Skip to main content
NCBI home page
Therapeutic Advances in Medical Oncology logoLink to Therapeutic Advances in Medical Oncology
. 2013 Mar;5(2):143–151. doi: 10.1177/1758834012469429

Gastric cancer and trastuzumab: first biologic therapy in gastric cancer

Krishna S Gunturu 1, Yanghee Woo 2, Nike Beaubier 3, Helen E Remotti 4, M Wasif Saif 5,✉
PMCID: PMC3556876  PMID: 23450234

Abstract

Gastric cancer remains difficult to cure and has a poor overall prognosis. Chemotherapy and multimodality therapy has shown some benefit in the treatment of gastric cancer. Current therapies for gastric cancer have their limitations; thus, we are in need of newer treatment options including targeted therapies. Here, we review the biologic therapy with trastuzumab in human epidermal growth factor receptor 2 (HER2)+ gastric cancer.

Keywords: gastric cancer, trastuzumab

Introduction

Gastric cancer is defined as a cancer arising from any portion of the gastroesophageal junction (GEJ) to the pylorus. If it involves the GEJ, the origin of the tumor, whether esophageal or gastric, might be difficult to determine. In 2011, an estimated 21,520 new gastric cancer cases in the United States accounted for 8% of new cancer diagnosis [Siegel et al. 2011]. Stomach cancer mortality has decreased by ~4% in males and ~1.4% in females from 1990 to 2007. The histological pattern of gastric cancer is changing with a decline in the intestinal type in comparison with the diffuse type. The prognosis for advanced gastric cancer remains poor and 5- year survival rate for all stages is 26%.

Gastric cancer is associated with several inherited cancer syndromes in 1–3% of patients, including familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer (Lynch syndrome) and Peutz–Jeghers syndrome. Hereditary diffuse gastric cancer is known to be caused by mutations in the E-cadherin (CDH1) gene. It occurs in approximately 25% of families in an autosomal dominant fashion [Fitzgerald and Caldas, 2004]. The presenting symptoms of gastric cancer can be nonspecific and may include vague abdominal discomfort and dyspepsia. Owing to a lack of explicit symptoms, gastric cancer is more often diagnosed in the advanced stages.

Upper endoscopy with biopsy is the gold standard for diagnosis of gastric cancer. Endoscopic ultrasonography (EUS) aids in the staging by providing information about the depth of the tumor and regional lymph node evaluation, but is operator dependent. CT scan of the chest, abdomen and pelvis is helpful in delineating the extent of the disease and is routinely used for pre-operative staging. Positron emission tomography (PET) is also used in staging. Combined modality PET-CT has higher accuracy in preoperative staging (68%) than PET (47%) or CT (53%) alone [Dassen et al. 2009; Lim et al. 2006].

Adenocarcinoma is the predominant type of gastric cancer, accounting for 95% of all solid stomach malignancies. Adenocarcinomas are subtyped by the Lauren Classification as intestinal, diffuse or mixed type. Other rare types of tumor include squamous cell carcinoma, small-cell carcinoma and neuroendocrine tumors.

The American Joint Committee on Cancer (AJCC) TNM staging system for epithelial gastric cancer has been used widely in the United States. The recent 7th edition AJCC TNM staging system for gastric cancer has been adapted internationally and may allow for improved outcome analysis [Rice et al. 2010].

Treatment

Depending on the site and extent of the tumor, surgical resection with total or subtotal gastrectomy is performed. For nonulcerated T1N0 cancers endoscopic mucosal resection (EMR) is performed more frequently in Japan. Extensive lymphadenectomy (D2) which removes retroperitoneal lymphnodes in addition to perigastric lymphnodes had shown improved lower recurrence rates compared to D1 resection. D1 showed improved survival. The 15-year follow up of the Dutch D1/D2 trial showed D2 lymphadenectomy was associated with lower locoregional recurrence and gastric-cancer-related deaths than D1 surgery [Songun et al. 2010]. Other trials described below had evaluated chemoradiation or chemotherapy in an adjuvant or peri-operative setting.

