Yonsei Med J.  2015 Sep;56(5):1177-1185. 10.3349/ymj.2015.56.5.1177.

Evolution of Gastric Cancer Treatment: From the Golden Age of Surgery to an Era of Precision Medicine

• Choi YY
• Noh SH
• Cheong JH

• KMID: 2163607
• DOI: http://doi.org/10.3349/ymj.2015.56.5.1177

Abstract

Gastric cancer imposes a global health burden. Although multimodal therapies have proven to benefit patients with advanced diseases after curative surgery, the prognosis of most advanced cancer patients still needs to be improved. Surgical extirpation is the mainstay of gastric cancer treatment. Indeed, without curative surgery, variations and combinations of chemotherapy and/or radiation cannot bring clinically meaningful success. Centered around D2 surgery, adjuvant and peri-operative multimodal therapies have improved survival in a certain group of gastric cancer patients. Moving toward a personalized cancer therapy era, molecular targeted strategies have been tested in clinical trials for gastric cancer. With some success and failures, we have learned valuable lessons regarding the biology of gastric cancer and the clinical relevance of biological therapies in addition to conventional treatments. Future treatment of gastric cancer will be shifted to molecularly tailored and genome information-based personalized therapy. Collaboration across disciplines and actively adopting emerging anti-cancer strategies, along with in-depth understanding of molecular and genetic underpinnings of tumor development and progression, are imperative to realizing personalized therapy for gastric cancer. Although many challenges remain to be overcome, we envision that the era of precision cancer medicine for gastric cancer has already arrived and anticipate that current knowledge and discoveries will be transformed into near-future clinical practice for managing gastric cancer patients.

Keyword

Gastric cancer; precision medicine; treatment

MeSH Terms

Combined Modality Therapy
Female
Gastrectomy
Humans
*Precision Medicine
Prognosis
Stomach Neoplasms/*surgery

Reference

1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136:E359–E386.

2. Lee KS, Oh DK, Han MA, Lee HY, Jun JK, Choi KS, et al. Gastric cancer screening in Korea: report on the national cancer screening program in 2008. Cancer Res Treat. 2011; 43:83–88.

3. Hamashima C, Shibuya D, Yamazaki H, Inoue K, Fukao A, Saito H, et al. The Japanese guidelines for gastric cancer screening. Jpn J Clin Oncol. 2008; 38:259–267.

4. Jung KW, Won YJ, Kong HJ, Oh CM, Cho H, Lee DH, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2012. Cancer Res Treat. 2015; 47:127–141.

5. Jung KW, Won YJ, Oh CM, Kong HJ, Cho H, Lee DH, et al. Prediction of cancer incidence and mortality in Korea, 2015. Cancer Res Treat. 2015; 47:142–148.

6. Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW, et al. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol. 2014; 15:1389–1396.

7. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010; 376:687–697.

8. Nakajima T, Nashimoto A, Kitamura M, Kito T, Iwanaga T, Okabayashi K, et al. Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer: a randomised trial. Gastric Cancer Surgical Study Group. Lancet. 1999; 354:273–277.

9. Macdonald JS, Fleming TR, Peterson RF, Berenberg JL, McClure S, Chapman RA, et al. Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: A Southwest Oncology Group study. Ann Surg Oncol. 1995; 2:488–494.

10. Engstrom PF, Lavin PT, Douglass HO Jr, Brunner KW. Eastern Cooperative Oncology Group study (EST 3275). Postoperative adjuvant 5-fluorouracil plus methyl-CCNU therapy for gastric cancer patients. Cancer. 1985; 55:1868–1873.

11. Krook JE, O'Connell MJ, Wieand HS, Beart RW Jr, Leigh JE, Kugler JW, et al. A prospective, randomized evaluation of intensive-course 5-fluorouracil plus doxorubicin as surgical adjuvant chemotherapy for resected gastric cancer. Cancer. 1991; 67:2454–2458.

12. Cunningham D, Chua YJ. East meets west in the treatment of gastric cancer. N Engl J Med. 2007; 357:1863–1865.

13. Japanese Gastric Cancer Association. Japanese Classification of Gastric Carcinoma - 2nd English Edition -. Gastric Cancer. 1998; 1:10–24.

14. Cancer JRSfG: Japenese classification of gastric carcinoma. 1st ed (English). Tokyo: Kanehara;1995.

15. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer. 2011; 14:113–123.

16. Wu CW, Hsiung CA, Lo SS, Hsieh MC, Chen JH, Li AF, et al. Nodal dissection for patients with gastric cancer: a randomised controlled trial. Lancet Oncol. 2006; 7:309–315.

