Esophageal carcinoma: Towards targeted therapies



Patients with esophageal cancer are confronted with high mortality rates. Whether it is esophageal squamous cell carcinoma (ESCC) or esophageal adenocarcinoma (EAC), patients usually present at advanced stages, with treatment options traditionally involving chemotherapy in metastatic settings. With the comprehensive genomic characterization of esophageal cancers, targeted therapies are gaining interest and agents such as ramucirumab, trastuzumab and pembrolizumab are already being used for the treatment of EAC.


Pembrolizumab has recently been FDA-approved for PD-L1 positive, locally advanced or metastatic ESCC. Despite comprehensive molecular characterization, however, available targed therapies for ESCC are still lagging behind. Herein, we discuss current trends towards more targeted therapies in esophageal cancers, taking into consideration unique features of ESCCs and EACs. Patients progressing on standard therapies should be subjected to genomic profiling and considered for clinical trials aimed at testing targeted therapies. Future targeted therapies may include CDK4/6 inhibitors, PARP inhibitors and inhibitors targeting the NRF2 and Wnt signaling pathways. Ultimately, optimized biomarker assays and next generation sequencing platforms may allow for the identification of subcategories of ESCC and EAC patients that will benefit from selective targeted therapies and/or combinations thereof.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

Fig. 1


  1. 1.

    J. Lagergren, E. Smyth, D. Cunningham, P. Lagergren, Oesophageal cancer. Lancet 390, 2383–2396 (2017)

  2. 2.

    Cancer Genome Atlas Research Network; Analysis Working Group: Asan University; BC Cancer Agency; Brigham and Women’s Hospital; Broad Institute; Brown University; Case Western Reserve University; Dana-Farber Cancer Institute; Duke University; Greater Poland Cancer Centre; Harvard Medical School; Institute for Systems Biology; KU Leuven; Mayo Clinic; Memorial Sloan Kettering Cancer Center; National Cancer Institute; Nationwide Children’s Hospital; Stanford University; University of Alabama; University of Michigan; University of North Carolina; University of Pittsburgh; University of Rochester; University of Southern California; University of Texas MD Anderson Cancer Center; University of Washington; Van Andel Research Institute; Vanderbilt University; Washington University; Genome Sequencing Center: Broad Institute; Washington University in St. Louis; Genome Characterization Centers: BC Cancer Agency; Broad Institute; Harvard Medical School; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University; University of North Carolina; University of Southern California Epigenome Center; University of Texas MD Anderson Cancer Center; Van Andel Research Institute; Genome Data Analysis Centers: Broad Institute; Brown University:; Harvard Medical School; Institute for Systems Biology; Memorial Sloan Kettering Cancer Center; University of California Santa Cruz; University of Texas MD Anderson Cancer Center; Biospecimen Core Resource: International Genomics Consortium; Research Institute at Nationwide Children’s Hospital; Tissue Source Sites: Analytic Biologic Services; Asan Medical Center; Asterand Bioscience; Barretos Cancer Hospital; BioreclamationIVT; Botkin Municipal Clinic; Chonnam National University Medical School; Christiana Care Health System; Cureline; Duke University; Emory University; Erasmus University; Indiana University School of Medicine; Institute of Oncology of Moldova; International Genomics Consortium; Invidumed; Israelitisches Krankenhaus Hamburg; Keimyung University School of Medicine; Memorial Sloan Kettering Cancer Center; National Cancer Center Goyang; Ontario Tumour Bank; Peter MacCallum Cancer Centre; Pusan National University Medical School; Ribeirão Preto Medical School; St. Joseph’s Hospital &Medical Center; St. Petersburg Academic University; Tayside Tissue Bank; University of Dundee; University of Kansas Medical Center; University of Michigan; University of North Carolina at Chapel Hill; University of Pittsburgh School of Medicine; University of Texas MD Anderson Cancer Center; Disease Working Group: Duke University; Memorial Sloan Kettering Cancer Center; National Cancer Institute; University of Texas MD Anderson Cancer Center; Yonsei University College of Medicine; Data Coordination Center: CSRA Inc.; Project Team: National Institutes of Health, Integrated genomic characterization of oesophageal carcinoma. Nature 541, 169–175 (2017)

  3. 3.

    Y.B. Gao, Z.L. Chen, J.G. Li, X.D. Hu, X.J. Shi, Z.M. Sun, F. Zhang, Z.R. Zhao, Z.T. Li, Z.Y. Liu, Y.D. Zhao, J. Sun, C.C. Zhou, R. Yao, S.Y. Wang, P. Wang, N. Sun, B.H. Zhang, J.S. Dong, Y. Yu, M. Luo, X.L. Feng, S.S. Shi, F. Zhou, F.W. Tan, B. Qiu, N. Li, K. Shao, L.J. Zhang, Q. Xue, S.G. Gao, J. He, Genetic landscape of esophageal squamous cell carcinoma. Nat Genet 46, 1097–1102 (2014)

  4. 4.

    D.C. Lin, J.J. Hao, Y. Nagata, L. Xu, L. Shang, X. Meng, Y. Sato, Y. Okuno, A.M. Varela, L.W. Ding, M. Garg, L.Z. Liu, H. Yang, D. Yin, Z.Z. Shi, Y.Y. Jiang, W.Y. Gu, T. Gong, Y. Zhang, X. Xu, O. Kalid, S. Shacham, S. Ogawa, M.R. Wang, H.P. Koeffler, Genomic and molecular characterization of esophageal squamous cell carcinoma. Nat Genet 46, 467–473 (2014)

  5. 5.

