Semin Respir Crit Care Med 2016; 37(05): 760-770
DOI: 10.1055/s-0036-1592337
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Predictive and Prognostic Biomarkers in Non-Small Cell Lung Cancer

Manish K. Thakur
1   Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
,
Shirish M. Gadgeel
1   Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
› Author Affiliations
Further Information

Publication History

Publication Date:
12 October 2016 (online)

Abstract

Therapy of non-small cell lung cancer (NSCLC) patients has evolved over the past few years with the incorporation of targeted therapy and immune therapy. These changes have increased the importance of prognostic and predictive biomarkers to enable practicing physicians in making the most appropriate treatment decisions for NSCLC patients. A variety of prognostic factors based on clinical and pathologic features determine the overall outcome of the patient and these factors do influence decisions regarding initiation of therapy. The most important prognostic factors remain stage of the disease at diagnosis and performance status. For years, the only approved systemic therapy for NSCLC patients was chemotherapy. Despite attempts at defining factors that influence efficacy of chemotherapeutic agents, pemetrexed is the only chemotherapy drug that has differential activity based on a specific factor. In recent years, there is increasing focus on defining the molecular alterations critical to the oncogenic phenotype of NSCLC and targeting these alterations for therapeutic benefit. In addition, there is increasing use of immune-modulating drugs, specifically anti-PD-1 drugs, in advanced NSCLC patients. Several studies have shown that the probability of clinical benefit from these agents is greater in patients with NSCLCs that express PD-L1. The totality of these data suggests that determination of predictive markers prior to initiation of therapy is critical.

 
  • References

  • 1 Chansky K, Sculier JP, Crowley JJ, Giroux D, Van Meerbeeck J, Goldstraw P ; International Staging Committee and Participating Institutions. The International Association for the Study of Lung Cancer Staging Project: prognostic factors and pathologic TNM stage in surgically managed non-small cell lung cancer. J Thorac Oncol 2009; 4 (7) 792-801
  • 2 Standfield L, Weston AR, Barraclough H, Van Kooten M, Pavlakis N. Histology as a treatment effect modifier in advanced non-small cell lung cancer: a systematic review of the evidence. Respirology 2011; 16 (8) 1210-1220
  • 3 Scagliotti GV, Parikh P, von Pawel J , et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008; 26 (21) 3543-3551
  • 4 Sigmond J, Backus HH, Wouters D, Temmink OH, Jansen G, Peters GJ. Induction of resistance to the multitargeted antifolate Pemetrexed (ALIMTA) in WiDr human colon cancer cells is associated with thymidylate synthase overexpression. Biochem Pharmacol 2003; 66 (3) 431-438
  • 5 Takezawa K, Okamoto I, Okamoto W , et al. Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer. Br J Cancer 2011; 104 (10) 1594-1601
  • 6 Ardizzoni A, Boni L, Tiseo M , et al; CISCA (CISplatin versus CArboplatin) Meta-analysis Group. Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst 2007; 99 (11) 847-857
  • 7 Sandler A, Gray R, Perry MC , et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355 (24) 2542-2550
  • 8 Johnson DH, Fehrenbacher L, Novotny WF , et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004; 22 (11) 2184-2191
  • 9 Cagini L, Monacelli M, Giustozzi G , et al. Biological prognostic factors for early stage completely resected non-small cell lung cancer. J Surg Oncol 2000; 74 (1) 53-60
