Domper Arnal MJ, Ferrández Arenas Á, Lanas Arbeloa Á. Esophageal cancer: risk factors, screening and endoscopic treatment in Western and Eastern countries. World J Gastroenterol. 2015;21(26):7933-43. https://doi.org/10.3748/wjg.v21.i26.7933.

Chakravarty D, Johnson A, Sklar J, et al. Somatic genomic testing in patients with metastatic or advanced cancer: ASCO provisional clinical opinion. J Clin Oncol. 2022;40(11):1231-1258. https://doi.org/10.1200/JCO.21.02767.

Alsaab HO, Sau S, Alzhrani R, et al. PD-1 and PD-L1 Checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol. 2017;8:561. https://doi.org/10.3389/fphar.2017.00561.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887–95. https://doi.org/10.1002/j.1460-2075.1992.tb05481.x.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tsao MS, Kerr KM, Kockx M, et al. PD-L1 immunohistochemistry comparability study in real-life clinical samples: results of blueprint phase 2 project. J Thorac Oncol. 2018;13(9):1302–11. https://doi.org/10.1016/j.jtho.2018.05.013.

Article  PubMed  PubMed Central  Google Scholar 

Keytruda (pembrolizumab) for injection, for intravenous use [package insert]. Whitehouse Station, NJ : Merck Sharpe & Dohme Corp; 2017.

Ahn S, Kim KM. PD-L1 expression in gastric cancer: interchangeability of 22C3 and 28-8 pharmDx assays for responses to immunotherapy. Mod Pathol. 2021;34(9):1719–27. https://doi.org/10.1038/s41379-021-00823-9.

Article  CAS  PubMed  Google Scholar 

Rimm DL, Han G, Taube JM, et al. A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-l1 expression in non-small cell lung cancer. JAMA Oncol. 2017;3(8):1051-1058. https://doi.org/10.1001/jamaoncol.2017.0013.

• Salem ME, Puccini A, Grothey A, et al. Landscape of tumor mutation load, mismatch repair deficiency, and PD-L1 expression in a large patient cohort of gastrointestinal cancers. Mol Cancer Res. 2018;16(5):805-812. https://doi.org/10.1158/1541-7786.MCR-17-0735. The association between PD-L1 expression, tumor mutational load, and mismatch repair status was evaluated to determine the influence of tumor location and histology. These differences were independent of HER2 mutation, dMMR and EBV. This emphasizes the importance of unique trials for histologic type and the importance of biomarker evaluataion.

Yeong J, Lum HYJ, Teo CB, et al. Choice of PD-L1 immunohistochemistry assay influences clinical eligibility for gastric cancer immunotherapy. Gastric Cancer. 2022;25(4):741–50. https://doi.org/10.1007/s10120-022-01301-0.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jin Z, Yoon HH. The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability. J Gastrointest Oncol. 2016;7(5):771-788. https://doi.org/10.21037/jgo.2016.08.06.

• Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398(10294):27-40. https://doi.org/10.1016/s0140-6736(21)00797-2. Checkmate 649 evaluated efficacy of front line nivolumab and platinum based chemotherapy and noted improved median overall survival in all patients. This trial led to FDA approval of chemoimmunotherapy as front-line treatment.

Lei M, Siemers NO, Pandya D, et al. Analyses of PD-L1 and inflammatory gene expression association with efficacy of Nivolumab ± Ipilimumab in gastric cancer/gastroesophageal junction cancer. Clin Cancer Res. 2021;27(14):3926-3935. https://doi.org/10.1158/1078-0432.CCR-20-2790.

Fassan M, Brignola S, Pennelli G, et al. PD-L1 expression in gastroesophageal dysplastic lesions. Virchows Arch. 2020;477(1):151–6. https://doi.org/10.1007/s00428-019-02693-8.

Article  CAS  PubMed  Google Scholar 

Hagi T, Kurokawa Y, Kawabata R, et al. Multicentre biomarker cohort study on the efficacy of nivolumab treatment for gastric cancer. Br J Cancer. 2020;123(6):965-972. https://doi.org/10.1038/s41416-020-0975-7.