    C.C. Abnet, M. Arnold, W.Q. Wei, Epidemiology of esophageal squamous cell carcinoma. Gastroenterology 154, 360–373 (2018)

  6. 6.

    E.C. Smyth, J. Lagergren, R.C. Fitzgerald, F. Lordick, M.A. Shah, P. Lagergren, D. Cunningham, Oesophageal cancer. Nat Rev Dis Primers 3, 17048 (2017)

  7. 7.

    J. Rüdiger Siewert, M. Feith, M. Werner, H.J. Stein, Adenocarcinoma of the esophagogastric junction: Results of surgical therapy based on anatomical/topographic classification in 1,002 consecutive patients. Ann Surg 232, 353–361 (2000)

  8. 8.

    F.L. Huang, S.J. Yu, Esophageal cancer: Risk factors, genetic association, and treatment. Asian J Surg 41, 210–215 (2018)

  9. 9.

    M.Q. Lin, Y.P. Li, S.G. Wu, J.Y. Sun, H.X. Lin, S.Y. Zhang, Z.Y. He, Differences in esophageal cancer characteristics and survival between Chinese and Caucasian patients in the SEER database. Onco Targets Ther 9, 6435–6444 (2016)

  10. 10.

    Y. Kitagawa, T. Uno, T. Oyama, K. Kato, H. Kato, H. Kawakubo, O. Kawamura, M. Kusano, H. Kuwano, H. Takeuchi, Y. Toh, Y. Doki, Y. Naomoto, K. Nemoto, E. Booka, H. Matsubara, T. Miyazaki, M. Muto, A. Yanagisawa, M. Yoshida, Esophageal cancer practice guidelines 2017 edited by the Japan esophageal society: Part 2. Esophagus 16, 25–43 (2019)

  11. 11.

    F. Lordick, C. Mariette, K. Haustermans, R. Obermannová, D. Arnold, E.G. Committee, Oesophageal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 27(suppl 5), v50–v57 (2016)

  12. 12.

    J.A. Ajani, T.A. D’Amico, D.J. Bentrem, J. Chao, C. Corvera, P. Das, C.S. Denlinger, P.C. Enzinger, P. Fanta, F. Farjah, H. Gerdes, M. Gibson, R.E. Glasgow, J.A. Hayman, S. Hochwald, W.L. Hofstetter, D.H. Ilson, D. Jaroszewski, K.L. Johung, R.N. Keswani, L.R. Kleinberg, S. Leong, Q.P. Ly, K.A. Matkowskyj, M. McNamara, M.F. Mulcahy, R.K. Paluri, H. Park, K.A. Perry, J. Pimiento, G.A. Poultsides, R. Roses, V.E. Strong, G. Wiesner, C.G. Willett, C.D. Wright, N.R. McMillian, L.A. Pluchino, Esophageal and esophagogastric junction cancers. J Natl Compr Cancer Netw 17(7), 855–883 (2019)

  13. 13.

    T.W. Rice, D.T. Patil, E.H. Blackstone, 8th edition AJCC/UICC staging of cancers of the esophagus and esophagogastric junction: Application to clinical practice. Ann Cardiothorac Surg 6, 119–130 (2017)

  14. 14.

    T.N. Walsh, N. Noonan, D. Hollywood, A. Kelly, N. Keeling, T.P. Hennessy, A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335, 462–467 (1996)

  15. 15.

    V. Gebski, B. Burmeister, B.M. Smithers, K. Foo, J. Zalcberg, J. Simes, Australasian Gastro-Intestinal Trials Group, Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: A meta-analysis. Lancet Oncol 8, 226–234 (2007)

  16. 16.

    J. Shapiro, J.J.B. van Lanschot, M.C.C.M. Hulshof, P. van Hagen, M.I. van Berge Henegouwen, B.P.L. Wijnhoven, H.W.M. van Laarhoven, G.A.P. Nieuwenhuijzen, G.A.P. Hospers, J.J. Bonenkamp, M.A. Cuesta, R.J.B. Blaisse, O.R.C. Busch, F.J.W. Ten Kate, G.M. Creemers, C.J.A. Punt, J.T.M. Plukker, H.M.W. Verheul, E.J.S. Bilgen, H. van Dekken, M.J.C. van der Sangen, T. Rozema, K. Biermann, J.C. Beukema, A.H.M. Piet, C.M. van Rij, J.G. Reinders, H.W. Tilanus, E.W. Steyerberg, A. van der Gaast, CROSS Study Group, Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): Long-term results of a randomised controlled trial. Lancet Oncol 16, 1090–1098 (2015)

  17. 17.

    J. Tepper, M.J. Krasna, D. Niedzwiecki, D. Hollis, C.E. Reed, R. Goldberg, K. Kiel, C. Willett, D. Sugarbaker, R. Mayer, Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 26, 1086–1092 (2008)

  18. 18.

    J.S. Cooper, M.D. Guo, A. Herskovic, J.S. Macdonald, J.A. Martenson, M. Al-Sarraf, R. Byhardt, A.H. Russell, J.J. Beitler, S. Spencer, S.O. Asbell, M.V. Graham, L.L. Leichman, Chemoradiotherapy of locally advanced esophageal cancer: Long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 281, 1623–1627 (1999)

  19. 19.

    S. Paul, N. Altorki, Outcomes in the management of esophageal cancer. J Surg Oncol 110, 599–610 (2014)

  20. 20.