The United States (US) Intergroup 116/SWOG 9008 trial evaluated postoperative chemoradiation after resection of gastric or GEJ adenocarcinoma [Macdonald et al. 2001]. After the resection, patients were randomized to observation versus five cycles of 5-flourouracil (5-FU)/leucovorin (LV) and radiation up to 45 Gy. The 10-year follow up of this study showed the chemoradiation group had significant overall survival (OS) and disease-free survival (DFS) at >7 years of follow up. Overall, postoperative chemotherapy is relatively poorly tolerated in gastric cancer patients.

The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial tested peri-operative chemotherapy with epirubicin, cisplatin and 5-FU in adenocarcinoma of the GEJ or lower esophagus [Cunningham et al. 2006]. The median diameter of the resected tumor was smaller in the chemotherapy group than in the surgery alone group (3 cm versus 5 cm, p < 0.001) which was consistent with tumor response in the chemotherapy group. Patients in the peri-operative chemotherapy group had a significantly higher OS and progression-free survival (PFS) (5-year OS 36 % in peri-operative chemotherapy versus 23% for surgery alone).

The CRITICS trial (ChemoRadiotherapy after Induction chemoTherapy In Cancer of the Stomach) is comparing Intergroup 0116 with the MAGIC trial [Dikken et al. 2011]. The phase III TAX 325 study evaluated the benefits of adding Taxotere® (docetaxel) with a standard chemotherapy regimen: TCF (Taxotere® 75 mg/m2 day (d) 1, cisplatin (C) 75 mg/m2 d 1, and 5-FU 750 mg/m2/d continuous infusion days 1-5 q3 weeks) versus CF (C 100 mg/m2 d 1 and 5-FU 1000 mg/m2/d on days 1–5 q4weeks) in locally recurrent or metastatic gastric and GEJ adenocarcinoma patients [Van Cutsem et al. 2006]. Time to progression (TTP) was the primary endpoint. The TTP was statistically higher in the DCF group compared with the CF group (5.6 months versus 3.7 months, respectively, p = 0.0004). OS was longer in the TCF arm (9.2 months compared with 8.6 months in the CF arm, p = 0.0201), and response rate was 37% in the TCF arm versus 25% in the CF arm. Grade 3 and 4 neutropenia, stomatitis, diarrhea, lethargy and complicated neutropenia were more frequent in the DCF arm.

REAL-2 is a phase III trial compared ECF (epirubicin, cisplatin and 5-FU), ECX (epirubicin, cisplatin and capecitabine), EOF (epirubicin, oxaliplatin and 5-FU) and EOX (epirubicin, oxaliplatin and capecitabine) in a 2 × 2 design in advanced gastric cancer [Cunningham et al. 2008]. Median OS was 9.9 months in the ECF arm, 9.9 months in the ECX arm, 9.3 months in the EOF arm and 11.2 months in the EOX arm. OS in EOX arm was longer than in the ECF arm in the secondary analysis. PFS and response rate were the same in all arms.

The addition of bevacizumab to chemotherapy in gastric cancer patients showed no improvement in the OS, but prolonged PFS and response rate in AVAGAST trial [Ohtsu et al. 2011]. The primary endpoint was OS in this study. Median OS in the bevacizumab and cisplatin/fluoropyrimidine group was 12.1 months versus 10.1 months in the chemotherapy alone arm (p = 0.1002). Overall response rate and median PFS (6.7 versus 5.3 months) were also improved in the bevacizumab arm versus the chemotherapy alone arm. This study did not reach the primary endpoint, but showed improvement in PFS and response rate. The MAGIC-B trial is currently accruing patients to compare peri-operative chemotherapy with or without bevacizumab.

The combination of FOLFIRI and cetuximab showed activity in a phase II trial of advanced gastric cancer [Pinto et al. 2007]. Cetuximab monotherapy showed no activity and tyrosine kinase inhibitors (TKIs) had no activity in gastric tumors. A phase II trial of a modified FOLFOX6 regimen and erlotinib in previously untreated advanced or metastatic esophageal or GEJ adenocarcinoma showed an objective response rate of 51.5% [Wainberg et al. 2011]. The median OS was 11 months and median PFS was 5.5 months. KRAS mutations were detected in 8%, epidermal growth factor receptor (EGFR) mutations in 0% and human epidermal growth factor receptor 2 (HER2) amplification in 19% of those tumors. This study showed that erlotinib was tolerable and had activity in esophageal and GEJ tumors.

