mutation Analysis of Cell-Free DNA and Single Circulating Tumor Cells in Metastatic Breast Cancer Patients with High Circulating Tumor Cell Counts. Clin Cancer Res 2017; 23: 88-96
- 29 Oshiro C, Kagara N, Naoi Y. et al. PIK3CA mutations in serum DNA are predictive of recurrence in primary breast cancer patients. Breast Cancer Res Treat 2015; 150: 299-307
- 30 Fehm T, Neubauer H, Banys-Paluchowski M. Liquid Biopsy. In: Untch M, Harbeck N, Thomssen C. Hrsg. Colloquium Senologie 2019/2020. München: LUKON Verlag; 2019
- 31 Rack B, Schindlbeck C, Juckstock J. et al. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst 2014; 106: dju066
- 32 Riethdorf S, Muller V, Zhang L. et al. Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clin Cancer Res 2010; 16: 2634-2645
- 33 Kasimir-Bauer S, Bittner AK, Konig L. et al. Does primary neoadjuvant systemic therapy eradicate minimal residual disease? Analysis of disseminated and circulating tumor cells before and after therapy. Breast Cancer Res 2016; 18: 20
- 34 Li S, Lai H, Liu J. et al. Circulating Tumor DNA Predicts the Response and Prognosis in Patients With Early Breast Cancer Receiving Neoadjuvant Chemotherapy. JCO Precision Oncology 2020; 4: 244-257
- 35 Magbanua MJM, Brown-Swigart L, Wu H-T. et al. Circulating tumor DNA in neoadjuvant treated breast cancer reflects response and survival. medRxiv 2020; DOI: 10.1101/2020.02.03.20019760.
- 36 Takahashi H, Kagara N, Tanei T. et al. Correlation of Methylated Circulating Tumor DNA With Response to Neoadjuvant Chemotherapy in Breast Cancer Patients. Clin Breast Cancer 2017; 17: 61-69.e3
- 37 Rothe F, Silva MJ, Venet D. et al. Circulating Tumor DNA in HER2-Amplified Breast Cancer: A Translational Research Substudy of the NeoALTTO Phase III Trial. Clin Cancer Res 2019; 25: 3581-3588
- 38 Garcia-Murillas I, Schiavon G, Weigelt B. et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med 2015; 7: 302ra133
- 39 Sharma G, Mirza S, Parshad R. et al. DNA methylation of circulating DNA: a marker for monitoring efficacy of neoadjuvant chemotherapy in breast cancer patients. Tumour Biol 2012; 33: 1837-1843
- 40 Moss J, Zick A, Grinshpun A. et al. Circulating breast-derived DNA allows universal detection and monitoring of localized breast cancer. Ann Oncol 2020; 31: 395-403
- 41 Diagnostik und Therapie früher und fortgeschrittener Mammakarzinome. Herausgegeben von der Kommission Mamma (vertreten durch: Wolfgang Janni) der Arbeitsgemeinschaft Gynäkologische Onkologie e. V. in der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe e. V. sowie in der Deutschen Krebsgesellschaft e.V. 2020.
- 42 Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): S3-Leitlinie Früherkennung, Diagnose, Therapie und Nachsorge des Mammakarzinoms, Version 4.3, AWMF Registernummer: 032–045OL. 2020 Online (last access: 18.09.2020): http://www.leitlinienprogramm-onkologie.de/leitlinien/mammakarzinom/
- 43 Fiegl H, Millinger S, Mueller-Holzner E. et al. Circulating tumor-specific DNA: a marker for monitoring efficacy of adjuvant therapy in cancer patients. Cancer Res 2005; 65: 1141-1145
- 44 Garcia-Murillas I, Chopra N, Comino-Mendez I. et al. Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer. JAMA Oncol 2019; DOI: 10.1001/jamaoncol.2019.1838.
