Current perspective
Trastuzumab in gastric cancer

https://doi.org/10.1016/j.ejca.2010.05.003Get rights and content

Abstract

Trastuzumab is a fully humanised monoclonal antibody directed at the human epidermal growth factor receptor-2 (HER-2) which has been a component of standard therapy for advanced and resected HER-2-positive breast cancers for almost a decade.

HER-2 over-expression, defined as HER-2 protein over-expression using immunohistochemistry scored as 3+ and/or erbB-2 amplification detected by fluorescent in situ hybridisation, was detected in 22.1% of 3807 patients with advanced gastric and oesophagogastric junction (OGJ) adenocarcinoma screened for eligibility for the phase III ToGA study. The validated scoring system for HER-2 positivity in gastric cancers differs from that recommended for breast cancer due to an increased frequency of incomplete membranous immunoreactivity and heterogeneity of HER-2 expression in gastric cancers. The highest rates of HER-2 over-expression are observed in patients with OGJ rather than gastric tumours and intestinal-type rather than diffuse or mixed histology.

The international multicentre randomised phase III ToGA study assessed the addition of trastuzumab to a cisplatin plus fluoropyrimidine (FP) chemotherapy doublet for patients with HER-2-positive advanced gastric or OGJ adenocarcinoma. The investigators reported a clinically and statistically significant benefit in terms of response rate (47.3% versus 34.5%, p = 0.0017), median progression-free survival (6.7 versus 5.5 months, p = 0.0002) and median overall survival (13.8 versus 11.1 months, p = 0.0046). Trastuzumab plus FP chemotherapy is now the standard of care for patients with advanced gastric and OGJ cancers which over-express HER-2.

Further research to evaluate trastuzumab delivered beyond progression, in combination with alternative first-line chemotherapy regimens, and in the perioperative and adjuvant setting is urgently needed. Additionally, research into mechanisms of resistance and strategies to overcome primary or acquired resistance to trastuzumab must now be expedited, using lessons learnt over the past decade in HER-2-positive breast cancer to maximise the benefit from this agent.

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.

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