nach oben

Journal of Cancer Research and Clinical Oncology

Erschienen in:

15.07.2020 | Original Article – Clinical Oncology

Remnant gastric cancer: a neglected group with high potential for immunotherapy

verfasst von: Marcus Fernando Kodama Pertille Ramos, Marina Alessandra Pereira, Tiago Biachi de Castria, Renan Ribeiro e Ribeiro, Leonardo Cardili, Evandro Sobroza de Mello, Bruno Zilberstein, Ulysses Ribeiro-Júnior, Ivan Cecconello

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 12/2020

Einloggen, um Zugang zu erhalten

Abstract

Purpose

The importance of targeted therapy and interest in the study of predictive markers in gastric cancer (GC) have increased in recent years with the use of anti-HER2 therapy and immunotherapy with anti-PD1/PD-L1 for microsatellite instability (MSI) and PD-L1 + tumors. However, the behavior of remnant GC (RGC) in this scenario is poorly reported. Thus, this study aims to evaluate the clinicopathological characteristics and prognosis of RGC and its association with the expression of current markers for targeted therapy.

Methods

All RGC resections performed in a single center from 2009 to 2019 were retrospectively reviewed. As a comparison group, 53 primary proximal GC (PGC) who underwent total D2-gastrectomy were selected. HER2, MSI status and PD-L1 expression were analyzed by immunohistochemistry. Combined Positive Score (CPS) was used to determine PD-L1 positivity.

Results

A total of 40 RGC were included. RGC patients were older (p = 0.001), had lower BMI (p = 0.001) and number of resected lymph nodes (p < 0.001) compared to the PGC. Regarding markers expression, MSI was higher in RGC than PGC (27.5% vs 9.4%, p = 0.022). The frequency of CPS-positive was 32.5% and 26.4% in RGC and PGC, respectively (p = 0.522). HER2 positivity was 17.5% and 22.6% for RGC and PGC, respectively (p = 0.543). In survival analysis, DFS was better for RGC CPS-positive than RGC CPS-negative (p = 0.039) patients. There was no difference in survival considering MSI status.

Conclusion

RGC had higher incidence of MSI than PGC, and CPS-positive RGC was associated with better survival. The immunological profile of RGC patients suggests that they would be good candidates for immunotherapy.

Aya M, Yashiro M, Nishioka N, Onoda N, Hirakawa K (2006) Carcinogenesis in the remnant stomach following distal gastrectomy with billroth II reconstruction is associated with high-level microsatellite instability. Anticancer Res 26(2B):1403–1411PubMed

Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK (2010) 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 (London, England) 376(9742):687–697. https://doi.org/10.1016/s0140-6736(10)61121-xCrossRef

Bang YJ, Kang YK, Catenacci DV, Muro K, Fuchs CS, Geva R, Hara H, Golan T, Garrido M, Jalal SI, Borg C, Doi T, Yoon HH, Savage MJ, Wang J, Dalal RP, Shah S, Wainberg ZA, Chung HC (2019) 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 22(4):828–837. https://doi.org/10.1007/s10120-018-00909-5CrossRefPubMedPubMedCentral

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424. https://doi.org/10.3322/caac.21492CrossRefPubMed

Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40(5):373–383CrossRefPubMed

Correa P (1992) Human gastric carcinogenesis: a multistep and multifactorial process—first American Cancer Society Award Lecture on cancer epidemiology and prevention. Can Res 52(24):6735–6740

Costa-Pinho A, Pinto-de-Sousa J, Barbosa J, Costa-Maia J (2013) Gastric stump cancer: more than just another proximal gastric cancer and demanding a more suitable TNM staging system. Biomed Res Int 2013:781896. https://doi.org/10.1155/2013/781896CrossRefPubMedPubMedCentral

Di Leo A, Pedrazzani C, Bencivenga M, Coniglio A, Rosa F, Morgani P, Marrelli D, Marchet A, Cozzaglio L, Giacopuzzi S, Tiberio GA, Doglietto GB, Vittimberga G, Roviello F, Ricci F (2014) Gastric stump cancer after distal gastrectomy for benign disease: clinicopathological features and surgical outcomes. Ann Surg Oncol 21(8):2594–2600. https://doi.org/10.1245/s10434-014-3633-6CrossRefPubMed

