The use of liquid biopsy in early breast cancer: clinical evidence and future perspectives

Abstract

Liquid biopsy, including both circulating tumor cells and circulating tumor DNA, is gaining momentum as a diagnostic modality adopted in the clinical management of breast cancer. Prospective studies testing several technologies demonstrated clinical validity and, in some cases, achieved the United States Food and Drug Administration approval. The initial testing and clinical application of liquid biopsy focused primarily on the diagnosis, while molecular characterization and monitoring of metastatic disease, with larger data from prospective studies, came in the last two decades. Although its role in metastatic setting is thus widely recognized, the current evidence does not provide support for the routine clinical use of liquid biopsy methods for the earlier stage of this disease. Considering the relevance of early detection, characterization, and management of breast cancer in the early-stage, this clinical setting is the most suitable to increase the chances for effective treatment selection and improved prognosis, and a better understanding of the main application of liquid biopsy tools in the earlier stage of breast cancer is therefore crucial. The aim of this review is to provide an overview of the clinical evidence and subsequent potential applications of liquid biopsy in early breast cancer, identifying the main existing caveats and the possible future scenarios.

Keywords

Liquid biopsy / early breast cancer / circulating tumor cells / circulating tumor DNA / clinical trials / screening / early detection / minimal residual disease

References

[1] Society A cancer. Cancer Facts and Figures 2020. Available from: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2020.html. [Last accessed on 21 Sep 2020]

[2] Colleoni M,Price KN.Annual hazard rates of recurrence for breast cancer during 24 years of follow-up: results from the international breast cancer study group trials I to V..J Clin Oncol2016;34:927-35 PMCID:PMC4933127

[3] Howlader N, Noone AM, Krapcho M, et al. SEER cancer statistics review, 1975-2016 National Cancer Institute. Bethesda MD. Posted to the SEER web site, April 2019. Available from: https://seer.cancer.gov/csr/1975_2016. [Last accessed on 21 Sep 2020]

[4] Cristofanilli M,Ellis MJ.Circulating tumor cells, disease progression, and survival in metastatic breast cancer..N Engl J Med2004;351:781-91

[5] Bredemeier M,Kolberg HC.Comparison of the PI3KCA pathway in circulating tumor cells and corresponding tumor tissue of patients with metastatic breast cancer..Mol Med Rep2017;15:2957-68 PMCID:PMC5428904

[6] Huang ZH,Hua D.Quantitative analysis of plasma circulating DNA at diagnosis and during follow-up of breast cancer patients..Cancer Lett2006;243:64-70

[7] Bettegowda C,Leary RJ.Detection of circulating tumor DNA in early- and late-stage human malignancies..Sci Transl Med2014;6:224ra24 PMCID:PMC4017867

[8] Dawson SJ,Murtaza M.Analysis of circulating tumor DNA to monitor metastatic breast cancer..N Engl J Med2013;368:1199-209

[9] Madic J,Bidard FC.Circulating tumor DNA and circulating tumor cells in metastatic triple negative breast cancer patients..Int J Cancer2015;136:2158-65

[10] Rodriguez BJ,Aranda AG.Detection of TP53 and PIK3CA Mutations in Circulating Tumor DNA Using Next-Generation Sequencing in the Screening Process for Early Breast Cancer Diagnosis..J Clin Med2019;8:1183 PMCID:PMC6723048

[11] Alimirzaie S,Akbari MR.Liquid biopsy in breast cancer: A comprehensive review..Clin Genet2019;95:643-60

[12] Chen KZ,Yang F.Circulating tumor DNA detection in early-stage non-small cell lung cancer patients by targeted sequencing..Sci Rep2016;6:31985 PMCID:PMC4995492

[13] Zhang XF,Wang XD.Advances in liquid biopsy using circulating tumor cells and circulating cell-free tumor DNA for detection and monitoring of breast cancer..Clin Exp Med2019;19:271-9

[14] Beaver JA,Balukrishna S.Detection of cancer DNA in plasma of early stage breast cancer patients..Clin Cancer Res2014;20:2643-50 PMCID:PMC4024333

