FGFR2-amplified tumor clones are markedly heterogeneously distributed in carcinomas of the upper gastrointestinal tract.
Esophageal adenocarcinoma
FGFR2 amplification
Gastric carcinoma
Morphological heterogeneity
Tumor heterogeneity
Journal
Journal of cancer research and clinical oncology
ISSN: 1432-1335
Titre abrégé: J Cancer Res Clin Oncol
Pays: Germany
ID NLM: 7902060
Informations de publication
Date de publication:
Jul 2023
Jul 2023
Historique:
received:
02
09
2022
accepted:
01
11
2022
medline:
19
7
2023
pubmed:
24
11
2022
entrez:
23
11
2022
Statut:
ppublish
Résumé
FGFR2 is a therapy-relevant target in tumors of the upper gastrointestinal tract (GIT), and clinical trials are currently underway to test the efficacy of FGFR2 inhibitors. Tumor heterogeneity is one of the relevant causes of treatment failure. Almost nothing is known about the heterogeneous distribution of FGFR2-amplified clones in adenocarcinomas of the upper GIT. To assess FGFR2 gene copy number alteration and intratumoral heterogeneity of upper GIT adenocarcinomas, we analyzed 893 patient-derived formalin-fixed paraffin-embedded tumor specimens, including primary operated and neoadjuvant-treated tumors (462 gastric carcinomas and 429 esophageal adenocarcinomas) as well as complementary lymph node and distant metastasis by fluorescence in situ hybridization. Twenty-six gastric tumors (5.6%) and 21 esophageal adenocarcinomas (4.9%) showed FGFR2 amplification. Overall, 93% of gastric carcinomas and 83% of esophageal carcinomas showed heterogeneous amplification. FGFR2 amplification was found in different histological growth patterns, including intestinal and diffuse type according to the Lauren classification. In the primary gastric carcinoma group, FGFR2 amplification was associated with poor prognosis (p = 0.005). Homogeneous FGFR2 amplification in tumors of the upper GIT is the exception. This has highly relevant implications in the nature of FGFR2 diagnostics (sufficient tumor cell number, determination of amplification at metastasis versus primary tumor, etc.) and on the response probability of appropriate inhibitors. It is relevant that the often poorly treatable and aggressive subtype of diffuse carcinomas (poorly cohesive carcinomas) also shows FGFR2 amplification and that an individualized therapy option with FGFR2 inhibitors could be an option in this group.
Sections du résumé
BACKGROUND
BACKGROUND
FGFR2 is a therapy-relevant target in tumors of the upper gastrointestinal tract (GIT), and clinical trials are currently underway to test the efficacy of FGFR2 inhibitors. Tumor heterogeneity is one of the relevant causes of treatment failure. Almost nothing is known about the heterogeneous distribution of FGFR2-amplified clones in adenocarcinomas of the upper GIT.
PATIENTS AND METHODS
METHODS
To assess FGFR2 gene copy number alteration and intratumoral heterogeneity of upper GIT adenocarcinomas, we analyzed 893 patient-derived formalin-fixed paraffin-embedded tumor specimens, including primary operated and neoadjuvant-treated tumors (462 gastric carcinomas and 429 esophageal adenocarcinomas) as well as complementary lymph node and distant metastasis by fluorescence in situ hybridization.
RESULTS
RESULTS
Twenty-six gastric tumors (5.6%) and 21 esophageal adenocarcinomas (4.9%) showed FGFR2 amplification. Overall, 93% of gastric carcinomas and 83% of esophageal carcinomas showed heterogeneous amplification. FGFR2 amplification was found in different histological growth patterns, including intestinal and diffuse type according to the Lauren classification. In the primary gastric carcinoma group, FGFR2 amplification was associated with poor prognosis (p = 0.005).
CONCLUSION
CONCLUSIONS
Homogeneous FGFR2 amplification in tumors of the upper GIT is the exception. This has highly relevant implications in the nature of FGFR2 diagnostics (sufficient tumor cell number, determination of amplification at metastasis versus primary tumor, etc.) and on the response probability of appropriate inhibitors. It is relevant that the often poorly treatable and aggressive subtype of diffuse carcinomas (poorly cohesive carcinomas) also shows FGFR2 amplification and that an individualized therapy option with FGFR2 inhibitors could be an option in this group.
Identifiants
pubmed: 36416959
doi: 10.1007/s00432-022-04460-w
pii: 10.1007/s00432-022-04460-w
pmc: PMC10349760
doi:
Substances chimiques
FGFR2 protein, human
EC 2.7.10.1
Receptor, Fibroblast Growth Factor, Type 2
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5289-5300Informations de copyright
© 2022. The Author(s).
