Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Gastric Cancer
Published in: Gastric Cancer 1/2014

Open Access 01-01-2014 | Review Article

HER2-positive gastric cancer

Author: Narikazu Boku

Published in: Gastric Cancer | Issue 1/2014

Login to get access

Abstract

Human epidermal growth factor receptor 2 (HER2) is involved in the pathogenesis and poor outcomes of several types of cancer, including advanced gastric and gastroesophageal junction cancer. Molecular-targeted drugs, such as trastuzumab, which prolong overall survival and progression-free survival in HER2-positive breast cancer, may also be beneficial in patients with HER2-positive gastric cancer. Several studies have examined this possibility, such as the Trastuzumab for Gastric Cancer trial. In this context, the first part of this review provides an update on our knowledge of HER2 in breast and gastric cancer, including the detection and prognostic relevance of HER2 in gastric cancer. The second part of the review discusses the results of pivotal clinical trials that examined the potential for using trastuzumab to treat this disease. This section also summarizes the trials that have been conducted or that are underway to determine the optimal uses of trastuzumab in gastric cancer, including its use as monotherapy and continuation beyond disease progression. The final section discusses the future prospects of other anti-HER2 drugs, including lapatinib, trastuzumab emtansine, and pertuzumab, for the treatment of HER2-positive gastric cancer. The introduction of trastuzumab led to the establishment of a new disease entity, “HER2-positive gastric cancer,” similar to HER2-positive breast cancer. It is expected that more anti-HER2 drugs will be developed and introduced into clinical practice to treat HER2-positive cancers, including gastric cancer.
Literature
1.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.PubMedCrossRef
2.
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–92. doi:10.​1056/​nejm200103153441​101.PubMedCrossRef
3.
Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20:719–26.PubMedCrossRef
4.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72. doi:10.​1056/​NEJMoa052306.PubMedCrossRef
5.
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–84. doi:10.​1056/​NEJMoa052122.PubMedCrossRef
6.
7.
Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633–40. doi:10.​1016/​s0140-6736(11)61847-3.PubMedCrossRef
8.
Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;375:377–84. doi:10.​1016/​s0140-6736(09)61964-4.PubMedCrossRef
9.
10.
11.
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki 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. 2010;376:687–97. doi:10.​1016/​s0140-6736(10)61121-x.PubMedCrossRef
12.
Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 1985;230:1132–9.PubMedCrossRef
13.
Olayioye MA. Update on HER-2 as a target for cancer therapy: intracellular signaling pathways of ErbB2/HER-2 and family members. Breast Cancer Res. 2001;3:385–9.PubMedCentralPubMedCrossRef
14.
Yamamoto T, Ikawa S, Akiyama T, Semba K, Nomura N, Miyajima N, et al. Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor. Nature. 1986;319:230–4. doi:10.​1038/​319230a0.PubMedCrossRef
15.
Neve RM, Lane HA, Hynes NE. The role of overexpressed HER2 in transformation. Ann Oncol. 2001;12(Suppl 1):S9–13.PubMedCrossRef
16.
17.
18.
Varley JM, Swallow JE, Brammar WJ, Whittaker JL, Walker RA. Alterations to either c-erbB-2(neu) or c-myc proto-oncogenes in breast carcinomas correlate with poor short-term prognosis. Oncogene. 1987;1:423–30.PubMed