Recently, the ToGA trial evaluated the addition of trastuzumab to chemotherapy in gastric cancer which will be discussed here.

Markers in gastric cancer

Gastric carcinomas show somatic KRAS mutations in <5–10% and BRAF in ~2.2% of gastric cancers [Lee et al. 2003]. Mammano and colleagues evaluated EGFR protein expression and gene mutations in exons 18, 19 and 21 in 49 gastric adenocarcinomas. The EGFR gene mutation was not identified, but EGFR protein expression was seen in 6% of the cases [Mammano et al. 2006]. EGFR is a cellular transmembrane glycoprotein receptor for the members of EGF family of extracellular protein ligands. It constitutes one of four members of erbB family of tyrosine kinase receptors: HER1, HER2 (c-erbB-2), HER3 (c-erbB-3) and HER4 (c-erbB-4) [Herbst, 2004]. EGFR consists of extracellular receptor domain, a transmembrane region and an intracellular domain with tyrosine kinase function [Yarden and Sliwkowski, 2001]. EGFR binding with a ligand results in receptor homodimerization or heterodimerization at the cell surface which causes internalization of the dimerized receptor. After the internalization and dimerization, autophosphorylation of the intracytoplasmic EGFR tyrosine kinase domains occur and this in turn stimulates an intracellular signal transduction cascade [Franklin et al. 2002]. EGFR is overexpressed in a majority of solid tumors and has been associated with poor prognosis and decreased survival [Browne et al. 2009]. Galizia and colleagues tested 82 gastric cancer patients who were surgically resected and 25 normal gastric mucosa specimens from noncancer patients for EGFR positivity by immunohistochemistry (IHC) [Galizia et al. 2007]. A total of 44% of these patients were EGFR positive. Their results showed that EGFR overexpression correlated with disease recurrence and poorer survival.

HER2 and trastuzumab

HER2 is overexpressed in 10–25% of gastric cancers. HER2 protein is a tyrosine kinase receptor and after binding to the extracellular ligand-binding domain initiates a signal transduction cascade that affects tumor cell biology in several ways including by cell proliferation, apoptosis, adhesion, migration, and differentiation [Yakes et al. 2002]. Yano and colleagues showed HER2 was overexpressed in 23% of cases in gastric cancer patients by IHC [Yano et al. 2006]. Fluorescence in situ hybridization (FISH) assay showed 99.5% concordance. HER2 overexpression was evaluated by both IHC and FISH in advanced gastric carcinoma by Song and colleagues and was shown to have a worse prognosis [Song et al. 2010]. In HER2-amplified patients the median survival was 5.5 months compared with 12.6 months in nonamplified patients. HER2 overexpression was more commonly seen in the intestinal-type than diffuse-type cancers (32% versus 6%) [Bang et al. 2009]. There was also a high concordance rate noted between IHC and FISH HER2 results from primary and metastatic sites [Bozzetti et al. 2011].

Trastuzumab (Trastuzumab®) is a recombinant humanized monoclonal antibody that targets the extracellular domain IV of the HER2 protein. Yakes and colleagues showed that trastuzumab inhibits HER2 gene-amplified breast cancer cell lines and also inhibits HER2 downstream signals PI3KCA and AKT kinases in HER2 gene-amplified cells [Yakes et al. 2002]. Trastuzumab blocks the HER2 causing redirection of Cdk inhibitor to p27 to Cdk2 which leads to growth arrest of HER2 overexpressing cells. Binding of trastuzumab to the HER2 receptor was proposed to trigger HER2 internalization and degradation through a tyrosine kinase called ubiquitin ligase c-Cbl [Klapper et al. 2000]. Preclinical studies had shown that trastuzumab activates antibody-dependent cellular toxicity and trastuzumab bound HER2 receptors recruit cytotoxic T lymphocytes to destroy the cell [Bianco, 2004]. As HER2 is overexpressed in gastric cancer and associated with poor prognosis, trastuzumab with its mechanism of interacting with HER2 protein and causing cell apoptosis and interfering with downstream signals is a relevant target. The HER2 protein is a tyrosine kinase receptor which initiates signal transduction cascade causing cell proliferation, apoptosis, adhesion, migration and differentiation after binding to the extracellular ligand binding domain.

