The optimal choice of cancer therapy depends upon analysis of the tumor genome for druggable molecular alterations. The spatial and temporal intratumor heterogeneity of cancers creates substantial challenges, as molecular profile depends on time and site of tumor tissue collection. To capture the entire molecular profile, multiple biopsies from primary and metastatic sites at different time points would be required, which is not feasible for ethical or economic reasons. Molecular analysis of circulating cell-free DNA offers a novel, minimally invasive method that can be performed at multiple time-points and plausibly better represents the prevailing molecular profile of the cancer. Molecular analysis of this cell-free DNA offers multiple clinically useful applications, such as identification of molecular targets for cancer therapy, monitoring of tumor molecular profile in real time, detection of emerging molecular aberrations associated with resistance to particular therapy, determination of cancer prognosis and diagnosis of cancer recurrence or progression.

b Department of Neurology Faculty Hospital Plzen Plzen Czech Republic

c Department of Biology Faculty of Medicine in Plzen Charles University Prague Plzen Czech Republic

Department of Histology and Embryology and Biomedical Centre Faculty of Medicine in Plzen Charles University Prague Plzen Czech Republic

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Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147(2):275–292. PubMed PMC

Yates LR, Campbell PJ. Evolution of the cancer genome. Nat Rev Genet. 2012;13(11):795–806. PubMed PMC

Burrell RA, Swanton C. The evolution of the unstable cancer genome. Curr Opin Genet Dev. 2014;24:61–67. PubMed

Garrido-Laguna I, Hidalgo M, Kurzrock R. The inverted pyramid of biomarker-driven trials. Nat Rev Clin Oncol. 2011;8(9):562–566. PubMed

Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883–892. The paper demonstrated the tumor intrinsic heterogeneity. The cancer-related aberrations can differ among tumor regions and distinct metastatic disease sites. PubMed PMC

Diamantis A, Magiorkinis E, Koutselini H. Fine-needle aspiration (FNA) biopsy: historical aspects. Folia Histochem Cytobiol. 2009;47(2):191–197. PubMed

Mandel P, Metais P. Les acides nucleiques du plasma sanguin chez l’homme [in French] Comptes Rendus Séances Société Biol Ses Fil. 1948;142(3–4):241–243. PubMed

Diaz LA, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32(6):579–586. PubMed PMC

Benn P, Cuckle H, Pergament E. Non-invasive prenatal testing for aneuploidy: current status and future prospects. Ultrasound Obstet Gynecol. 2013;42(1):15–33. PubMed

Macher H, Egea-Guerrero JJ, Revuelto-Rey J, et al. Role of early cell-free DNA levels decrease as a predictive marker of fatal outcome after severe traumatic brain injury. Clin Chim Acta. 2012;414:12–17. PubMed

Jing R-R, Wang H-M, Cui M, et al. A sensitive method to quantify human cell-free circulating DNA in blood: relevance to myocardial infarction screening. Clin Biochem. 2011;44(13):1074–1079. PubMed

Tsai N-W, Lin T-K, Chen S-D, et al. The value of serial plasma nuclear and mitochondrial DNA levels in patients with acute ischemic stroke. Clin Chim Acta. 2011;412(5–6):476–479. PubMed

Wang H-C, Lin Y-J, Lin W-C, et al. The value of serial plasma nuclear and mitochondrial DNA levels in acute spontaneous intra-cerebral haemorrhage. Eur J Neurol. 2012;19(12):1532–1538. PubMed

Crowley E, Di Nicolantonio F, Loupakis F, et al. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10(8):472–484. PubMed

Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985–990. This pilot study demonstrated that the tumor unique molecular signature could be found in cfDNA from patients with colorectal cancer and the patients at risk of recurrence after the surgical intervention could be detected. PubMed PMC

Diaz LA, Williams RT, Wu J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486(7404):537–540. This landmark study demonstrated the possibility to detect KRAS mutations in serum of colorectal cancer patients receiving panitumumab whose tumor and cfDNA were initially KRAS wild-type. PubMed PMC

