Applications of DNA-Based Liquid Biopsy for Central Nervous System Neoplasms
2016; Elsevier BV; Volume: 19; Issue: 1 Linguagem: Inglês
10.1016/j.jmoldx.2016.08.007
ISSN1943-7811
AutoresJoanna Wang, Chetan Bettegowda,
Tópico(s)Extracellular vesicles in disease
ResumoThe management of central nervous system malignancies remains reliant on histopathological analysis and neuroimaging, despite their complex genetic profile. The intratumoral heterogeneity displayed by these tumors necessitates a more sophisticated method of tumor analysis and monitoring, with the ability to assess tumors over space and time. Circulating biomarkers, including circulating tumor cells, circulating tumor DNA, and extracellular vesicles, hold promise as a type of real-time liquid biopsy able to provide dynamic information not only regarding tumor burden to monitor disease progression and treatment response, but also regarding genetic profile to enable changes in management to match a constantly evolving tumor. In numerous cancer types, including glioma, they have demonstrated their clinical utility as a minimally invasive means for diagnosis, prognostication, and prediction. In addition, they can be used in the laboratory to probe mechanisms of acquired drug resistance and tumor invasion and dissemination. The management of central nervous system malignancies remains reliant on histopathological analysis and neuroimaging, despite their complex genetic profile. The intratumoral heterogeneity displayed by these tumors necessitates a more sophisticated method of tumor analysis and monitoring, with the ability to assess tumors over space and time. Circulating biomarkers, including circulating tumor cells, circulating tumor DNA, and extracellular vesicles, hold promise as a type of real-time liquid biopsy able to provide dynamic information not only regarding tumor burden to monitor disease progression and treatment response, but also regarding genetic profile to enable changes in management to match a constantly evolving tumor. In numerous cancer types, including glioma, they have demonstrated their clinical utility as a minimally invasive means for diagnosis, prognostication, and prediction. In addition, they can be used in the laboratory to probe mechanisms of acquired drug resistance and tumor invasion and dissemination. CME Accreditation Statement: This activity (“JMD 2017 CME Program in Molecular Diagnostics”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“JMD 2017 CME Program in Molecular Diagnostics”) for a maximum of 36 AMA PRA Category 1 Credit(s)™. Physicians should claim only credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. CME Accreditation Statement: This activity (“JMD 2017 CME Program in Molecular Diagnostics”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity (“JMD 2017 CME Program in Molecular Diagnostics”) for a maximum of 36 AMA PRA Category 1 Credit(s)™. Physicians should claim only credit commensurate with the extent of their participation in the activity. CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. As more is understood about the genetic basis of gliomas, it has become increasingly clear that they are a dynamic and complex tumor, difficult to neatly categorize. Patel et al,1Patel A.P. Tirosh I. Trombetta J.J. Shalek A.K. Gillespie S.M. Wakimoto H. Cahill D.P. Nahed B.V. Curry W.T. Martuza R.L. Louis D.N. Rozenblatt-Rosen O. Suva M.L. Regev A. Bernstein B.E. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma.Science. 