Dindo D, Demartines N, Clavien P-A (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240(2):205–213. https://doi.org/10.1097/01.sla.0000133083.54934.aeCrossRefPubMedPubMedCentral

Doyle DJ, Garmon EH (2017) American Society of Anesthesiologists Classification (ASA Class). StatPearls Publishing LLC, Treasure Island

Fuchs CS, Doi T, Jang RW-J, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges J-P, Garrido M, Golan T, Mandala M, Wainberg ZA, Catenacci DVT, Bang Y-J, Wang J, Koshiji M, Dalal RP, Yoon HH (2017) KEYNOTE-059 cohort 1: efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. J Clin Oncol 35(15_suppl):4003. https://doi.org/10.1200/JCO.2017.35.15_suppl.4003CrossRef

Gu L, Chen M, Guo D, Zhu H, Zhang W, Pan J, Zhong X, Li X, Qian H, Wang X (2017) PD-L1 and gastric cancer prognosis: a systematic review and meta-analysis. PLoS ONE 12(8):e0182692. https://doi.org/10.1371/journal.pone.0182692CrossRefPubMedPubMedCentral

Hanyu T, Wakai A, Ishikawa T, Ichikawa H, Kameyama H, Wakai T (2018) Carcinoma in the remnant stomach during long-term follow-up after distal gastrectomy for gastric cancer: analysis of cumulative incidence and associated risk factors. World J Surg 42(3):782–787. https://doi.org/10.1007/s00268-017-4227-9CrossRefPubMed

Hofmann M, Stoss O, Shi D, Buttner R, van de Vijver M, Kim W, Ochiai A, Ruschoff J, Henkel T (2008) Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 52(7):797–805. https://doi.org/10.1111/j.1365-2559.2008.03028.xCrossRefPubMed

Huang H, Wang W, Chen Z, Jin JJ, Long ZW, Cai H, Liu XW, Zhou Y, Wang YN (2015) Prognostic factors and survival in patients with gastric stump cancer. World J Gastroenterol 21(6):1865–1871. https://doi.org/10.3748/wjg.v21.i6.1865CrossRefPubMedPubMedCentral

Jin Z, Yoon HH (2016) The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability vs. PD-L1. J Gastrointest Oncol 7(5):771–788. https://doi.org/10.21037/jgo.2016.08.06CrossRefPubMedPubMedCentral

Kataoka Y, Okabe H, Yoshizawa A, Minamiguchi S, Yoshimura K, Haga H, Sakai Y (2013) HER2 expression and its clinicopathological features in resectable gastric cancer. Gastric Cancer 16(1):84–93. https://doi.org/10.1007/s10120-012-0150-9CrossRefPubMed

Kim KC, Koh YW, Chang HM, Kim TH, Yook JH, Kim BS, Jang SJ, Park YS (2011) Evaluation of HER2 protein expression in gastric carcinomas: comparative analysis of 1,414 cases of whole-tissue sections and 595 cases of tissue microarrays. Ann Surg Oncol 18(10):2833–2840. https://doi.org/10.1245/s10434-011-1695-2CrossRefPubMed

Kim HS, Shin SJ, Beom SH, Jung M, Choi YY, Son T, Kim HI, Cheong JH, Hyung WJ, Noh SH, Chung H, Park JC, Shin SK, Lee SK, Lee YC, Koom WS, Lim JS, Chung HC, Rha SY (2016) Comprehensive expression profiles of gastric cancer molecular subtypes by immunohistochemistry: implications for individualized therapy. Oncotarget 7(28):44608–44620. https://doi.org/10.18632/oncotarget.10115CrossRefPubMedPubMedCentral

Kim WH, Gomez-Izquierdo L, Vilardell F, Chu KM, Soucy G, Dos Santos LV, Monges G, Viale G, Brito MJ, Osborne S, Noe J, Du X (2018) HER2 status in gastric and gastroesophageal junction cancer: results of the large, multinational HER-EAGLE study. Appl Immunohistochem Mol Morphol 26(4):239–245. https://doi.org/10.1097/pai.0000000000000423CrossRefPubMed