Janku F, Vibat CRT, Kosco K, et al. BRAF V600E mutations in urine and plasma cell-free DNA from patients with Erdheim-Chester disease. Oncotarget. 2014;5(11):3607–3610. PubMed PMC

Hyman DM, Diamond EL, Vibat CRT, et al. Prospective Blinded Study of BRAFV600E Mutation Detection in Cell-Free DNA of Patients with Systemic Histiocytic Disorders. Cancer Discov. 2015;5(1):64–71. PubMed PMC

Pan W, Gu W, Nagpal S, et al. Brain tumor mutations detected in cerebral spinal fluid. Clin Chem. 2015;61(3):514–522. PubMed PMC

Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486(7404):532–536. The emergence of KRAS aberrations was found in colorectal cancer tissue samples from metastatic sites obtained after initiation of anti-EGFR therapy. Corresponding plasma samples also showed emergence of KRAS mutation in cfDNA. PubMed PMC

Husain H, Venkatapathy S, Gomez G, et al. Cell-free DNA derived from ascites: Detection of copy number and somatic mutations using OncoScan FFPE® Assay [abstract]. Proc Annu Meet Am Assoc Cancer Res; 2015 Apr 18–22; Washington, DC. Philadelphia (PA): AACR; 2015. Abstract nr 2410.

Fleischhacker M, Schmidt B. Circulating nucleic acids (CNAs) and cancer--a survey. Biochim Biophys Acta. 2007;1775(1):181–232. PubMed

Schwarzenbach H, Hoon DSB, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11(6):426–437. PubMed

Paci M, Maramotti S, Bellesia E, et al. Circulating plasma DNA as diagnostic biomarker in non-small cell lung cancer. Lung Cancer. 2009;64(1):92–97. PubMed

Ulivi P, Mercatali L, Casoni G-L, et al. Multiple marker detection in peripheral blood for NSCLC diagnosis. PloS One. 2013;8(2):e57401. PubMed PMC

Yoon K-A, Park S, Lee SH, et al. Comparison of circulating plasma DNA levels between lung cancer patients and healthy controls. J Mol Diagn. 2009;11(3):182–185. PubMed PMC

Catarino R, Ferreira MM, Rodrigues H, et al. Quantification of free circulating tumor DNA as a diagnostic marker for breast cancer. DNA Cell Biol. 2008;27(8):415–421. PubMed

Hashad D, Sorour A, Ghazal A, et al. Free circulating tumor DNA as a diagnostic marker for breast cancer. J Clin Lab Anal. 2012;26(6):467–472. PubMed PMC

Gong B, Xue J, Yu J, et al. Cell-free DNA in blood is a potential diagnostic biomarker of breast cancer. Oncol Lett. 2012;3(4):897–900. PubMed PMC

Kamat AA, Baldwin M, Urbauer D, et al. Plasma cell-free DNA in ovarian cancer: an independent prognostic biomarker. Cancer. 2010;116(8):1918–1925. PubMed PMC

Zachariah RR, Schmid S, Buerki N, et al. Levels of circulating cell-free nuclear and mitochondrial DNA in benign and malignant ovarian tumors. Obstet Gynecol. 2008;112(4):843–850. PubMed

Schwarzenbach H, Stoehlmacher J, Pantel K, et al. Detection and monitoring of cell-free DNA in blood of patients with colorectal cancer. Ann N Y Acad Sci. 2008;1137:190–196. PubMed

Boni L, Cassinotti E, Canziani M, et al. Free circulating DNA as possible tumour marker in colorectal cancer. Surg Oncol. 2007;16(Suppl 1):S29–31. PubMed

Danese E, Montagnana M, Minicozzi AM, et al. Real-time polymerase chain reaction quantification of free DNA in serum of patients with polyps and colorectal cancers. Clin Chem Lab Med. 2010;48(11):1665–1668. PubMed

Marzese DM, Hirose H, Hoon DSB. Diagnostic and prognostic value of circulating tumor-related DNA in cancer patients. Expert Rev Mol Diagn. 2013;13(8):827–844. PubMed

Jahr S, Hentze H, Englisch S, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001;61(4):1659–1665. PubMed