17. Sano T, Sasako M, Yamamoto S, Nashimoto A, Kurita A, Hiratsuka M, et al. Gastric cancer surgery: morbidity and mortality results from a prospective randomized controlled trial comparing D2 and extended para-aortic lymphadenectomy--Japan Clinical Oncology Group study 9501. J Clin Oncol. 2004; 22:2767–2773.

18. Sasako M, Sano T, Yamamoto S, Kurokawa Y, Nashimoto A, Kurita A, et al. D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. N Engl J Med. 2008; 359:453–462.

19. Hyung WJ, Kim SS, Choi WH, Cheong JH, Choi SH, Kim CB, et al. Changes in treatment outcomes of gastric cancer surgery over 45 years at a single institution. Yonsei Med J. 2008; 49:409–415.

20. Bonenkamp JJ, Hermans J, Sasako M, van de Velde CJ, Welvaart K, Songun I, et al. Extended lymph-node dissection for gastric cancer. N Engl J Med. 1999; 340:908–914.

21. Cuschieri A, Weeden S, Fielding J, Bancewicz J, Craven J, Joypaul V, et al. Surgical Co-operative Group. Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Br J Cancer. 1999; 79:1522–1530.

22. Cuschieri A, Fayers P, Fielding J, Craven J, Bancewicz J, Joypaul V, et al. The Surgical Cooperative Group. Postoperative morbidity and mortality after D1 and D2 resections for gastric cancer: preliminary results of the MRC randomised controlled surgical trial. Lancet. 1996; 347:995–999.

23. Bonenkamp JJ, Songun I, Hermans J, Sasako M, Welvaart K, Plukker JT, et al. Randomised comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients. Lancet. 1995; 345:745–748.

24. Kim KM, An JY, Kim HI, Cheong JH, Hyung WJ, Noh SH. Major early complications following open, laparoscopic and robotic gastrectomy. Br J Surg. 2012; 99:1681–1687.

25. Songun I, Putter H, Kranenbarg EM, Sasako M, van de Velde CJ. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol. 2010; 11:439–449.

26. Martin RC 2nd, Jaques DP, Brennan MF, Karpeh M. Extended local resection for advanced gastric cancer: increased survival versus increased morbidity. Ann Surg. 2002; 236:159–165.

27. Mansfield PF. Lymphadenectomy for gastric cancer. J Clin Oncol. 2004; 22:2759–2761.

28. Waddell T, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D, et al. Gastric cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013; 24:Suppl 6. vi57–vi63.

29. Ajani JA, Bentrem DJ, Besh S, D'Amico TA, Das P, Denlinger C, et al. Gastric cancer, version 2.2013: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw. 2013; 11:531–546.

30. Ohashi I, Takagi K, Ota H, Kamiya J, Nakagoe T, Kajitani T. Pancreatosplenectomy for advanced gastric carcinoma with special reference to lymph nodes metastasis. Jpn J Gastroenterol Surg. 1979; 12:993–999.

31. Maruyama K, Sasako M, Kinoshita T, Sano T, Katai H, Okajima K. Pancreas-preserving total gastrectomy for proximal gastric cancer. World J Surg. 1995; 19:532–536.

32. Choi YY, An JY, Kim HI, Cheong JH, Hyung WJ, Noh SH. Current practice of gastric cancer treatment. . Chin Med J (Engl). 2014; 127:547–553.

33. Oh SJ, Hyung WJ, Li C, Song J, Kang W, Rha SY, et al. The effect of spleen-preserving lymphadenectomy on surgical outcomes of locally advanced proximal gastric cancer. J Surg Oncol. 2009; 99:275–280.

34. Lee KY, Noh SH, Hyung WJ, Lee JH, Lah KH, Choi SH, et al. Impact of splenectomy for lymph node dissection on long-term surgical outcome in gastric cancer. Ann Surg Oncol. 2001; 8:402–406.

35. Bartlett EK, Roses RE, Kelz RR, Drebin JA, Fraker DL, Karakousis GC. Morbidity and mortality after total gastrectomy for gastric malignancy using the American College of Surgeons National Surgical Quality Improvement Program database. Surgery. 2014; 156:298–304.

36. Yu W, Choi GS, Chung HY. Randomized clinical trial of splenectomy versus splenic preservation in patients with proximal gastric cancer. Br J Surg. 2006; 93:559–563.

37. Kosuga T, Ichikawa D, Okamoto K, Komatsu S, Shiozaki A, Fujiwara H, et al. Survival benefits from splenic hilar lymph node dissection by splenectomy in gastric cancer patients: relative comparison of the benefits in subgroups of patients. Gastric Cancer. 2011; 14:172–177.

38. Mönig SP, Collet PH, Baldus SE, Schmackpfeffer K, Schröder W, Thiele J, et al. Splenectomy in proximal gastric cancer: frequency of lymph node metastasis to the splenic hilus. J Surg Oncol. 2001; 76:89–92.