  • 10 Shimada Y, Saji H, Kato Y , et al. The frequency and prognostic impact of pathological microscopic vascular invasion according to tumor size in non-small cell lung cancer. Chest 2016; 149 (3) 775-785
  • 11 Schuchert MJ, Schumacher L, Kilic A , et al. Impact of angiolymphatic and pleural invasion on surgical outcomes for stage I non-small cell lung cancer. Ann Thorac Surg 2011; 91 (4) 1059-1065 , discussion 1065
  • 12 Kudo Y, Saji H, Shimada Y , et al. Impact of visceral pleural invasion on the survival of patients with non-small cell lung cancer. Lung Cancer 2012; 78 (2) 153-160
  • 13 Fibla JJ, Cassivi SD, Brunelli A , et al. Re-evaluation of the prognostic value of visceral pleura invasion in Stage IB non-small cell lung cancer using the prospective multicenter ACOSOG Z0030 trial data set. Lung Cancer 2012; 78 (3) 259-262
  • 14 Rusch VW, Hawes D, Decker PA , et al. Occult metastases in lymph nodes predict survival in resectable non-small-cell lung cancer: report of the ACOSOG Z0040 trial. J Clin Oncol 2011; 29 (32) 4313-4319
  • 15 Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer 2011; 105 (1) 93-103
  • 16 Bremnes RM, Busund LT, Kilvær TL , et al. The role of tumor-infiltrating lymphocytes in development, progression, and prognosis of non-small cell lung cancer. J Thorac Oncol 2016; 11 (6) 789-800
  • 17 Altaha R, Liang X, Yu JJ, Reed E. Excision repair cross complementing-group 1: gene expression and platinum resistance. Int J Mol Med 2004; 14 (6) 959-970
  • 18 Olaussen KA, Dunant A, Fouret P , et al; IALT Bio Investigators. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006; 355 (10) 983-991
  • 19 Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J ; International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004; 350 (4) 351-360
  • 20 Choi CM, Yang SC, Jo HJ , et al. Proteins involved in DNA damage response pathways and survival of stage I non-small-cell lung cancer patients. Ann Oncol 2012; 23 (8) 2088-2093
  • 21 Lord RV, Brabender J, Gandara D , et al. Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res 2002; 8 (7) 2286-2291
  • 22 Bepler G, Williams C, Schell MJ , et al. Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2013; 31 (19) 2404-2412
  • 23 Friboulet L, Olaussen KA, Pignon JP , et al. ERCC1 isoform expression and DNA repair in non-small-cell lung cancer. N Engl J Med 2013; 368 (12) 1101-1110
  • 24 Gautam A, Li ZR, Bepler G. RRM1-induced metastasis suppression through PTEN-regulated pathways. Oncogene 2003; 22 (14) 2135-2142
  • 25 Zheng Z, Chen T, Li X, Haura E, Sharma A, Bepler G. DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med 2007; 356 (8) 800-808
  • 26 Bergman AM, Eijk PP, Ruiz van Haperen VW , et al. In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as the major determinant. Cancer Res 2005; 65 (20) 9510-9516
  • 27 Rosell R, Danenberg KD, Alberola V , et al; Spanish Lung Cancer Group. Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res 2004; 10 (4) 1318-1325
  • 28 Bepler G, Kusmartseva I, Sharma S , et al. RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol 2006; 24 (29) 4731-4737
  • 29 Wachters FM, Wong LS, Timens W, Kampinga HH, Groen HJ. ERCC1, hRad51, and BRCA1 protein expression in relation to tumour response and survival of stage III/IV NSCLC patients treated with chemotherapy. Lung Cancer 2005; 50 (2) 211-219
  • 30 Rosell R, Skrzypski M, Jassem E , et al. BRCA1: a novel prognostic factor in resected non-small-cell lung cancer. PLoS ONE 2007; 2 (11) e1129
  • 31 Wang L, Wei J, Qian X , et al. ERCC1 and BRCA1 mRNA expression levels in metastatic malignant effusions is associated with chemosensitivity to cisplatin and/or docetaxel. BMC Cancer 2008; 8: 97