2014; 344: 1396-1401Crossref PubMed Scopus (327) Google Scholar using single-cell RNA sequencing, found that subpopulations of cells with each the four gene expression signatures detailed by The Cancer Genome Atlas can exist within a single glioblastoma (GBM) lesion. Practically, genetic heterogeneity results in a spectrum of cells with varying capacities for differentiation and proliferation, and unique gene expression profiles with redundancies in aberrant signaling pathways. This has enormous therapeutic significance, as therapies aimed at a single target will only be effective against a proportion of tumor cells and will not be curative. Indeed, the degree of heterogeneity is inversely related to survival in GBM patients, suggesting that effective treatment regimens must be both selective yet generalizable to all tumor cells.1Patel A.P. Tirosh I. Trombetta J.J. Shalek A.K. Gillespie S.M. Wakimoto H. Cahill D.P. Nahed B.V. Curry W.T. Martuza R.L. Louis D.N. Rozenblatt-Rosen O. Suva M.L. Regev A. Bernstein B.E. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma.Science. 2014; 344: 1396-1401Crossref PubMed Scopus (327) Google Scholar Adding an additional layer of complexity, gliomas and other tumor types are known to mutate in response to various therapies.2Hunter C. Smith R. Cahill D.P. Stephens P. Stevens C. Teague J. et al.A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy.Cancer Res. 2006; 66: 3987-3991Crossref PubMed Scopus (154) Google Scholar, 3Johnson B.E. Mazor T. Hong C. Barnes M. Aihara K. McLean C.Y. Fouse S.D. Yamamoto S. Ueda H. Tatsuno K. Asthana S. Jalbert L.E. Nelson S.J. Bollen A.W. Gustafson W.C. Charron E. Weiss W.A. Smirnov I.V. Song J.S. Olshen A.B. Cha S. Zhao Y. Moore R.A. Mungall A.J. Jones S.J. Hirst M. Marra M.A. Saito N. Aburatani H. Mukasa A. Berger M.S. Chang S.M. Taylor B.S. Costello J.F. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma.Science. 2014; 343: 189-193Crossref PubMed Scopus (226) Google Scholar, 4Kim J.W. Wieckowski E. Taylor D.D. Reichert T.E. Watkins S. Whiteside T.L. Fas ligand-positive membranous vesicles isolated from sera of patients with oral cancer induce apoptosis of activated T lymphocytes.Clin Cancer Res. 2005; 11: 1010-1020Crossref PubMed Google Scholar Johnson et al3Johnson B.E. Mazor T. Hong C. Barnes M. Aihara K. McLean C.Y. Fouse S.D. Yamamoto S. Ueda H. Tatsuno K. Asthana S. Jalbert L.E. Nelson S.J. Bollen A.W. Gustafson W.C. Charron E. Weiss W.A. Smirnov I.V. Song J.S. Olshen A.B. Cha S. Zhao Y. Moore R.A. Mungall A.J. Jones S.J. Hirst M. Marra M.A. Saito N. Aburatani H. Mukasa A. Berger M.S. Chang S.M. Taylor B.S. Costello J.F. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma.Science. 2014; 343: 189-193Crossref PubMed Scopus (226) Google Scholar found that in >40% of their low-grade glioma cases, most mutations present at the time of diagnosis were not found at the time of tumor recurrence. Selective pressure applied by chemotherapeutic agents, most notably temozolomide, results in a hypermutated genotype at recurrence.3Johnson B.E. Mazor T. Hong C. Barnes M. Aihara K. McLean C.Y. Fouse S.D. Yamamoto S. Ueda H. Tatsuno K. Asthana S. Jalbert L.E. Nelson S.J. Bollen A.W. Gustafson W.C. Charron E. Weiss W.A. Smirnov I.V. Song J.S. Olshen A.B. Cha S. Zhao Y. Moore R.A. Mungall A.J. Jones S.J. Hirst M. Marra M.A. Saito N. Aburatani H. Mukasa A. Berger M.S. Chang S.M. Taylor B.S. Costello J.F. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma.Science. 2014; 343: 189-193Crossref PubMed Scopus (226) Google Scholar Before attempting to adapt treatment regimens to address this temporal and spatial heterogeneity, a better method of evaluating and monitoring tumor molecular composition is needed.5Swanton C. Intratumor heterogeneity: evolution through space and time.Cancer Res. 2012; 72: 4875-4882Crossref PubMed Scopus (236) Google Scholar, 6Sottoriva A. Spiteri I. Piccirillo S.G. Touloumis A. Collins V.P. Marioni J.C. Curtis C. Watts C. Tavare S. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics.Proc Natl Acad Sci U S A. 2013; 110: 4009-4014Crossref PubMed Scopus (0) Google Scholar Tissue biopsy and neuroimaging are the only means available to assess central nervous system (CNS) tumors, but in their current form, offer incomplete information and are often fraught with interpretation issues. Even when the entirety of a lesion is available for analysis, only thoughtful and deliberate multiple sampling can provide an accurate representation of the genetic profile of the tumor and the heterogeneity present.6Sottoriva A. Spiteri I. Piccirillo S.G. Touloumis A. Collins V.P. Marioni J.C. Curtis C. Watts C. Tavare S. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics.Proc Natl Acad Sci U S A. 2013; 110: 4009-4014Crossref PubMed Scopus (0) Google Scholar, 7Kumar A. Boyle E.A. Tokita M. Mikheev A.M. Sanger M.C. Girard E. Silber J.R. Gonzalez-Cuyar L.F. Hiatt J.B. Adey A. Lee C. Kitzman J.O. Born D.E. Silbergeld D.L. Olson J.M. Rostomily R.C. Shendure J. Deep sequencing of multiple regions of glial tumors reveals spatial heterogeneity for mutations in clinically relevant genes.Genome Biol. 2014; 15: 530Crossref PubMed Scopus (7) Google Scholar Furthermore, tissue recovered after surgical resection or biopsy only offers insight into disease burden and tumor characteristics at a single moment in time. Neuroimaging is currently the only modality capable of monitoring tumors over time, but lacks sensitivity and specificity. Treatment with antiangiogenic therapies can often result in the false appearance of tumor regression, or pseudoresponse.8Brandsma D. van den Bent M.J. Pseudoprogression and pseudoresponse in the treatment of gliomas.Curr Opin Neurol. 2009; 22: 633-638Crossref PubMed Scopus (0) Google Scholar The converse, pseudoprogression, can be seen in up to 30% of cases after treatment with chemotherapy and radiation therapy. What is sorely needed is a minimally invasive real-time tumor biomarker that provides quantitative information regarding tumor burden and qualitative information about tumor genetic profile, which could be applied for screening, diagnosis, prognostication, and prediction. In 1996, the National Comprehensive Cancer Network put forth the Tumor Marker Utility Grading System, a scale for assessing the diagnostic, prognostic, or predictive value of biomarkers based on technical and clinical factors.9Hayes D.F. Bast R.C. Desch C.E. Fritsche Jr., H. Kemeny N.E. Jessup J.M. Locker G.Y. Macdonald J.S. Mennel R.G. Norton L. Ravdin P. Taube S. Winn R.J. Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers.J Natl Cancer Inst. 1996; 88: 1456-1466Crossref PubMed Scopus (530) Google Scholar The assay in question must accurately and reliably measure the substance or the molecular event of interest with reasonable sensitivity and specificity, and its use must have a significant impact on overall survival, disease-free survival, quality of life, and cost of care. Ultimately, even if a promising biomarker is associated with an improved clinical outcome, for it to enter clinical practice, it must provide clinically actionable information that can help guide management and ultimately change outcomes. In 2011, the National Comprehensive Cancer Network evaluated the current state of biomarkers in oncology, finding few biomarkers with adequate evidence to incorporate into the standard of care across six cancer types. Only three met criteria for clinical utility for glioma: 1p/19q codeletion, IDH1/2 mutation, and MGMT promoter methylation.10Febbo P.G. Ladanyi M. Aldape K.D. De Marzo A.M. Hammond M.E. Hayes D.F. Iafrate A.J. Kelley R.K. Marcucci G. Ogino S. Pao W. Sgroi D.C. Birkeland M.L. NCCN Task Force report: evaluating the clinical utility of tumor markers in oncology.J Natl Compr Cancer Netw. 2011; 9 Suppl 5 (quiz S3): S1-S32PubMed Google Scholar Given the current state of glioma management, additional validated biomarkers are sorely needed. Circulating biomarkers, including circulating tumor nucleic acids, circulating tumor cells (CTCs), and extracellular vesicles (EVs), which contain tumor DNA as well as other macromolecules, have shown tremendous promise as a type of liquid biopsy in oncology (Figure 1).11Westphal M. Lamszus K. Circulating biomarkers for gliomas.Nat Rev Neurol. 