    J. Chang, W. Tan, Z. Ling, R. Xi, M. Shao, M. Chen, Y. Luo, Y. Zhao, Y. Liu, X. Huang, Y. Xia, J. Hu, J.S. Parker, D. Marron, Q. Cui, L. Peng, J. Chu, H. Li, Z. Du, Y. Han, Z. Liu, Q. Zhan, Y. Li, W. Mao, C. Wu, D. Lin, Genomic analysis of oesophageal squamous-cell carcinoma identifies alcohol drinking-related mutation signature and genomic alterations. Nat Commun 8, 15290 (2017)

  21. 21.

    C. Cheng, Y. Zhou, H. Li, T. Xiong, S. Li, Y. Bi, P. Kong, F. Wang, H. Cui, Y. Li, X. Fang, T. Yan, J. Wang, B. Yang, L. Zhang, Z. Jia, B. Song, X. Hu, J. Yang, H. Qiu, G. Zhang, J. Liu, E. Xu, R. Shi, Y. Zhang, H. Liu, C. He, Z. Zhao, Y. Qian, R. Rong, Z. Han, W. Luo, S. Peng, X. Yang, X. Li, L. Li, H. Fang, X. Liu, L. Ma, Y. Chen, S. Guo, X. Chen, Y. Xi, G. Li, J. Liang, J. Guo, J. Jia, Q. Li, X. Cheng, Q. Zhan, Y. Cui, Whole-genome sequencing reveals diverse models of structural variations in esophageal squamous cell carcinoma. Am J Hum Genet 98, 256–274 (2016)

  22. 22.

    J. Deng, H. Chen, D. Zhou, J. Zhang, Y. Chen, Q. Liu, D. Ai, H. Zhu, L. Chu, W. Ren, X. Zhang, Y. Xia, M. Sun, H. Zhang, J. Li, X. Peng, L. Li, L. Han, H. Lin, X. Cai, J. Xiang, S. Chen, Y. Sun, Y. Zhang, S. Zhang, Y. Zhao, Y. Liu, H. Liang, K. Zhao, Comparative genomic analysis of esophageal squamous cell carcinoma between Asian and Caucasian patient populations. Nat Commun 8, 1533 (2017)

  23. 23.

    J. Deng, X. Weng, J. Ye, D. Zhou, Y. Liu, K. Zhao, Identification of the germline mutation profile in esophageal squamous cell carcinoma by whole exome sequencing. Front Genet 10, 47 (2019)

  24. 24.

    H.D. Qin, X.Y. Liao, Y.B. Chen, S.Y. Huang, W.Q. Xue, F.F. Li, X.S. Ge, D.Q. Liu, Q. Cai, J. Long, X.Z. Li, Y.Z. Hu, S.D. Zhang, L.J. Zhang, B. Lehrman, A.F. Scott, D. Lin, Y.X. Zeng, Y.Y. Shugart, W.H. Jia, Genomic characterization of esophageal squamous cell carcinoma reveals critical genes underlying tumorigenesis and poor prognosis. Am J Hum Genet 98, 709–727 (2016)

  25. 25.

    Y. Song, L. Li, Y. Ou, Z. Gao, E. Li, X. Li, W. Zhang, J. Wang, L. Xu, Y. Zhou, X. Ma, L. Liu, Z. Zhao, X. Huang, J. Fan, L. Dong, G. Chen, L. Ma, J. Yang, L. Chen, M. He, M. Li, X. Zhuang, K. Huang, K. Qiu, G. Yin, G. Guo, Q. Feng, P. Chen, Z. Wu, J. Wu, J. Zhao, L. Luo, M. Fu, B. Xu, B. Chen, Y. Li, T. Tong, M. Wang, Z. Liu, D. Lin, X. Zhang, H. Yang, Q. Zhan, Identification of genomic alterations in oesophageal squamous cell cancer. Nature 509, 91–95 (2014)

  26. 26.

    T. Xiong, M. Wang, J. Zhao, Q. Liu, C. Yang, W. Luo, X. Li, H. Yang, K. Kristiansen, B. Roy, Y. Zhou, An esophageal squamous cell carcinoma classification system that reveals potential targets for therapy. Oncotarget 8, 49851–49860 (2017)

  27. 27.

    L. Zhang, Y. Zhou, C. Cheng, H. Cui, L. Cheng, P. Kong, J. Wang, Y. Li, W. Chen, B. Song, F. Wang, Z. Jia, L. Li, B. Yang, J. Liu, R. Shi, Y. Bi, Y. Zhang, Z. Zhao, X. Hu, J. Yang, H. Li, Z. Gao, G. Chen, X. Huang, X. Yang, S. Wan, C. Chen, B. Li, Y. Tan, L. Chen, M. He, S. Xie, X. Li, X. Zhuang, M. Wang, Z. Xia, L. Luo, J. Ma, B. Dong, J. Zhao, Y. Song, Y. Ou, E. Li, L. Xu, Y. Xi, G. Li, E. Xu, J. Liang, J. Guo, X. Chen, Q. Li, L. Liu, X. Zhang, H. Yang, D. Lin, X. Cheng, Y. Guo, Q. Zhan, Y. Cui, Genomic analyses reveal mutational signatures and frequently altered genes in esophageal squamous cell carcinoma. Am J Hum Genet 96, 597–611 (2015)

  28. 28.

    M. Hazawa, D.C. Lin, H. Handral, L. Xu, Y. Chen, Y.Y. Jiang, A. Mayakonda, L.W. Ding, X. Meng, A. Sharma, S. Samuel, M.M. Movahednia, R.W. Wong, H. Yang, C. Tong, H.P. Koeffler, ZNF750 is a lineage-specific tumour suppressor in squamous cell carcinoma. Oncogene 36, 2243–2254 (2017)

  29. 29.