Nagata S, Nagase H, Kawane K, et al. Degradation of chromosomal DNA during apoptosis. Cell Death Differ. 2003;10(1):108–116. PubMed

Mouliere F, Robert B, Arnau Peyrotte E, et al. High fragmentation characterizes tumour-derived circulating DNA. PloS One. 2011;6(9):e23418. PubMed PMC

Wang BG, Huang H-Y, Chen Y-C, et al. Increased plasma DNA integrity in cancer patients. Cancer Res. 2003;63(14):3966–3968. PubMed

Thierry AR, Mouliere F, Gongora C, et al. Origin and quantification of circulating DNA in mice with human colorectal cancer xenografts. Nucleic Acids Res. 2010;38(18):6159–6175. PubMed PMC

García-Olmo DC, García-Olmo D. Biological role of cell-free nucleic acids in cancer: the theory of genometastasis. Crit Rev Oncog. 2013;18(1–2):153–161. PubMed

García-Olmo DC, Picazo MG, García-Olmo D. Transformation of non-tumor host cells during tumor progression: theories and evidence. Expert Opin Biol Ther. 2012;12(Suppl 1):S199–207. PubMed

García-Olmo DC, Domínguez C, García-Arranz M, et al. Cell-free nucleic acids circulating in the plasma of colorectal cancer patients induce the oncogenic transformation of susceptible cultured cells. Cancer Res. 2010;70(2):560–567. PubMed

Emlen W, Mannik M. Effect of DNA size and strandedness on the in vivo clearance and organ localization of DNA. Clin Exp Immunol. 1984;56(1):185–192. PubMed PMC

El Messaoudi S, Rolet F, Mouliere F, et al. Circulating cell free DNA: Preanalytical considerations. Clin Chim Acta. 2013;424:222–230. The paper discussed the important preanalytical considerations that could influence cfDNA analysis.”. PubMed

Ignatiadis M, Dawson S-J. Circulating tumor cells and circulating tumor DNA for precision medicine: dream or reality? Ann Oncol. 2014;25(12):2304–2313. PubMed

Wong D, Moturi S, Angkachatchai V, et al. Optimizing blood collection, transport and storage conditions for cell free DNA increases access to prenatal testing. Clin Biochem. 2013;46(12):1099–1104. PubMed

Qin J, Williams TL, Fernando MR. A novel blood collection device stabilizes cell-free RNA in blood during sample shipping and storage. BMC Res Notes. 2013;6:380. PubMed PMC

Tuaeva NO, Abramova ZI, Sofronov VV. The origin of elevated levels of circulating DNA in blood plasma of premature neonates. Ann N Y Acad Sci. 2008;1137:27–30. PubMed

Björkman L, Reich CF, Pisetsky DS. The use of fluorometric assays to assess the immune response to DNA in murine systemic lupus erythematosus. Scand J Immunol. 2003;57(6):525–533. PubMed

Szpechcinski A, Struniawska R, Zaleska J, et al. Evaluation of fluorescence-based methods for total vs. amplifiable DNA quantification in plasma of lung cancer patients. J Physiol Pharmacol. 2008;59(Suppl 6):675–681. PubMed

Goldshtein H, Hausmann MJ, Douvdevani A. A rapid direct fluorescent assay for cell-free DNA quantification in biological fluids. Ann Clin Biochem. 2009;46(Pt 6):488–494. PubMed

Legendre C, Gooden G, Johnson K, et al. Whole genome bisulfite sequencing from plasma of patients with metastatic breast cancer identifies putative biomarkers [abstract]. Proc Annu Meet Am Assoc Cancer Res; 2015 Apr 18–22; Washington, DC. Philadelphia (PA): AACR; 2015. Abstract nr 3825.