39. Sasada S, Ninomiya M, Nishizaki M, Harano M, Ojima Y, Matsukawa H, et al. Frequency of lymph node metastasis to the splenic hilus and effect of splenectomy in proximal gastric cancer. Anticancer Res. 2009; 29:3347–3351.

40. Sano T, Yamamoto S, Sasako M. Japan Clinical Oncology Group Study LCOG 0110-MF. Randomized controlled trial to evaluate splenectomy in total gastrectomy for proximal gastric carcinoma: Japan clinical oncology group study JCOG 0110-MF. Jpn J Clin Oncol. 2002; 32:363–364.

41. Kitano S, Iso Y, Moriyama M, Sugimachi K. Laparoscopy-assisted Billroth I gastrectomy. Surg Laparosc Endosc. 1994; 4:146–148.

42. Kim HH, Hyung WJ, Cho GS, Kim MC, Han SU, Kim W, et al. Morbidity and mortality of laparoscopic gastrectomy versus open gastrectomy for gastric cancer: an interim report--a phase III multicenter, prospective, randomized Trial (KLASS Trial). Ann Surg. 2010; 251:417–420.

43. Nakamura K, Katai H, Mizusawa J, Yoshikawa T, Ando M, Terashima M, et al. A phase III study of laparoscopy-assisted versus open distal gastrectomy with nodal dissection for clinical stage IA/IB gastric Cancer (JCOG0912). Jpn J Clin Oncol. 2013; 43:324–327.

44. Kim HH, Han SU, Kim MC, Hyung WJ, Kim W, Lee HJ, et al. Long-term results of laparoscopic gastrectomy for gastric cancer: a large-scale case-control and case-matched Korean multicenter study. J Clin Oncol. 2014; 32:627–633.

45. Choi YY, Bae JM, An JY, Hyung WJ, Noh SH. Laparoscopic gastrectomy for advanced gastric cancer: are the long-term results comparable with conventional open gastrectomy? A systematic review and meta-analysis. J Surg Oncol. 2013; 108:550–556.

46. Cai J, Wei D, Gao CF, Zhang CS, Zhang H, Zhao T. A prospective randomized study comparing open versus laparoscopy-assisted D2 radical gastrectomy in advanced gastric cancer. Dig Surg. 2011; 28:331–337.

47. Song J, Oh SJ, Kang WH, Hyung WJ, Choi SH, Noh SH. Robot-assisted gastrectomy with lymph node dissection for gastric cancer: lessons learned from an initial 100 consecutive procedures. Ann Surg. 2009; 249:927–932.

48. Park SS, Kim MC, Park MS, Hyung WJ. Rapid adaptation of robotic gastrectomy for gastric cancer by experienced laparoscopic surgeons. Surg Endosc. 2012; 26:60–67.

49. Son T, Kwon IG, Hyung WJ. Minimally invasive surgery for gastric cancer treatment: current status and future perspectives. Gut Liver. 2014; 8:229–236.

50. Marano A, Choi YY, Hyung WJ, Kim YM, Kim J, Noh SH. Robotic versus Laparoscopic versus Open Gastrectomy: A Meta-Analysis. J Gastric Cancer. 2013; 13:136–148.

51. Coratti A, Annecchiarico M, Di Marino M, Gentile E, Coratti F, Giulianotti PC. Robot-assisted gastrectomy for gastric cancer: current status and technical considerations. World J Surg. 2013; 37:2771–2781.

52. Kunisaki C, Akiyama H, Nomura M, Matsuda G, Otsuka Y, Ono H, et al. Significance of long-term follow-up of early gastric cancer. Ann Surg Oncol. 2006; 13:363–369.

53. Miyashiro I. What is the problem in clinical application of sentinel node concept to gastric cancer surgery? J Gastric Cancer. 2012; 12:7–12.

54. Kitagawa Y, Takeuchi H, Takagi Y, Natsugoe S, Terashima M, Murakami N, et al. Sentinel node mapping for gastric cancer: a prospective multicenter trial in Japan. J Clin Oncol. 2013; 31:3704–3710.

55. Ryu KW. The future of sentinel node oriented tailored approach in patients with early gastric cancer. J Gastric Cancer. 2012; 12:1–2.

56. Ono H, Kondo H, Gotoda T, Shirao K, Yamaguchi H, Saito D, et al. Endoscopic mucosal resection for treatment of early gastric cancer. Gut. 2001; 48:225–229.

57. Gotoda T, Yanagisawa A, Sasako M, Ono H, Nakanishi Y, Shimoda T, et al. Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at two large centers. Gastric Cancer. 2000; 3:219–225.

58. Lian J, Chen S, Zhang Y, Qiu F. A meta-analysis of endoscopic submucosal dissection and EMR for early gastric cancer. Gastrointest Endosc. 2012; 76:763–770.