    M. Secrier, X. Li, N. de Silva, M.D. Eldridge, G. Contino, J. Bornschein, S. MacRae, N. Grehan, M. O'Donovan, A. Miremadi, T.P. Yang, L. Bower, H. Chettouh, J. Crawte, N. Galeano-Dalmau, A. Grabowska, J. Saunders, T. Underwood, N. Waddell, A.P. Barbour, B. Nutzinger, A. Achilleos, P.A. Edwards, A.G. Lynch, S. Tavaré, R.C. Fitzgerald, Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nat Genet 48, 1131–1141 (2016)

  30. 30.

    Y.J. Bang, E. Van Cutsem, A. Feyereislova, H.C. Chung, L. Shen, A. Sawaki, F. Lordick, A. Ohtsu, Y. Omuro, T. Satoh, G. Aprile, E. Kulikov, J. Hill, M. Lehle, J. Rüschoff, Y.K. Kang, T.T. Investigators, 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 376, 687–697 (2010)

  31. 31.

    C.S. Fuchs, T. Doi, R.W. Jang, K. Muro, T. Satoh, M. Machado, W. Sun, S.I. Jalal, M.A. Shah, J.P. Metges, M. Garrido, T. Golan, M. Mandala, Z.A. Wainberg, D.V. Catenacci, A. Ohtsu, K. Shitara, R. Geva, J. Bleeker, A.H. Ko, G. Ku, P. Philip, P.C. Enzinger, Y.J. Bang, D. Levitan, J. Wang, M. Rosales, R.P. Dalal, H.H. Yoon, Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: Phase 2 clinical KEYNOTE-059 Trial. JAMA Oncol 4, e180013 (2018)

  32. 32.

    C.S. Fuchs, J. Tomasek, C.J. Yong, F. Dumitru, R. Passalacqua, C. Goswami, H. Safran, L.V.D. Santos, G. Aprile, D.R. Ferry, B. Melichar, M. Tehfe, E. Topuzov, J.R. Zalcberg, I. Chau, W. Campbell, C. Sivanandan, J. Pikiel, M. Koshiji, Y. Hsu, A.M. Liepa, L. Gao, J.D. Schwartz, J. Tabernero, R.T. Investigators, Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383, 31–39 (2014)

  33. 33.

    M.A. Shah, T. Kojima, D. Hochhauser, P. Enzinger, J. Raimbourg, A. Hollebecque, F. Lordick, S.B. Kim, M. Tajika, H.T. Kim, A.C. Lockhart, H.T. Arkenau, F. El-Hajbi, M. Gupta, P. Pfeiffer, Q. Liu, J. Lunceford, S.P. Kang, P. Bhagia, K. Kato, Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: The phase 2 KEYNOTE-180 study. JAMA Oncol 5, 546-550 (2019)

  34. 34.

    H. Wilke, K. Muro, E. Van Cutsem, S.C. Oh, G. Bodoky, Y. Shimada, S. Hironaka, N. Sugimoto, O. Lipatov, T.Y. Kim, D. Cunningham, P. Rougier, Y. Komatsu, J. Ajani, M. Emig, R. Carlesi, D. Ferry, K. Chandrawansa, J.D. Schwartz, A. Ohtsu, RAINBOW Study Group, Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial. Lancet Oncol 15, 1224–1235 (2014)

  35. 35.

    S. Kasper, M. Schuler, Targeted therapies in gastroesophageal cancer. Eur J Cancer 50, 1247–1258 (2014)

  36. 36.

    P. Samson, A.C. Lockhart, Biologic therapy in esophageal and gastric malignancies: Current therapies and future directions. J Gastrointest Oncol 8, 418–429 (2017)

  37. 37.

    J. Tabernero, P.M. Hoff, L. Shen, A. Ohtsu, M.A. Shah, K. Cheng, C. Song, H. Wu, J. Eng-Wong, K. Kim, Y.K. Kang, Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): Final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol 19, 1372–1384 (2018)

  38. 38.

    P.C. Thuss-Patience, M.A. Shah, A. Ohtsu, E. Van Cutsem, J.A. Ajani, H. Castro, W. Mansoor, H.C. Chung, G. Bodoky, K. Shitara, G.D.L. Phillips, T. van der Horst, M.L. Harle-Yge, B.L. Althaus, Y.K. Kang, Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): An international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol 18, 640–653 (2017)

  39. 39.

    T. Waddell, I. Chau, D. Cunningham, D. Gonzalez, A.F. Okines, A. Frances, C. Okines, A. Wotherspoon, C. Saffery, G. Middleton, J. Wadsley, D. Ferry, W. Mansoor, T. Crosby, F. Coxon, D. Smith, J. Waters, T. Iveson, S. Falk, S. Slater, C. Peckitt, Y. Barbachano, Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): A randomised, open-label phase 3 trial. Lancet Oncol 14, 481–489 (2013)

  40. 40.

