Clinical and translational research on cancer of the stomach and gastroesophageal junction: A pathologist’s view
Christoph Röcken
Clinical and translational research on cancer of the stomach and gastroesophageal junction: A pathologist’s view
Adenocarcinomas of the stomach and gastroesophageal junction remain one of the most common malignant tumours in humans worldwide, often with a poor prognosis. Particularly in countries without upper gastrointestinal tract screening endoscopy, tumours that have been asymptomatic for a long time are only diagnosed at an advanced stage. This limits the therapeutic options. Often only palliative therapy concepts are available. Great progress has been made in the last two decades. The genetic basis of adenocarcinomas of the stomach and gastroesophageal junction has been deciphered and new targeted drugs have been developed. Cell and tissue-based predictive diagnostics are becoming increasingly important in therapy planning. Here, surgical pathology forms an important link between basic research, clinical trials, and translation into clinical application. This review article summarizes the experiences made in translational tumour research, which point to the problems of spatial and temporal intratumoral heterogeneity of adenocarcinomas of the stomach and gastroesophageal, the development and continuous re-assessment of therapeutically relevant cut-off values, resistance mechanisms, tumour microenvironment, sexual dimorphism and the pitfalls molecular tumour boards may face.
gastroesophageal cancer / surgical pathology / translational research
[1] |
VaronC, Megraud F. Stomach cancer: still one of the main cancer types worldwide. World cancer report: cancer research for cancer prevention. Int Agency Res Cancer. 2020:10.
|
[2] |
LaurenP. The two histologic main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. Acta Pathol Microbiol Scand. 1965;64:31-49. In File.
|
[3] |
WHO. Digestive System Tumours. 5th ed. vol 1. WHO classification of tumours. International Agency for Research on Cancer; 2019.
|
[4] |
WarnekeV, Behrens HM, HaagJ, et al. Prognostic and putative predictive biomarkers of gastric cancer for personalized medicine. Diagn Mol Pathol. 2013;22(3):127-137.
CrossRef
Google scholar
|
[5] |
WarnekeVS, Behrens HM, HartmannJT, et al. Cohort study based on the seventh edition of the TNM classification for gastric cancer: proposal of a new staging system. J Clin Oncol. 2011;29(17):2364-2371.
CrossRef
Google scholar
|
[6] |
MoehlerM, Al-Batran SE, AndusT, et al. S3-Leitlinie Magenkarzinom—Diagnostik und Therapie der Adenokarzinome des Magens und des ösophagogastralen Übergangs – Langversion 2.0 – August 2019. AWMF-Registernummer: 032/009OL. Z Gastroenterol. 2019;57(12):1517-1632.
CrossRef
Google scholar
|
[7] |
ZENTRUM FÜR KREBSREGISTERDATEN. Krebs in Deutschland für 2019/2020. 14th ed. Robert Koch-Institut; 2023.
|
[8] |
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202-209.
CrossRef
Google scholar
|
[9] |
Cancer Genome Atlas Research Network. Integrated genomic characterization of oesophageal carcinoma. Nature. 2017;541(7636):169-175.
CrossRef
Google scholar
|
[10] |
BangYJ, VanCE, FeyereislovaA, 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(9742):687-697.
CrossRef
Google scholar
|
[11] |
HofmannM, StossO, ShiD, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52(7):797-805.
CrossRef
Google scholar
|
[12] |
RuschoffJ, HannaW, BilousM, et al. HER2 testing in gastric cancer: a practical approach. Mod Pathol. 2012;25(5):637-650.
CrossRef
Google scholar
|
[13] |
WarnekeVS, Behrens HM, BogerC, et al. Her2/neu testing in gastric cancer: evaluating the risk of sampling errors. Ann Oncol. 2013;24(3):725-733.
CrossRef
Google scholar
|
[14] |
BartleyAN, Washington MK, ColasaccoC, et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017;35(4):446-464.
CrossRef
Google scholar
|
[15] |
KuwataT. Molecular classification and intratumoral heterogeneity of gastric adenocarcinoma. Pathol Int. Published online: Apr 23, 2024.
CrossRef
Google scholar
|
[16] |
WakatsukiT, Yamamoto N, SanoT, et al. Clinical impact of intratumoral HER2 heterogeneity on trastuzumab efficacy in patients with HER2-positive gastric cancer. J Gastroenterol. 2018;53(11):1186-1195.
CrossRef
Google scholar
|
[17] |
YagiS, Wakatsuki T, YamamotoN, et al. Clinical significance of intratumoral HER2 heterogeneity on trastuzumab efficacy using endoscopic biopsy specimens in patients with advanced HER2 positive gastric cancer. Gastric Cancer. 2019;22(3):518-525.
CrossRef
Google scholar
|
[18] |
HaffnerI, Schierle K, RaimúndezE, et al. HER2 expression, test deviations, and their impact on survival in metastatic gastric cancer: results from the prospective multicenter VARIANZ study. J Clin Oncol. 2021;39(13):1468-1478.
