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Treatment of lung adenocarcinoma by molecular-targeted therapy and immunotherapy

Surgery Today volume 48, pages 1–8 (2018)Cite this article

Abstract

Lung adenocarcinoma (LADC) is a cancer treatable using targeted therapies against driver gene aberrations. EGFR mutations and ALK fusions are frequent gene aberrations in LADC, and personalized therapies against those aberrations have become a standard therapy. These targeted therapies have shown significant positive efficacy and tolerable toxicity compared to conventional chemotherapy, so it is necessary to identify additional druggable genetic aberrations. Other than EGFR mutations and ALK fusions, mutations in KRAS, HER2, and BRAF, and driver fusions involving RET and ROS1, have also been identified in LADC. Interestingly, the frequency of driver gene aberrations differs according to ethnicity, sex, and smoking, which leads to differences in treatment efficacy. To date, several molecular-targeted drugs against driver genes have been developed, and several clinical trials have been conducted to evaluate the efficacy. However, targeted therapies against driver-gene-negative cases have not yet been well developed. Efforts to identify a new druggable target for such cases are currently underway. Furthermore, immune checkpoint blockade therapy might be effective for driver-negative cases, especially those with accumulated mutations.

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References

  1. Garraway LA. Genomics-driven oncology: framework for an emerging paradigm. J Clin Oncol. 2013;31:1806–14.

    Article  PubMed  Google Scholar 

  2. Katayama H, Kurokawa Y, Nakamura K, Ito H, Kanemitsu Y, Masuda N, et al. Extended Clavien–Dindo classification of surgical complications: Japan Clinical Oncology Group postoperative complications criteria. Surg Today. 2016;46:668–85.

    Article  PubMed  Google Scholar 

  3. Saito M, Schetter AJ, Mollerup S, Kohno T, Skaug V, Bowman ED, et al. The association of microRNA expression with prognosis and progression in early-stage, non-small cell lung adenocarcinoma: a retrospective analysis of three cohorts. Clin Cancer Res. 2011;17:1875–82.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Saito M, Shiraishi K, Matsumoto K, Schetter AJ, Ogata-Kawata H, Tsuchiya N, et al. A three-microRNA signature predicts responses to platinum-based doublet chemotherapy in patients with lung adenocarcinoma. Clin Cancer Res. 2014;20:4784–93.

    CAS  Article  PubMed  Google Scholar 

  5. Seki Y, Fujiwara Y, Kohno T, Takai E, Sunami K, Goto Y, et al. Picoliter–Droplet digital polymerase chain reaction-based analysis of cell-free plasma DNA to assess EGFR mutations in lung adenocarcinoma that confer resistance to tyrosine-kinase inhibitors. Oncologist. 2016;21:156–64.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Ojima T, Nakamori M, Nakamura M, Katsuda M, Hayata K, Nakamura Y, et al. Expression of BRCA1, a factor closely associated with relapse-free survival, in patients who underwent neoadjuvant chemotherapy with docetaxel, cisplatin, and fluorouracil for squamous cell carcinoma of the esophagus. Surg Today. 2017;47:65–73.

    CAS  Article  PubMed  Google Scholar 

  7. Gately K, O’Flaherty J, Cappuzzo F, Pirker R, Kerr K, O’Byrne K. The role of the molecular footprint of EGFR in tailoring treatment decisions in NSCLC. J Clin Pathol. 2012;65:1–7.

    CAS  Article  PubMed  Google Scholar 

  8. Forde PM, Ettinger DS. Targeted therapy for non-small-cell lung cancer: past, present and future. Expert Rev Anticancer Ther. 2013;13:745–58.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Minuti G, D’Incecco A, Cappuzzo F. Targeted therapy for NSCLC with driver mutations. Expert Opin Biol Ther. 2013;13:1401–12.

    CAS  Article  PubMed  Google Scholar 

  10. Kohno T, Ichikawa H, Totoki Y, Yasuda K, Hiramoto M, Nammo T, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med. 2012;18:375–7.

    CAS  Article  PubMed  Google Scholar 

  11. Lipson D, Capelletti M, Yelensky R, Otto G, Parker A, Jarosz M, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 2012;18:382–4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Vaishnavi A, Capelletti M, Le AT, Kako S, Butaney M, Ercan D, et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med. 2013;19:1469–72.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Saito M, Shiraishi K, Kunitoh H, Takenoshita S, Yokota J, Kohno T. Gene aberrations for precision medicine against lung adenocarcinoma. Cancer Sci. 2016;107:713–20.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Saito M, Shimada Y, Shiraishi K, Sakamoto H, Tsuta K, Totsuka H, et al. Development of lung adenocarcinomas with exclusive dependence on oncogene fusions. Cancer Res. 2015;75:2264–71.