    N. Mavaddat, D. Barrowdale, I.L. Andrulis, S.M. Domchek, D. Eccles, H. Nevanlinna, S.J. Ramus, A. Spurdle, M. Robson, M. Sherman, A.M. Mulligan, F.J. Couch, C. Engel, L. McGuffog, S. Healey, O.M. Sinilnikova, M.C. Southey, M.B. Terry, D. Goldgar, F. O'Malley, E.M. John, R. Janavicius, L. Tihomirova, T.V. Hansen, F.C. Nielsen, A. Osorio, A. Stavropoulou, J. Benítez, S. Manoukian, B. Peissel, M. Barile, S. Volorio, B. Pasini, R. Dolcetti, A.L. Putignano, L. Ottini, P. Radice, U. Hamann, M.U. Rashid, F.B. Hogervorst, M. Kriege, R.B. van der Luijt, S. Peock, D. Frost, D.G. Evans, C. Brewer, L. Walker, M.T. Rogers, L.E. Side, C. Houghton, J. Weaver, A.K. Godwin, R.K. Schmutzler, B. Wappenschmidt, A. Meindl, K. Kast, N. Arnold, D. Niederacher, C. Sutter, H. Deissler, D. Gadzicki, S. Preisler-Adams, R. Varon-Mateeva, I. Schönbuchner, H. Gevensleben, D. Stoppa-Lyonnet, M. Belotti, L. Barjhoux, C. Isaacs, B.N. Peshkin, T. Caldes, M. de la Hoya, C. Cañadas, T. Heikkinen, P. Heikkilä, K. Aittomäki, I. Blanco, C. Lazaro, J. Brunet, B.A. Agnarsson, A. Arason, R.B. Barkardottir, M. Dumont, J. Simard, M. Montagna, S. Agata, E. D'Andrea, M. Yan, S. Fox, T.R. Rebbeck, W. Rubinstein, N. Tung, J.E. Garber, X. Wang, Z. Fredericksen, V.S. Pankratz, N.M. Lindor, C. Szabo, K. Offit, R. Sakr, M.M. Gaudet, C.F. Singer, M.K. Tea, C. Rappaport, P.L. Mai, M.H. Greene, A. Sokolenko, E. Imyanitov, A.E. Toland, L. Senter, K. Sweet, M. Thomassen, A.M. Gerdes, T. Kruse, M. Caligo, P. Aretini, J. Rantala, A. von Wachenfeld, K. Henriksson, L. Steele, S.L. Neuhausen, R. Nussbaum, M. Beattie, K. Odunsi, L. Sucheston, S.A. Gayther, K. Nathanson, J. Gross, C. Walsh, B. Karlan, G. Chenevix-Trench, D.F. Easton, A.C. Antoniou, HEBON, EMBRACE, GEMO Study Collaborators, kConFab Investigators, SWE-BRCA Collaborators and Consortium of Investigators of Modifiers of BRCA1/2, Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 21, 134–147 (2012)

  41. 41.

    A.D. Wagner, H.I. Grabsch, M. Mauer, S. Marreaud, C. Caballero, P. Thuss-Patience, L. Mueller, A. Elme, M.H. Moehler, U. Martens, Y.K. Kang, S.Y. Rha, A. Cats, M. Tokunaga, F. Lordick, EORTC-1203-GITCG – The “INNOVATION”-trial: Effect of chemotherapy alone versus chemotherapy plus trastuzumab, versus chemotherapy plus trastuzumab plus pertuzumab, in the perioperative treatment of HER2 positive, gastric and gastroesophageal junction adenocarcinoma on pathologic response rate: A randomized phase II-intergroup trial of the EORTC-Gastrointestinal Tract Cancer Group, Korean Cancer Study Group and Dutch Upper GI-Cancer group. BMC Cancer 19, 494 (2019)

  42. 42.

    J.R. Hecht, Y.J. Bang, S.K. Qin, H.C. Chung, J.M. Xu, J.O. Park, K. Jeziorski, Y. Shparyk, P.M. Hoff, A. Sobrero, P. Salman, J. Li, S.A. Protsenko, Z.A. Wainberg, M. Buyse, K. Afenjar, V. Houé, A. Garcia, T. Kaneko, Y. Huang, S. Khan-Wasti, S. Santillana, M.F. Press, D. Slamon, Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC – A randomized phase III trial. J Clin Oncol 34, 443–451 (2016)

  43. 43.

    R.J. Kelly, The emerging role of immunotherapy for esophageal cancer. Curr Opin Gastroenterol, 35(4), 337–343 (2019).

  44. 44.

    A. Ghahremanloo, A. Soltani, S.M.S. Modaresi, S.I. Hashemy, Recent advances in the clinical development of immune checkpoint blockade therapy. Cell Oncol 42, 609–626 (2019)

  45. 45.

    L. Fashoyin-Aje, M. Donoghue, H. Chen, K. He, J. Veeraraghavan, K.B. Goldberg, P. Keegan, A.E. McKee, R. Pazdur, FDA approval summary: Pembrolizumab for recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma expressing PD-L1. Oncologist 24, 103–109 (2019)

  46. 46.

    T.A. Post, KEYNOTE-181: Pembrolizumab vs chemotherapy in second-line treatment of advanced esophageal cancer. 2019; Available from: Accessed 19 October 2019

  47. 47.

    FDA. FDA approves pembrolizumab for advanced esophageal squamous cell cancer. July 31; Available from: Accessed 19 October 2019

  48. 48.

    K. Shitara, M. Özgüroğlu, Y.J. Bang, M. Di Bartolomeo, M. Mandalà, M.H. Ryu, L. Fornaro, T. Olesiński, C. Caglevic, H.C. Chung, K. Muro, E. Goekkurt, W. Mansoor, R.S. McDermott, E. Shacham-Shmueli, X. Chen, C. Mayo, S.P. Kang, A. Ohtsu, C.S. Fuchs, KEYNOTE-061 Investigators, Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): A randomised, open-label, controlled, phase 3 trial. Lancet 392, 123–133 (2018)

  49. 49.

