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Mutations as Predictive Biomarkers for Adenocarcinoma

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Precision Molecular Pathology of Lung Cancer

Part of the book series: Molecular Pathology Library ((MPLB))

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Abstract

The diagnosis and treatment of lung adenocarcinoma has been revolutionized by the discovery of oncogenic driver alterations and the parallel development and testing of genetically targeted agents, leading to the era of “precision medicine” in solid tumor oncology. Understanding and interpreting the molecular pathology of lung adenocarcinoma is now key in the stratification of patients for appropriate initial targeted therapy and downstream resistance profiling. Multiple complementary methods to assess the molecular phenotype of lung adenocarcinoma exist, including gene sequencing, FISH, and immunohistochemistry. Next-generation sequencing now allows for quantitative multiparametric genetic profiling (single nucleotide, copy number, and structural variants) of lung adenocarcinoma at diagnosis and during tumor evolution and will likely become the molecular assay of choice for less biased profiling of lung adenocarcinoma. Resulting molecular pathology data must be carefully integrated into the plan of care by a multidisciplinary team comprised of surgeons, oncologists, and pathologists, to ensure accurate diagnosis and appropriate treatment of lung adenocarcinoma.

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References

  1. Howlader N, Noone A, Krapcho M, Garshell J, Miller D, Altekruse S, Kosary C, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis D, Chen H, Feuer E, Cronin K, editors. SEER cancer statistics review, 1975–2011. Bethesda: National Cancer Institute; 2014.

    Google Scholar 

  2. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, Chirieac LR, Dacic S, Duhig E, Flieder DB, Geisinger K, Hirsch FR, Ishikawa Y, Kerr KM, Noguchi M, Pelosi G, Powell CA, Tsao MS, Wistuba I, WHO Panel. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10(9):1243–60.

    Article  PubMed  Google Scholar 

  3. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar J-S, Squire J, Thunnissen E, Ladanyi M. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors. J Thorac Oncol. 2013;8(7):823–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gerber DE, Gandhi L, Costa DB. Management and future directions in non-small cell lung cancer with known activating mutations. Am Soc Clin Oncol Educ Book. 2014;34:e353–65.

    Article  Google Scholar 

  5. Sacher AG, Jänne PA, Oxnard GR. Management of acquired resistance to epidermal growth factor receptor kinase inhibitors in patients with advanced non-small cell lung cancer. Cancer. 2014;120(15):2289–98.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Cortot AB, Jänne PA. Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas. Eur Respir Rev. 2014;23(133):356–66.

    Article  PubMed  Google Scholar 

  7. Jänne PA, Yang JC-H, Kim D-W, Planchard D, Ohe Y, Ramalingam SS, Ahn M-J, Kim S-W, Su W-C, Horn L, Haggstrom D, Felip E, Kim J-H, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689–99.

    Article  PubMed  Google Scholar 

  8. Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WSME, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA, AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629–40.

    Article  CAS  PubMed  Google Scholar 

  9. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, Akhavanfard S, Heist RS, Temel J, Christensen JG, Wain JC, Lynch TJ, Vernovsky K, Mark EJ, Lanuti M, Iafrate AJ, Mino-Kenudson M, Engelman JA. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Xu L, Kikuchi E, Xu C, Ebi H, Ercan D, Cheng KA, Padera R, Engelman JA, Jänne PA, Shapiro GI, Shimamura T, Wong KK. Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET. Cancer Res. 2012;72(13):3302–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Takezawa K, Pirazzoli V, Arcila ME, Nebhan CA, Song X, de Stanchina E, Ohashi K, Janjigian YY, Spitzler PJ, Melnick MA, Riely GJ, Kris MG, Miller VA, Ladanyi M, Politi K, Pao W. HER2 amplification: A potential mechanism of acquired resistance to egfr inhibition in EGFR -mutant lung cancers that lack the second-site EGFR T790M mutation. Cancer Discov. 2012;2(10):922–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Oxnard GR, Thress KS, Alden RS, Lawrance R, Paweletz CP, Cantarini M, Yang JCH, Barrett JC, Jänne PA. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol. 2016;34(28):3375–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pilotto S, Gkountakos A, Carbognin L, Scarpa A, Tortora G, Bria E. MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy. Ann Transl Med. 2017;5(1):2.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Peschard P, Fournier TM, Lamorte L, Naujokas MA, Band H, Langdon WY, Park M. Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein. Mol Cell. 2001;8(5):995–1004.

    Article  CAS  PubMed  Google Scholar 

  15. Lee J-H, Gao CF, Lee CC, Kim MD, Vande Woude GF. An alternatively spliced form of Met receptor is tumorigenic. Exp Mol Med. 2006;38(5):565–73.