[15] Phallen J,Adleff V.Direct detection of early-stage cancers using circulating tumor DNA..Sci Transl Med2017;9:eaan2415 PMCID:PMC6714979

[16] Cohen JD,Wang Y.Detection and localization of surgically resectable cancers with a multi-analyte blood test..Science2018;359:926-30 PMCID:PMC6080308

[17] Salido-Guadarrama I,Peralta-Zaragoza O,Rodríguez-Dorantes M.MicroRNAs transported by exosomes in body fluids as mediators of intercellular communication in cancer..Onco Targets Ther2014;7:1327-38 PMCID:PMC4114916

[18] Gold B,Furtado LV,Gocke CD.Do circulating tumor cells, exosomes, and circulating tumor nucleic acids have clinical utility? A report of the association for molecular pathology..J Mol Diagn2015;17:209-24 PMCID:PMC4411248

[19] Shen SY,Fehringer G.Sensitive tumour detection and classification using plasma cell-free DNA methylomes..Nature2018;563:579-83

[20] Liu M,Klein E.Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA..Annals of Oncology2020;31:745-59

[21] Cristiano S,Phallen J.Genome-wide cell-free DNA fragmentation in patients with cancer..Nature2019;570:385-9 PMCID:PMC6774252

[22] Gerratana L,Shah AN,Corvaja C.Emerging Role of Genomics and Cell-Free DNA in Breast Cancer..Curr Treat Options Oncol2019;20:68

[23] Koboldt DC,McLellan MD.Comprehensive molecular portraits of human breast tumors..Nature2013;490:61-70 PMCID:PMC3465532

[24] Silva JM,Sanchez A.Tumor DNA in plasma at diagnosis of breast cancer patients is a valuable predictor of disease-free survival..Clin Cancer Res2002;8:3761-6

[25] Rothé F,Venet D.Circulating tumor DNA in HER2-amplified breast cancer: a translational research substudy of the NeoALTTO phase III trial..Clin Cancer Res2019;25:3581-8

[26] Garcia-Murillas I,Weigelt B.Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer..Sci Transl Med2015;7:302ra133

[27] Garcia-Murillas I,Comino-Méndez I.Assessment of molecular relapse detection in early-stage breast cancer..JAMA Oncol2019;5:1473-8 PMCID:PMC6681568

[28] Chen YH,Solzak JP.Next-generation sequencing of circulating tumor DNA to predict recurrence in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy..NPJ Breast Cancer2017;3:24 PMCID:PMC5495776

[29] Radovich M,Hancock BA.Association of circulating tumor DNA and circulating tumor cells after neoadjuvant chemotherapy with disease recurrence in patients with triple-negative breast cancer: preplanned secondary analysis of the BRE12-158 randomized clinical trial..JAMA Oncol2020;6:1410-5 PMCID:PMC7349081

[30] Swanton C,Abbosh C.Phylogenetic ctDNA analysis depicts early stage lung cancer evolution..Nature2017;545:446-51 PMCID:PMC5812436

[31] Coombes RC,Salari R.Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence..Clin Cancer Res2019;25:4255-63

[32] McDonald BR,Sammut SJ.Detection of residual disease after neoadjuvant therapy in breast cancer using personalized circulating tumor DNA analysis..Sci Transl Med2019;7392:1-14 PMCID:PMC7236617

[33] Krishnamurthy S,Singh B.Detection of minimal residual disease in blood and bone marrow in early stage breast cancer..Cancer2010;116:3330-7

[34] Tibbe AG,Terstappen LW.Statistical considerations for enumeration of circulating tumor cells..Cytometry A2007;71:154-62

[35] Xenidis N,Kafousi M.Predictive and prognostic value of peripheral blood cytokeratin-19 mRNA-positive cells detected by real-time polymerase chain reaction in node-negative breast cancer patients..J Clin Oncol2006;24:3756-62

[36] Rack B,Jückstock J.Circulating tumor cells predict survival in early average-to-high risk breast cancer patients..J Natl Cancer Inst2014;106:dju066 PMCID:PMC4112925

[37] Pierga JY,Mathiot C.Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial..Clin Cancer Res2008;14:7004-10