    Y.K. Kang, N. Boku, T. Satoh, M.H. Ryu, Y. Chao, K. Kato, H.C. Chung, J.S. Chen, K. Muro, W.K. Kang, K.H. Yeh, T. Yoshikawa, S.C. Oh, L.Y. Bai, T. Tamura, K.W. Lee, Y. Hamamoto, J.G. Kim, K. Chin, D.Y. Oh, K. Minashi, J.Y. Cho, M. Tsuda, L.T. Chen, Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390, 2461–2471 (2017)

  50. 50.

    N. Boku, M.H. Ryu, K. Kato, H.C. Chung, K. Minashi, K.W. Lee, H. Cho, W.K. Kang, Y. Komatsu, M. Tsuda, K. Yamaguchi, H. Hara, S. Fumita, M. Azuma, L.T. Chen, Y.K. Kang, Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: Interim results of a randomized, phase II trial (ATTRACTION-4). Ann Oncol 30, 250–258 (2019)

  51. 51.

    Y.J. Bang, E.Y. Ruiz, E. Van Cutsem, K.W. Lee, L. Wyrwicz, M. Schenker, M. Alsina, M.H. Ryu, H.C. Chung, L. Evesque, S.E. Al-Batran, S.H. Park, M. Lichinitser, N. Boku, M.H. Moehler, J. Hong, H. Xiong, R. Hallwachs, I. Conti, J. Taieb, Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: Primary analysis of JAVELIN Gastric 300. Ann Oncol 29, 2052–2060 (2018)

  52. 52.

    Y.J. Bang, J.Y. Cho, Y.H. Kim, J.W. Kim, M. Di Bartolomeo, J.A. Ajani, K. Yamaguchi, A. Balogh, T. Sanchez, M. Moehler, Efficacy of sequential ipilimumab monotherapy versus best supportive care for unresectable locally advanced/metastatic gastric or gastroesophageal junction cancer. Clin Cancer Res 23, 5671–5678 (2017)

  53. 53.

    Y.Y. Janjigian, J. Bendell, E. Calvo, J.W. Kim, P.A. Ascierto, P. Sharma, P.A. Ott, K. Peltola, D. Jaeger, J. Evans, F. de Braud, I. Chau, C.T. Harbison, C. Dorange, M. Tschaika, D.T. Le, CheckMate-032 study: Efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J Clin Oncol 36, 2836–2844 (2018)

  54. 54.

    T.A. Post, 2019 ASCO: KEYNOTE-062: Pembrolizumab with or without chemotherapy vs chemotherapy in advanced gastric or GEJ adenocarcinoma; Available from: Accessed 7 July 2019

  55. 55.

    Health, N.I.o. An investigational immuno-therapy study of nivolumab or placebo in patients with resected esophageal or gastroesophageal junction cancer (CheckMate 577); Available from: Accessed 24 July 2019

  56. 56.

    Health, N.I.o. Efficacy study of nivolumab plus ipilimumab or nivolumab plus chemotherapy against chemotherapy in stomach cancer or stomach/esophagus junction cancer (CheckMate649); Available from: Accessed 29 July 2019

  57. 57.

    D.N. Ionescu, M.R. Downes, A. Christofides, M.S. Tsao, Harmonization of PD-L1 testing in oncology: A Canadian pathology perspective. Curr Oncol 25, e209–e216 (2018)

  58. 58.

    H. Polioudaki, A. Chantziou, K. Kalyvianaki, P. Malamos, G. Notas, D. Mavroudis, M. Kampa, E. Castanas, P.A. Theodoropoulos, Nuclear localization of PD-L1: Artifact or reality? Cell Oncol 42, 237–242 (2019)

  59. 59.

    M. Yi, S. Qin, W. Zhao, S. Yu, Q. Chu, K. Wu, The role of neoantigen in immune checkpoint blockade therapy. Exp Hematol Oncol 7, 28 (2018)

  60. 60.

    C. Luchini, F. Bibeau, M.J.L. Ligtenberg, N. Singh, A. Nottegar, T. Bosse, R. Miller, N. Riaz, J.Y. Douillard, F. Andre, A. Scarpa, ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: A systematic review-based approach. Ann Oncol, doi: 10.1093/annonc/mdz116 (2019)

  61. 61.

    F. Schettini, I. De Santo, C.G. Rea, P. De Placido, L. Formisano, M. Giuliano, G. Arpino, M. De Laurentiis, F. Puglisi, S. De Placido, L. Del Mastro, CDK 4/6 inhibitors as single agent in advanced solid tumors. Front Oncol 8, 608 (2018)

  62. 62.

    L. Chen, J. Pan, Dual cyclin-dependent kinase 4/6 inhibition by PD-0332991 induces apoptosis and senescence in oesophageal squamous cell carcinoma cells. Br J Pharmacol 174, 2427–2443 (2017)

  63. 63.

    Health, N.I.o. Korean Cancer Study Group: Translational bIomarker Driven UMbrella Project for Head and Neck (TRIUMPH), Esophageal Squamous Cell Carcinoma- Part 1 (HNSCC); Available from: Accessed 11 October 2017

  64. 64.

    Health, N.I.o. Phase Ib study of TNO155 in combination with spartalizumab or ribociclib in selected malignancies; Available from: Accessed 16 July 2019

  65. 65.

    Q. Zhang, J.E. Burdette, J.P. Wang, Integrative network analysis of TCGA data for ovarian cancer. BMC Syst Biol 8, 1338 (2014)

  66. 66.

