Current perspectiveTrastuzumab in gastric cancer
Section snippets
Background
Gastric cancer was the fifth most commonly diagnosed cancer in Europe in 2006, yet only modest gains in survival have been achieved when compared to two of the most common cancers; breast and colorectal.1 This is exemplified by the recent integration of trastuzumab into the first-line treatment of HER-2-positive advanced gastric cancer, almost a decade after a survival benefit was demonstrated from its addition to standard first-line chemotherapy for HER-2-positive advanced breast cancer.2
The human epidermal growth factor receptor-2 (HER-2)
HER-2 was the second member of the epidermal growth factor (EGF) receptor family to be identified,27, 28 following the earlier landmark discoveries of EGF29 and its receptor.30 The discovery followed the observation that the neu oncogene, found in rat neuroglioblastomas,31 was homologous to erbB, which encodes the EGF receptor (EGFR).27 The same group reported that whilst homologous to erbB in the tyrosine kinase domain, the neu oncogene was a distinct novel gene located on q21 of chromosome 17,
Pre-clinical rationale for targeting HER-2 in gastric cancer
Amplification of erbB-2/neu was described in a breast cancer cell line (MAC117) in 1985,42 and subsequently in a gastric cancer cell line in 1986 (MKN-7).43 These results were confirmed in breast and gastric cancer resection samples in the same year,44 indicating a potential role in oncogenesis. Further investigation in 668 breast cancer and 120 ovarian cancer specimens with correlation to outcome quickly identified HER-2/neu amplification to be an independent predictor of prognosis in terms of
Clinical data: trastuzumab in gastric cancer
Prior to the presentation of results of the ToGA trial in 2009,26 three phase II studies evaluating trastuzumab in patients with gastric cancer have been presented, although all three remain unpublished.60, 61, 62 Early data from a small phase II evaluation of trastuzumab combined with a cisplatin/docetaxel doublet were reported in 2006, with a radiological response observed in 4/5 patients with HER-2-positive (defined as IHC 3+ or FISH+) metastatic gastric or OGJ carcinoma treated.60 In a
Other agents targeting HER-2: lapatinib in gastric cancer
Lapatinib is an orally active, small molecule dual tyrosine kinase inhibitor of EGFR and HER-2 with known efficacy in trastuzumab-resistant advanced breast cancer.75, 76 Activity has been reported in the HER-2-amplified gastric cancer cell lines SNU-216 and NCI-N87 with unexpected additional activity in selected HER-2- and EGFR-negative cell lines such as SNU-484.77 Additive or synergistic anti-tumour effect with 5-FU, cisplatin, oxaliplatin, paclitaxel,77 irinotecan78 and trastuzumab79 has
Future directions
There are no current clinical trials of trastuzumab in gastric cancer in the advanced or operable disease settings at this time. A randomised placebo-controlled phase III study (LOGiC) will evaluate the addition of lapatinib to first-line capecitabine plus oxaliplatin in patients with HER-2-positive advanced gastro-oesophageal cancer, with a target accrual of 410 patients. Additionally, two phase II studies in advanced HER-2-positive gastric cancer are open to recruitment, evaluating lapatinib
Conflict of interest statement
Dr. Okines previously received an honorarium from Roche for a presentation. Professor Cunningham has received research funding from Roche.
Acknowledgement
The authors acknowledge NHS funding to the NIHR Biomedical Research Centre.
References (99)
- et al.
Estimates of the cancer incidence and mortality in Europe in 2006
Ann Oncol
(2007) - et al.
Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study
Lancet Oncol
(2009) - et al.
A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer
Ann Oncol
(2004) - et al.
S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial
Lancet Oncol
(2008) - et al.
Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction
Ann Oncol
(2008) Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal
J Biol Chem
(1962)- et al.
ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors
J Biol Chem
(1999) - et al.
The erbB3 gene product is a receptor for heregulin
J Biol Chem
(1994) - et al.
Amplification of c-erbB-2 oncogene in human adenocarcinomas in vivo
Lancet
(1986) - 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)
Growth inhibitory effects of trastuzumab and chemotherapeutic drugs in gastric cancer cell lines
Cancer Lett
Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial
Ann Oncol
The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines
Cancer Lett
PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients
Cancer Cell
A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer
Cancer Cell
Epidermal growth factor receptor coexpression modulates susceptibility to herceptin in HER2/neu overexpressing breast cancer cells via specific erbB-receptor interaction and activation
Exp Cell Res
2-Year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial
Lancet
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2
New Engl J Med
Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world
J Clin Oncol
Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer
New Engl J Med
Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction
New Engl J Med
Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine
New Engl J Med
Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer
Cancer
Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer
Brit J Cancer
Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer
J Clin Oncol
Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer
J Clin Oncol
Capecitabine and oxaliplatin for advanced esophagogastric cancer
New Engl J Med
Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group
J Clin Oncol
Phase II study of a 4-week capecitabine regimen in advanced or recurrent gastric cancer
Anticancer Drugs
Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. For the S-1 Cooperative Gastric Cancer Study Group
Oncology
Phase II trial of oral UFT and leucovorin in advanced gastric carcinoma
Am J Clin Oncol
Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205)
J Clin Oncol
Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie
J Clin Oncol
Paclitaxel versus docetaxel for advanced gastric cancer: a randomized phase II trial in combination with infusional 5-fluorouracil
Anticancer Drugs
Capecitabine and oxaliplatin for advanced esophagogastric cancer
New Engl J Med
The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen
Nature
The neu gene: an erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor
Science
Specific radiolabeling of a cell surface receptor for epidermal growth factor
Proc Natl Acad Sci USA
Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts
Nature
The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity
Science
Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene
Science
Morphogenetic and proliferative responses to heregulin of mammary epithelial cells in vitro are dependent on HER2 and HER3 and differ from the responses to HER2 homodimerisation or hepatocyte growth factor
Int J Oncol
ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner
Mol Cell Biol
Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions
Embo J
Heregulin induces tyrosine phosphorylation of HER4/p180erbB4
Nature
Signal transduction pathways induced by heregulin in MDA-MB-453 breast cancer cells
Oncogene
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