[38] Lucci A,Lodhi AK.Circulating tumour cells in non-metastatic breast cancer: a prospective study..The Lancet Oncology2012;13:688-95

[39] Pierga JY,Lévy C.Pathological response and circulating tumor cell count identifies treated HER2+ inflammatory breast cancer patients with excellent prognosis: BEVERLY-2 survival data..Clin Cancer Res2015;21:1298-304

[40] Pierga JY,Autret A.Circulating tumour cells and pathological complete response: independent prognostic factors in inflammatory breast cancer in a pooled analysis of two multicentre phase II trials (BEVERLY-1 and -2) of neoadjuvant chemotherapy combined with bevacizumab..Ann Oncol2017;28:103-9

[41] Riethdorf S,Zhang L.Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial..Clin Cancer Res2010;16:2634-45

[42] Trapp E,Schindlbeck C.Presence of circulating tumor cells in high-risk early breast cancer during follow-up and prognosis..J Natl Cancer Inst2019;111:380-7

[43] Sparano JA.Surveillance after treatment of localized breast cancer: time for reappraisal?.J Natl Cancer Inst2019;111:339-41 PMCID:PMC6934435

[44] Bidard FC,Delaloge S.Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer..Ann Oncol2010;21:729-33

[45] Azim HA Jr,Aura CM.Circulating tumor cells and response to neoadjuvant paclitaxel and HER2-targeted therapy: a sub-study from the NeoALTTO phase III trial..Breast2013;22:1060-5

[46] Bidard FC,Kiavue N.Efficacy of circulating tumor cell count-driven vs clinician-driven first-line therapy choice in hormone receptor-positive, ERBB2-negative metastatic breast cancer: the STIC CTC randomized clinical trial..JAMA Oncol2020;5:e205660 PMCID:PMC7645742

[47] Bauer ECA,Widschwendter P.Prevalence of circulating tumor cells in early breast cancer patients 2 and 5 years after adjuvant treatment..Breast Cancer Res Treat2018;171:571-80

[48] Hall C,Laubacher B.Circulating tumor cells after neoadjuvant chemotherapy in stage I-III triple-negative breast cancer..Ann Surg Oncol2015;22:S552-8

[49] Janni WJ,Terstappen LW.Pooled analysis of the prognostic relevance of circulating tumor cells in primary breast cancer..Clin Cancer Res2016;22:2583-93

[50] Bidard FC,Riethdorf S.Circulating tumor cells in breast cancer patients treated by neoadjuvant chemotherapy: a meta-analysis..J Natl Cancer Inst2018;110:560-7

[51] Davis AA,Gerratana L.Abstract P5-01-08: landscape of circulating tumor DNA (ctDNA) in metastatic breast cancer..Cancer Res2020;80:P5-01-08

[52] Paweletz CP,Oxnard GR.Does testing error underlie liquid biopsy discordance?.JCO Precision Oncology2019;3:1-3

[53] Gerratana L,Shah AN.Performance of a novel next generation sequencing circulating tumor DNA (ctDNA) platform for the evaluation of samples from patients with metastatic breast cancer (MBC)..Crit Rev Oncol Hematol2020;145:102856

[54] Serpas L,Jiang P.Dnase1l3 deletion causes aberrations in length and end-motif frequencies in plasma DNA..Proc Natl Acad Sci U S A2019;116:641-9 PMCID:PMC6329986

[55] Mouliere F,Piskorz AM.Enhanced detection of circulating tumor DNA by fragment size analysis..Sci Transl Med2018;10:eaat4921 PMCID:PMC6483061

[56] Liu L,Jassowicz AF.Targeted methylation sequencing of plasma cell-free DNA for cancer detection and classification..Ann Oncol2018;29:1445-53 PMCID:PMC6005020

[57] Gerratana L,Franzoni A.Plasma-based longitudinal evaluation of ESR1 epigenetic status in hormone receptor-positive HER2-negative metastatic breast cancer..Front Oncol2020;10:550185 PMCID:PMC7531252