Kim MH, Zhang X, Jung M, Jung I, Park HS, Beom SH, Kim HS, Rha SY, Kim H, Choi YY, Son T, Kim HI, Cheong JH, Hyung WJ, Noh SH, Chung HC (2019) Immunohistochemistry biomarkers predict survival in stage II/III gastric cancer patients: from a prospective clinical trial. Cancer Res Treat 51(2):819–831. https://doi.org/10.4143/crt.2018.331CrossRefPubMed

Lagergren J, Lindam A, Mason RM (2012) Gastric stump cancer after distal gastrectomy for benign gastric ulcer in a population-based study. Int J Cancer 131(6):E1048–1052. https://doi.org/10.1002/ijc.27614CrossRefPubMed

Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520. https://doi.org/10.1056/NEJMoa1500596CrossRefPubMedPubMedCentral

Ma C, Patel K, Singhi AD, Ren B, Zhu B, Shaikh F, Sun W (2016) Programmed death-ligand 1 expression is common in gastric cancer associated with epstein-barr virus or microsatellite instability. Am J Surg Pathol 40(11):1496–1506. https://doi.org/10.1097/pas.0000000000000698CrossRefPubMed

Mathiak M, Warneke VS, Behrens HM, Haag J, Boger C, Kruger S, Rocken C (2017) Clinicopathologic characteristics of microsatellite instable gastric carcinomas revisited: urgent need for standardization. Appl Immunohistochem Mol Morphol 25(1):12–24. https://doi.org/10.1097/pai.0000000000000264CrossRefPubMed

Mezhir JJ, Gonen M, Ammori JB, Strong VE, Brennan MF, Coit DG (2011) Treatment and outcome of patients with gastric remnant cancer after resection for peptic ulcer disease. Ann Surg Oncol 18(3):670–676. https://doi.org/10.1245/s10434-010-1425-1CrossRefPubMed

Nakachi A, Miyazato H, Shimoji H, Hiroyasu S, Isa T, Shiraishi M, Muto Y (1999) Microsatellite instability in patients with gastric remnant cancer. Gastric Cancer 2(4):210–214. https://doi.org/10.1007/s101200050065CrossRefPubMed

Nakajima T, Akiyama Y, Shiraishi J, Arai T, Yanagisawa Y, Ara M, Fukuda Y, Sawabe M, Saitoh K, Kamiyama R, Hirokawa K, Yuasa Y (2001) Age-related hypermethylation of the hMLH1 promoter in gastric cancers. Int J Cancer 94(2):208–211CrossRefPubMed

Ohira M, Toyokawa T, Sakurai K, Kubo N, Tanaka H, Muguruma K, Yashiro M, Onoda N, Hirakawa K (2016) Current status in remnant gastric cancer after distal gastrectomy. World J Gastroenterol 22(8):2424–2433. https://doi.org/10.3748/wjg.v22.i8.2424CrossRefPubMedPubMedCentral

Payne CM, Bernstein C, Dvorak K, Bernstein H (2008) Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis. Clin Exp Gastroenterol 1:19–47. https://doi.org/10.2147/ceg.s4343CrossRefPubMedPubMedCentral

Pereira MA, Ramos M, Faraj SF, Dias AR, Yagi OK, Zilberstein B, Cecconello I, Alves VAF, de Mello ES, Ribeiro U Jr (2018) Clinicopathological and prognostic features of Epstein-Barr virus infection, microsatellite instability, and PD-L1 expression in gastric cancer. J Surg Oncol. https://doi.org/10.1002/jso.25022CrossRefPubMed

Pereira MA, Ramos M, Dias AR, Faraj SF, Ribeiro RRE, de Castria TB, Zilberstein B, Alves VAF, Ribeiro U Jr, de Mello ES (2019) Expression profile of markers for targeted therapy in gastric cancer patients: HER-2, microsatellite instability and PD-L1. Mol Diagn Ther 23(6):761–771. https://doi.org/10.1007/s40291-019-00424-yCrossRefPubMed

Polom K, Marano L, Marrelli D, De Luca R, Roviello G, Savelli V, Tan P, Roviello F (2018) Meta-analysis of microsatellite instability in relation to clinicopathological characteristics and overall survival in gastric cancer. Br J Surg 105(3):159–167. https://doi.org/10.1002/bjs.10663CrossRefPubMed

