Abstract
An accurate profiling of the genomic landscape is mandatory to establish the best clinical and therapeutic approach for patients with solid malignancies. Moreover, tumor cells constantly adapt to external pressures—i.e., systemic treatment—with the selection and expansion of resistant subclones and the emergence of heterogeneous overlapping genomic alterations of resistance. The current standard for molecular characterization in cancer is the performance of a tissue tumor biopsy at the time of diagnosis and, when possible, a re-biopsy at the time of progression. However, tissue biopsy is not always feasible or practical and may underestimate tumor heterogeneity and clonal dynamics. Circulating DNA fragments carrying tumor-specific sequence alterations (circulating tumor DNA, ctDNA) are released from cancer cells into the bloodstream, representing a variable and generally small fraction of the total circulating cell-free DNA. Tumor genotyping in ctDNA (liquid biopsy) offers potential advantages versus the standard tumor tissue biopsy, including non-invasiveness and representation of molecular heterogeneity. Technical advances in sequencing platforms have led to dramatic improvements in variant detection sensitivity and specificity that allow for the detection and quantification of low levels of ctDNA. This provides valuable information on both actionable mutations and captures real-time variations in tumor dynamics. Liquid biopsy clinical applications include molecular diagnosis, determination of tumor load as a surrogate marker of early response, monitoring of mutations of resistance to targeted therapy and detection of minimal residual disease after cancer surgery. The aim of this chapter is to provide an overview of the biological rational and technical background of ctDNA analysis, as well as on the main clinical applications of liquid biopsy in dynamic treatment stratification in solid tumors. Special emphasis will be made on the current and potential benefits of the implementation of ctDNA in clinical practice, mainly in melanoma, lung, and colorectal cancer.
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References
Arena S, Bellosillo B, Siravegna G, Martinez A, Canadas I, Lazzari L et al (2015) Emergence of multiple EGFR extracellular mutations during cetuximab treatment in colorectal cancer. Clin Cancer Res 21(9):2157–2166
Bardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G et al (2013) Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov 3(6):658–673
Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N et al (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6(224):224ra24
Cabel L, Riva F, Servois V, Livartowski A, Daniel C, Rampanou A et al (2017) Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a proof-of-concept study. Ann Oncol 28(8):1996–2001
Cremolini C, Rossini D, Dell’Aquila E, Lonardi S, Conca E, Del Re M, Busico A, Pietrantonio F, Danesi R, Aprile G, Tamburini E, Barone C, Masi G, Pantano F, Pucci F, Corsi DC, Pella N, Bergamo F, Rofi E, Barbara C, Falcone A, Santini D (2018) Rechallenge for patients with RAS and BRAF wild-type metastatic colorectal cancer with acquired resistance to first-line Cetuximab and Irinotecan: a phase 2 single-arm clinical trial. JAMA Oncol (Epub ahead of print)
Dawson S-J, Tsui DWY, Murtaza M, Biggs H, Rueda OM, Chin S-F et al (2013) Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 368(13):1199–1209
Diaz LA, Bardelli A (2014) Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 32(6):579
Diaz LA, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J et al (2012) The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486(7404):537–540
Diaz LA, Sausen M, Fisher GA, Velculescu VE (2013) Insights into therapeutic resistance from whole-genome analyses of circulating tumor DNA. Oncotarget 4(10):1856–1857
Goldberg SB, Narayan A, Kole AJ, Decker RH, Teysir J, Carriero NJ et al (2018) Early assessment of lung cancer immunotherapy response via circulating tumor DNA. Clin Cancer Res [Internet] 24(8):clincanres.1341.2017. Available from: http://clincancerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-17-1341
Iijima Y, Hirotsu Y, Amemiya K, Ooka Y, Mochizuki H, Oyama T et al (2017) Very early response of circulating tumour–derived DNA in plasma predicts efficacy of nivolumab treatment in patients with non–small cell lung cancer. Eur J Cancer [Internet] 86:349–57. Available from: https://doi.org/10.1016/j.ejca.2017.09.004
Iwama E, Sakai K, Azuma K, Harada T, Harada D, Nosaki K et al (2017) Monitoring of somatic mutations in circulating cell-free DNA by digital PCR and next-generation sequencing during afatinib treatment in patients with lung adenocarcinoma positive for EGFR activating mutations. Ann Oncol Off J Eur Soc Med Oncol 28(1):136–141
Lee JH, Long GV, Boyd S, Lo S, Menzies AM, Tembe V et al (2017) Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic melanoma. Ann Oncol 28(5):1130–1136
Lipson EJ, Velculescu VE, Pritchard TS, Sausen M, Pardoll DM, Topalian SL et al (2014) Circulating tumor DNA analysis as a real-time method for monitoring tumor burden in melanoma patients undergoing treatment with immune checkpoint blockade. J Immunother Cancer [Internet] 2(1):42. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25516806%5Cn/http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4267741