    Article  CAS  PubMed  Google Scholar 

  16. Awad MM, Oxnard GR, Jackman DM, Savukoski DO, Hall D, Shivdasani P, Heng JC, Dahlberg SE, Jänne PA, Verma S, Christensen J, Hammerman PS, Sholl LM. MET Exon 14 mutations in non–small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression. J Clin Oncol. 2016;34(7):721–30.

    Article  CAS  PubMed  Google Scholar 

  17. Liu X, Jia Y, Stoopler MB, Shen Y, Cheng H, Chen J, Mansukhani M, Koul S, Halmos B, Borczuk AC. Next-generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET gene mutations. J Clin Oncol. 2016;34(8):794–802.

    Article  CAS  PubMed  Google Scholar 

  18. Paik PK, Drilon A, Fan P-D, Yu H, Rekhtman N, Ginsberg MS, Borsu L, Schultz N, Berger MF, Rudin CM, Ladanyi M. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov. 2015;5(8):842–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bahcall M, Sim T, Paweletz CP, Patel JD, Alden RS, Kuang Y, Sacher AG, Kim ND, Lydon CA, Awad MM, Jaklitsch MT, Sholl LM, Jänne PA, Oxnard GR. Acquired METD1228V mutation and resistance to MET inhibition in lung cancer. Cancer Discov. 2016;6(12):1334–41.

    Article  CAS  PubMed  Google Scholar 

  20. Cardarella S, Ogino A, Nishino M, Butaney M, Shen J, Lydon C, Yeap BY, Sholl LM, Johnson BE, Jänne PA. Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res. 2013;19(16):4532–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543–50.

    Article  Google Scholar 

  22. de Langen AJ, Smit EF. Therapeutic approach to treating patients with BRAF-mutant lung cancer: latest evidence and clinical implications. Ther Adv Med Oncol. 2017;9(1):46–58.

    Article  PubMed  Google Scholar 

  23. Planchard D, Besse B, Groen HJM, Souquet P-J, Quoix E, Baik CS, Barlesi F, Kim TM, Mazieres J, Novello S, Rigas JR, Upalawanna A, D’Amelio AM, Zhang P, Mookerjee B, Johnson BE. Dabrafenib plus trametinib in patients with previously treated BRAFV600E-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17(7):984–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, Stevens C, O’Meara S, Smith R, Parker A, Barthorpe A, Blow M, Brackenbury L, Butler A, Clarke O, Cole J, Dicks E, Dike A, Drozd A, Edwards K, Forbes S, Foster R, Gray K, Greenman C, Halliday K, Hills K, Kosmidou V, Lugg R, Menzies A, Perry J, Petty R, Raine K, Ratford L, Shepherd R, Small A, Stephens Y, Tofts C, Varian J, West S, Widaa S, Yates A, Brasseur F, Cooper CS, Flanagan AM, Knowles M, Leung SY, Louis DN, Looijenga LHJ, Malkowicz B, Pierotti MA, Teh B, Chenevix-Trench G, Weber BL, Yuen ST, Harris G, Goldstraw P, Nicholson AG, Futreal PA, Wooster R, Stratton MR. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature. 2004;431(7008):525–6.

    Article  CAS  PubMed  Google Scholar 

  25. Wang SE, Narasanna A, Perez-Torres M, Xiang B, Wu FY, Yang S, Carpenter G, Gazdar AF, Muthuswamy SK, Arteaga CL. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell. 2006;10(1):25–38.

    Article  PubMed  Google Scholar 

  26. Shigematsu H. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res. 2005;65(5):1642–6.

    Article  CAS  PubMed  Google Scholar 

  27. Sholl LM, Aisner DL, Varella-Garcia M, Berry LD, Dias-Santagata D, Wistuba II, Chen H, Fujimoto J, Kugler K, Franklin WA, Iafrate AJ, Ladanyi M, Kris MG, Johnson BE, Bunn PA, Minna JD, Kwiatkowski DJ, LCMC Investigators. Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: the lung cancer mutation consortium experience. J Thorac Oncol. 2015;10(5):768–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Arcila ME, Chaft JE, Nafa K, Roy-Chowdhuri S, Lau C, Zaidinski M, Paik PK, Zakowski MF, Kris MG, Ladanyi M. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res. 2012;18(18):4910–8.

    Article  CAS  PubMed  Google Scholar 

  29. De Grève J, Moran T, Graas M-P, Galdermans D, Vuylsteke P, Canon J-L, Schallier D, Decoster L, Teugels E, Massey D, Chand VK, Vansteenkiste J. Phase II study of afatinib, an irreversible ErbB family blocker, in demographically and genotypically defined lung adenocarcinoma. Lung Cancer. 2015;88(1):63–9.

    Article  PubMed  Google Scholar 

  30. Cappuzzo F, Bemis L, Varella-Garcia M. HER2 mutation and response to trastuzumab therapy in non–small-cell lung cancer. N Engl J Med. 2006;354(24):2619–21.