- 45 Coombes RC, Page K, Salari R. et al. Personalized Detection of Circulating Tumor DNA Antedates Breast Cancer Metastatic Recurrence. Clin Cancer Res 2019; 25: 4255-4263
- 46 Olsson E, Winter C, George A. 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: 1034-1047
- 47 Sparano JA, OʼNeill A, Alpaugh K. et al. Circulating tumor cells (CTCs) five years after diagnosis are prognostic for late recurrence in operable stage II – III breast cancer. San Antonio Breast Cancer Symposium 2017; Abstr. GS6-03.
- 48 Sparano J, OʼNeill A, Alpaugh K. et al. Association of Circulating Tumor Cells With Late Recurrence of Estrogen Receptor-Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol 2018; DOI: 10.1001/jamaoncol.2018.2574.
- 49 Janni W, Rack B, Fasching P. et al. Persistence of circulating tumor cells in high risk early breast cancer patients five years after adjuvant chemotherapy and late recurrence: Results from the adjuvant SUCCESS A trial. J Clin Oncol 2018; 36 (15_suppl): 515 doi:10.1200/JCO.2018.36.15_suppl.515
- 50 Banys-Paluchowski M, Fehm T, Janni W. et al. Circulating and Disseminated Tumor Cells in Breast Carcinoma: Report from the Consensus Conference on Tumor Cell Dissemination during the 39th Annual Meeting of the German Society of Senology, Berlin, 27 June 2019. Geburtshilfe Frauenheilkd 2019; 79: 1320-1327
- 51 Smerage JB, Barlow WE, Hortobagyi GN. et al. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol 2014; 32: 3483-3489
- 52 Martin M, Custodio S, de Las Casas ML. et al. Circulating tumor cells following first chemotherapy cycle: an early and strong predictor of outcome in patients with metastatic breast cancer. Oncologist 2013; 18: 917-923
- 53 Hrebien S, Citi V, Garcia-Murillas I. et al. Early ctDNA dynamics as a surrogate for progression-free survival in advanced breast cancer in the BEECH trial. Ann Oncol 2019; 30: 945-952
- 54 OʼLeary B, Hrebien S, Morden JP. et al. Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. Nat Commun 2018; 9: 896
- 55 Andre F, Su F, Solovieff N. et al. Pooled ctDNA analysis of the MONALEESA (ML) phase III advanced breast cancer (ABC) trials. J Clin Oncol 2020; 38 (Suppl.) Abstr.. 1009
- 56 Bidard FC, Callens C, Dalenc F. et al. Prognostic impact of ESR1 mutations in ER+ HER2- MBC patients prior treated with first line AI and palbociclib: An exploratory analysis of the PADA-1 trial. J Clin Oncol 2020; 38 (no. 15_suppl): 1010 doi:10.1200/JCO.2020.38.15_suppl.1010
- 57 Schrijver W, Suijkerbuijk KPM, van Gils CH. et al. Receptor Conversion in Distant Breast Cancer Metastases: A Systematic Review and Meta-analysis. J Natl Cancer Inst 2018; 110: 568-580
- 58 Bidard F-C, Jacot W, Dureau S. et al. Abstract GS3-07: Clinical utility of circulating tumor cell count as a tool to chose between first line hormone therapy and chemotherapy for ER+ HER2- metastatic breast cancer: Results of the phase III STIC CTC trial. Cancer Res 2019; DOI: 10.1158/1538-7445.SABCS18-GS3-07.
- 59 Jacot W, Cottu P, Berger F. et al. Actionability of HER2-amplified circulating tumor cells in HER2-negative metastatic breast cancer: the CirCe T-DM1 trial. Breast Cancer Res 2019; 21: 121
- 60 Turner N, Kingston B, Kilburn L. et al. Results from the plasmaMATCH trial: A multiple parallel cohort, multi-centre clinical trial of circulating tumour DNA testing to direct targeted therapies in patients with advanced breast cancer (CRUK/15/010). San Antonio Breast Cancer Symposium 2019; Abstr. GS3-06.