2015; 11: 556-566Crossref PubMed Scopus (0) Google Scholar, 12Gold B. Cankovic M. Furtado L.V. Meier F. Gocke C.D. Do circulating tumor cells, exosomes, and circulating tumor nucleic acids have clinical utility? a report of the Association for Molecular Pathology.J Mol Diagn. 2015; 17: 209-224Abstract Full Text Full Text PDF PubMed Google Scholar Although the technical aspects of biomarker detection require further optimization, these tools have already demonstrated their diagnostic, prognostic, and predictive value in several tumor types, including breast, colorectal (CRC), non-small cell lung, and prostate cancers, and melanoma.12Gold B. Cankovic M. Furtado L.V. Meier F. Gocke C.D. Do circulating tumor cells, exosomes, and circulating tumor nucleic acids have clinical utility? a report of the Association for Molecular Pathology.J Mol Diagn. 2015; 17: 209-224Abstract Full Text Full Text PDF PubMed Google Scholar Furthermore, they have also been used to study mechanisms of acquired treatment resistance and tumor invasion and dissemination. Although there have yet to be large studies showing that use of these biomarkers can improve outcomes, hundreds of clinical trials involving the use of these circulating biomarkers are currently underway. The progress made in these other tumor types has outpaced that for CNS malignancies, but circulating tumor DNA (ctDNA), CTCs, and EVs have all been identified in patients with glioma and early studies are promising. The first description of the detection of DNA fragments circulating freely in blood, or cell-free DNA, was by Mandel and Metais in 1948.13Mandel P. Metais P. Les acides nucléiques du plasma sanguin chez l'homme.C R Seances Soc Biol Fil. 1948; 142: 241-243PubMed Google Scholar Since then, it has become clear that all cells shed fragments of nucleic acid, typically 180 to 200 bp in length, likely originating as a by-product of apoptosis.14Jahr S. Hentze H. Englisch S. Hardt D. Fackelmayer F.O. Hesch R.D. Knippers R. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells.Cancer Res. 2001; 61: 1659-1665PubMed Google Scholar, 15Diehl F. Schmidt K. Choti M.A. Romans K. Goodman S. Li M. Thornton K. Agrawal N. Sokoll L. Szabo S.A. Kinzler K.W. Vogelstein B. Diaz Jr., L.A. Circulating mutant DNA to assess tumor dynamics.Nat Med. 2008; 14: 985-990Crossref PubMed Scopus (511) Google Scholar, 16Diehl F. Li M. Dressman D. He Y. Shen D. Szabo S. Diaz Jr., L.A. Goodman S.N. David K.A. Juhl H. Kinzler K.W. Vogelstein B. Detection and quantification of mutations in the plasma of patients with colorectal tumors.Proc Natl Acad Sci U S A. 2005; 102: 16368-16373Crossref PubMed Scopus (0) Google Scholar Under physiological conditions, most DNA fragments are typically cleared by phagocytes, and a background level of cell-free DNA exists in the circulation. With disease states such as cancer, the production of DNA fragments outpaces clearance mechanisms and results in the accumulation of ctDNA in the circulation. It has been proposed that tumor cells possess active DNA release mechanisms, which may result in malignant transformation of distant cells.17Crowley E. Di Nicolantonio F. Loupakis F. Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood.Nat Rev Clin Oncol. 2013; 10: 472-484Crossref PubMed Scopus (212) Google Scholar, 18Garcia-Olmo D.C. Dominguez C. Garcia-Arranz M. Anker P. Stroun M. Garcia-Verdugo J.M. Garcia-Olmo D. Cell-free nucleic acids circulating in the plasma of colorectal cancer patients induce the oncogenic transformation of susceptible cultured cells.Cancer Res. 2010; 70: 560-567Crossref PubMed Scopus (0) Google Scholar As a biomarker, ctDNA displays several favorable features. Its short half-life of <1.5 hours makes it ideal for studying dynamic changes in tumor homeostasis.15Diehl F. Schmidt K. Choti M.A. Romans K. Goodman S. Li M. Thornton K. Agrawal N. Sokoll L. Szabo S.A. Kinzler K.W. Vogelstein B. Diaz Jr., L.A. Circulating mutant DNA to assess tumor dynamics.Nat Med. 2008; 14: 985-990Crossref PubMed Scopus (511) Google Scholar Across several studies, ctDNA carrying tumor-specific mutations can represent as little as 0.01% of the total cell-free DNA in the circulation or up to 90%.15Diehl F. Schmidt K. Choti M.A. Romans K. Goodman S. Li M. Thornton K. Agrawal N. Sokoll L. Szabo S.A. Kinzler K.W. Vogelstein B. Diaz Jr., L.A. Circulating mutant DNA to assess tumor dynamics.Nat Med. 2008; 14: 985-990Crossref PubMed Scopus (511) Google Scholar, 19Dawson S.J. Tsui D.W. Murtaza M. Biggs H. Rueda O.M. Chin S.F. Dunning M.J. 