  • 32 Lafarge S, Sylvain V, Ferrara M, Bignon YJ. Inhibition of BRCA1 leads to increased chemoresistance to microtubule-interfering agents, an effect that involves the JNK pathway. Oncogene 2001; 20 (45) 6597-6606
  • 33 Aggarwal C, Somaiah N, Simon GR. Biomarkers with predictive and prognostic function in non-small cell lung cancer: ready for prime time?. J Natl Compr Canc Netw 2010; 8 (7) 822-832
  • 34 Yang Y, Xie Y, Xian L. Breast cancer susceptibility gene 1 (BRCA1) predict clinical outcome in platinum- and toxal-based chemotherapy in non-small-cell lung cancer (NSCLC) patients: a system review and meta-analysis. . J Exp Clin Cancer Res 2013; 32: 15
  • 35 Moran T, Wei J, Cobo M , et al; Spanish Lung Cancer Group; French Lung Cancer Group; Comprehensive Cancer Centre of Drum Tower Hospital in Nanjing. Two biomarker-directed randomized trials in European and Chinese patients with nonsmall-cell lung cancer: the BRCA1-RAP80 Expression Customization (BREC) studies. Ann Oncol 2014; 25 (11) 2147-2155
  • 36 Monzó M, Rosell R, Sánchez JJ , et al. Paclitaxel resistance in non-small-cell lung cancer associated with beta-tubulin gene mutations. J Clin Oncol 1999; 17 (6) 1786-1793
  • 37 Sève P, Dumontet C. Is class III beta-tubulin a predictive factor in patients receiving tubulin-binding agents?. Lancet Oncol 2008; 9 (2) 168-175
  • 38 Reiman T, Lai R, Veillard AS , et al; LACE-Bio Group. Cross-validation study of class III beta-tubulin as a predictive marker for benefit from adjuvant chemotherapy in resected non-small-cell lung cancer: analysis of four randomized trials. Ann Oncol 2012; 23 (1) 86-93
  • 39 Burstein HJ, Mangu PB, Somerfield MR , et al; American Society of Clinical Oncology. American Society of Clinical Oncology clinical practice guideline update on the use of chemotherapy sensitivity and resistance assays. J Clin Oncol 2011; 29 (24) 3328-3330
  • 40 Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 2010; 10 (11) 760-774
  • 41 Kuan FC, Kuo LT, Chen MC , et al. Overall survival benefits of first-line EGFR tyrosine kinase inhibitors in EGFR-mutated non-small-cell lung cancers: a systematic review and meta-analysis. Br J Cancer 2015; 113 (10) 1519-1528
  • 42 Balak MN, Gong Y, Riely GJ , et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 2006; 12 (21) 6494-6501
  • 43 Godin-Heymann N, Ulkus L, Brannigan BW , et al. The T790M “gatekeeper” mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor. Mol Cancer Ther 2008; 7 (4) 874-879
  • 44 Jänne PA, Yang JC, Kim DW , et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015; 372 (18) 1689-1699
  • 45 D'Angelo SP, Janjigian YY, Ahye N , et al. Distinct clinical course of EGFR-mutant resected lung cancers: results of testing of 1118 surgical specimens and effects of adjuvant gefitinib and erlotinib. J Thorac Oncol 2012; 7 (12) 1815-1822
  • 46 Goss GD, O'Callaghan C, Lorimer I , et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol 2013; 31 (27) 3320-3326
  • 47 Kelly K, Altorki NK, Eberhardt WE , et al. Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): a randomized, double-blind, phase III trial. J Clin Oncol 2015; 33 (34) 4007-4014
  • 48 Kris MG, Johnson BE, Berry LD , et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014; 311 (19) 1998-2006
  • 49 Doebele RC, Camidge DR. Targeting ALK, ROS1, and BRAF kinases. J Thorac Oncol 2012; 7 (16) (Suppl. 05) S375-S376
  • 50 Shaw AT, Kim DW, Nakagawa K , et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368 (25) 2385-2394