[58] Maltoni R,Ravaioli S.Cell-free DNA detected by “liquid biopsy” as a potential prognostic biomarker in early breast cancer..Oncotarget2017;8:16642-9 PMCID:PMC5369991

[59] Yizhak K,Kim J.RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues expansion across normal tissues..Science2019;364:eaaw0726 PMCID:PMC7350423

[60] Hu Y,Supplee J.False-positive plasma genotyping due to clonal hematopoiesis..Clin Cancer Res2018;24:4437-43

[61] Swanton C,Aravanis A.Prevalence of clonal hematopoiesis of indeterminate potential (CHIP) measured by an ultra-sensitive sequencing assay: exploratory analysis of the Circulating Cancer Genome Atlas (CCGA) study..J Clin Oncol2018;36:12003

[62] Heuser M,Ganser A.Clonal hematopoiesis of indeterminate potential..Dtsch Arztebl Int2016;113:317-22 PMCID:PMC4961884

[63] Diehl F,He YP,Vogelstein B.BEAMing: single-molecule PCR on microparticles in water-in-oil emulsions..Nat Methods2006;3:551-9

[64] Kinde I,Papadopoulos N,Vogelstein B.Detection and quantification of rare mutations with massively parallel sequencing..Proc Natl Acad Sci U S A2011;108:9530-5 PMCID:PMC3111315

[65] Forshew T,Parkinson C.Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA..Sci Transl Med2012;4:136ra68

[66] Newman AM,To J.An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage..Nat Med2014;20:548-54 PMCID:PMC4016134

[67] Kim AS,Bridge JA.Comparison of laboratory-developed tests and FDA-approved assays for BRAF, EGFR, and KRAS testing..JAMA Oncol2018;4:838-41 PMCID:PMC6145687

[68] Gorges TM,Schalk T.Enumeration and Molecular Characterization of Tumor Cells in Lung Cancer Patients Using a Novel In vivo Device for Capturing Circulating Tumor Cells..Clin Cancer Res2016;22:2197-206

[69] Hyun KA,Han H.Epithelial-to-mesenchymal transition leads to loss of EpCAM and different physical properties in circulating tumor cells from metastatic breast cancer..Oncotarget2016;7:24677-87 PMCID:PMC5029733

[70] Yu M,Wittner BS.Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition..Science2013;339:580-4 PMCID:PMC3760262

[71] Raimondi C,Gradilone A.Circulating tumor cells isolation: the “post-EpCAM era”..Chin J Cancer Res2015;27:461-70 PMCID:PMC4626820

[72] Loeian MS,Farhadi F.Liquid biopsy using the nanotube-CTC-chip: capture of invasive CTCs with high purity using preferential adherence in breast cancer patients..Lab Chip2019;19:1899-915

[73] Bidard FC,Delaloge S.Time-dependent prognostic impact of circulating tumor cells detection in non-metastatic breast cancer: 70-month analysis of the REMAGUS02 study..Int J Breast Cancer2013;2013:130470 PMCID:PMC3665249

[74] Riethdorf S,Loibl S.Prognostic impact of circulating tumor cells for breast cancer patients treated in the neoadjuvant “Geparquattro” trial..Clin Cancer Res2017;23:5384-93

[75] Goodman CR,Friedl TWP.Association of circulating tumor cell status with benefit of radiotherapy and survival in early-stage breast cancer..JAMA Oncol2018;4:e180163 PMCID:PMC6143053

[76] Sparano J,Alpaugh K.Association of circulating tumor cells with late recurrence of estrogen receptor-positive breast cancer: a secondary analysis of a randomized clinical trial..JAMA Oncol2018;4:1700-6 PMCID:PMC6385891

[77] Ignatiadis M,Rothe F.Trastuzumab versus observation for HER2 nonamplified early breast cancer with circulating tumor cells (EORTC 90091-10093, BIG 1-12, Treat CTC): a randomized phase II trial..Ann Oncol2018;29:1777-83

[78] Kasimir-Bauer S,König L.Does primary neoadjuvant systemic therapy eradicate minimal residual disease? Analysis of disseminated and circulating tumor cells before and after therapy..Breast Cancer Res2016;18:20 PMCID:PMC4751719