59. Choi JH, Kim ES, Lee YJ, Cho KB, Park KS, Jang BK, et al. Comparison of quality of life and worry of cancer recurrence between endoscopic and surgical treatment for early gastric cancer. Gastrointest Endosc. 2015; 04. 17. [Epub]. DOI: 10.1016/j.gie.2015.01.019.

60. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001; 345:725–730.

61. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006; 355:11–20.

62. Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007; 357:1810–1820.

63. Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011; 29:4387–4393.

64. Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012; 379:315–321.

65. GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) Group. Paoletti X, Oba K, Burzykowski T, Michiels S, Ohashi Y, et al. Benefit of adjuvant chemotherapyfor resectable gastric cancer: a meta-analysis. JAMA. 2010; 303:1729–1729.

66. Choi YY, Cheong JH, Noh SH. Advanced gastric cancer: is chemotherapy needed after surgery? Expert Rev Gastroenterol Hepatol. 2013; 7:673–675.

67. Lee J, Lim do H, Kim S, Park SH, Park JO, Park YS, et al. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol. 2012; 30:268–273.

68. Park SH, Sohn TS, Lee J, Lim DH, Hong ME, Kim KM, et al. Phase III Trial to Compare Adjuvant Chemotherapy With Capecitabine and Cisplatin Versus Concurrent Chemoradiotherapy in Gastric Cancer: Final Report of the Adjuvant Chemoradiotherapy in Stomach Tumors Trial, Including Survival and Subset Analyses. J ClinOncol. 2015; 01. 05. [Epub]. DOI: 10.1200/JCO.2014.58.3930.

69. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350:2335–2342.

70. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006; 355:2542–2550.

71. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009; 27:740–745.

72. Shah MA, Jhawer M, Ilson DH, Lefkowitz RA, Robinson E, Capanu M, et al. Phase II study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J Clin Oncol. 2011; 29:868–874.

73. Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011; 29:3968–3976.

74. Van Cutsem E, de Haas S, Kang YK, Ohtsu A, Tebbutt NC, Ming Xu J, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol. 2012; 30:2119–2127.

75. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebocontrolled, phase 3 trial. Lancet. 2014; 383:31–39.

76. Shah MA. Gastrointestinal cancer: targeted therapies in gastric cancer-the dawn of a new era. Nat Rev Clin Oncol. 2014; 11:10–11.

77. Committee on a Framework for Development a New Taxonomy of Disease, Board on Life Sciences, Division on Earth and Life Studies, National Research Council. Toward precision medicine: building a Knowledge network for biomedical research and a new taxonomy of disease. Washington, DC: The national Academies press;2011.

78. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965; 64:31–49.

79. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon: International Agency for Research on Cancer;2010.

80. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003; 349:247–257.

81. Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010; 28:3219–3226.

82. An JY, Kim H, Cheong JH, Hyung WJ, Kim H, Noh SH. Microsatellite instability in sporadic gastric cancer: its prognostic role and guidance for 5-FU based chemotherapy after R0 resection. Int J Cancer. 2012; 131:505–511.

83. Choi YY, Bae JM, An JY, Kwon IG, Cho I, Shin HB, et al. Is microsatellite instability a prognostic marker in gastric cancer? A systematic review with meta-analysis. J Surg Oncol. 2014; 110:129–135.

84. Kim SY, Choi YY, An JY, Shin HB, Jo A, Choi H, et al. The benefit of microsatellite instability is attenuated by chemotherapy in stage II and stage III gastric cancer: results from a large cohort with subgroup analyses. Int J Cancer. 2015; 137:819–825.

85. Cho JY, Lim JY, Cheong JH, Park YY, Yoon SL, Kim SM, et al. Gene expression signature-based prognostic risk score in gastric cancer. Clin Cancer Res. 2011; 17:1850–1857.

86. Wang K, Kan J, Yuen ST, Shi ST, Chu KM, Law S, et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet. 2011; 43:1219–1223.

87. Boussioutas A, Li H, Liu J, Waring P, Lade S, Holloway AJ, et al. Distinctive patterns of gene expression in premalignant gastric mucosa and gastric cancer. Cancer Res. 2003; 63:2569–2577.

88. Tan IB, Ivanova T, Lim KH, Ong CW, Deng N, Lee J, et al. Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology. 2011; 141:476–485. 485.e1–485.e11.

89. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014; 513:202–209.

90. Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015; 21:449–456.

91. US Food and Drug Administration. Paving the Way for Personalized Medicine: FDA's Role in a New Era of Medical Product Development. US Department of Health And Human Services, FDA;2013.

92. Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, et al. Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2015; 33:2004–2012.

93. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014; 371:2189–2199.