Références
Ahn S, Lee J, Hong M et al (2016) FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival. Mod Pathol 29:1095–1103
pubmed: 27230412
Bang YJ, Van Cutsem E, Feyereislova A et al (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 376:687–697
pubmed: 20728210
Catenacci DV, Tesfaye A, Tejani M et al (2019) Bemarituzumab with modified FOLFOX6 for advanced FGFR2-positive gastroesophageal cancer: FIGHT Phase III study design. Future Oncol 15:2073–2082
pubmed: 31094225
Cristescu R, Lee J, Nebozhyn M et al (2015) Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 21:449–456
pubmed: 25894828
Gebauer F, Krämer M, Bruns C et al (2020) Lymphocyte activation gene-3 (LAG3) mRNA and protein expression on tumour infiltrating lymphocytes (TILs) in oesophageal adenocarcinoma. J Cancer Res Clin Oncol 146:2319–2327
pubmed: 32592066
pmcid: 7382658
Gemo AT, Deshpande AM, Palencia S et al (2014) Abstract 5446: FPA144: A therapeutic antibody for treating patients with gastric cancers bearing FGFR2 gene amplification. Can Res 74:5446–5446
Grabsch H, Sivakumar S, Gray S et al (2010) HER2 expression in gastric cancer: Rare, heterogeneous and of no prognostic value—conclusions from 924 cases of two independent series. Cell Oncol 32:57–65
pubmed: 20208134
pmcid: 4619246
Grillo F, Fassan M, Sarocchi F et al (2016) HER2 heterogeneity in gastric/gastroesophageal cancers: from benchside to practice. World J Gastroenterol 22:5879–5887
pubmed: 27468182
pmcid: 4948273
Gu W, Yang J, Wang Y et al (2021) Comprehensive identification of FGFR1-4 alterations in 5 557 Chinese patients with solid tumors by next-generation sequencing. Am J Cancer Res 11:3893–3906
pubmed: 34522456
pmcid: 8414391
Hanna W, Nofech-Mozes S, Kahn HJ (2007) Intratumoral heterogeneity of HER2/neu in breast cancer—a rare event. Breast J 13:122–129
pubmed: 17319852
Helbig D, Ihle MA, Pütz K et al (2016) Oncogene and therapeutic target analyses in atypical fibroxanthomas and pleomorphic dermal sarcomas. Oncotarget 7:21763–21774
pubmed: 26943575
pmcid: 5008321
Holscher AH, Schneider PM, Gutschow C, Schroder W (2007) Laparoscopic ischemic conditioning of the stomach for esophageal replacement. Ann Surg 245:241–246
pubmed: 17245177
pmcid: 1876980
Hou Y, Nitta H, Wei L et al (2017) HER2 intratumoral heterogeneity is independently associated with incomplete response to anti-HER2 neoadjuvant chemotherapy in HER2-positive breast carcinoma. Breast Cancer Res Treat 166:447–457
pubmed: 28799059
Hur JY, Chao J, Kim K et al (2020) High-level FGFR2 amplification is associated with poor prognosis and Lower response to chemotherapy in gastric cancers. Pathol Res Pract 216:152878
pubmed: 32089408
Klempner SJ, Madison R, Pujara V et al (2019) FGFR2-Altered gastroesophageal adenocarcinomas are an uncommon clinicopathologic entity with a distinct genomic landscape. Oncologist 24:1462–1468
pubmed: 31249137
pmcid: 6853122
Kuboki Y, Schatz CA, Koechert K et al (2018) In situ analysis of FGFR2 mRNA and comparison with FGFR2 gene copy number by dual-color in situ hybridization in a large cohort of gastric cancer patients. Gastric Cancer 21:401–412
pubmed: 28852882
Lau WM, Teng E, Huang KK et al (2018) Acquired resistance to FGFR inhibitor in diffuse-type gastric cancer through an AKT-independent PKC-mediated phosphorylation of GSK3β. Mol Cancer Ther 17:232–242
pubmed: 28978722
Loeser H, Waldschmidt D, Kuetting F et al (2017) Copy-number variation and protein expression of DOT1L in pancreatic adenocarcinoma as a potential drug target. Mol Clin Oncol 6:639–642
pubmed: 28529740
pmcid: 5432215
Lordick F, Al-Batran SE, Dietel M et al (2017) HER2 testing in gastric cancer: results of a German expert meeting. J Cancer Res Clin Oncol 143:835–841
pubmed: 28285403
pmcid: 5384945
Matsumoto K, Arao T, Hamaguchi T et al (2012) FGFR2 gene amplification and clinicopathological features in gastric cancer. Br J Cancer 106:727–732
pubmed: 22240789
pmcid: 3322955