ToGA study

Trastuzumab was evaluated in HER2 overexpressing gastric and GEJ cancer patients in the ToGA trial (Trastuzumab for Gastric Cancer) [Bang et al. 2010]. Patients whose gastric or GEJ tumors showed HER2 overexpression by IHC or gene amplification by FISH were eligible for the study. Physicians were able to choose 5-FU or capecitabine along with cisplatin. Patients were randomized 1:1 to capecitabine 1000 mg/m2/day on days 1–14 followed by 1 week rest (or 5-FU 800 mg/ m2/day on days 1–5 continuous infusion), cisplatin 80 mg/ m2/day on day 1 every 3 weeks for six cycles or to capecitabine (or 5-FU), cisplatin and trastuzumab 8 mg/kg loading dose on day 1 followed by 6 mg/kg every 3 weeks (Figure 1). Trastuzumab was continued until progression of the disease. The primary endpoint was OS in the two treatment arms. Secondary endpoints included PFS, overall response rate, time to progression, duration of response and safety.

Figure 1.

Figure 1.

Open in a new tab

ToGA trial design (Bang et al. 2010). GC, gastric cancer; GEJC, gastroesophageal junction cancer; HER2, human epidermal growth factor receptor 2; 5-FU, 5-fluorouracil.

Treatment

Trastuzumab and chemotherapy was given to 294 patients and chemotherapy alone was given to 290 patients. Trastuzumab was given for a median of eight cycles for 4.9 months and with 100% dose intensity. Cisplatin was given for median of six cycles for 3.5 months at 89.4% dose intensity, capecitabine for a median of six cycles for 3.9 months at 85.9% dose intensity and 5-FU for a median of six cycles for 3.6 months and at dose intensity of 98.3% in the trastuzumab and chemotherapy arm. In the chemotherapy arm, cisplatin was administered for a median of five cycles for 3.4 months at 91.1% dose intensity, capecitabine for a median of five cycles for 3.9 months at a dose intensity of approximately 86.7% and 5-FU for a median of four cycles lasting 2.9 months at a dose intensity of 95.7%.

Survival

In this study, 22% (n = 810) of the patients with gastric or GEJ cancer were HER2 positive. The final analysis showed that median OS was 13.8 months in trastuzumab arm compared with 11.1 months in the chemotherapy alone arm (p = 0.0046). OS was improved significantly with the addition of trastuzumab versus chemotherapy alone with a hazard ratio (HR) of 0.73. The addition of trastuzumab improved median survival by 2.5 months. Median PFS was 6.7 months in the trastuzumab arm versus 5.5 months in the chemotherapy alone arm (p = 0.0002). The overall response rate was 47.3% versus 34.5% in trastuzumab plus chemotherapy and chemotherapy, respectively (p = 0.0017). Patients receiving trastuzumab were able to follow planned treatment, with an average dose intensity of trastuzumab of 100.1% and a median duration of treatment of 4.9 months. In addition, patients on trastuzumab treatment arm received more chemotherapy, with a median of 6 cycles. In the updated survival, OS was improved with a HR of 0.80 for the addition of trastuzumab versus chemotherapy alone. The addition of trastuzumab improved median survival by 1.4 months. The overall tumor response rate, time to progression and duration of response were improved in the trastuzumab plus chemotherapy arm.

Post hoc exploratory analysis showed that trastuzumab and chemotherapy improved OS in patients with IHC 2+ and FISH positive or IHC 3+ patients compared with IHC 0 or 1+ and FISH-positive patients. Thus, trastuzumab should be considered for patients with advanced gastric or GEJ cancers that are either IHC 2+ and FISH positive or IHC 3+ as it has shown survival benefit and is tolerable [Bang et al. 2010].