Madore J, Vilain RE, Menzies AM, Kakavand H, Wilmott JS, Hyman J et al (2015) PD-L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti-PD-1/PD-L1 clinical trials. Pigm Cell Melanoma Res [Internet] 28(3):245–253, May 2015 [cited 18 Apr 2018]. Available from: http://doi.wiley.com/10.1111/pcmr.12340
Marchetti A, Palma JF, Felicioni L, De Pas TM, Chiari R, Del Grammastro M et al (2015) Early prediction of response to tyrosine kinase inhibitors by quantification of EGFR mutations in plasma of NSCLC patients. J Thorac Oncol 10(10):1437–1443
Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D et al (2012) Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486(7404):532–536
Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M et al (2012) Identification of a mutation in the extracellular domain of the epidermal growth factor receptor conferring cetuximab resistance in colorectal cancer. Nat Med 18(2):221–223
Montagut C, Argilés G, Ciardiello F, Poulsen TT, Dienstmann R, Kragh M et al (2018) Efficacy of Sym004 in patients with metastatic colorectal cancer with acquired resistance to anti-EGFR therapy and molecularly selected by circulating tumor DNA analyses. JAMA Oncol [Internet], e175245. Available from: http://oncology.jamanetwork.com/article.aspx?doi=10.1001/jamaoncol.2017.525
Morelli MP, Overman MJ, Dasari A (2015) Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment. Ann Oncol Off J Eur Soc Med Oncol/ESMO 26(4):731–736
O’Leary B, Hrebien S, Morden JP, Beaney M, Fribbens C, Huang X et al (2018) Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. Nat Commun [Internet] 9(1):896, 1 Dec 2018 [cited 18 Apr 2018]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29497091
Oxnard GR, Thress KS, Alden RS, Lawrance R, Paweletz CP, Cantarini M et al (2016) Association between plasma genotyping and outcomes of treatment with Osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol 34(28):3375–3382
Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF et al (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:0225–0235
Sanmamed MF, Fernandez-Landazuri S, Rodriguez C, Zarate R, Lozano MD, Zubiri L et al (2015) Quantitative cell-free circulating BRAFV600E mutation analysis by use of droplet digital PCR in the follow-up of patients with melanoma being treated with BRAF inhibitors. Clin Chem 61(1):297–304
Schiavon G, Hrebien S, Garcia-Murillas I, Cutts RJ, Pearson A, Tarazona N et al (2015) Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med [Internet] 7(313):313ra182, 11 Nov 2015 [cited 18 Apr 2018]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26560360
Schwaederle M, Zhao M, Lee JJ, Eggermont AM, Schilsky RL, Mendelsohn J et al (2015) Impact of precision medicine in diverse cancers: a meta-analysis of phase II clinical trials. J Clin Oncol 33(32):3817–3825
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S et al (2017) iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 18(3):e143–e152
Siegel RL, Miller KD, Jemal A (2017) Cancer statistics 2017 67(1):7–30
Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G et al (2015) Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med 21(7):827
Taniguchi K, Uchida J, Nishino K, Kumagai T, Okuyama T, Okami J et al (2011) Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas. Clin Cancer Res 17(24):7808–7815
Taus Á, Camacho L, Rocha P, Hardy-Werbin M, Pijuan L, Piquer G et al (2018) Dynamics of EGFR mutation load in plasma for prediction of treatment response and disease progression in patients with EGFR-mutant lung adenocarcinoma. Clin Lung Cancer [Internet], 23 Mar 2018 [cited 18 Apr 2018]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29656868
Tie J, Kinde I, Wang Y, Wong HL, Roebert J, Christie M et al (2015) Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol Off J Eur Soc Med Oncol 26(8):1715–1722
Toledo RA, Cubillo A, Vega E, Garralda E, Alvarez R, de la Varga LU et al (2015) Clinical validation of prospective liquid biopsy monitoring in patients with wild-type RAS metastatic colorectal cancer treated with FOLFIRI-cetuximab. Oncotarget [Internet]. Available from: http://www.oncotarget.com/abstract/13311
Van Emburgh BO, Arena S, Siravegna G, Lazzari L, Crisafulli G, Corti G et al (2016) Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer. Nat Commun 7:13665
Vidal J, Muinelo L, Dalmases A, Jones F, Edelstein D, Iglesias M et al (2017) Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients. Ann Oncol 13(28):1325–1332
Xi L, Pham THT, Payabyab EC, Sherry RM, Rosenberg SA, Raffeld M (2016) Circulating tumor DNA as an early indicator of response to T-cell transfer immunotherapy in metastatic melanoma. Clin Cancer Res 22(22):5480–5486
Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J et al (2011) Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med [Internet] 3(99):99ra86, 7 Sep 2011 [cited 22 May 2017]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21900593
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Vidal, J., Taus, A., Montagut, C. (2020). Dynamic Treatment Stratification Using ctDNA. In: Schaffner, F., Merlin, JL., von Bubnoff, N. (eds) Tumor Liquid Biopsies. Recent Results in Cancer Research, vol 215. Springer, Cham. https://doi.org/10.1007/978-3-030-26439-0_14
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DOI: https://doi.org/10.1007/978-3-030-26439-0_14
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