    Article  CAS  PubMed  Google Scholar 

  31. Gandhi L, Bahleda R, Tolaney SM, Kwak EL, Cleary JM, Pandya SS, Hollebecque A, Abbas R, Ananthakrishnan R, Berkenblit A, Krygowski M, Liang Y, Turnbull KW, Shapiro GI, Soria J-C. Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors. J Clin Oncol. 2014;32(2):68–75.

    Article  CAS  PubMed  Google Scholar 

  32. Mazières J, Barlesi F, Filleron T, Besse B, Monnet I, Beau-Faller M, Peters S, Dansin E, Früh M, Pless M, Rosell R, Wislez M, Fournel P, Westeel V, Cappuzzo F, Cortot A, Moro-Sibilot D, Milia J, Gautschi O. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort. Ann Oncol. 2016;27(2):281–6.

    Article  PubMed  Google Scholar 

  33. Li C, Sun Y, Fang R, Han X, Luo X, Wang R, Pan Y, Hu H, Zhang Y, Pao W, Shen L, Ji H, Chen H. Lung adenocarcinomas with HER2-activating mutations are associated with distinct clinical features and HER2/EGFR copy number gains. J Thorac Oncol. 2012;7(1):85–9.

    Article  CAS  PubMed  Google Scholar 

  34. Li BT, Ross DS, Aisner DL, Chaft JE, Hsu M, Kako SL, Kris MG, Varella-Garcia M, Arcila ME. HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers. J Thorac Oncol. 2016;11(3):414–9.

    Article  PubMed  Google Scholar 

  35. Sacher AG, Gandhi L. Biomarkers for the clinical use of PD-1/PD-L1 inhibitors in non–small-cell lung cancer. JAMA Oncol. 2016;2(9):1217.

    Article  PubMed  Google Scholar 

  36. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dong Z-Y, Zhong W-Z, Zhang X-C, Su J, Xie Z, Liu S-Y, Tu H-Y, Chen H-J, Sun Y-L, Zhou Q, Yang J-J, Yang X-N, Lin J-X, Yan H-H, Zhai H-R, Yan L-X, Liao R-Q, Wu S-P, Wu Y-L. Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma. Clin Cancer Res. 2016;23:3012–24.

    Article  PubMed  Google Scholar 

  38. McGranahan N, Furness AJS, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, Watkins TBK, Shafi S, Murugaesu N, Mitter R, Akarca AU, Linares J, Marafioti T, Henry JY, Van Allen EM, Miao D, Schilling B, Schadendorf D, Garraway LA, Makarov V, Rizvi NA, Snyder A, Hellmann MD, Merghoub T, Wolchok JD, Shukla SA, Wu CJ, Peggs KS, Chan TA, Hadrup SR, Quezada SA, Swanton C. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gros A, Parkhurst MR, Tran E, Pasetto A, Robbins PF, Ilyas S, Prickett TD, Gartner JJ, Crystal JS, Roberts IM, Trebska-McGowan K, Wunderlich JR, Yang JC, Rosenberg SA. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med. 2016;22(4):433–8.

    Article  CAS  PubMed  Google Scholar 

  40. Boolell V, Alamgeer M, Watkins D, Ganju V. The Evolution of Therapies in Non-Small Cell Lung Cancer. Cancer. 2015;7(3):1815–46.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, 02115, USA

    Navin R. Mahadevan & Lynette M. Sholl

Authors
  1. Navin R. Mahadevan
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  2. Lynette M. Sholl
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Correspondence to Lynette M. Sholl .

Editor information

Editors and Affiliations

  1. Department of Pathology & Genomic Medici, Houston Methodist Hospital, Houston, Texas, USA

    Philip T. Cagle

  2. Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA

    Timothy Craig Allen

  3. Department of Pathology, Mount Sinai Medical Center, New York, New York, USA

    Mary Beth Beasley

  4. Department of Pathology, Brigham & Women’s Hospital, Boston, Massachusetts, USA

    Lucian R. Chirieac

  5. Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

    Sanja Dacic

  6. Department of Pathology, Weill Cornell Medicine, New York, New York, USA

    Alain C. Borczuk

  7. Department of Pathology, Aberdeen University Medical School, Aberdeen, United Kingdom

    Keith M. Kerr

  8. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Lynette M. Sholl

  9. Medical Innovation, Roche Tissue Diagnostics, Ventana Medical Systems, Tucson, Arizona, USA

    Bryce Portier

  10. Cancer Center, Houston Methodist Hospital, Houston, Texas, USA

    Eric H. Bernicker

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Mahadevan, N.R., Sholl, L.M. (2018). Mutations as Predictive Biomarkers for Adenocarcinoma. In: Cagle, P., et al. Precision Molecular Pathology of Lung Cancer. Molecular Pathology Library. Springer, Cham. https://doi.org/10.1007/978-3-319-62941-4_11

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  • DOI: https://doi.org/10.1007/978-3-319-62941-4_11

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