    G. Sawada, A. Niida, R. Uchi, H. Hirata, T. Shimamura, Y. Suzuki, Y. Shiraishi, K. Chiba, S. Imoto, Y. Takahashi, T. Iwaya, T. Sudo, T. Hayashi, H. Takai, Y. Kawasaki, T. Matsukawa, H. Eguchi, K. Sugimachi, F. Tanaka, H. Suzuki, K. Yamamoto, H. Ishii, M. Shimizu, H. Yamazaki, M. Yamazaki, Y. Tachimori, Y. Kajiyama, S. Natsugoe, H. Fujita, K. Mafune, Y. Tanaka, D.P. Kelsell, C.A. Scott, S. Tsuji, S. Yachida, T. Shibata, S. Sugano, Y. Doki, T. Akiyama, H. Aburatani, S. Ogawa, S. Miyano, M. Mori, K. Mimori, Genomic landscape of esophageal squamous cell carcinoma in a Japanese population. Gastroenterology 150, 1171–1182 (2016)

  67. 67.

    N. Wakabayashi, K. Itoh, J. Wakabayashi, H. Motohashi, S. Noda, S. Takahashi, S. Imakado, T. Kotsuji, F. Otsuka, D.R. Roop, T. Harada, J.D. Engel, M. Yamamoto, Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet 35, 238–245 (2003)

  68. 68.

    Y. Kawasaki, H. Okumura, Y. Uchikado, Y. Kita, K. Sasaki, T. Owaki, S. Ishigami, S. Natsugoe, Nrf2 is useful for predicting the effect of chemoradiation therapy on esophageal squamous cell carcinoma. Ann Surg Oncol 21, 2347–2352 (2014)

  69. 69.

    T. Shibata, A. Kokubu, S. Saito, M. Narisawa-Saito, H. Sasaki, K. Aoyagi, Y. Yoshimatsu, Y. Tachimori, R. Kushima, T. Kiyono, M. Yamamoto, NRF2 mutation confers malignant potential and resistance to chemoradiation therapy in advanced esophageal squamous cancer. Neoplasia 13, 864–873 (2011)

  70. 70.

    J. Zhang, Q. Jiao, L. Kong, J. Yu, A. Fang, M. Li, Nrf2 and Keap1 abnormalities in esophageal squamous cell carcinoma and association with the effect of chemoradiotherapy. Thorac Cancer 9, 726–735 (2018)

  71. 71.

    C. Gorrini, P.S. Baniasadi, I.S. Harris, J. Silvester, S. Inoue, B. Snow, P.A. Joshi, A. Wakeham, S.D. Molyneux, B. Martin, P. Bouwman, D.W. Cescon, A.J. Elia, Z. Winterton-Perks, J. Cruickshank, D. Brenner, A. Tseng, M. Musgrave, H.K. Berman, R. Khokha, J. Jonkers, T.W. Mak, M.L. Gauthier, BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival. J Exp Med 210, 1529–1544 (2013)

  72. 72.

    S. Ma, C. Paiboonrungruan, T. Yan, K.P. Williams, M.B. Major, X.L. Chen, Targeted therapy of esophageal squamous cell carcinoma: The NRF2 signaling pathway as target. Ann N Y Acad Sci 1434, 164–172 (2018)

  73. 73.

    M. Seervi, S. Sumi, A. Chandrasekharan, A.K. Sharma, T.R. SanthoshKumar, Molecular profiling of anastatic cancer cells: Potential role of the nuclear export pathway. Cell Oncol 42, 645–661 (2019)

  74. 74.

    A. Mizumoto, S. Ohashi, M. Kamada, T. Saito, Y. Nakai, K. Baba, K. Hirohashi, Y. Mitani, O. Kikuchi, J. Matsubara, A. Yamada, T. Takahashi, H. Lee, Y. Okuno, M. Kanai, M. Muto, Combination treatment with highly bioavailable curcumin and NQO1 inhibitor exhibits potent antitumor effects on esophageal squamous cell carcinoma. J Gastroenterol 54, 687-698 (2019)

  75. 75.

    T. Yan, H. Cui, Y. Zhou, B. Yang, P. Kong, Y. Zhang, Y. Liu, B. Wang, Y. Cheng, J. Li, S. Guo, E. Xu, H. Liu, C. Cheng, L. Zhang, L. Chen, X. Zhuang, Y. Qian, J. Yang, Y. Ma, H. Li, F. Wang, J. Liu, X. Liu, D. Su, Y. Wang, R. Sun, Y. Li, X. Cheng, Z. Liu, Q. Zhan, Y. Cui, Multi-region sequencing unveils novel actionable targets and spatial heterogeneity in esophageal squamous cell carcinoma. Nat Commun 10, 1670 (2019)

  76. 76.

    A. Ashworth, C.J. Lord, Synthetic lethal therapies for cancer: What’s next after PARP inhibitors? Nat Rev Clin Oncol 15, 564–576 (2018)

  77. 77.

    J.K. Litton, H.S. Rugo, J. Ettl, S.A. Hurvitz, A. Gonçalves, K.H. Lee, L. Fehrenbacher, R. Yerushalmi, L.A. Mina, M. Martin, H. Roché, Y.H. Im, R.G.W. Quek, D. Markova, I.C. Tudor, A.L. Hannah, W. Eiermann, J.L. Blum, Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 379, 753–763 (2018)

  78. 78.

    M. Robson, C. Goessl, S. Domchek, Olaparib for metastatic germline BRCA-mutated breast cancer. N Engl J Med 377, 1792–1793 (2017)

  79. 79.

