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Abstract
Introduction. Gastric cancer heterogeneity includes not only intertumor heterogeneity from patient to patient, but also variation within a single tumor (intratumor heterogeneity).
Materials and methods. The analysis included 69 patients with verified stage I-III gastric cancer who received treatment and observation at the St. Petersburg City Clinical Oncology Dispensary from January 2021 to March 2024. Using an immunohistochemical study in 138 available postoperative samples (from 69 patients), we assessed: HER2/neu expression level, presence/absence of MSI signs, PD-L1 expression level, FGFR2 receptor expression level/amplification, Epstein-Barr virus encoded RNAs (EBER1) in the primary tumor and in the metastatic regional lymph node.
Results. Heterogeneity in HER2/neu expression levels was recorded in 5 (7.2 %) samples. Signs of MSI were detected in 6/69 (8.7 %) samples and were always characterized by loss of PMS2 and MLH1. Heterogeneity was observed in 2 cases. Overexpression/amplification of FGFR2 (3+) was detected in 5 cases (7.2 %), heterogeneity was detected only in 1 sample. No cases of Epstein-Barr virus encoded RNAs (EBER1) have been identified. In 15/69 samples (21.7 %), there was heterogeneity in the level of PD-L1 expression. In both primary tumor samples and regional lymph node material, immune cells rather than tumor cells were the main PD-L1 expressers. Multivariate analysis showed a significant effect of PD-L1 expression in metastatic lymph node tumor cells (TPS) ≥ 1 (p = 0.014), PD-L1 expression on immune cells of the primary tumor (as a percentage of the area under positive immune cells relative to the tumor area) £ 3 (p = 0.009), PD-L1 expression on immune cells of metastatic lymph nodes £ 1 (p = 0.044).
Conclusions. The data obtained raise the question of the need for additional biopsies from the primary tumor and metastatic lesions to correctly identify the molecular genetic subtype of the disease.
References
Smyth E.C., Verheij M., Allum W., et al. Gastric cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016; 27: v38-49.-DOI: https://doi.org/10.1093/annonc/mdw350.
Tan I.B., Ivanova T., Lim K.H., et al. Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology. 2011; 141: 476-485.-DOI: https://doi.org/10.1053/j.gastro.2011.04.042.
Bang Y.J., van Cutsem E., Feyereislova 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 (London). 2010; 376: 687-697.-DOI: https://doi.org/10.1016/S0140-6736(10)61121-X.
Fuchs C.S., Tomasek J., Yong C.J., et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet (London) 2014; 383: 31-39.-DOI: https://doi.org/10.1016/S0140-6736(13)61719-5.
Wilke H., Muro K., Van Cutsem E., et al. 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. 2014; 15: 1224-1235.-DOI: https://doi.org/10.1016/S1470-2045(14)70420-6.
Fuchs C.S., Tabernero J., Tomasek J., et al. Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab. Br J Cancer. 2016; 115: 974-982.-DOI: https://doi.org/10.1038/bjc.2016.293.
Lordick F., Janjigian Y.Y. Clinical impact of tumour biology in the management of gastro-esophageal cancer. Nat Rev Clin Oncol. 2016; 13: 348-360.-DOI: https://doi.org/10.1038/nrclinonc.2016.15.
Lordick F., Kang Y.K., Chung H.C., et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013; 14: 490-499.-DOI: https://doi.org/10.1016/S1470-2045(13)70102-5.
Ralph C., Elkord E., Burt D.J., et al. Modulation of lymphocyte regulation for cancer therapy: a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin Cancer Res. 2010; 16: 1662-1672.-DOI: https://doi.org/10.1158/1078-0432.CCR-09-2870.
Muro K., Chung H.C., Shankaran V., et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016; 17: 717-726.-DOI: https://doi.org/10.1016/S1470-2045(16)00175-3.
Alsina M., Moehler M., Hierro C., et al. Immunotherapy for gastric cancer: a focus on immune checkpoints. Target Oncol. 2016; 11: 469-477.-DOI: https://doi.org/10.1007/s11523-016-0421-1.
Silva R., Gullo I., Carneiro F. The PD-1/PD-L1 immune inhibitory checkpoint in Helicobacter pylori infection and gastric cancer: a comprehensive review and future perspectives. Porto Biomed J. 2016; 1: 4-11.-DOI: https://doi.org/10.1016/j.pbj.2016.03.004.
Cristescu R., Lee J., Nebozhyn M., et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015; 21: 449-456.-DOI: https://doi.org/10.1038/nm.3850.
Kakiuchi M., Nishizawa T., Ueda H., et al. Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet. 2014; 46: 583-587.-DOI: https://doi.org/10.1038/ng.2984.
Lee Y.S., Cho Y.S., Lee G.K., et al. Genomic profile analysis of diffuse-type gastric cancers. Genome Biol. 2014; 15: 1-15.-DOI: https://doi.org/10.1186/gb-2014-15-4-r55.
Wang H.H., Wu M.S., Shun C.T., et al. Lymphoepithelioma-like carcinoma of the stomach: a subset of gastric carcinoma with distinct clinicopathological features and high prevalence of Epstein-Barr virus infection. Hepatogastroenterology. 1999; 46: 1214-1219.
Klein C.A. Selection and adaptation during metastatic cancer progression. Nature. 2013; 501: 365-372.-DOI: https://doi.org/10.1038/nature12628.
Gerlinger M., Rowan A.J., Horswell S., et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012; 366: 883-892.-DOI: https://doi.org/10.1056/NEJMoa1113205.
Meric-Bernstam F., Mills G.B. Overcoming implementation challenges of personalized cancer therapy. Nat Rev Clin Oncol. 2012; 9: 542-548.-DOI: https://doi.org/10.1038/nrclinonc.2012.127.
Ryska A. Molecular pathology in real time. Cancer Metastasis Rev. 2016; 35: 129-140.-DOI: https://doi.org/10.1007/s10555-016-9607-3.
Stelzner S., Emmrich P. The mixed type in Laurén’s classification of gastric carcinoma: histologic description and biologic behavior. Gen Diagn Pathol. 1997; 143: 39-48.
Japanese Gastric Cancer Association: Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011; 14: 101- 112.
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