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; 368: 1199-1209Crossref PubMed Scopus (509) Google Scholar The detection rate is higher in cases of advanced, metastatic disease as compared to localized disease, where ctDNA can be undetectable with 7- to 10-mL blood samples.20Newman A.M. Bratman S.V. To J. Wynne J.F. Eclov N.C. Modlin L.A. Liu C.L. Neal J.W. Wakelee H.A. Merritt R.E. Shrager J.B. Loo Jr., B.W. Alizadeh A.A. Diehn M. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage.Nat Med. 2014; 20: 548-554Crossref PubMed Scopus (213) Google Scholar, 21Bettegowda C. Sausen M. Leary R.J. Kinde I. Wang Y. Agrawal N. et al.Detection of circulating tumor DNA in early- and late-stage human malignancies.Sci Transl Med. 2014; 6: 224ra24Crossref PubMed Scopus (486) Google Scholar, 22Beaver J.A. Jelovac D. Balukrishna S. Cochran R.L. Croessmann S. Zabransky D.J. Wong H.Y. Valda Toro P. Cidado J. Blair B.G. Chu D. Burns T. Higgins M.J. Stearns V. Jacobs L. Habibi M. Lange J. Hurley P.J. Lauring J. VanDenBerg D.A. Kessler J. Jeter S. Samuels M.L. Maar D. Cope L. Cimino-Mathews A. Argani P. Wolff A.C. Park B.H. Detection of cancer DNA in plasma of patients with early-stage breast cancer.Clin Cancer Res. 2014; 20: 2643-2650Crossref PubMed Scopus (0) Google Scholar Yet, this remains a relatively sensitive measure, as only 50 × 106 cells are necessary to produce a detectable amount of ctDNA.23Diaz Jr., L.A. Williams R.T. Wu J. Kinde I. Hecht J.R. Berlin J. Allen B. Bozic I. Reiter J.G. Nowak M.A. Kinzler K.W. Oliner K.S. Vogelstein B. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers.Nature. 2012; 486: 537-540Crossref PubMed Scopus (586) Google Scholar One of the primary advantages offered by ctDNA is its high specificity, as measurement relies on the detection of specific genetic alterations that are not present in normal DNA at appreciable levels. However, each method of detection has its own limitations. The methods most commonly used for ctDNA detection are based on digital PCR and next-generation sequencing (NGS), by which point mutations, copy number variations, and chromosomal rearrangements can all be assessed.24Diaz Jr., L.A. Bardelli A. Liquid biopsies: genotyping circulating tumor DNA.J Clin Oncol. 2014; 32: 579-586Crossref PubMed Scopus (277) Google Scholar Early proof-of-principle studies used data from an initial tissue biopsy to inform their PCR-based approach to probe for specific, known mutations. Despite the high sensitivity of this method, for ctDNA to reach its full potential as a biomarker, it cannot be assumed that the genetic profile of the tumor, or even the presence of a tumor, is known. Even if a mutational panel is used, problems arise in selecting which mutations are the most relevant for an individual patient. Detection platforms must offer broad enough genomic coverage to fully characterize the spatial and temporal heterogeneity of tumors, but deep-sequencing approaches produce data with high levels of background noise, which can obscure true genetic alterations. Newer NGS-based ctDNA detection methods, including SafeSeq, TAm-Seq, CAPP-Seq, and Ampli-Seq, have improved but not completely resolved the sensitivity problem, which remains difficult to optimize with broad coverage assays.25Kinde I. Wu J. Papadopoulos N. Kinzler K.W. Vogelstein B. Detection and quantification of rare mutations with massively parallel sequencing.Proc Natl Acad Sci U S A. 2011; 108: 9530-9535Crossref PubMed Scopus (228) Google Scholar, 26Forshew T. Murtaza M. Parkinson C. Gale D. Tsui D.W. Kaper F. Dawson S.J. Piskorz A.M. Jimenez-Linan M. Bentley D. Hadfield J. May A.P. Caldas C. Brenton J.D. Rosenfeld N. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA.Sci Transl Med. 2012; 4: 136ra68Crossref PubMed Scopus (0) Google Scholar, 27Rothe F. Laes J.F. Lambrechts D. Smeets D. Vincent D. Maetens M. Fumagalli D. Michiels S. Drisis S. Moerman C. Detiffe J.P. Larsimont D. Awada A. Piccart M. Sotiriou C. Ignatiadis M. Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer.Ann Oncol. 2014; 25: 1959-1965Crossref PubMed Scopus (0) Google Scholar, 28Narayan A. Carriero N.J. Gettinger S.N. Kluytenaar J. Kozak K.R. Yock T.I. Muscato N.E. Ugarelli P. Decker R.H. Patel A.A. Ultrasensitive measurement of hotspot mutations in tumor DNA in blood using error-suppressed multiplexed deep sequencing.Cancer Res. 2012; 72: 3492-3498Crossref PubMed Scopus (0) Google Scholar Although progress continues to be made in improving ctDNA detection assays, the clinical value of this tool has already been demonstrated. Molecular profiling of paired tumor and ctDNA samples has revealed high concordance rates in identifying clinically relevant mutations in metastatic breast, colorectal, and non-small cell lung cancers, suggesting that this is a viable means of liquid biopsy.15Diehl F. Schmidt K. Choti M.A. Romans K. Goodman S. Li M. Thornton K. Agrawal N. Sokoll L. Szabo S.A. Kinzler K.W. Vogelstein B. Diaz Jr., L.A. Circulating mutant DNA to assess tumor dynamics.Nat Med. 2008; 14: 985-990Crossref PubMed Scopus (511) Google Scholar, 19Dawson S.J. Tsui D.W. Murtaza M. Biggs H. Rueda O.M. Chin S.F. Dunning M.J. 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; 368: 1199-1209Crossref PubMed Scopus (509) Google Scholar, 20Newman A.M. Bratman S.V. To J. Wynne J.F. Eclov N.C. Modlin L.A. Liu C.L. Neal J.W. Wakelee H.A. Merritt R.E. Shrager J.B. Loo Jr., B.W. Alizadeh A.A. Diehn M. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage.Nat Med. 2014; 20: 548-554Crossref PubMed Scopus (213) Google Scholar, 21Bettegowda C. Sausen M. Leary R.J. Kinde I. Wang Y. Agrawal N. et al.Detection of circulating tumor DNA in early- and late-stage human malignancies.Sci Transl Med. 2014; 6: 224ra24Crossref PubMed Scopus (486) Google Scholar, 27Rothe F. Laes J.F. Lambrechts D. Smeets D. Vincent D. Maetens M. Fumagalli D. Michiels S. Drisis S. Moerman C. Detiffe J.P. Larsimont D. Awada A. Piccart M. Sotiriou C. Ignatiadis M. Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer.Ann Oncol. 2014; 25: 1959-1965Crossref PubMed Scopus (0) Google Scholar, 28Narayan A. Carriero N.J. Gettinger S.N. Kluytenaar J. Kozak K.R. Yock T.I. Muscato N.E. Ugarelli P. Decker R.H. Patel A.A. Ultrasensitive measurement of hotspot mutations in tumor DNA in blood using error-suppressed multiplexed deep sequencing.Cancer Res. 2012; 72: 3492-3498Crossref PubMed Scopus (0) Google Scholar, 29Higgins M.J. Jelovac D. Barnathan E. Blair B. Slater S. Powers P. Zorzi J. Jeter S.C. Oliver G.R. Fetting J. Emens L. Riley C. Stearns V. Diehl F. Angenendt P. Huang P. Cope L. Argani P. Murphy K.M. Bachman K.E. Greshock J. Wolff A.C. Park B.H. Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood.Clin Cancer Res. 2012; 18: 3462-3469Crossref PubMed Scopus (0) Google Scholar, 30Board R.E. Wardley A.M. Dixon J.M. Armstrong A.C. Howell S. Renshaw L. Donald E. Greystoke A. Ranson M. Hughes A. Dive C. Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer.Breast Cancer Res Treat. 2010; 120: 461-467Crossref PubMed Scopus (0) Google Scholar, 31Thierry A.R. Mouliere F. El Messaoudi S. Mollevi C. Lopez-Crapez E. Rolet F. Gillet B. Gongora C. Dechelotte P. Robert B. Del Rio M. Lamy P.J. Bibeau F. Nouaille M. Loriot V. Jarrousse A.S. Molina F. Mathonnet M. Pezet D. Ychou M. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA.Nat Med. 2014; 20: 430-435Crossref PubMed Scopus (110) Google Scholar, 32Punnoose E.A. Atwal S. Liu W. Raja R. Fine B.M. Hughes B.G. Hicks R.J. Hampton G.M. Amler L.C. Pirzkall A. Lackner M.R. Evaluation of circulating tumor cells and circulating tumor DNA in non-small cell lung cancer: association with clinical endpoints in a phase II clinical trial of pertuzumab and erlotinib.Clin Cancer Res. 2012; 18: 2391-2401Crossref PubMed Scopus (0) Google Scholar Furthermore, genome-wide sequencing of plasma DNA in patients with different tumor types suggests that ctDNA is representative of the entire tumor genome, and can be an accurate reflection of tumoral heterogeneity.33Lebofsky R. Decraene C. Bernard V. Kamal M. Blin A. Leroy Q. Rio Frio T. Pierron G. Callens C. Bieche I. Saliou A. Madic J. Rouleau E. Bidard F.C. Lantz O. Stern M.H. Le Tourneau C. Pierga J.Y. Circulating tumor DNA as a non-invasive substitute to metastasis biopsy for tumor genotyping and personalized medicine in a prospective trial across all tumor types.Mol Oncol. 2015; 9: 783-790Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 34Murtaza M. Dawson S.J. Tsui D.W. Gale D. Forshew T. Piskorz A.M. Parkinson C. Chin S.F. Kingsbury Z. Wong A.S. Marass F. Humphray S. Hadfield J. Bentley D. Chin T.M. Brenton J.D. Caldas C. Rosenfeld N. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA.Nature. 2013; 497: 108-112Crossref PubMed Scopus (449) Google Scholar, 35Leary R.J. Sausen M. Kinde I. Papadopoulos N. Carpten J.D. Craig D. O'Shaughnessy J. Kinzler K.W. Parmigiani G. Vogelstein B. Diaz Jr., L.A. Velculescu V.E. Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing.Sci Transl Med. 2012; 4: 162ra54Crossref Scopus (0) Google Scholar, 36Chan K.C. Jiang P. Zheng Y.W. Liao G.J. Sun H. Wong J. Siu S.S. Chan W.C. Chan S.L. Chan A.T. Lai P.B. Chiu R.W. Lo Y.M. 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: 211-224Crossref PubMed Scopus (0) Google Scholar Similarly, measurement of ctDNA levels also appears to be a viable proxy for tumor burden as a noninvasive means of disease monitoring. In a study of 18 patients with CRC who underwent surgical resection, ctDNA levels corresponded to the extent of resection, with patients who underwent complete resection experiencing a significant decrease in ctDNA levels on postoperative day 1, and further decline by the day of discharge.15Diehl F. Schmidt K. Choti M.A. Romans K. Goodman S. Li M. Thornton K. Agrawal N. Sokoll L. Szabo S.A. Kinzler K.W. Vogelstein B. Diaz Jr., L.A. Circulating mutant DNA to assess tumor dynamics.Nat Med. 2008; 14: 985-990Crossref PubMed Scopus (511) Google Scholar Preliminary data in CRC also demonstrated that ctDNA may be useful in predicting tumor recurrence.16Diehl F. Li M. Dressman D. He Y. Shen D. Szabo S. Diaz Jr., L.A. Goodman S.N. David K.A. Juhl H. Kinzler K.W. Vogelstein B. Detection and quantification of mutations in the plasma of patients with colorectal tumors.Proc Natl Acad Sci U S A. 2005; 102: 16368-16373Crossref PubMed Scopus (0) Google Scholar In breast, colon, and ovarian cancers and melanoma, ctDNA levels have been shown to be clinically useful and correlate with clinical outcomes, with an inverse relationship between ctDNA levels and survival.15Diehl F. Schmidt K. Choti M.A. Romans K. Goodman S. Li M. Thornton K. Agrawal N. Sokoll L. Szabo S.A. Kinzler K.W. Vogelstein B. Diaz Jr., L.A. Circulating mutant DNA to assess tumor dynamics.Nat Med. 2008; 14: 985-990Crossref PubMed Scopus (511) Google Scholar, 19Dawson S.J. Tsui D.W. Murtaza M. Biggs H. Rueda O.M. Chin S.F. Dunning M.J. 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; 368: 1199-1209Crossref PubMed Scopus (509) Google Scholar, 21Bettegowda C. Sausen M. Leary R.J. Kinde I. Wang Y. Agrawal N. et al.Detection of circulating tumor DNA in early- and late-stage human malignancies.Sci Transl Med. 2014; 6: 224ra24Crossref PubMed Scopus (486) G
Referência(s)