Diehl F, Li M, Dressman D, et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci. 2005;102(45):16368–16373. PubMed PMC

Board RE, Wardley AM, Dixon JM, et al. Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer. Breast Cancer Res Treat. 2010;120(2):461–467. PubMed

Chen Z, Feng J, Buzin CH, et al. Analysis of cancer mutation signatures in blood by a novel ultra-sensitive assay: monitoring of therapy or recurrence in non-metastatic breast cancer. PloS One. 2009;4(9):e7220. PubMed PMC

Wang J-Y, Hsieh J-S, Chang M-Y, et al. Molecular detection of APC, K- ras, and p53 mutations in the serum of colorectal cancer patients as circulating biomarkers. World J Surg. 2004;28(7):721–726. PubMed

Frattini M, Gallino G, Signoroni S, et al. Quantitative and qualitative characterization of plasma DNA identifies primary and recurrent colorectal cancer. Cancer Lett. 2008;263(2):170–181. PubMed

Yamada T, Nakamori S, Ohzato H, et al. Detection of K-ras gene mutations in plasma DNA of patients with pancreatic adenocarcinoma: correlation with clinicopathological features. Clin Cancer Res. 1998;4(6):1527–1532. PubMed

Castells A, Puig P, Móra J, et al. K-ras mutations in DNA extracted from the plasma of patients with pancreatic carcinoma: diagnostic utility and prognostic significance. J Clin Oncol. 1999;17(2):578–584. PubMed

Beaver JA, Jelovac D, Balukrishna S, et al. Detection of cancer DNA in plasma of patients with early-stage breast cancer. Clin Cancer Res. 2014;20(10):2643–2650. PubMed PMC

Higgins MJ, Jelovac D, Barnathan E, et al. Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood. Clin Cancer Res. 2012;18(12):3462–3469. PubMed PMC

Dawson S-J, Tsui DWY, Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368(13):1199–1209. PubMed

Yung TKF, Chan KCA, Mok TSK, et al. Single-molecule detection of epidermal growth factor receptor mutations in plasma by microfluidics digital PCR in non-small cell lung cancer patients. Clin Cancer Res. 2009;15(6):2076–2084. PubMed

Carreira S, Romanel A, Goodall J, et al. Tumor clone dynamics in lethal prostate cancer. Sci Transl Med. 2014;6(254):254ra125. PubMed PMC

Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24. PubMed PMC

Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20(5):548–554. PubMed PMC

Murtaza M, Dawson S-J, Tsui DWY, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013;497(7447):108–112. A proof-of-principle study successfully monitored the acquisition of secondary resistance mutations to various anticancer treatments in cfDNA from six advanced cancer patients using unbiased whole-exome sequencing. PubMed

Chan KCA, Jiang P, Zheng YWL, et al. Cancer genome scanning in plasma: detection of tumor-associated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by massively parallel sequencing. Clin Chem. 2013;59(1):211–224. PubMed

Heitzer E, Ulz P, Belic J, et al. Tumor-associated copy number changes in the circulation of patients with prostate cancer identified through whole-genome sequencing. Genome Med. 2013;5(4):30. PubMed PMC

Janku F, Angenendt P, Tsimberidou AM, et al. Actionable mutations in plasma cell-free DNA in patients with advanced cancers referred for experimental targeted therapies. Oncotarget. 2015;6(14):12809–21. PubMed PMC

Thierry AR, Mouliere F, El Messaoudi S, et al. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med. 2014;20(4):430–435. PubMed

Aung KL, Donald E, Ellison G, et al. Analytical validation of BRAF mutation testing from circulating free DNA using the amplification refractory mutation testing system. J Mol Diagn. 2014;16(3):343–349. PubMed

Panka DJ, Buchbinder E, Giobbie-Hurder A, et al. Clinical utility of a blood-based BRAF(V600E) mutation assay in melanoma. Mol Cancer Ther. 2014;13(12):3210–3218. PubMed PMC

Pupilli C, Pinzani P, Salvianti F, et al. Circulating BRAFV600E in the diagnosis and follow-up of differentiated papillary thyroid carcinoma. J Clin Endocrinol Metab. 2013;98(8):3359–3365. PubMed

Zill OA, Greene C, Sebisanovic D, et al. Cell-Free DNA Next-Generation Sequencing in Pancreatobiliary Carcinomas. Cancer Discov. 2015 doi: 10.1158/2159-8290.CD-15-0274. PubMed DOI PMC

Forshew T, Murtaza M, Parkinson C, et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med. 2012;4(136):136ra68. PubMed