19.
Fukushige S, Matsubara K, Yoshida M, Sasaki M, Suzuki T, Semba K, et al. Localization of a novel v-erbB-related gene, c-erbB-2, on human chromosome 17 and its amplification in a gastric cancer cell line. Mol Cell Biol. 1986;6:955–8.PubMedCentralPubMed
20.
Semba K, Kamata N, Toyoshima K, Yamamoto T. A v-erbB-related protooncogene, c-erbB-2, is distinct from the c-erbB-1/epidermal growth factor-receptor gene and is amplified in a human salivary gland adenocarcinoma. Proc Natl Acad Sci USA. 1985;82:6497–501.PubMedCrossRef
21.
Yokota J, Yamamoto T, Toyoshima K, Terada M, Sugimura T, Battifora H, et al. Amplification of c-erbB-2 oncogene in human adenocarcinomas in vivo. Lancet. 1986;1:765–7.PubMedCrossRef
22.
Tsuda H, Hirohashi S, Shimosato Y, Hirota T, Tsugane S, Yamamoto H, et al. Correlation between long-term survival in breast cancer patients and amplification of two putative oncogene-coamplification units: hst-1/int-2 and c-erbB-2/ear-1. Cancer Res. 1989;49:3104–8.PubMed
23.
24.
25.
Janjigian YY, Werner D, Pauligk C, Steinmetz K, Kelsen DP, Jager E, et al. Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis. Ann Oncol. 2012;. doi:10.​1093/​annonc/​mds104.PubMed
26.
27.
Kataoka Y, Okabe H, Yoshizawa A, Minamiguchi S, Yoshimura K, Haga H, et al. HER2 expression and its clinicopathological features in resectable gastric cancer. Gastric Cancer. 2012;. doi:10.​1007/​s10120-012-0150-9.PubMed
28.
Kim JW, Im SA, Kim M, Cha Y, Lee KH, Keam B, et al. The prognostic significance of HER2 positivity for advanced gastric cancer patients undergoing first-line modified FOLFOX-6 regimen. Anticancer Res. 2012;32:1547–53.PubMed
29.
Phillips BE, Tubbs RR, Rice TW, Rybicki LA, Plesec T, Rodriguez CP, et al. Clinicopathologic features and treatment outcomes of patients with human epidermal growth factor receptor 2-positive adenocarcinoma of the esophagus and gastroesophageal junction. Dis Esophagus. 2012;. doi:10.​1111/​j.​1442-2050.​2012.​01369.​x.PubMed
30.
31.
32.
Tanner M, Hollmen M, Junttila TT, Kapanen AI, Tommola S, Soini Y, et al. Amplification of HER-2 in gastric carcinoma: association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol. 2005;16:273–8. doi:10.​1093/​annonc/​mdi064.PubMedCrossRef
33.
Terashima M, Ochiai A, Kitada K, Ichikawa W, Kurahashi I, Sakuramoto S, et al. Impact of human epidermal growth factor receptor (EGFR) and ERBB2 (HER2) expressions on survival in patients with stage II/III gastric cancer, enrolled in the ACTS-GC study. J Clin Oncol. 2011;29:Abstract 4013.
34.
Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25:118–45. doi:10.​1200/​jco.​2006.​09.​2775.PubMedCrossRef
35.
36.
Bang Y, Chung H, Xu J, Lordick F, Sawaki A, Al-Sakaff N, et al. Pathological features of advanced gastric cancer (GC): Relationship to human epidermal growth factor receptor 2 (HER2) positivity in the global screening programme of the ToGA trial. J Clin Oncol. 2009;27:Abstract 4556.
37.
38.
39.
40.
Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007;369:29–36. doi:10.​1016/​s0140-6736(07)60028-2.PubMedCrossRef
41.
Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 2011;12:236–44. doi:10.​1016/​s1470-2045(11)70033-x.PubMedCrossRef
42.
Goldhirsch A, Piccart-Gebhart M, Procter M, De Azambuja E, Weber H, Untch M, et al. HERA Trial: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow-up. Ann Oncol. 2012;23:LBA6_PR.
43.
