A Cross-Sectional Comparison of Druggable Mutations in Primary Tumors, Metastatic Tissue, Circulating Tumor Cells, and Cell-Free Circulating DNA in Patients with Metastatic Breast Cancer: The MIRROR Study Protocol

Milagros Gonzalez-Rivera, Antoni C Picornell, Enrique L Alvarez, Miguel Martin, Milagros Gonzalez-Rivera, Antoni C Picornell, Enrique L Alvarez, Miguel Martin

Abstract

Background: Characterization of the driver mutations in an individual metastatic breast cancer (MBC) patient is critical to selecting effective targeted therapies. Currently, it is believed that the limited efficacy of many targeted drugs may be due to the expansion of drug resistant clones with different genotypes that were already present in the primary tumor. Identifying the genomic alterations of these clones, and introducing combined or sequential targeted drug regimens, could lead to a significant increase in the efficacy of currently available targeted therapies.

Objective: The primary objective of this study is to assess the concordance/discordance of mutations between the primary tumor and metastatic tissue in MBC patients. Secondary objectives include comparing the genomic profiles of circulating tumor cells (CTCs) and circulating free DNA (cfDNA) from peripheral blood with those of the primary tumor and metastatic tissue for each patient, evaluating these mutations in the signaling pathways that are relevant to the disease, and testing the feasibility of introducing liquid biopsy as a translational laboratory tool in clinical practice.

Methods: The multicenter, transversal, observational MIRROR study is currently ongoing in three participating hospitals. All consecutive patients with MBC confirmed by radiologic findings will be screened for eligibility, either at first relapse or if tumor regrowth occurs while on treatment for metastatic disease.

Results: Patient recruitment is currently ongoing. To date, 41 patients have a complete set of tissue samples available (plasma, CTCs, and formalin-fixed, paraffin-embedded primary tumor and metastatic tumor). However, none of these samples have undergone nucleic acids extraction or targeted deep sequencing.

Conclusions: The results of this study may have a significant influence on the practical management of patients with MBC, and may provide clues to clinicians that lead towards a better stratification of patients, resulting in more selective and less toxic treatments. Additionally, if genomic mutations found in metastatic tissues are similar to those detected in CTCs and/or cfDNA, liquid biopsies could prove to be a more convenient, non-invasive, and easily accessible source of genomic material for the analysis of mutations and other genomic aberrations in MBC.

Trial registration: ClinicalTrials.gov NCT02626039; https://ichgcp.net/clinical-trials-registry/NCT02626039 (Archived by WebCite at http://www.webcitation.org/6jlneVyoz).

Keywords: breast neoplasm; drug therapy; genetics; molecular targeted therapy; sequence analysis..

Conflict of interest statement

Conflicts of Interest: None declared.

Figures

Figure 1
Figure 1
Flowchart of participants, specimens, and samples through the study.