Merz V, Zecchetto C, Simionato F et al (2020) A phase II trial of the FGFR inhibitor pemigatinib in patients with metastatic esophageal-gastric junction/gastric cancer trastuzumab resistant: the FiGhTeR trial. Ther Adv Med Oncol 12:1758835920937889
pubmed: 32684989
pmcid: 7346700
Miki T, Bottaro DP, Fleming TP et al (1992) Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene. Proc Natl Acad Sci U S A 89:246–250
pubmed: 1309608
pmcid: 48213
O’Sullivan CC, Moon DH, Kohn EC, Lee JM (2014) Beyond breast and ovarian cancers: PARP inhibitors for BRCA mutation-associated and BRCA-like solid Tumors. Front Oncol 4:42
pubmed: 24616882
pmcid: 3937815
Pectasides E, Stachler MD, Derks S et al (2018) Genomic heterogeneity as a barrier to precision medicine in gastroesophageal adenocarcinoma. Cancer Discov 8:37–48
pubmed: 28978556
Pierce KL, Deshpande AM, Stohr BA et al (2014) FPA144, a humanized monoclonal antibody for both FGFR2-amplified and nonamplified, FGFR2b-overexpressing gastric cancer patients. J Clin Oncol 32:e15074–e15074
Quaas A, Pamuk A, Klein S et al (2021) Sex-specific prognostic effect of CD66b-positive tumor-infiltrating neutrophils (TANs) in gastric and esophageal adenocarcinoma. Gastric Cancer 24:1213–1226
pubmed: 34009535
pmcid: 8502159
Ruschoff J, Hanna W, Bilous M et al (2012) HER2 testing in gastric cancer: a practical approach. Mod Pathol 25:637–650
pubmed: 22222640
Schneider PM, Metzger R, Schaefer H et al (2008) Response evaluation by endoscopy, rebiopsy, and endoscopic ultrasound does not accurately predict histopathologic regression after neoadjuvant chemoradiation for esophageal cancer. Ann Surg 248:902–908
pubmed: 19092334
Schoemig-Markiefka B, Eschbach J, Scheel AH et al (2021) Optimized PD-L1 scoring of gastric cancer. Gastric Cancer 24:1115–1122
pubmed: 33954872
pmcid: 8338825
Schrumpf T, Behrens HM, Haag J et al (2022) FGFR2 overexpression and compromised survival in diffuse-type gastric cancer in a large central European cohort. PLoS ONE 17:e0264011
pubmed: 35167603
pmcid: 8846517
Shoji H, Yamada Y, Okita N et al (2015) Amplification of FGFR2 gene in patients with advanced gastric cancer receiving chemotherapy: prevalence and prognostic significance. Anticancer Res 35:5055–5061
pubmed: 26254407
Simon R, Mirlacher M, Sauter G (2004) Tissue microarrays. Biotechniques 36:98–105
pubmed: 14740491
Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249
pubmed: 33538338
Thuss-Patience PC, Shah MA, Ohtsu A et al (2017) 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
pubmed: 28343975
Tokunaga R, Imamura Y, Nakamura K et al (2016) Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma. Oncotarget 7:19748–19761
pubmed: 26933914
pmcid: 4991416
Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10:116–129
pubmed: 20094046
Van Cutsem E, Bang YJ, Feng-Yi F et al (2015) HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 18:476–484
pubmed: 25038874
Wainberg ZA, Enzinger PC, Kang Y-K et al (2021) Randomized double-blind placebo-controlled phase 2 study of bemarituzumab combined with modified FOLFOX6 (mFOLFOX6) in first-line (1L) treatment of advanced gastric/gastroesophageal junction adenocarcinoma (FIGHT). J Clin Oncol 39:160–160
Wallander K, Eisfeldt J, Lindblad M et al (2021) Cell-free tumour DNA analysis detects copy number alterations in gastro-oesophageal cancer patients. PLoS ONE 16:e0245488
pubmed: 33539436
pmcid: 7861431
Yashiro M, Kuroda K, Masuda G et al (2021) Clinical difference between fibroblast growth factor receptor 2 subclass, type IIIb and type IIIc, in gastric cancer. Sci Rep 11:4698
pubmed: 33633310
pmcid: 7907198
Ye P, Zhang M, Fan S et al (2015) Intra-tumoral heterogeneity of HER2, FGFR2, cMET and ATM in gastric cancer: optimizing personalized healthcare through innovative pathological and statistical analysis. PLoS ONE 10:e0143207
pubmed: 26587992
pmcid: 4654477
Zubarayev M, Min EK, Son T (2019) Clinical and molecular prognostic markers of survival after surgery for gastric cancer: tumor-node-metastasis staging system and beyond. Transl Gastroenterol Hepatol 4:59
pubmed: 31559340
pmcid: 6737396