• Kang YK, Chen LT, Ryu MH, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022;23(2):234-247. https://doi.org/10.1016/s1470-2045(21)00692-6. Attraction 4 evaluated the efficacy of front-line nivolumab and platinum based chemotherapy in a prodominantly Asian population. This trial failed to show improvement in median OS. This higlights the importance of geographical heterogeneity.

• Xu J, Jiang H, Pan Y, et al. LBA53 Sintilimab plus chemotherapy (chemo) versus chemo as first-line treatment for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (ORIENT-16): First results of a randomized, double-blind, phase III study. Ann Oncol. 2021;32:S1331. https://doi.org/10.1016/j.annonc.2021.08.2133. Orient 16 evaluated the efficacy of Sintilimab in combination with capecitabine and oxaliplatin. This combination showed prolonged median overall survival and progression free survival in all patients.

• Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398(10302):759-771. https://doi.org/10.1016/S0140-6736(21)01234-4. Keynote 590 evaluated platinum based chemotherapy +/- pembrolizumab and noted superiority in the small subset of patients with esophageal ACs and did not show an OS benefit in the the full analysis cohort. It was also noted that the overall survival was increased in the Asian population as compared to the non-Asian population.

• Shitara K, Van Cutsem E, Bang YJ, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 2020;6(10):1571-1580. https://doi.org/10.1001/jamaoncol.2020.3370. Keynote 062 showed the non-inferiority of pembrolizumab and platinum based chemotehrapy to chemotherapy and placebo. Superiority criteria were not met but pembrolizumab was non-inferior to chemotherapy.

Zhou KI, Peterson B, Serritella A, et al. Spatial and temporal heterogeneity of PD-L1 expression and tumor mutational burden in gastroesophageal adenocarcinoma at baseline diagnosis and after chemotherapy. Clin Cancer Res. 2020;26(24):6453-6463. https://doi.org/10.1158/1078-0432.CCR-20-2085.

Wainberg ZA, Fuchs CS, Tabernero J, et al. Efficacy of pembrolizumab monotherapy for advanced gastric/gastroesophageal junction cancer with programmed death ligand 1 combined positive score ≥10. Clin Cancer Res. 2021;27(7):1923-1931. https://doi.org/10.1158/1078-0432.CCR-20-2980.

Shitara K, Ajani JA, Moehler M, et al. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022;603(7903):942-948. https://doi.org/10.1038/s41586-022-04508-4.

Moehler M, Dvorkin M, Boku N, et al. Phase III trial of avelumab maintenance after first-line induction chemotherapy versus continuation of chemotherapy in patients with gastric cancers: results From JAVELIN gastric 100. J Clin Oncol. 2021;39(9):966-977. https://doi.org/10.1200/JCO.20.00892.

Guo Y, Xiong BH, Zhang T, Cheng Y, Ma L. XELOX vs. FOLFOX in metastatic colorectal cancer: an updated meta-analysis. Cancer Invest. 2016;34(2):94–104. https://doi.org/10.3109/07357907.2015.1104689.

Article  CAS  PubMed  Google Scholar 

Yin X, Fang T, Wang Y, Li C, Zhang D, Xue Y. Efficacy of postoperative FOLFOX versus XELOX chemotherapy for gastric cancer and prognostic value of platelet-lymphocyte ratio in patients receiving XELOX. Front Oncol. 2020;10:584772. https://doi.org/10.3389/fonc.2020.584772.

Article  PubMed  PubMed Central  Google Scholar 

Kang YK, Kang WK, Shin DB, et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009;20(4):666–73. https://doi.org/10.1093/annonc/mdn717.

Article  PubMed  Google Scholar 

Cunningham D, Okines AF, Ashley S. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2010;362(9):858-9. https://doi.org/10.1056/NEJMc0911925.

Kim GM, Jeung HC, Rha SY, et al. A randomized phase II trial of S-1-oxaliplatin versus capecitabine-oxaliplatin in advanced gastric cancer. Eur J Cancer. 2012;48(4):518–26. https://doi.org/10.1016/j.ejca.2011.12.017.