  • 51 Solomon BJ, Mok T, Kim DW , et al; PROFILE 1014 Investigators. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014; 371 (23) 2167-2177
  • 52 Choi YL, Soda M, Yamashita Y , et al; ALK Lung Cancer Study Group. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 2010; 363 (18) 1734-1739
  • 53 Kodama T, Tsukaguchi T, Yoshida M, Kondoh O, Sakamoto H. Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance. Cancer Lett 2014; 351 (2) 215-221
  • 54 Toyokawa G, Hirai F, Inamasu E , et al. Secondary mutations at I1171 in the ALK gene confer resistance to both Crizotinib and Alectinib. J Thorac Oncol 2014; 9 (12) e86-e87
  • 55 Doebele RC, Pilling AB, Aisner DL , et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 2012; 18 (5) 1472-1482
  • 56 Katayama R, Shaw AT, Khan TM , et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med 2012; 4 (120) 120ra17
  • 57 Ou SH, Ahn JS, De Petris L , et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase II global study. J Clin Oncol 2016; 34 (7) 661-668
  • 58 Camidge DR, Kono SA, Lu X , et al. Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol 2011; 6 (4) 774-780
  • 59 Roberts PJ, Stinchcombe TE. KRAS mutation: should we test for it, and does it matter?. J Clin Oncol 2013; 31 (8) 1112-1121
  • 60 Mascaux C, Iannino N, Martin B , et al. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer 2005; 92 (1) 131-139
  • 61 Shepherd FA, Domerg C, Hainaut P , et al. Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol 2013; 31 (17) 2173-2181
  • 62 Johnson ML, Sima CS, Chaft J , et al. Association of KRAS and EGFR mutations with survival in patients with advanced lung adenocarcinomas. Cancer 2013; 119 (2) 356-362
  • 63 Brugger W, Triller N, Blasinska-Morawiec M , et al. Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol 2011; 29 (31) 4113-4120
  • 64 Jänne PA, Shaw AT, Pereira JR , et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 2013; 14 (1) 38-47
  • 65 Chen Z, Cheng K, Walton Z , et al. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 2012; 483 (7391) 613-617
  • 66 Bergethon K, Shaw AT, Ou SH , et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012; 30 (8) 863-870
  • 67 Shaw AT, Ou SH, Bang YJ , et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 2014; 371 (21) 1963-1971
  • 68 Hyman DM, Puzanov I, Subbiah V , et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 2015; 373 (8) 726-736
  • 69 Planchard D, Besse B, Groen HJ , et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 2016; 17 (7) 984-993
  • 70 Camidge DR, Ou S-HI, Shapiro G , et al. Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts 2014 32:8001
  • 71 Paik PK, Drilon A, Fan PD , et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov 2015; 5 (8) 842-849
  • 72 Drilon AE, Sima CS, Somwar R , et al. Phase II study of cabozantinib for patients with advanced RET-rearranged lung cancers. ASCO Meeting Abstracts 2015 33:8007
  • 73 Mazières J, Peters S, Lepage B , et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol 2013; 31 (16) 1997-2003
  • 74 Weeden CE, Solomon B, Asselin-Labat ML. FGFR1 inhibition in lung squamous cell carcinoma: questions and controversies. Cell Death Dis 2015; 1: 15049
  • 75 Chen HY, Yu SL, Chen CH , et al. A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med 2007; 356 (1) 11-20
  • 76 Zhu CQ, Ding K, Strumpf D , et al. Prognostic and predictive gene signature for adjuvant chemotherapy in resected non-small-cell lung cancer. J Clin Oncol 2010; 28 (29) 4417-4424
  • 77 Kratz JR, He J, Van Den Eeden SK , et al. A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung cancer: development and international validation studies. Lancet 2012; 379 (9818) 823-832