Toxicity

Trastuzumab addition did not increase the toxicity profile of chemotherapy and was well tolerated. However, trastuzumab administration is known to result in subclinical and clinical cardiac failure. Trastuzumab treatment should be withheld in patients with metastatic disease with reduced left ventricular function. Cardiac function should be evaluated prior to and during treatment. Trastuzumab administration can result in serious and fatal infusion reactions and pulmonary toxicity and symptoms usually occur during or within 24 hours of administration. Trastuzumab should be excluded for anaphylaxis, angioedema, interstitial pneumonitis or acute respiratory distress syndrome. Exposure to trastuzumab during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities and neonatal death. Women of child-bearing age should be advised about the potential hazard to the fetus resulting from trastuzumab exposure during pregnancy and provide contraception counseling to women of child-bearing potential. In randomized, controlled clinical trials, the per-patient incidences of NCI CTC Grade 3–4 neutropenia and of febrile neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared with those who received chemotherapy alone.

The most common adverse reactions associated with trastuzumab in metastatic gastric cancer were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis and dysgeusia.

HER2 testing

Heterogeneity of the HER2 genotype can lead to discrepancies in the results from IHC and FISH testing [Wolff et al. 2007]. Tumor heterogeneity is more prominent in gastric cancer than in breast cancer. Tumor heterogeneity was seen in roughly 4.8% of samples with moderate or strong HER2 staining, and was higher than what was experienced in breast cancer (1.4%) [Hofmann et al. 2008]. ASCO/CAP guidelines state that intratumoral heterogeneity may contribute to HER2 testing inaccuracy. Incomplete basolateral membrane HER2 IHC staining is also more common in gastric cancer than in breast cancer. This is due to the higher frequency of glandular formations that occur in gastric tissue. In gastric tissue the basolateral membrane is stained, not the luminal membrane resulting in the heterogeneity (Figure 2).

Figure 2.

Figure 2.

Open in a new tab

Heterogeneity of HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). (A) HER2 IHC showing heterogeneity of staining in an esophageal adenocarcinoma. The most intense staining in this case (3+), with surrounding region showing 2+ staining. (B) HER2-FISH results correlate with HER2-IHC results. In the areas in which there was 3+ IHC staining, there is significant amplification of HER2; ratio of HER2:CEP17 > 6.0. (C) In the areas that showed HER2 2+ IHC staining aneuploidy was noted, with low level or no amplification.

HER2 testing in the ToGA trial required both IHC and FISH and only one positive test is needed to indicate eligibility for HER2-targeted therapy (IHC 3+ or FISH+). Currently, there are no ASCO/CAP-approved HER2 testing guidelines for gastric cancer. Of the randomized patients included in the ToGA trial, 25% (146/584) of the population could have been missed using the current US Federal Drug Administration (FDA) approved breast cancer HER2 testing algorithm if only one HER2 test was used (i.e. IHC 0/FISH+, IHC 1+/FISH+, IHC 3+/FISH-).

Consensus panel recommendations on HER-2 scoring for gastric/esophageal cancer includes the following (Figure 3) [Hofmann et al. 2008; Ruschoff et al. 2010] :

3+ /POSITIVE: Moderate to strong incomplete (basolateral) membranous staining in >10% of tumor cells (resection); in biopsies only one cohesive cluster of >5 cells is required.

2+/EQUIVOCAL: Weak to moderate incomplete (basolateral) membranous staining in >10% of tumor cells (resection); in biopsies only one cohesive cluster of >5 cells is required.

1+/NEGATIVE: Faint membranous reactivity in >10% of tumor cells (resection); in biopsies only one cohesive cluster of >5 cells is required.

0 /NEGATIVE: No reactivity or membranous reactivity in <10% of cells (resection); in biopsies only one cohesive cluster of >5 cells is required.

Figure 3.

Figure 3.

Open in a new tab

Consensus panel recommendations on HER-2 scoring for gastric/esophageal cancer [Hofmann et al. 2008, Ruschoff et al. 2010]. See the text for details.

Owing to assay limitations, one should not rely on a single detection method for HER2 testing. A HER2+ patient with an IHC score of 3+ or positive FISH should be treated with trastuzumab. The National Comprehensive Cancer Network (NCCN) guidelines panel recommended that less than 3+ overexpression of HER2-neu by IHC should be additionally examined by FISH or other in situ hybridization methods. Gastric cancers with HER2 IHC overexpression of 3+ or FISH positive are considered positive and thus be treated with trastuzumab. Thus, HER2 3+ or FISH +/ HER2 IHC 1+, FISH +/HER2 IHC 2+, FISH +/HER2 IHC 3+ gastric cancer patients should be treated with trastuzumab.

Summary

In summary, gastric cancer remains difficult to cure and has a poor overall prognosis. Locoregional control by radical surgical resection remains the only curative treatment and effective only in a select group of early stage gastric cancer patients. Recurrence rates in the patients with advanced gastric cancer are high with most patients eventually dying from their disease. If patients did not receive pre-operative treatment and had T3–4 and any N disease, post-operative chemoradiation is recommended per the intergroup 0116 trial or chemotherapy per the CLASSIC trial [Bang et al. 2012]. In patients diagnosed with clinical T2 + and any N tumors, peri-operative chemotherapy is also an option as per the results of the MAGIC trial. For recurrent and metastatic disease, any of the combination chemotherapies such as ECF, DCF, FOLFIRI or trastuzumab-based regimens versus best supportive care is recommended.

Gastric cancer is shown to overexpress HER2 and is targetable with trastuzumab. The recent ToGA trial successfully demonstrated trastuzumab as the first biologic therapy to have activity in advanced gastric cancer. Trastuzumab was given with concurrent chemotherapy in 584 HER2 overexpressing gastric and GEJ cancer patients. These patients whose gastric or GEJ tumors showed HER2 overexpression by IHC or gene amplification by FISH were eligible as discussed earlier.

The median OS and PFS improved significantly with the addition of trastuzumab to chemotherapy. The overall response rate was 47.3% versus 34.5% in trastuzumab plus chemotherapy and chemotherapy, respectively. Trastuzumab showed no worsening of toxicities and was well tolerated. Trastuzumab showed improved survival in HER2 IHC 2+ and FISH positive or IHC 3+ metastatic gastric and GEJ adenocarcinoma in the ToGA trial. As tumor heterogeneity is more common in gastric cancer than breast cancer, FISH evaluation is warranted in IHC 2+ HER2 overexpressing gastric cancers (Figure 4).

Figure 4.

Figure 4.

Open in a new tab

Trastuzumab treatment algorithm in HER2 overexpressing gastric cancers. FISH, fluorescent in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry.

Future directions

Trastuzumab is indicated in combination with cisplatin and 5-FU or capecitabine for HER2 overexpressing metastatic gastric or GEJ adenocarcinoma with no prior treatments. Currently pertuzumab, a novel HER2-targeting agent is under investigation in gastric cancer. Pertuzumab activates antibody-dependent cellular cytotoxicity (ADCC) and has a major effect on the role of HER2 as a co-receptor for HER3 or EGFR, thus inhibiting multiple HER-mediated signaling pathways. The combination of trastuzumab and pertuzumab has shown a synergistic effect in cancer xenografts [Yamashita-Kashima et al. 2011]. Another phase III trial of capecitabine and oxaliplatin with and without lapatinib is currently accruing. Currently, a phase III trial of RTOG 1010 is evaluating the addition of trastuzumab with chemoradiation in the neoadjuvant fashion. Patients with stage T1, N1–2 or T2–3, N0–2 GEJ adenocarcinoma or esophageal carcinoma are eligible to participate in the study.

Adjuvant and neoadjuvant trials evaluating novel targeted therapies need to be considered in gastric cancer treatment. As many mutations that we know of are not expressed highly or not responsive to the treatments we have in hand, future direction requires both the identification of the right target and the development of new therapeutic regimens.

Footnotes

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: The authors declare no conflicts of interest in preparing this article.

Contributor Information

Krishna S. Gunturu, Division of Hematology/Oncology, Tufts Medical Center, Boston, MA, USA

Yanghee Woo, Columbia University College of Physicians and Surgeons and the Herbert Irving Cancer Center, New York, NY, USA.

Nike Beaubier, Columbia University College of Physicians and Surgeons and the Herbert Irving Cancer Center, New York, NY, USA.

Helen E. Remotti, Columbia University College of Physicians and Surgeons and the Herbert Irving Cancer Center, New York, NY, USA

M. Wasif Saif, Department of Medicine and Cancer Center, Tufts Medical Center, 800 Washington Street Box 245, Boston, MA 02111, USA.

References

  1. Bang Y., Chung H., Xu J., Lordick F., Sawaki A., Lipatov O., Al-Sakaff N., et al. (2009) 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 27(215 Suppl.): abstract 4556. [Google Scholar]
  2. Bang Y., Kim Y., Yang H., Chung H., Park Y., Lee K., et al. (2012) Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 379: 315–321 [DOI] [PubMed] [Google Scholar]
  3. Bang Y., Van Cutsem E., Feyereislova A., Chung H., Shen L., Sawaki 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 [DOI] [PubMed] [Google Scholar]
  4. Bianco A. (2004) Targeting c-erbB2 and other receptors of the c-erbB family: rationale and clinical applications. J Chemother 16(Suppl. 4): 52–54 [DOI] [PubMed] [Google Scholar]
  5. Bozzetti C., Negri F., Lagrasta C., Crafa P., Bassano C., Tamagnini I., et al. (2011) Comparison of HER2 status in primary and paired metastatic sites of gastric carcinoma. Br J Cancer 104: 1372–1376 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Browne B., O’Brien N., Duffy M., Crown J., O’Donovan N. (2009) HER-2 signaling and inhibition in breast cancer. Curr Cancer Drug Targets 9: 419–438 [DOI] [PubMed] [Google Scholar]
  7. Cunningham D., Allum W., Stenning S., Thompson J., Van de Velde C., Nicolson M., et al. (2006) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355: 11–20 [DOI] [PubMed] [Google Scholar]
  8. Cunningham D., Starling N., Rao S., Iveson T., Nicolson M., Coxon F., et al. (2008) Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358: 36–46 [DOI] [PubMed] [Google Scholar]
  9. Dassen A., Lips D., Hoekstra C., Pruijt J., Bosscha K. (2009) FDG-PET has no definite role in preoperative imaging in gastric cancer. Eur J Surg Oncol 35: 449–455 [DOI] [PubMed] [Google Scholar]
  10. Dikken J., van Sandick J., Maurits Swellengrebel H., Lind P., Putter H., Jansen E., et al. (2011) Neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy for patients with resectable gastric cancer (CRITICS). BMC Cancer 11: 329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fitzgerald R., Caldas C. (2004) Clinical implications of E-cadherin associated hereditary diffuse gastric cancer. Gut 53: 775–778 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Franklin W., Veve R., Hirsch F., Helfrich B., Bunn P., Jr. (2002) Epidermal growth factor receptor family in lung cancer and premalignancy. Semin Oncol 29(1 Suppl. 4): 3–14 [DOI] [PubMed] [Google Scholar]
  13. Galizia G., Lieto E., Orditura M., Castellano P., Mura A., Imperatore V., et al. (2007) Epidermal growth factor receptor (EGFR) expression is associated with a worse prognosis in gastric cancer patients undergoing curative surgery. World J Surg 31: 1458–1468 [DOI] [PubMed] [Google Scholar]
  14. Herbst R. (2004) Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys 59(2 Suppl.): 21–26 [DOI] [PubMed] [Google Scholar]
  15. Hofmann M., Stoss O., Shi D., Buttner R., van de Vijver M., Kim W., et al. (2008) Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 52: 797–805 [DOI] [PubMed] [Google Scholar]
  16. Klapper L., Waterman H., Sela M., Yarden Y. (2000) Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2. Cancer Res 60: 3384–3388 [PubMed] [Google Scholar]
  17. Lee S., Lee J., Soung Y., Kim H., Park W., Kim S., et al. (2003) BRAF and KRAS mutations in stomach cancer. Oncogene 22: 6942–6945 [DOI] [PubMed] [Google Scholar]
  18. Lim J., Yun M., Kim M., Hyung W., Park M., Choi J., et al. (2006) CT and PET in stomach cancer: preoperative staging and monitoring of response to therapy. Radiographics 26: 143–156 [DOI] [PubMed] [Google Scholar]
  19. Macdonald J., Smalley S., Benedetti J., Hundahl S., Estes N., Stemmermann G., et al. (2001) Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345: 725–730 [DOI] [PubMed] [Google Scholar]
  20. Mammano E., Belluco C., Sciro M., Mencarelli R., Agostini M., Michelotto M., et al. (2006) Epidermal growth factor receptor (EGFR): mutational and protein expression analysis in gastric cancer. Anticancer Res 26(5A): 3547–3550 [PubMed] [Google Scholar]
  21. Ohtsu A., Shah M., Van Cutsem E., Rha S., Sawaki A., Park S., et al. (2011) Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 29: 3968–3976 [DOI] [PubMed] [Google Scholar]
  22. Pinto C., Di Fabio F., Siena S., Cascinu S., Rojas Llimpe F., Ceccarelli C., et al. (2007) Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol 18: 510–517 [DOI] [PubMed] [Google Scholar]
  23. Rice T., Blackstone E., Rusch V. (2010) 7th edition of the AJCC Cancer Staging Manual: esophagus and esophagogastric junction. Ann Surg Oncol 17: 1721–1724 [DOI] [PubMed] [Google Scholar]
  24. Ruschoff J., Dietel M., Baretton G., Arbogast S., Walch A., Monges G., et al. (2010) HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing. Virchows Arch 457: 299–307 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Siegel R., Ward E., Brawley O., Jemal A. (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61: 212–236 [DOI] [PubMed] [Google Scholar]
  26. Song Y., Huang J., Wang J. (2010) [Relationship between HER2/neu gene amplification and protein expression and prognosis in patients with advanced gastric carcinoma]. Chin J Cancer 29: 76–81 [DOI] [PubMed] [Google Scholar]
  27. Songun I., Putter H., Kranenbarg E., Sasako M., van de Velde C. (2010) Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol 11: 439–449 [DOI] [PubMed] [Google Scholar]
  28. Van Cutsem E., Moiseyenko V., Tjulandin S., Majlis A., Constenla M., Boni C., et al. (2006) 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 24: 4991–4997 [DOI] [PubMed] [Google Scholar]
  29. Wainberg Z., Lin L., DiCarlo B., Dao K., Patel R., Park D., et al. (2011) Phase II trial of modified FOLFOX6 and erlotinib in patients with metastatic or advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction. Br J Cancer 105: 760–765 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wolff A., Hammond M., Schwartz J., Hagerty K., Allred D., Cote R., et al. (2007) 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 25: 118–145 [DOI] [PubMed] [Google Scholar]
  31. Yakes F., Chinratanalab W., Ritter C., King W., Seelig S., Arteaga C. (2002) Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 62: 4132–4141 [PubMed] [Google Scholar]
  32. Yamashita-Kashima Y., Iijima S., Yorozu K., Furugaki K., Kurasawa M., Ohta M., et al. (2011) Pertuzumab in combination with trastuzumab shows significantly enhanced antitumor activity in HER2-positive human gastric cancer xenograft models. Clin Cancer Res 17: 5060–5070 [DOI] [PubMed] [Google Scholar]
  33. Yano T., Doi T., Ohtsu A., Boku N., Hashizume K., Nakanishi M., et al. (2006) Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. Oncol Rep 15: 65–71 [PubMed] [Google Scholar]
  34. Yarden Y., Sliwkowski M. (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2: 127–137 [DOI] [PubMed] [Google Scholar]

Articles from Therapeutic Advances in Medical Oncology are provided here courtesy of SAGE Publications

RESOURCES