Gastroesophageal Junction Cancer Patients Research Articles

HER2 expression and relevant clinicopathological features in gastric and gastroesophageal junction adenocarcinoma in a Chinese population

BackgroundWith varied immunohistochemistry scoring criteria and patient cohorts, HER2-positivity rates in gastric cancer (GC) and gastroesophageal junction (GEJ) adenocarcinoma have been reported with a wide range. Recently standardized scoring criteria for GC and GEJ cancer has been established and recommended. In this study, the frequency of HER2 expression and the relationship between HER2 expression and clinicopathological features were examined in a large cohort of Chinese GC and GEJ cancer patients.MethodsA total of 1463 patients, including 929 primary GCs and 534 primary GEJ adenocarcinomas, was retrospectively analyzed for HER2 overexpression by immunohistochemistry (IHC). Fluorescence in situ hybridization (FISH) analysis was used in 308 GCs and GEJ adenocarcinoma cases to assess HER2 gene amplification.ResultsHER2 overexpression (3+) was detected in 9.8% of carcinomas and more frequently observed in GEJ cancer cases, in the intestinal type, and in the well or moderately differentiated type (P=0.003, 0.000, and 0.000, respectively). HER2 equivocal (2+) was detected in 14.4% of cases. As for the 308 cases analyzed by FISH, 39 (of 40, 97.5%) IHC 3+ cases, 11 (of 38, 28.9%) IHC 2+ cases, and 3 (of 230, 1.3%) IHC 1+/0 cases showed HER2 gene amplification. A high concordance rate (98.5%) between IHC and FISH was demonstrated.ConclusionsApproximately 10% of Chinese patients with primary GC and GEJ adenocarcinoma were HER2-positive on IHC. HER2 overexpression was associated with GEJ site, intestinal cancer subtype, and well or moderately differentiated carcinomas.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1935951199941072.

Assessment of HER2 status from an epidemiology study in tumor tissue samples of gastric and gastro-esophageal junction cancer: Results from the french cohort of the HER-EAGLE study.

26 Background: HER2 is an important prognostic and also a predictive biomarker for trastuzumab response in gastric cancer. Therefore, HER2 status should be tested in all gastro-esophageal junction (GEJ) and gastric cancer (GC) patients. ToGA phase III study showed a benefit in overall survival of trastuzumab added to standard chemotherapy in patients with HER2-positive advanced GEJ/GC. The objective of the HER-EAGLE study was to assess the incidence of HER2 positivity in GEJ/GC cancer. Methods: HER-EAGLE was an international epidemiological, non-interventional study assessing HER2 status by IHC/ISH in tumor samples from any stage in patients with GEJ/GC. Samples were obtained by excision or core biopsy and routinely analyzed via validated Ventana or Dako methods and scoring criteria used in ToGA: HER2-positive if IHC 3+ or IHC 2+ (FISH/SISH confirmed; HER2/CEP17 ratio ≥ 2.0); HER2-negative if IHC 0 or IHC 1+ or IHC 2+ if FISH/SISH negative ratio < 2.0. Overall and subgroup estimates calculated with 95% CI. Data from the French cohort are presented. Results: The HER-EAGLE French cohort included 267 patients (68.6% males) from 7 centers (May 2007 to March 2012), with 150 biopsies (56.2%) and 117 excisions (43.8%). Tumor locations were 65.9% stomach and 34.1% GEJ, and adenocarcinoma types were according to Lauren classification: 170 intestinal (63.7%), 72 diffused (27%), 22 mixed (8.2%) and 3 not available (1.1%). HER2 status was: 36 cases IHC 3+ (13.5%), 51 IHC 2+ (19.1%) whereof 18 ISH positive (35.3%), 35 IHC 1+ (13.1%) and 145 IHC 0 (54.3%). Overall HER2 positivity (IHC 3+ or IHC 2+/ISH+) was 20.2%. Heterogeneity for HER2 staining was observed in 81 samples (30.3%). No statistical difference was found according to cancer stage. HER2 positivity was higher in GEJ (31.9%) than in GC (14.2%), p<0,001, and higher in intestinal (28.2%) compared to diffused adenocarcinomas (5.6%), p<0,001. Conclusions: HER-EAGLE French cohort results confirmed the feasibility of HER2 testing in GEJ/GC in routine practice. The incidence of HER2 overexpression was similar to the literature review, and it was higher in GEJ and intestinal adenocarcinomas type.

Analysis of biomarker expression (ki67, EGFR, HER2, ERK, NFkB, and mTOR) in patients with advanced gastric and gastroesophageal junction (GEJ) cancer treated with cetuximab plus cisplatin/docetaxel: DOCETUX study.