References

    1. Curigliano G. New drugs for breast cancer subtypes: targeting driver pathways to overcome resistance. Cancer Treat Rev. 2012 Jun;38(4):303–10. doi: 10.1016/j.ctrv.2011.06.006.
    1. Zardavas D, Baselga J, Piccart M. Emerging targeted agents in metastatic breast cancer. Nat Rev Clin Oncol. 2013 Apr;10(4):191–210. doi: 10.1038/nrclinonc.2013.29.
    1. Fribbens C, O'Leary B, Kilburn L, Hrebien S, Garcia-Murillas I, Beaney M, Cristofanilli M, Andre F, Loi S, Loibl S, Jiang J, Bartlett CH, Koehler M, Dowsett M, Bliss JM, Johnston SR, Turner NC. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2016 Jun 6; doi: 10.1200/JCO.2016.67.3061.
    1. Aparicio S, Caldas C. The implications of clonal genome evolution for cancer medicine. N Engl J Med. 2013 Feb 28;368(9):842–51. doi: 10.1056/NEJMra1204892.
    1. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976 Oct 1;194(4260):23–8.
    1. Marusyk A, Almendro V, Polyak K. Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer. 2012 May;12(5):323–34. doi: 10.1038/nrc3261.
    1. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012 Mar 8;366(10):883–92. doi: 10.1056/NEJMoa1113205.
    1. Ng CK, Pemberton HN, Reis-Filho JS. Breast cancer intratumor genetic heterogeneity: causes and implications. Expert Rev Anticancer Ther. 2012 Aug;12(8):1021–32. doi: 10.1586/era.12.85.
    1. Barker HE, Paget JT, Khan AA, Harrington KJ. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer. 2015 Jul;15(7):409–25. doi: 10.1038/nrc3958.
    1. Jeselsohn R, Buchwalter G, De Angelis C, Brown M, Schiff R. ESR1 mutation - mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol. 2015 Oct;12(10):573–83. doi: 10.1038/nrclinonc.2015.117.
    1. Schmitt MW, Loeb LA, Salk JJ. The influence of subclonal resistance mutations on targeted cancer therapy. Nat Rev Clin Oncol. 2016 Jun;13(6):335–47. doi: 10.1038/nrclinonc.2015.175.
    1. Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta. 2010 Jan;1805(1):105–17. doi: 10.1016/j.bbcan.2009.11.002.
    1. Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, Cook K, Stepansky A, Levy D, Esposito D, Muthuswamy L, Krasnitz A, McCombie WR, Hicks J, Wigler M. Tumour evolution inferred by single-cell sequencing. Nature. 2011 Apr 7;472(7341):90–4. doi: 10.1038/nature09807.
    1. Navin N, Krasnitz A, Rodgers L, Cook K, Meth J, Kendall J, Riggs M, Eberling Y, Troge J, Grubor V, Levy D, Lundin P, Månér S, Zetterberg A, Hicks J, Wigler M. Inferring tumor progression from genomic heterogeneity. Genome Res. 2010 Jan;20(1):68–80. doi: 10.1101/gr.099622.109.
    1. Parker JS, Perou CM. Tumor Heterogeneity: focus on the leaves, the trees, or the forest? Cancer Cell. 2015 Aug 10;28(2):149–50. doi: 10.1016/j.ccell.2015.07.011.
    1. Yates LR, Gerstung M, Knappskog S, Desmedt C, Gundem G, Van Loo P, Aas T, Alexandrov LB, Larsimont D, Davies H, Li Y, Ju YS, Ramakrishna M, Haugland HK, Lilleng PK, Nik-Zainal S, McLaren S, Butler A, Martin S, Glodzik D, Menzies A, Raine K, Hinton J, Jones D, Mudie LJ, Jiang B, Vincent D, Greene-Colozzi A, Adnet P, Fatima A, Maetens M, Ignatiadis M, Stratton MR, Sotiriou C, Richardson AL, Lønning PE, Wedge DC, Campbell PJ. Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nat Med. 2015 Jul;21(7):751–9. doi: 10.1038/nm.3886.
    1. Vignot S, Frampton GM, Soria J, Yelensky R, Commo F, Brambilla C, Palmer G, Moro-Sibilot D, Ross JS, Cronin MT, André F, Stephens PJ, Lazar V, Miller VA, Brambilla E. Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer. J Clin Oncol. 2013 Jun 10;31(17):2167–72. doi: 10.1200/JCO.2012.47.7737.
    1. Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer. 2009 Apr;9(4):302–12. doi: 10.1038/nrc2627.
    1. Dawson S, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin S, Dunning MJ, Gale D, Forshew T, Mahler-Araujo B, Rajan S, Humphray S, Becq J, Halsall D, Wallis M, Bentley D, Caldas C, Rosenfeld N. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013 Mar 28;368(13):1199–209. doi: 10.1056/NEJMoa1213261.
    1. Forshew T, Murtaza M, Parkinson C, Gale D, Tsui DW, Kaper F, Dawson S, Piskorz AM, Jimenez-Linan M, Bentley D, Hadfield J, May AP, Caldas C, Brenton JD, Rosenfeld N. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med. 2012 May 30;4(136):136ra68. doi: 10.1126/scitranslmed.3003726.
    1. Cancer Genome Atlas Network Comprehensive molecular portraits of human breast tumours. Nature. 2012 Oct 4;490(7418):61–70. doi: 10.1038/nature11412.
    1. Murtaza M, Dawson S, Tsui DW, Gale D, Forshew T, Piskorz AM, Parkinson C, Chin S, Kingsbury Z, Wong AS, Marass F, Humphray S, Hadfield J, Bentley D, Chin TM, Brenton JD, Caldas C, Rosenfeld N. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013 May 2;497(7447):108–12. doi: 10.1038/nature12065.
    1. Jung K, Fleischhacker M, Rabien A. Cell-free DNA in the blood as a solid tumor biomarker--a critical appraisal of the literature. Clin Chim Acta. 2010 Nov 11;411(21-22):1611–24. doi: 10.1016/j.cca.2010.07.032.
    1. Hart SN, Therneau TM, Zhang Y, Poland GA, Kocher J. Calculating sample size estimates for RNA sequencing data. J Comput Biol. 2013 Dec;20(12):970–8. doi: 10.1089/cmb.2012.0283.

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