    CAS  Article  PubMed  Google Scholar 

  15. Cancer Genome Atlas Research N. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–50.

    Article  Google Scholar 

  16. Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371:1963–71.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Mazieres J, Zalcman G, Crino L, Biondani P, Barlesi F, Filleron T, et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J Clin Oncol. 2015;33:992–9.

    CAS  Article  PubMed  Google Scholar 

  18. Hirsch FR, Suda K, Wiens J, Bunn PA Jr. New and emerging targeted treatments in advanced non-small-cell lung cancer. The Lancet. 2016;388:1012–24.

    Article  Google Scholar 

  19. Sunami K, Furuta K, Tsuta K, Sasada S, Izumo T, Nakaoku T, et al. Multiplex diagnosis of oncogenic fusion and MET exon skipping by molecular counting using formalin-fixed paraffin embedded lung adenocarcinoma tissues. J Thorac Oncol. 2016;11:203–12.

    Article  PubMed  Google Scholar 

  20. Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18:378–81.

    CAS  Article  PubMed  Google Scholar 

  21. Saito M, Ishigame T, Tsuta K, Kumamoto K, Imai T, Kohno T. A mouse model of KIF5B-RET fusion-dependent lung tumorigenesis. Carcinogenesis. 2014;35:2452–6.

    CAS  Article  PubMed  Google Scholar 

  22. Drilon A, Wang L, Hasanovic A, Suehara Y, Lipson D, Stephens P, et al. Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer discovery. 2013;3:630–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Wu H, Shih JY, Yang JC. Rapid response to sunitinib in a patient with lung adenocarcinoma harboring KIF5B-RET fusion gene. J Thorac Oncol. 2015;10:e95–e6.

    Article  PubMed  Google Scholar 

  24. Gautschi O, Zander T, Keller FA, Strobel K, Hirschmann A, Aebi S, et al. A patient with lung adenocarcinoma and RET fusion treated with vandetanib. J Thorac Oncol. 2013;8:e43–e4.

    Article  PubMed  Google Scholar 

  25. Mukhopadhyay S, Pennell NA, Ali SM, Ross JS, Ma PC, Velcheti V. RET-rearranged lung adenocarcinomas with lymphangitic spread, psammoma bodies, and clinical responses to cabozantinib. J Thorac Oncol. 2014;9:1714–9.

    CAS  Article  PubMed  Google Scholar 

  26. Falchook GS, Ordonez NG, Bastida CC, Stephens PJ, Miller VA, Gaido L, et al. Effect of the RET inhibitor Vandetanib in a patient with RET fusion-positive metastatic non-small-cell lung cancer. J Clin Oncol. 2016;34:e141–e4.

    CAS  Article  PubMed  Google Scholar 

  27. Yoh K, Seto T, Satouchi M, Nishio M, Yamamoto N, Murakami H, et al. Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial. Lancet Respir Med. 2016.

  28. Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014; 11:473–81.

    CAS  Article  PubMed  Google Scholar 

  29. Kawamura T, Kenmotsu H, Taira T, Omori S, Nakashima K, Wakuda K, et al. Rebiopsy for patients with non-small-cell lung cancer after epidermal growth factor receptor-tyrosine kinase inhibitor failure. Cancer Sci. 2016;107:1001–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Gainor JF, Dardaei L, Yoda S, Friboulet L, Leshchiner I, Katayama R, et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged Lung cancer. Cancer Discov. 2016;6:1118–33.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Gainor JF, Shaw AT. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol. 2013;31:3987–96.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372:1689–99.

    Article  PubMed  Google Scholar 

  34. Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18:1472–82.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Tan CS, Gilligan D, Pacey S. Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer. Lancet Oncol. 2015;16:e447–e59.

    CAS  Article  PubMed  Google Scholar 

  36. Kohno T, Nakaoku T, Tsuta K, Tsuchihara K, Matsumoto S, Yoh K, et al. Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer. Transl Lung Cancer Res. 2015;4:156–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Ohba T, Toyokawa G, Osoegawa A, Hirai F, Yamaguchi M, Taguchi K, et al. Mutations of the EGFR, K-ras, EML4-ALK, and BRAF genes in resected pathological stage I lung adenocarcinoma. Surg Today. 2016;46:1091–8.