Rothé F, Laes J-F, Lambrechts D, et al. Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer. Ann Oncol. 2014;25(10):1959–1965. PubMed

Spindler K-LG, Pallisgaard N, Vogelius I, et al. Quantitative cell-free DNA, KRAS, and BRAF mutations in plasma from patients with metastatic colorectal cancer during treatment with cetuximab and irinotecan. Clin Cancer Res. 2012;18(4):1177–1185. The study demonstrated the prognostic value of the amount of total cfDNA as well as KRAS mutant cfDNA for metastatic colorectal cancer patients. PubMed

Nygaard AD, Garm Spindler K-L, Pallisgaard N, et al. The prognostic value of KRAS mutated plasma DNA in advanced non-small cell lung cancer. Lung Cancer. 2013;79(3):312–317. PubMed

Divella R, Tommasi S, Lacalamita R, et al. Circulating hTERT DNA in early breast cancer. Anticancer Res. 2009;29(7):2845–2849. PubMed

Wang S, An T, Wang J, et al. Potential clinical significance of a plasma-based KRAS mutation analysis in patients with advanced non-small cell lung cancer. Clin Cancer Res. 2010;16(4):1324–1330. PubMed

Shinozaki M, O’Day SJ, Kitago M, et al. Utility of circulating B-RAF DNA mutation in serum for monitoring melanoma patients receiving biochemotherapy. Clin Cancer Res. 2007;13(7):2068–2074. PubMed PMC

Silva JM, Silva J, Sanchez A, et al. Tumor DNA in plasma at diagnosis of breast cancer patients is a valuable predictor of disease-free survival. Clin Cancer Res. 2002;8(12):3761–3766. PubMed

Lefebure B, Charbonnier F, Di Fiore F, et al. Prognostic value of circulating mutant DNA in unresectable metastatic colorectal cancer. Ann Surg. 2010;251(2):275–280. PubMed

Trevisiol C, Di Fabio F, Nascimbeni R, et al. Prognostic value of circulating KRAS2 gene mutations in colorectal cancer with distant metastases. Int J Biol Markers. 2006;21(4):223–228. PubMed

Swisher EM, Wollan M, Mahtani SM, et al. Tumor-specific p53 sequences in blood and peritoneal fluid of women with epithelial ovarian cancer. Am J Obstet Gynecol. 2005;193(3 Pt 1):662–667. PubMed

Schwarzenbach H, Eichelser C, Kropidlowski J, et al. Loss of heterozygosity at tumor suppressor genes detectable on fractionated circulating cell-free tumor DNA as indicator of breast cancer progression. Clin Cancer Res. 2012;18(20):5719–5730. PubMed

Kuhlmann JD, Schwarzenbach H, Wimberger P, et al. LOH at 6q and 10q in fractionated circulating DNA of ovarian cancer patients is predictive for tumor cell spread and overall survival. BMC Cancer. 2012;12:325. PubMed PMC

Fujimoto A, O’Day SJ, Taback B, et al. Allelic imbalance on 12q22–23 in serum circulating DNA of melanoma patients predicts disease outcome. Cancer Res. 2004;64(12):4085–4088. PubMed

Sozzi G, Conte D, Mariani L, et al. Analysis of circulating tumor DNA in plasma at diagnosis and during follow-up of lung cancer patients. Cancer Res. 2001;61(12):4675–4678. PubMed

Esteller M, Sanchez-Cespedes M, Rosell R, et al. Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients. Cancer Res. 1999;59(1):67–70. PubMed

Silva JM, Dominguez G, Villanueva MJ, et al. Aberrant DNA methylation of the p16INK4a gene in plasma DNA of breast cancer patients. Br J Cancer. 1999;80(8):1262–1264. PubMed PMC

Wong IH, Lo YM, Zhang J, et al. Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients. Cancer Res. 1999;59(1):71–73. PubMed

Sharma G, Mirza S, Parshad R, et al. Clinical significance of promoter hypermethylation of DNA repair genes in tumor and serum DNA in invasive ductal breast carcinoma patients. Life Sci. 2010;87(3–4):83–91. PubMed