Ramos M, Ribeiro Junior U, Viscondi JKY, Zilberstein B, Cecconello I, Eluf-Neto J (2018a) Risk factors associated with the development of gastric cancer—case-control study. Rev Assoc Med Bras 64(7):611–619. https://doi.org/10.1590/1806-9282.64.07.611CrossRefPubMed

Ramos M, Pereira MA, Yagi OK, Dias AR, Charruf AZ, Oliveira RJ, Zaidan EP, Zilberstein B, Ribeiro-Junior U, Cecconello I (2018b) Surgical treatment of gastric cancer: a 10-year experience in a high-volume university hospital. Clinics (Sao Paulo, Brazil) 73(suppl 1):e543s. https://doi.org/10.6061/clinics/2018/e543sCrossRef

Safatle-Ribeiro AV, Ribeiro Junior U, Sakai P, Iriya K, Ishioka S, Gama-Rodrigues J (2001) Gastric stump mucosa: is there a risk for carcinoma? Arq Gastroenterol 38(4):227–231. https://doi.org/10.1590/s0004-28032001000400004CrossRefPubMed

Shimada H, Fukagawa T, Haga Y, Oba K (2016) Does remnant gastric cancer really differ from primary gastric cancer? A systematic review of the literature by the Task Force of Japanese Gastric Cancer Association. Gastric Cancer 19(2):339–349. https://doi.org/10.1007/s10120-015-0582-0CrossRefPubMed

Shitara K, Ozguroglu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, Fornaro L, Olesinski T, Caglevic C, Chung HC, Muro K, Goekkurt E, Mansoor W, McDermott RS, Shacham-Shmueli E, Chen X, Mayo C, Kang SP, Ohtsu A, Fuchs CS (2018) Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet (London, England) 392(10142):123–133. https://doi.org/10.1016/s0140-6736(18)31257-1CrossRef

Smyth EC, Wotherspoon A, Peckitt C, Gonzalez D, Hulkki-Wilson S, Eltahir Z, Fassan M, Rugge M, Valeri N, Okines A, Hewish M, Allum W, Stenning S, Nankivell M, Langley R, Cunningham D (2017) Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the medical research council adjuvant gastric infusional chemotherapy (MAGIC) trial. JAMA Oncol 3(9):1197–1203. https://doi.org/10.1001/jamaoncol.2016.6762CrossRefPubMed

Smyth EC, Knoedler MK, Nilsson M, Wagner AD, Moehler MH, Grieken NCTV, Giraut A, Mauer ME, Lordick F (2020) EORTC 1707 VESTIGE: adjuvant immunotherapy in patients with resected gastric cancer following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1): an open-label randomized controlled phase II study. J Clin Oncol 38(4_suppl):TPS467. https://doi.org/10.1200/JCO.2020.38.4_suppl.TPS467CrossRef

Song XH, Liu K, Sun LF, Chen XL, Zhao LY, Zhang WH, Chen XZ, Yang K, Zhang B, Chen ZX, Chen JP, Zhou ZG, Hu JK (2018a) Clinicopathological characteristics and prognostic factors of remnant gastric cancer: a single-center retrospective analysis of 90 patients. Int J Surg (London, England) 51:97–103. https://doi.org/10.1016/j.ijsu.2018.01.019CrossRef

Song X-H, Liu K, Sun L-F, Chen X-L, Zhao L-Y, Zhang W-H, Chen X-Z, Yang K, Zhang B, Chen Z-X, Chen J-P, Zhou Z-G, Hu J-K (2018b) Clinicopathological characteristics and prognostic factors of remnant gastric cancer: a single-center retrospective analysis of 90 patients. Int J Surg 51:97–103. https://doi.org/10.1016/j.ijsu.2018.01.019CrossRefPubMed

St-Louis E, Gowing SD, Mossallanejad P, Leimanis ML, Mueller C, Ferri LE (2018) Outcomes after completion total gastrectomy for gastric remnant cancer: experience from a Canadian tertiary centre. Can J Surg J canadien de chirurgie 61(4):270–277CrossRef

Tanigawa N, Nomura E, Lee SW, Kaminishi M, Sugiyama M, Aikou T, Kitajima M, Society for the Study of Postoperative Morbidity after G (2010) Current state of gastric stump carcinoma in Japan: based on the results of a nationwide survey. World J Surg 34(7):1540–1547. https://doi.org/10.1007/s00268-010-0505-5CrossRefPubMedPubMedCentral

Tokunaga M, Sano T, Ohyama S, Hiki N, Fukunaga T, Yamada K, Yamaguchi T (2013) Clinicopathological characteristics and survival difference between gastric stump carcinoma and primary upper third gastric cancer. J Gastrointest Surg 17(2):313–318. https://doi.org/10.1007/s11605-012-2114-0CrossRefPubMed

Tran TB, Hatzaras I, Worhunsky DJ, Vitiello GA, Squires MH 3rd, Jin LX, Spolverato G, Votanopoulos KI, Schmidt C, Weber S, Bloomston M, Cho CS, Levine EA, Fields RC, Pawlik TM, Maithel SK, Norton JA, Poultsides GA (2015) Gastric remnant cancer: a distinct entity or simply another proximal gastric cancer? J Surg Oncol 112(8):877–882. https://doi.org/10.1002/jso.24080CrossRefPubMed

Van Cutsem E, Bang YJ, Feng-Yi F, Xu JM, Lee KW, Jiao SC, Chong JL, Lopez-Sanchez RI, Price T, Gladkov O, Stoss O, Hill J, Ng V, Lehle M, Thomas M, Kiermaier A, Ruschoff J (2015) HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 18(3):476–484. https://doi.org/10.1007/s10120-014-0402-yCrossRefPubMed

Washington K (2010) 7th edition of the AJCC cancer staging manual: stomach. Ann Surg Oncol 17(12):3077–3079. https://doi.org/10.1245/s10434-010-1362-zCrossRefPubMed

Yamashita K, Iwatsuki M, Harada K, Eto K, Hiyoshi Y, Ishimoto T, Nagai Y, Iwagami S, Miyamoto Y, Yoshida N, Komohara Y, Ajani JA, Baba H (2019) Prognostic impacts of the combined positive score and the tumor proportion score for programmed death ligand-1 expression by double immunohistochemical staining in patients with advanced gastric cancer. Gastric Cancer. https://doi.org/10.1007/s10120-019-00999-9CrossRefPubMed

Zilberstein B, Malheiros C, Lourenco LG, Kassab P, Jacob CE, Weston AC, Bresciani CJ, Castro O, Gama-Rodrigues J, Borin AA, Buchpiegel C, Montagnini A, Leite CV, Deutsch CR, Kruel CD, Mucerino D, Wohnrath D, Ilias E, Mrue F, Maluf-Filho F, Rocha F, de Souza F, Tomasich FS, Ishak G, Laporte G, de Souza HP, Cecconello I, Eisig J, Ohana J, Sabagga J, del Grande JC, de Jesus JP, Soares J, Dias LA, Moreira LF, Correa M, Carvalho M, Andreollo NA, Aquila ND, Czeczko NG, Kruel N, Forones NM, da Motta OM, Malafaia O, Assumpcao P, Leonardi P, Sakai P, Rocha PR, Colleoni R, Gurgel R, Coral RP, Chalub S, Ribeiro- Junior U, Alves VA, Vasquez Vde L, Nadalin V (2013) Brazilian consensus in gastric cancer: guidelines for gastric cancer in Brazil. Arquivos brasileiros de cirurgia digestiva ABCD Braz Arch Dig Surg 26(1):2–6

Titel: Remnant gastric cancer: a neglected group with high potential for immunotherapy
verfasst von: Marcus Fernando Kodama Pertille Ramos
Marina Alessandra Pereira
Tiago Biachi de Castria
Renan Ribeiro e Ribeiro
Leonardo Cardili
Evandro Sobroza de Mello
Bruno Zilberstein
Ulysses Ribeiro-Júnior
Ivan Cecconello
Publikationsdatum: 15.07.2020
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 12/2020
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-020-03322-7

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Remnant gastric cancer: a neglected group with high potential for immunotherapy