Article  CAS  PubMed  Google Scholar 

Vrána D, Matzenauer M, Neoral Č, et al. From tumor immunology to immunotherapy in gastric and esophageal cancer. Int J Mol Sci. 2018;20(1) https://doi.org/10.3390/ijms20010013.

Bang YJ, Kang YK, Catenacci DV, et al. Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study. Gastric Cancer. 2019;22(4):828-837. https://doi.org/10.1007/s10120-018-00909-5.

Shitara K, Özgüroğlu M, Bang YJ, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018;392(10142):123-133. https://doi.org/10.1016/S0140-6736(18)31257-1.

Andre T, Tougeron D, Piessen G, et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in patients (pts) with localized microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) oeso-gastric adenocarcinoma (OGA): The GERCOR NEONIPIGA phase II study. J Clin Oncol. 2022;40(4_suppl):244-244. https://doi.org/10.1200/JCO.2022.40.4_suppl.244.

Bartley AN, Washington MK, Ventura CB, et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med. 2016;140(12):1345–63. https://doi.org/10.5858/arpa.2016-0331-CP.

Article  PubMed  Google Scholar 

Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52(7):797–805. https://doi.org/10.1111/j.1365-2559.2008.03028.x.

Article  CAS  PubMed  Google Scholar 

Hecht JR, Bang YJ, Qin SK, et al. 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. 2016;34(5):443-51. https://doi.org/10.1200/JCO.2015.62.6598.

Chaganty BKR, Qiu S, Gest A, et al. Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNγ secretion. Cancer Lett. 2018;430:47-56. https://doi.org/10.1016/j.canlet.2018.05.009.

Chung HC, Bang YJ, S Fuchs C, et al. First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. Future Oncol. 2021;17(5):491-501. https://doi.org/10.2217/fon-2020-0737.

Janjigian YY, Kawazoe A, Yañez P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021;600(7890):727-730. https://doi.org/10.1038/s41586-021-04161-3.

Salem ME, Puccini A, Xiu J, et al. Comparative molecular analyses of esophageal squamous cell carcinoma, esophageal adenocarcinoma, and gastric adenocarcinoma. Oncologist. 2018;23(11):1319-1327. https://doi.org/10.1634/theoncologist.2018-0143.

Hu Y, Bandla S, Godfrey TE, et al. HER2 amplification, overexpression and score criteria in esophageal adenocarcinoma. Mod Pathol. 2011;24(7):899–907. https://doi.org/10.1038/modpathol.2011.47.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Egebjerg K, Garbyal RS, Hasselby JP, Baeksgaard L, Mau-Sørensen M. Prevalence of HER2 overexpression and amplification in squamous cell carcinoma of the esophagus: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2021;161:103339. https://doi.org/10.1016/j.critrevonc.2021.103339.

Article  PubMed  Google Scholar 

Ratti M, Lampis A, Hahne JC, Passalacqua R, Valeri N. Microsatellite instability in gastric cancer: molecular bases, clinical perspectives, and new treatment approaches. Cell Mol Life Sci. 2018;75(22):4151–62. https://doi.org/10.1007/s00018-018-2906-9.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lee HK, Kwon MJ, Ra YJ, et al. Significance of druggable targets (PD-L1, KRAS, BRAF, PIK3CA, MSI, and HPV) on curatively resected esophageal squamous cell carcinoma. Diagn Pathol. 2020;15(1):126. https://doi.org/10.1186/s13000-020-01045-4.

Chang F, Syrjänen S, Shen Q, et al. Evaluation of HPV, CMV, HSV and EBV in esophageal squamous cell carcinomas from a high-incidence area of China. Anticancer Res. 2000;20(5C):3935-40.

Hewitt LC, Inam IZ, Saito Y, et al. Epstein-Barr virus and mismatch repair deficiency status differ between oesophageal and gastric cancer: A large multi-centre study. Eur J Cancer. 2018;94:104-114. https://doi.org/10.1016/j.ejca.2018.02.014.