    CAS  Article  PubMed  Google Scholar 

  38. Paik PK, Arcila ME, Fara M, Sima CS, Miller VA, Kris MG, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol. 2011;29:2046–51.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kinno T, Tsuta K, Shiraishi K, Mizukami T, Suzuki M, Yoshida A, et al. Clinicopathological features of nonsmall cell lung carcinomas with BRAF mutations. Ann Oncol. 2014;25:138–42.

    CAS  Article  PubMed  Google Scholar 

  40. Arcila ME, Drilon A, Sylvester BE, Lovly CM, Borsu L, Reva B, et al. MAP2K1 (MEK1) mutations define a distinct subset of lung adenocarcinoma associated with smoking. Clin Cancer Res. 2015;21:1935–43.

    CAS  Article  PubMed  Google Scholar 

  41. Wilson BG, Roberts CW. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer. 2011;11:481–92.

    CAS  Article  PubMed  Google Scholar 

  42. Bitler BG, Aird KM, Garipov A, Li H, Amatangelo M, Kossenkov AV, et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med. 2015;21:231–8.

    CAS  PubMed  Google Scholar 

  43. Oike T, Ogiwara H, Tominaga Y, Ito K, Ando O, Tsuta K, et al. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res. 2013;73:5508–18.

    CAS  Article  PubMed  Google Scholar 

  44. Kim KH, Kim W, Howard TP, Vazquez F, Tsherniak A, Wu JN, et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat Med. 2015;21:1491–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Shen J, Peng Y, Wei L, Zhang W, Yang L, Lan L, et al. ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors. Cancer Discov. 2015;5:752–67.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med. 2016;22:128–34.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568–71.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33:1974–82.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–9.

    Article  PubMed  Google Scholar 

  50. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–28.

    Article  PubMed  Google Scholar 

  51. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Gettinger S, Rizvi NA, Chow LQ, Borghaei H, Brahmer J, Ready N, et al. Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2016;34:2980–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016.

  54. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2016;34:2969–79.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–39.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389:255–65.

    Article  PubMed  Google Scholar 

  58. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. 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;387:1837–46.

    CAS  Article  PubMed  Google Scholar 

  59. Seo JS, Ju YS, Lee WC, Shin JY, Lee JK, Bleazard T, et al. The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res. 2012;22:2109–19.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 2012;150:1107–20.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. Suzuki A, Mimaki S, Yamane Y, Kawase A, Matsushima K, Suzuki M, et al. Identification and characterization of cancer mutations in Japanese lung adenocarcinoma without sequencing of normal tissue counterparts. PLoS One. 2013;8:e73484.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. Fernandez-Cuesta L, Plenker D, Osada H, Sun R, Menon R, Leenders F, et al. CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov. 2014;4:415–22.

    CAS  Article  PubMed  Google Scholar 

  63. Dhanasekaran SM, Balbin OA, Chen G, Nadal E, Kalyana-Sundaram S, Pan J, et al. Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes. Nature Commun. 2014;5:5893.

    CAS  Article  Google Scholar 

  64. Campbell JD, Alexandrov A, Kim J, Wala J, Berger AH, Pedamallu CS, et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat Genet. 2016;48:607–16.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. Kadara H, Choi M, Zhang J, Parra ER, Rodriguez-Canales J, Gaffney SG, et al. Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up. Ann Oncol. 2016 (in press).

  66. TCGA manuscript is Cancer Genome Atlas Research N. Comprehensive molecular profing of lung adenocarcinoma. Nature. 2014;511:543–50.

    Article  Google Scholar 

  67. Nakaoku T, Tsuta K, Ichikawa H, Shiraishi K, Sakamoto H, Enari M, et al. Druggable oncogene fusions in invasive mucinous lung adenocarcinoma. Clin Cancer Res. 2014;20(12):3087–93.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by JSPS KAKENHI Grant Number 15K10275.

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Affiliations

  1. Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan

    Motonobu Saito & Takashi Kohno

  2. Department of Chest Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan

    Motonobu Saito & Hiroyuki Suzuki

  3. Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan

    Motonobu Saito & Koji Kono

  4. Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, Japan

    Seiichi Takenoshita

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  1. Motonobu Saito
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  2. Hiroyuki Suzuki
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  4. Seiichi Takenoshita
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  5. Takashi Kohno
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Correspondence to Motonobu Saito.

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Saito, M., Suzuki, H., Kono, K. et al. Treatment of lung adenocarcinoma by molecular-targeted therapy and immunotherapy. Surg Today 48, 1–8 (2018). https://doi.org/10.1007/s00595-017-1497-7

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Keywords

  • Driver gene aberrations
  • Lung adenocarcinoma
  • Targeted therapy
  • Immunotherapy