Rech J, Arnold D, Folprecht G, Hejna M, Hofmann M, Gramatzki M. A pilot study of trastuzumab (Herceptin©) monotherapy in patients who progressed while on chemotherapy for metastatic or locally advanced HER2-positive gastric cancer. Ann Oncol. 2006;17:Abstract 1096P.
44.
Hamamoto Y. Evaluation of the appropriate use of trastuzumab for advanced or metastatic HER2-positive gastric cancer. In: Ohtsu A (ed) The 9th Annual Meeting of the Japanese Society of Medical Oncology. July 21–23, 2011; Yokohama, Japan, 2011.
45.
Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer–a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011;47:2306–14. doi:10.​1016/​j.​ejca.​2011.​06.​002.PubMedCrossRef
46.
Kang JH, Lee SI. Lim do H, Park KW, Oh SY, Kwon HC, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012;30:1513–8. doi:10.​1200/​jco.​2011.​39.​4585.PubMedCrossRef
47.
Nishina T, Kajiwara T, Hori S, Ikeda Y. A long-term survival case of HER2-positive unresectable advanced gastric cancer that markedly responded to trastuzumab + capecitabine + cisplatin combination therapy. 83rd Annual Meeting of the Japanese Gastric Cancer Association, March 3–5, 2011; Misawa, Japan.
48.
Hegewisch-Becker S, Moorahrend E, Kröning H, Petersen V, Hannig C, Pott D, et al. Trastuzumab (TRA) in combination with different first-line chemotherapies for treatment of HER2-positive metastatic gastric or gastroesophageal junction cancer (MGC): findings from the German noninterventional observational study HerMES. J Clin Oncol. 2012;30:Abstract 4065.
49.
50.
Sawaki M, Tokudome N, Mizuno T, Nakayama T, Taira N, Bando H, et al. Evaluation of trastuzumab without chemotherapy as a post-operative adjuvant therapy in HER2-positive elderly breast cancer patients: randomized controlled trial [RESPECT (N-SAS BC07)]. Jpn J Clin Oncol. 2011;41:709–12. doi:10.​1093/​jjco/​hyr011.PubMedCrossRef
51.
Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2012;. doi:10.​1016/​s1470-2045(12)70477-1.PubMed
52.
Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, et al. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28:1124–30. doi:10.​1200/​jco.​2008.​21.​4437.PubMedCrossRef
53.
Fountzilas G, Razis E, Tsavdaridis D, Karina M, Labropoulos S, Christodoulou C, et al. Continuation of trastuzumab beyond disease progression is feasible and safe in patients with metastatic breast cancer: a retrospective analysis of 80 cases by the Hellenic Cooperative Oncology Group. Clin Breast Cancer. 2003;4:120–5.PubMedCrossRef
54.
Fujimoto-Ouchi K, Sekiguchi F, Yamamoto K, Shirane M, Yamashita Y, Mori K. Preclinical study of prolonged administration of trastuzumab as combination therapy after disease progression during trastuzumab monotherapy. Cancer Chemother Pharmacol. 2010;66:269–76. doi:10.​1007/​s00280-009-1160-0.PubMedCrossRef
55.
Huober J, Baumann M, Rochlitz C, Aebi S, Guth U, von Moos R, et al. Trastuzumab treatment beyond progression in advanced breast cancer: patterns of care in six Swiss breast cancer centers. Oncology. 2011;81:160–6. doi:10.​1159/​000333396.PubMedCrossRef
56.
von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03–05 study. J Clin Oncol. 2009;27:1999–2006. doi:10.​1200/​jco.​2008.​19.​6618.CrossRef
57.
58.
59.
60.
61.
Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20. doi:10.​1056/​NEJMoa055531.PubMedCrossRef
62.
63.
64.
65.
66.
Bang Y, Xu R, Satoh T, Yeh K, Katsura K, Yoshida P, et al. A randomized, open-label, phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone in the second-line treatment of HER2 amplified advanced gastric cancer (AGC) in Asian population: Tytan study. J Clin Oncol. 2012;suppl 34:Abstract 11.
67.
68.
69.
70.
71.
72.
73.