CrossRef
Google scholar
|
[19] |
PietrantonioF, MancaP, BellomoSE, et al. HER2 copy number and resistance mechanisms in patients with HER2-positive advanced gastric cancer receiving initial trastuzumab-based therapy in JACOB trial. Clin Cancer Res. 2023;29(3):571-580.
CrossRef
Google scholar
|
[20] |
WangJ, SunN, KunzkeT, et al. Metabolic heterogeneity affects trastuzumab response and survival in HER2-positive advanced gastric cancer. Br J Cancer. 2024;130(6):1036-1045.
CrossRef
Google scholar
|
[21] |
MaronSB, XuJ, JanjigianYY. Ta rgeting EGFR in esophagogastric cancer. Front Oncol. 2020;10:553876.
CrossRef
Google scholar
|
[22] |
WainbergZA, KangYK, LeeKW, et al. Bemarituzumab as first-line treatment for locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma: final analysis of the randomized phase 2 FIGHT trial. Gastric Cancer. 2024;27(3):558-570.
CrossRef
Google scholar
|
[23] |
AnestisA, ZoiI, KaramouzisMV. Current advances of targeting HGF/c-Met pathway in gastric cancer. Ann Transl Med. 2018;6(12):247.
CrossRef
Google scholar
|
[24] |
MetzgerML, Behrens HM, BögerC, HaagJ, KrugerS, RöckenC. MET in gastric cancer—discarding a 10% cutoff rule. Histopathology. 2016;68(2):24153.
CrossRef
Google scholar
|
[25] |
CytrynSL, Janjigian YY. HER2 targeting in esophagogastric cancer: redefining the landscape and breaking barriers. J Natl Compr Canc Netw. 2023;21(4):423-429.
CrossRef
Google scholar
|
[26] |
Van CutsemE, di Bartolomeo M, SmythE, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study. Lancet Oncol. 2023;24(7):744-756.
CrossRef
Google scholar
|
[27] |
ShitaraK, Lordick F, BangYJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2023;401(10389):1655-1668.
CrossRef
Google scholar
|
[28] |
MathiakM, Warneke VS, BehrensHM, et al. Clinicopathologic characteristics of microsatellite instable gastric carcinomas revisited: urgent need for standardization. Appl Immunohistochem Mol Morphol. 2017;25:12-24.
CrossRef
Google scholar
|
[29] |
SmythEC, Wotherspoon A, PeckittC, et al. Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the medical research council adjuvant gastric infusional chemotherapy (MAGIC) trial. JAMA Oncol. 2017;3(9):1197-1203.
CrossRef
Google scholar
|
[30] |
PietrantonioF, MiceliR, RaimondiA, et al. Individual patient data meta-analysis of the value of microsatellite instability as a biomarker in gastric cancer. J Clin Oncol. 2019;37(35):3392-3400.
CrossRef
Google scholar
|
[31] |
LiS, XuQ, DaiX, et al. Neoadjuvant therapy with immune checkpoint inhibitors in gastric cancer: a systematic review and meta-analysis. Ann Surg Oncol. 2023;30(6):3594-3602.
CrossRef
Google scholar
|
[32] |
BögerC, Behrens HM, MathiakM, KrügerS, Kalthoff H, RöckenC. PD-L1 is an independent prognostic predictor in gastric cancer of Western patients. Oncotarget. 2016;7(17):24269-24283.
CrossRef
Google scholar
|
[33] |
TaiebJ, Bennouna J, Penault-LlorcaF, BasileD, Samalin E, ZaananA. Treatment of gastric adenocarcinoma: a rapidly evolving landscape. Eur J Cancer. 2023;195:113370.
CrossRef
Google scholar
|
[34] |
JanjigianYY, Kawazoe A, BaiY, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet. 2023;402(10418):2197-2208.
CrossRef
Google scholar
|
[35] |
ShahMA, Kennedy EB, Alarcon-RozasAE, et al. Immunotherapy and targeted therapy for advanced gastroesophageal cancer: ASCO guideline. J Clin Oncol. 2023;41(7):1470-1491.
CrossRef
Google scholar
|
[36] |
LinesJL, Sempere LF, BroughtonT, WangL, NoelleR. VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy. Cancer Immunol Res. 2014;2(6):510-517.
CrossRef
Google scholar
|
[37] |
ChenC, JungA, YangA, et al. Chimeric antigen receptor-T cell and oncolytic viral therapies for gastric cancer and peritoneal carcinomatosis of gastric origin: path to improving combination strategies. Cancers. 2023;15(23):5661.
CrossRef
Google scholar
|
[38] |
SchoopH, Bregenzer A, HalskeC, et al. Therapy resistance in neoadjuvantly treated gastric cancer and cancer of the gastroesophageal junction is associated with an increased expression of immune checkpoint inhibitors-comparison against a therapy naive cohort. Transl Oncol. 2020;13(2):165-176.
CrossRef
Google scholar
|
[39] |
KumarV, Ramnarayanan K, SundarR, et al. Single-cell atlas of lineage states, tumour microenvironment, and subtype-specific expression programs in gastric cancer. Cancer Discovery. 2022;12(3):670-691.
CrossRef
Google scholar
|
[40] |
LiuW, ZhouH, LaiW, et al. The immunosuppressive landscape in tumour microenvironment. Immunol Res. 2024.
CrossRef
Google scholar
|
[41] |
RoodJE, Maartens A, HupalowskaA, TeichmannSA, RegevA. Impact of the Human Cell Atlas on medicine. Nat Med. 2022;28(12):2486-2496.
CrossRef
Google scholar
|
[42] |
ClausenF, Behrens HM, KrügerS, RöckenC. Sexual dimorphism in gastric cancer: tumour-associated neutrophils predict patient outcome only for women. J Cancer Res Clin Oncol. 2020;146(1):53-66.
CrossRef
Google scholar
|
[43] |
ClocchiattiA, CoraE, ZhangY, Dotto GP. Sexual dimorphism in cancer. Nature Reviews Cancer. 2016;16(5):330-339.
CrossRef
Google scholar
|
[44] |
UngerJM, VaidyaR, AlbainKS, et al. Sex differences in risk of severe adverse events in patients receiving immunotherapy, targeted therapy, or chemotherapy in cancer clinical trials. J Clin Oncol. 2022;40(13):1474-1486.
CrossRef
Google scholar
|
[45] |
WagnerAD, Oertelt-Prigione S, AdjeiA, et al. Gender medicine and oncology: report and consensus of an ESMO workshop. Ann Oncol. 2019;30(12):1914-1924.
CrossRef
Google scholar
|
[46] |
KalffMC, Dijksterhuis WPM, WagnerAD, et al. Sex differences in treatment allocation and survival of potentially curable gastroesophageal cancer: a population-based study. Eur J Cancer. 2023;187:114-123.
CrossRef
Google scholar
|
[47] |
Japanese Gastric Cancer A. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14(2):101-112.
CrossRef
Google scholar
|
[48] |
BeckerK, Mueller JD, SchulmacherC, et al. Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy. Cancer. 2003;98(7):1521-1530.
CrossRef
Google scholar
|
[49] |
Kock Am BrinkM, DunstLS, BehrensHM, Krüger S, BeckerT, RöckenC. Intratumoral heterogeneity affects tumour regression and Ki67 proliferation index in perioperatively treated gastric carcinoma. Br J Cancer. 2023;128(2):375-386.
CrossRef
Google scholar
|
[50] |
BehrensHM, Warneke VS, BögerC, et al. Reproducibility of Her2/neu scoring in gastric cancer and assessment of the 10% cut-off rule. Cancer Med. 2015;4(2):235-244.
CrossRef
Google scholar
|
[51] |
UngureanuBS, Lungulescu CV, PiriciD, et al. Clinicopathologic relevance of Claudin 18.2 expression in gastric cancer: a meta-analysis. Front Oncol. 2021;11:643872.
CrossRef
Google scholar
|
[52] |
CaoW, XingH, LiY, et al. Claudin18.2 is a novel molecular biomarker for tumour-targeted immunotherapy. Biomark Res. 2022;10(1):38.
CrossRef
Google scholar
|
[53] |
SahinU, Türeci Ö, ManikhasG, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol. 2021;32(5):609-619.
CrossRef
Google scholar
|
[54] |
ShahMA, Shitara K, AjaniJA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. 2023;29(8):2133-2141.
CrossRef
Google scholar
|
[55] |
AjaniJA, D'Amico TA, BentremDJ, et al. Gastric cancer, version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(2):167-192.
CrossRef
Google scholar
|
[56] |
EdsjoA, Russnes HG, LehtioJ, et al. High-throughput molecular assays for inclusion in personalised oncology trials—State-of-the-art and beyond. J Intern Med. 2024;295(6):785-803.
CrossRef
Google scholar
|
[57] |
TotokiY, Saito-Adachi M, ShiraishiY, et al. Multiancestry genomic and transcriptomic analysis of gastric cancer. Nat Genet. 2023;55(4):581-594.
CrossRef
Google scholar
|
[58] |
PectasidesE, Stachler MD, DerksS, et al. Genomic heterogeneity as a barrier to precision medicine in gastroesophageal adenocarcinoma. Cancer Discov. 2018;8(1):37-48.
CrossRef
Google scholar
|
[59] |
von LogaK, Woolston A, PuntaM, et al. Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer. Nat Commun. 2020;11(1):139.
CrossRef
Google scholar
|
[60] |
RöckenC, Amallraja A, HalskeC, et al. Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine. Genome Med. 2021;13(1):177.
CrossRef
Google scholar
|
[61] |
LeeHH, KimSY, JungES, Yoo J, KimTM. Mutation heterogeneity between primary gastric cancers and their matched lymph node metastases. Gastric Cancer. 2019;22(2):323-334.
CrossRef
Google scholar
|
[62] |
BögerC, Krüger S, BehrensHM, et al. Epstein-Barr virus-associated gastric cancer reveals intratumoral heterogeneity of PIK3CA mutations. Ann Oncol. 2017;28(5):1005-1014.
CrossRef
Google scholar
|
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