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(5):273–282. PubMed

Göbel G, Auer D, Gaugg I, et al. Prognostic significance of methylated RASSF1A and PITX2 genes in blood- and bone marrow plasma of breast cancer patients. Breast Cancer Res Treat. 2011;130(1):109–117. PubMed

Philipp AB, Stieber P, Nagel D, et al. Prognostic role of methylated free circulating DNA in colorectal cancer. Int J Cancer. 2012;131(10):2308–2319. PubMed

Balgkouranidou I, Karayiannakis A, Matthaios D, et al. Assessment of SOX17 DNA methylation in cell free DNA from patients with operable gastric cancer. Association with prognostic variables and survival. Clin Chem Lab Med. 2013;51(7):1505–1510. PubMed

Sun F-K, Fan Y-C, Zhao J, et al. Detection of TFPI2 methylation in the serum of hepatocellular carcinoma patients. Dig Dis Sci. 2013;58(4):1010–1015. PubMed

Tseng J-S, Yang T-Y, Tsai C-R, et al. Dynamic plasma EGFR mutation status as a predictor of EGFR-TKI efficacy in patients with EGFR-mutant lung adenocarcinoma. J Thorac Oncol. 2015;10(4):603–10. PubMed

Oxnard GR, Paweletz CP, Kuang Y, et al. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res. 2014;20(6):1698–1705. PubMed PMC

Douillard J-Y, Ostoros G, Cobo M, et al. Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. J Thorac Oncol. 2014;9(9):1345–1353. This paper demonstrated that EGFR mutation status could be assessed in cfDNA from patients with advanced lung cancer and served as a positive predictive biomarker for targeted therapy with gefitinib. PubMed PMC

Janku F, Huang H, Claes B, et al. Rapid, automated BRAF mutation testing of cell-free DNA from plasma of patients with advanced cancers using the novel Idylla platform [abstract]. Proc Annu Meet Am Assoc Cancer Res; 2015 Apr 18–22; Washington, DC. Philadelphia (PA): AACR; 2015. Abstract nr 2413.

Normanno N, Rachiglio AM, Roma C, et al. Molecular diagnostics and personalized medicine in oncology: challenges and opportunities. J Cell Biochem. 2013;114(3):514–524. PubMed

Ramos P, Bentires-Alj M. Mechanism-based cancer therapy: resistance to therapy, therapy for resistance. Oncogene. 2015;34(28):3617–26. PubMed

Soverini S, Branford S, Nicolini FE, et al. Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia. Leuk Res. 2014;38(1):10–20. PubMed

Van Emburgh BO, Sartore-Bianchi A, Di Nicolantonio F, et al. Acquired resistance to EGFR-targeted therapies in colorectal cancer. Mol Oncol. 2014;8(6):1084–1094. PubMed PMC

Yun C-H, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci. 2008;105(6):2070–2075. PubMed PMC

Su K-Y, Chen H-Y, Li K-C, et al. Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J Clin Oncol. 2012;30(4):433–440. PubMed

Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010;363(18):1734–1739. PubMed

Holderfield M, Deuker MM, McCormick F, et al. Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer. 2014;14(7):455–467. PubMed PMC

Taniguchi K, Uchida J, Nishino K, et al. Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas. Clin Cancer Res. 2011;17(24):7808–7815. PubMed

Wang Z, Chen R, Wang S, et al. Quantification and dynamic monitoring of EGFR T790M in plasma cell-free DNA by digital PCR for prognosis of EGFR-TKI treatment in advanced NSCLC. PloS One. 2014;9(11):e110780. PubMed PMC

Morelli MP, Overman MJ, Dasari A, et al. Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment. Ann Oncol. 2015;26(4):731–6. PubMed PMC

Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351(8):781–791. PubMed

Hayes DF, Cristofanilli M, Budd GT, et al. Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res. 2006;12(14 Pt 1):4218–4224. PubMed

De Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14(19):6302–6309. PubMed

Cohen SJ, Punt CJA, Iannotti N, et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(19):3213–3221. PubMed

Kahlert C, Melo SA, Protopopov A, et al. Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem. 2014;289(7):3869–3875. PubMed PMC

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