  • 78 Tan X, Qin W, Zhang L , et al. A 5-microRNA signature for lung squamous cell carcinoma diagnosis and hsa-miR-31 for prognosis. Clin Cancer Res 2011; 17 (21) 6802-6811
  • 79 Tian L, Shan W, Zhang Y, Lv X, Li X, Wei C. Up-regulation of miR-21 expression predicate advanced clinicopathological features and poor prognosis in patients with non-small cell lung cancer. Pathol Oncol Res 2016; 22 (1) 161-167
  • 80 Johnson SM, Grosshans H, Shingara J , et al. RAS is regulated by the let-7 microRNA family. Cell 2005; 120 (5) 635-647
  • 81 Dai X, Jiang Y, Tan C. Let-7 sensitizes KRAS mutant tumor cells to chemotherapy. PLoS ONE 2015; 10 (5) e0126653
  • 82 Naidu S, Garofalo M. microRNAs: an emerging paradigm in lung cancer chemoresistance. Front Med (Lausanne) 2015; 2: 77
  • 83 Dong Z, Zhong Z, Yang L, Wang S, Gong Z. MicroRNA-31 inhibits cisplatin-induced apoptosis in non-small cell lung cancer cells by regulating the drug transporter ABCB9. Cancer Lett 2014; 343 (2) 249-257
  • 84 Shen H, Zhu F, Liu J , et al. Alteration in Mir-21/PTEN expression modulates gefitinib resistance in non-small cell lung cancer. PLoS ONE 2014; 9 (7) e103305
  • 85 Shukuya T, Carbone DP. Predictive markers for the efficacy of anti-PD-1/PD-L1 antibodies in lung cancer. J Thorac Oncol 2016; 11 (7) 976-988
  • 86 Brahmer J, Reckamp KL, Baas P , et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373 (2) 123-135
  • 87 Borghaei H, Paz-Ares L, Horn L , et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373 (17) 1627-1639
  • 88 Garon EB, Rizvi NA, Hui R , et al; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372 (21) 2018-2028
  • 89 Herbst RS, Baas P, Kim DW , et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016; 387 (10027) 1540-1550
  • 90 Fehrenbacher L, Spira A, Ballinger M , et al; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 2016; 387 (10030) 1837-1846
  • 91 Rizvi NA, Hellmann MD, Snyder A , et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 348 (6230) 124-128
  • 92 Taguchi F, Solomon B, Gregorc V , et al. Mass spectrometry to classify non-small-cell lung cancer patients for clinical outcome after treatment with epidermal growth factor receptor tyrosine kinase inhibitors: a multicohort cross-institutional study. J Natl Cancer Inst 2007; 99 (11) 838-846
  • 93 Carbone DP, Ding K, Roder H , et al. Prognostic and predictive role of the VeriStrat plasma test in patients with advanced non-small-cell lung cancer treated with erlotinib or placebo in the NCIC Clinical Trials Group BR.21 trial. J Thorac Oncol 2012; 7 (11) 1653-1660
  • 94 Gregorc V, Novello S, Lazzari C , et al. Predictive value of a proteomic signature in patients with non-small-cell lung cancer treated with second-line erlotinib or chemotherapy (PROSE): a biomarker-stratified, randomised phase 3 trial. Lancet Oncol 2014; 15 (7) 713-721
  • 95 Diaz Jr LA, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 2014; 32 (6) 579-586
  • 96 Wu YL, Zhou C, Liam CK , et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 2015; 26 (9) 1883-1889
  • 97 Zheng D, Ye X, Zhang MZ , et al. Plasma EGFR T790M ctDNA status is associated with clinical outcome in advanced NSCLC patients with acquired EGFR-TKI resistance. Sci Rep 2016; 6: 20913
  • 98 Zill OA, Mortimer S, Banks KC , et al. Somatic genomic landscape of over 15,000 patients with advanced-stage cancer from clinical next-generation sequencing analysis of circulating tumor DNA. ASCO Meeting Abstracts 2016 34:LBA11501
  • 99 Francis G, Stein S. Circulating cell-free tumour DNA in the management of cancer. Int J Mol Sci 2015; 16 (6) 14122-14142