    T.A. Post, 2019 ASCO: POLO: Maintenance olaparib in germline BRCA-mutated pancreatic cancer; Available from: Accessed 16 July 2019

  80. 80.

    K. Miyamoto, T. Minegaki, M. Tanahashi, A. Yamamoto, Y. Moriyama, A. Wada, A. Matsumoto, K. Ota, M. Tanaka, U. Masuda, M. Tsujimoto, K. Nishiguchi, Synergistic effects of olaparib and DNA-damaging agents in oesophageal squamous cell carcinoma cell lines. Anticancer Res 39, 1813–1820 (2019)

  81. 81.

    Health, N.I.o. Olaparib and ramucirumab in treating patients with metastatic or locally recurrent gastric or gastroesophageal junction cancer that cannot be removed by surgery; Available from: Accessed 7 July 2019

  82. 82.

    Health, N.I.o. Veliparib, paclitaxel, and carboplatin in treating patients with solid tumors that are metastatic or cannot be removed by surgery and liver or kidney dysfunction; Available from: Accessed 4 June 2019

  83. 83.

    A. Long, V. Giroux, K.A. Whelan, K.E. Hamilton, M.P. Tétreault, K. Tanaka, J.S. Lee, A.J. Klein-Szanto, H. Nakagawa, A.K. Rustgi, WNT10A promotes an invasive and self-renewing phenotype in esophageal squamous cell carcinoma. Carcinogenesis. 36, 598–606 (2015)

  84. 84.

    S.H. Yang, S.L. Li, Z.M. Dong, Q.C. Kan, Epigenetic inactivation of Wnt inhibitory factor-1 in human esophageal squamous cell carcinoma. Oncol Res 20, 123–130 (2012)

  85. 85.

    Health, N.I.o. A study of LGK974 in patients with malignancies dependent on Wnt ligands; Available from: Accessed 7 July 2019

  86. 86.

    A.M. Frankell, S. Jammula, X. Li, G. Contino, S. Killcoyne, S. Abbas, J. Perner, L. Bower, G. Devonshire, E. Ococks, N. Grehan, J. Mok, M. O'Donovan, S. MacRae, M.D. Eldridge, S. Tavaré, R.C. Fitzgerald, Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic. Nat Genet 51, 506–516 (2019)

  87. 87.

    G. Clément, D.M. Jablons, J. Benhattar, Targeting the Wnt signaling pathway to treat Barrett's esophagus. Expert Opin Ther Targets 11, 375–389 (2007)

  88. 88.

    O. Lyros, P. Rafiee, L. Nie, R. Medda, N. Jovanovic, M.F. Otterson, B. Behmaram, I. Gockel, A. Mackinnon, R. Shaker, Wnt/β-catenin signaling activation beyond robust nuclear β-catenin accumulation in nondysplastic Barrett’s esophagus: Regulation via Dickkopf-1. Neoplasia 17, 598–611 (2015)

  89. 89.

    L.H. Moyes, H. McEwan, S. Radulescu, J. Pawlikowski, C.G. Lamm, C. Nixon, O.J. Sansom, J.J. Going, G.M. Fullarton, P.D. Adams, Activation of Wnt signalling promotes development of dysplasia in Barrett’s oesophagus. J Pathol 228, 99–112 (2012)

  90. 90.

    Y. Kitagawa, T. Uno, T. Oyama, K. Kato, H. Kato, H. Kawakubo, O. Kawamura, M. Kusano, H. Kuwano, H. Takeuchi, Y. Toh, Y. Doki, Y. Naomoto, K. Nemoto, E. Booka, H. Matsubara, T. Miyazaki, M. Muto, A. Yanagisawa, M. Yoshida, Esophageal cancer practice guidelines 2017 edited by the Japan Esophageal Society: Part 1. Esophagus. 16, 1–24 (2019)

  91. 91.

    A.M. Dulak, P. Stojanov, S. Peng, M.S. Lawrence, C. Fox, C. Stewart, S. Bandla, Y. Imamura, S.E. Schumacher, E. Shefler, A. McKenna, S.L. Carter, K. Cibulskis, A. Sivachenko, G. Saksena, D. Voet, A.H. Ramos, D. Auclair, K. Thompson, C. Sougnez, R.C. Onofrio, C. Guiducci, R. Beroukhim, Z. Zhou, L. Lin, J. Lin, R. Reddy, A. Chang, R. Landrenau, A. Pennathur, S. Ogino, J.D. Luketich, T.R. Golub, S.B. Gabriel, E.S. Lander, D.G. Beer, T.E. Godfrey, G. Getz, A.J. Bass, Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet 45, 478–486 (2013)

  92. 92.

    J.Y. Dai, X. Wang, M.F. Buas, C. Zhang, J. Ma, B. Wei, Y. Li, B. Zhao, T.S. Hyun, X. Chen, K.R. Loeb, R. Odze, L. Yao, X. Sun, S. Self, T.L. Vaughan, Y. Guo, Whole-genome sequencing of esophageal adenocarcinoma in Chinese patients reveals distinct mutational signatures and genomic alterations. Commun Biol 1, 174 (2018)

Download references

Author information

Correspondence to Ali Fatehi Hassanabad.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.


No cell lines or human tissues were used for this manuscript.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fatehi Hassanabad, A., Chehade, R., Breadner, D. et al. Esophageal carcinoma: Towards targeted therapies. Cell Oncol. (2019) doi:10.1007/s13402-019-00488-2

Download citation


  • Esophageal carcinoma
  • Targeted therapies
  • Molecular pathways
  • Precision medicine
  • Clinical outcomes