Niculescu-Duvaz I. Trastuzumab emtansine, an antibody-drug conjugate for the treatment of HER2 + metastatic breast cancer. Curr Opin Mol Ther. 2010;12:350–60.PubMed
74.
75.
Hughes JB, Berger C, Rodland MS, Hasmann M, Stang E, Madshus IH. Pertuzumab increases epidermal growth factor receptor down-regulation by counteracting epidermal growth factor receptor-ErbB2 heterodimerization. Mol Cancer Ther. 2009;8:1885–92. doi:10.​1158/​1535-7163.​mct-09-0291.PubMedCrossRef
76.
Takehana T, Kunitomo K, Kono K, Kitahara F, Iizuka H, Matsumoto Y, et al. Status of c-erbB-2 in gastric adenocarcinoma: a comparative study of immunohistochemistry, fluorescence in situ hybridization and enzyme-linked immuno-sorbent assay. Int J Cancer. 2002;98:833–7.PubMedCrossRef
77.
Yano T, Doi T, Ohtsu A, Boku N, Hashizume K, Nakanishi M, et al. Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. Oncol Rep. 2006;15:65–71.
78.
Kim MA, Jung EJ, Lee HS, Lee HE, Jeon YK, Yang HK, et al. Evaluation of HER-2 gene status in gastric carcinoma using immunohistochemistry, fluorescence in situ hybridization, and real-time quantitative polymerase chain reaction. Hum Pathol. 2007;38:1386–93. doi:10.​1016/​j.​humpath.​2007.​02.​005.PubMedCrossRef
79.
Matsubara J, Yamada Y, Hirashima Y, Takahari D, Okita NT, Kato K, et al. Impact of insulin-like growth factor type 1 receptor, epidermal growth factor receptor, and HER2 expressions on outcomes of patients with gastric cancer. Clin Cancer Res. 2008;14:3022–9. doi:10.​1158/​1078-0432.​ccr-07-1898.PubMedCrossRef
80.
81.
82.
83.
84.
85.
86.
Tsapralis D, Panayiotides I, Peros G, Liakakos T, Karamitopoulou E. Human epidermal growth factor receptor-2 gene amplification in gastric cancer using tissue microarray technology. World J Gastroenterol. 2012;18:150–5. doi:10.​3748/​wjg.​v18.​i2.​150.PubMedCrossRef
87.
Wang Y, Xu JM, Liu JZ, Lin L, Ge FJ, Li SS, et al. [HER-2 expression in advanced gastric cancer and its correlation with clinical features, outcome and prognosis]. Zhonghua Zhong Liu Za Zhi. 2011;33:671–5 [In Chinese].
88.
Halon A, Donizy P, Biecek P, Rudno-Rudzinska J, Kielan W, Matkowski R. HER-2 expression in immunohistochemistry has no prognostic significance in gastric cancer patients. Sci World J. 2012;2012:941259. doi:10.​1100/​2012/​941259.
Metadata
Title
HER2-positive gastric cancer
Author
Narikazu Boku
Publication date
01-01-2014
Publisher
Springer Japan
Published in
Gastric Cancer / Issue 1/2014
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-013-0252-z

Other articles of this Issue 1/2014

Gastric Cancer 1/2014 Go to the issue

Original Article

Comparison of advanced adenocarcinomas of esophagogastric junction and distal stomach in Japanese patients

Review Article

Clinical significance of serum tumor markers for gastric cancer: a systematic review of literature by the Task Force of the Japanese Gastric Cancer Association

Original Article

Evaluation of HER2-based biology in 1,006 cases of gastric cancer in a Japanese population

Original Article

Quality of life of older adult patients receiving docetaxel-based chemotherapy triplets for esophagogastric adenocarcinoma: a randomized study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

Original Article

Effects of a human compact anti-ErbB2 antibody on gastric cancer

Original Article

Low ING4 protein expression detected by paraffin-section immunohistochemistry is associated with poor prognosis in untreated patients with gastrointestinal stromal tumors
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits