Trastuzumab For Gastric Cancer Research Articles

Trastuzumab in Gastric Cancer

Trastuzumab in Gastric Cancer

Where and by Whom Should Gastric Cancer HER2/neu Status Be Assessed?: Lessons From Breast Cancer

Where and by Whom Should Gastric Cancer HER2/<i>neu</i> Status Be Assessed?: Lessons From Breast Cancer

Exploratory biomarker assessment in the Trastuzumab for Gastric Cancer (ToGA) study.

e21029 Background: The global, randomized, Phase III ToGA study showed that trastuzumab (H) plus capecitabine or 5-fluorouracil and cisplatin (XP/FP) significantly improves overall survival (OS) vs...

Human epidermal growth factor receptor 2 (HER2) positivity shown by fluorescence in-situ hybridization in patients with advanced gastric cancer: A multicenter study in Taiwan.

e14576 Background: Based on the results of ToGA (Trastuzumab for Gastric Cancer) study, trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastro-esophageal junction (GEJ) cancer (Lancet 2010;376:687-97). In ToGA study, overall HER2-positivity rate was 22.1%; however, exceptionally low HER2-positivity rate was observed in some countries, including Taiwan (only 3%; ASCO-GI 2008:A11). The underlying factors contributing to low HER2-positivity rate in Taiwan remain obscured. Re-evaluation of HER2-positivity for Taiwanese GC patients in a larger sample size is highly warranted. Methods: We tested HER2-positivity by gene amplification using fluorescence in-situ hybridization (FISH) in formalin-fixed paraffin-embedded gastric or GEJ cancer samples. The testing was centralized to a single laboratory (Quest, UK). The PathVysion HER2 DNA probe Kit (Vysis, Abbott Molecular Inc., Germany) was used, which is FDA approved to detect the HER2 gene amplification. Results of hybridization on enumeration of 20 interphase nuclei from tumor cells are reported as the ratio of average HER2 copy number to that of CEP17, a specific region of the Chromosome 17’s centromere. Specimens with amplification showed a HER2 and CEP17 signal ratio of >/= 2.0. If the final ratio is calculated by the primary observer as near/at the cut-off point (1.8-2.2), an additional 20 cells is counted. The second observer will count an additional 20 cells. Results: Between Sep. 2007 and Nov. 2010, 180 patients (M:109, F:71) with gastric or GEJ adenocarcinoma from 8 medical centers in Taiwan were enrolled and evaluated by FISH testing. Among them, 47 patients (M:34, F:13) showed a HER2/CEP17 signal ratio of >/= 2.0, the overall HER2-positivity for Taiwanese GC patients was 26.1% (19.7%-32.5%, 95% CI). Conclusions: More than a quarter of Taiwanese advanced GC patients showed HER2-positivity by FISH, comparable with that of ToGA study. Novel HER2-targeted agents are justified for future active investigation in Taiwanese GC patients.

Trastuzumab: A New Treatment Option for HER2-Positive Metastatic Gastric and Gastroesophageal Junction Cancer

In patients with metastatic gastric cancer, median overall survival with standard chemotherapy remains under 1 year. As such, effective new treatments with acceptable tolerability are urgently needed. Amplification/overexpression of HER2 is reported in approximately 20% of gastric tumors, providing a rationale to investigate trastuzumab, a monoclonal antibody against HER2, in this setting. In the Phase III international Trastuzumab for Gastric Cancer (ToGA) study, the addition of trastuzumab to chemotherapy significantly improved overall survival without compromising safety in patients with HER2-positive metastatic gastric or gastroesophageal junction cancer. The purpose of this review is to discuss clinical data supporting the role of trastuzumab in metastatic gastric cancer, and consider the optimization of gastric cancer-specific HER2 testing and analysis.

The use of trastuzumab in Japanese patients with HER2-positive advanced or metastatic gastric cancer.

102 Background: The Trastuzumab for Gastric Cancer (ToGA) study showed the efficacy of trastuzumab for HER2-positive gastric cancer (HGA). The aim of this study is to evaluate the benefit of trastuzumab for Japanese HGA patients. Methods: ToGA was an open-label, international, phase III, randomized controlled trial undertaken in 122 centers in 24 countries. Median overall survival (OS) was 13.8 months in those assigned to trastuzumab plus chemotherapy (C+T) compared with 11.1 months in those assigned to chemotherapy alone (C) with hazard (HR) ratio of 0.74. Subgroup analyses of patients enrolled from Japan were undertaken to estimate the hazard ratio (HR) for OS in the Japanese population. Based upon the prescribed protocol for Japan, we calculated HR using multiple Cox regression model with prespecified covariates in the ToGA study in order to make up for the small number of Japanese patients and reduce the bias in the baseline characteristics between two groups. Results: Sixteen institutes participated and 102 patients were enrolled, of which 101 patients were evaluable for this research. The median OS was 15.9 months in C+T arm versus 17.7 months in C arm. The HR for OS was 1.00 [95% CI: 0.59-1.69]. However, the HR for OS adjusted for the above covariates was estimated to be 0.68 [95% CI: 0.36-1.27]. There were differences between C+T arm and C arm in some baseline characteristics. Higher frequencies were seen in C arm as follow: intestinal type, prior gastrectomy, and smaller number of metastatic sites. For HER2 status, the percentage of patients with IHC0/FISH+ was lower in C+T arm (5.9%) than in C arm (18.0%), while that of patients with HER2 status IHC2+/FISH+ was higher in C+T arm (35.3%) than in C arm (26.0%). Conclusions: Although ToGA's overall OS HR = 0.74 (p = 0.0046), in the Japan patient subgroup, the unadjusted hazard ratio was 1.00. However, there was an imbalance of the baseline characteristics between the treatment arms in Japanese population. When adjusted for these characteristics, the HR was 0.68 which is similar to those in the ToGA study. Adding trastuzumab to chemotherapy in Japanese population appears to confer a similar magnitude of benefit compared to the whole population enrolled in the ToGA study. [Table: see text]

Results and implications of the Trastuzumab for Gastric Cancer (ToGA) trial

Amplification of the HER2 gene and/or overexpression of its encoded protein have been observed in a proportion of patients with advanced gastric cancer (AGC). Activity of trastuzumab, a humanized monoclonal antibody against HER2, has been investigated in preclinical AGC models, anecdotal case reports and a few pilot trials. More recently, the Phase III Trastuzumab for Gastric Cancer (ToGA) trial found that trastuzumab treatment improved overall survival in AGC patients with amplification or overexpression of HER2. This article will describe the results of the ToGA trial, its impact on treatment of patients with AGC and the implications of these findings.

Research Highlights

Research Highlights

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

Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404. 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18.6 months (IQR 11-25) in the trastuzumab plus chemotherapy group and 17.1 months (9-25) in the chemotherapy alone group. Median overall survival was 13.8 months (95% CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10-13) in those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60-0.91; p=0.0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs 165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups. Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. F Hoffmann-La Roche.

Trastuzumab in gastric cancer

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.

(Q)-TWiST analysis of trastuzumab plus fluoropyrimidine/cisplatin (T-XP/FP) versus XP/FP alone as first-line therapy for advanced HER2-positive gastric cancer.

4048 Background: The international, randomized phase III Trastuzumab for Gastric Cancer (ToGA) study has shown that trastuzumab (T) in combination with capecitabine/5-FU and cisplatin (XP/FP) improves overall survival vs. XP/FP alone (median: 13.8 vs. 11.1 mo, HR=0.74, p=0.0046) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) cancer, without impacting on safety. Here we assess the OS gain in the trastuzumab arm, by applying the quality-adjusted time without disease symptoms or treatment toxicity (Q-TWiST) methodology. Methods: The area under the OS curve was partitioned into 3 health states: duration of toxicity (TOX: time spent experiencing grade 3/4 adverse events while in PFS and on study medication), TWiST (PFS minus TOX), and time from progression until end of follow-up or death (REL: OS minus PFS). To exclude treatment bias, clinical follow-up for this analysis was truncated to longest follow-up of the shortest curve (31.3 mo). In a scenario analysis, each health state was utility adjusted per the Q-TWiST methodology. Sensitivity analyses were conducted. Results: No significant difference in time spent in either TOX or REL was observed between arms. Time spent in TWiST was significantly longer for T-XP/FP vs. XP/FP (Table). Overall Q-TWiST results (utility adjusted for treatment toxicities and disease relapse) showed a mean difference of 2.42 mo (95% CI: 1.53–3.25) between treatment arms. Results were confirmed in sensitivity analyses. Conclusions: Per Q-TWiST analysis, the OS gain in HER2-positive advanced gastric or GEJ cancer patients seen with T-XP/FP vs. XP/FP translates into longer PFS without disease symptoms or treatment toxicity. These results confirm earlier findings that the improved OS comes without a negative impact on safety or QoL, which are considered main treatment objectives for advanced gastric cancer. Mean time in each health state by treatment arm, mo (95% CI) Health state XP/FP (n=290) T-XP/FP (n=294) Mean difference PFS 7.07 (6.24–7.89) 9.36 (8.27–10.45) 2.29 OS 13.01 (11.79–14.24) 15.54 (14.24–16.84) 2.52 TOX 2.52 (2.13–2.9) 2.54 (2.10–2.98) 0.02 TWiST 4.55 6.82 2.27 REL 5.95 6.18 0.23 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche Roche Roche

Trastuzumab for gastric cancer

Background: Gastric cancer is a disease with different management approaches in different regions, especially between Western and Asian countries. Surgery is the mainstay of treatment for non-metastatic disease. Perioperative chemotherapy or adjuvant radio-chemotherapy is recommended, since recurrences are common after curative resection. Unfortunately, advanced or metastatic gastric cancer constitutes the majority of patients in clinical practice. For these patients systemic chemotherapy is the standard treatment, to provide palliation and prolong survival; however, prognosis remains poor. Several molecular targeting agents are under evaluation in international randomized studies. Objective: To review chemotherapy and targeted therapies for gastric cancer, chemical and pharmacological characteristics of trastuzumab, and evidence for its clinical use in gastric cancer. Methods: Examination of relevant literature. Results/conclusions: HER-2 is overexpressed/amplified in approximately 22% of gastric cancer patients. Trastuzumab, a recombinant humanized anti-HER-2 monoclonal antibody, is, to our knowledge, the first biological therapy that has showed a survival improvement by nearly 3 months (reduced risk of death by 26%), thus trastuzumab in combination with chemotherapy is a treatment option for patients with HER2-positive advanced gastric cancer. Trastuzumab's role in curative gastric cancer treatment needs to be studied, as well as monotherapy, maintenance therapy and second line treatment in the palliative setting.

HER-2 amplification is highly homogenous in gastric cancer

Her-2 is the molecular target for antibody-based treatment of breast cancer (trastuzumab). The potential benefit of anti-Her-2 therapy is currently investigated in several other HER-2-amplified cancers including gastric cancer. Although HER-2 amplification occurs in more than 10% of gastric cancers, potential heterogeneity of HER-2 amplification and overexpression could represent a major drawback for anti-Her-2 therapy. To address the potential applicability of trastuzumab in gastric cancer, tissue microarray sections of 166 gastric adenocarcinomas and 69 lymph node metastases were analyzed for Her-2 overexpression and amplification using Food and Drug Administration-approved reagents for immunohistochemistry and fluorescence in situ hybridization. HER-2 amplification was seen in 27 (16%) of 166 gastric adenocarcinomas. Amplification was typically high level with more than 20 HER-2 copies per tumor cell and a HER-2/centromere 17 ratio >3. Amplification was associated with intestinal tumor phenotype but unrelated to survival, grading, pT, pN, or pM. Identical HER-2 status was found in primary tumor and their matched lymph node metastases. Moreover, HER-2 and Topoisomerase IIalpha coamplification analysis of 3 to 16 large sections from 8 Her-2-positive gastric cancers did not reveal any heterogeneity of the amplicon site. The high level of HER-2 amplification in combination with the homogeneity of its expression in primary and metastatic tumors argues for a possible therapeutic utility of trastuzumab in HER-2-amplified gastric adenocarcinomas.

Increasing Her2/Centromere17(CEP17) ratio predicts for greater sensitivity to trastuzumab based therapy in metastatic breast cancer (MBC)

HER2 gene amplification and protein over-expression are important factors in predicting clinical sensitivity to anti-HER2 therapies in breast, gastric or gastroesophageal junction cancer patients. The aim of this study was to evaluate the correlation between HER2 gene copy numbers and HER2 protein expressions in mucinous epithelial ovarian cancer (EOC). Of the 49 tissue microarray samples of mucinous EOC, we applied 2010 ToGA trial (Trastuzumab for Gastric Cancer) surgical specimen scoring criteria to analyze the HER2 protein expression by an immunohistochemistry (IHC) test with Dako (Carpenteria, CA), c-erb-B2 antibody, and the HER2 gene amplification by the fluorescence in situ hybridization (FISH) test with Abbott/Vysis PathVysion HER2 DNA Probe Kit (Abbott Molecular Inc., Des Plaines, IA). We achieved a high overall concordance of 97.56% between nonequivocal HER2 results by IHC and FISH tests. In addition, HER2 gene copies before chromosome-17 correction increased significantly in a stepwise order through the negative, equivocal and positive IHC result categories (P < .001), as did the HER2 gene copies after chromosome-17 correction (P < .001). On the other hand, HER2 IHC results correlated significantly with both chromosome-17–uncorrected HER2 gene copy numbers (ρ = 0.630, P < .001) and chromosome-17 corrected HER2 gene copy numbers (ρ = 0.558, P < .001). We concluded that both chromosome-17 corrected and uncorrected HER2 gene copies correlated significantly with HER2 IHC results. Tests for the HER2 gene copies per tumor cell either before or after correction of chromosome-17 can be applied as a potentially valuable tool to analyze the HER2 status in mucinous EOC.