4133 Background: The aim of this study was to evaluate the correlation between pathologic biomarkers and objective response (OR), time-to-progression (TTP) and overall survival (OS) in advanced gastric or GEJ cancer patients (pts) treated with cetuximab plus chemotherapy. Methods: We analysed 31/72 pts with gastric or GEJ locally advanced/metastatic adenocarcinoma enrolled in the DOCETUX Study (Pinto et al., Br. J. Cancer, 2009). The pts were treated as first-line with cetuximab weekly plus cispatin/docetaxel every 3 weeks, for a maximum of 6 cycles, then cetuximab alone in pts with CR/PR/SD. In these pts KRAS/BRAF mutations were infrequent and not associated with efficacy (Stella et al., ASCO 2009, Abs 15503). Analyses of ki67, EGFR, HER2, ERK, NFkB and mTOR were performed using immunohistochemistry on primary tumor by just one pathologist. Results: Pt characteristics: 27M/4F; median age 62 years (24-74); stomach 28 (90.3%), GEJ 3 (9.7%); intestinal histotype 24 (77.4%), nonintestinal 7 (22.6%); locally advanced disease 1(3.2%), metastatic disease 30(96.8.%). OR were: 15 (48.4%) CR+PR, 10 (32.3%) SD, 4 (12.9%) PD, 2 (6.5%) NE. Median TTP was 5 months (1-23), and median OS 11 months (1-26). The expression of pathological biomarkers was: ki67 > 40% in 83.9% of pts, EGFR score high in 26.1%, HER2 2+-3+ in 28.6%, ERK > 30% in 48.4%, NFkB > 5% in 43.5% and mTOR > 2% in 58.1%. In the multivariate analysis, the better OR was observed in pts with negative/low EGFR (p = 0.017) and high ERK (p = 0.035), and a longer TTP in pts with positive mTOR (p = 0.036). Any other statistically significant correlation was observed. Conclusions: This results suggest that negative/low EGFR score, high ERK and positive mTOR expressions are correlated to treatment efficacy. No significant financial relationships to disclose.

(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

Postoperative Radiation Combined with Triple Regimen Chemotherapy in Locally Advanced Adenocarcinoma of the Stomach and Gastroesophageal Junction

Materials/Methods: During April 2002 to July 2008, 97 consecutive and nonselected patients with stage T3-4, or N+ gastric and gastroesophageal junction cancer patients were treated postoperatively. Of them 51 (53%) underwent D2 dissection. Seventy-seven percent (77/97) patients received adjuvant concurrent chemoradiotherapy (5-fluorouracil or Capecitabine) and 23% patients were with radiation only. The radiation dose ranged from 43.2-50.4 Gy (median 45Gy). All patients received triple regimen adjuvant chemotherapy of ECF and variant. Patients were divided into two groups according to the cycles of chemotherapy received. Sixty-one percent (59/97) patients received $4cycles were recorded as group 1 and the rest 38 were in the group 2.

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.

Quality of Life With Docetaxel Plus Cisplatin and Fluorouracil Compared With Cisplatin and Fluorouracil From a Phase III Trial for Advanced Gastric or Gastroesophageal Adenocarcinoma: The V-325 Study Group

Therapy of patients with advanced gastric or gastroesophageal junction cancer should provide symptom relief and improve quality of life (QOL) because most patients are symptomatic at baseline. Using validated instruments, we prospectively assessed QOL (even after completion of protocol treatment) as one of the secondary end points of the V325 phase III trial. Four hundred forty-five patients randomly received either docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) each on day 1 plus fluorouracil 750 mg/m(2)/d continuous infusion on days 1 to 5 every 3 weeks (DCF) or cisplatin 100 mg/m(2) on day 1 plus fluorouracil 1,000 mg/m(2)/d continuous infusion on days 1 to 5 every 4 weeks (CF). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and, where available, the EuroQOL EQ-5D questionnaire were administered every 8 weeks from baseline until progression and then every 3 months. Time to definitive deterioration of QOL parameters was analyzed. The proportions of patients having assessable EORTC QLQ-C30 and EQ-5D questionnaires at baseline were 86.0% and 78.7% with DCF, respectively, and 89.7% and 92.8% with CF, respectively. Time to 5% deterioration of global health status (primary end point) significantly favored DCF over CF (log-rank test, P = .01). QOL was preserved longer for patients on DCF than those on CF for all time to deterioration analyses, demonstrating the statistical superiority of DCF compared with CF. V325 represents the largest trial with the longest prospectively controlled evaluations of QOL during protocol chemotherapy and follow-up in patients with advanced gastric or gastroesophageal junction cancer. In V325, advanced gastric or gastroesophageal junction cancer patients receiving DCF not only had statistically improved overall survival and time to tumor-progression, but they also had better preservation of QOL compared with patients receiving CF.

Prognostic significance of ki67, p53, TS and EGFR in advanced gastric and gastroesophageal junction cancer patients treated with cetuximab plus FOLFIRI (FOLCETUX study)

4604 Background: The aim of this study was to evaluate the correlation between pathologic biomarkers and objective response (OR), time to progression (TTP) and overall survival (OS) in advanced gastric or gastroesophageal junction (GEJ) cancer patients (pts) treated with cetuximab plus FOLFIRI. Methods: We analysed 32/38 pts with stomach or GEJ locally advanced/metastatic adenocarcinoma, EGFR+, enrolled in the Italian FOLCETUX study. The pts were treated as first line with cetuximab weekly at 400 mg/m2 iv loading dose, and then at 250 mg/m2 iv maintenance dose, plus FOLFIRI every 2 weeks, for a maximum of 24 weeks, then cetuximab alone was allowed in pts with CR/PR/SD. Expression of Ki67, p53, TS and EGFR was examined immunohistochemically in primary tumor and/or metastasis samples. Ki67, p53 and TS were categorized into a low and high value; EGFR was categorized into low, intermediate and high values. High cut-off was defined as: &gt;50% Ki67; &gt;20% p53; =9% cytoplasmatic and &gt;30% nuclear TS; EGFR score (combining % neoplastic cell positive and intensity) was: low=0–2, intermediate=3–5, high=6–7. To avoid any discrepant evaluation the assessment was carried out centrally by just one pathologist. Results: The pt characteristics were: 22M/10F; median age 64.5 years (39–83); stomach 29(90.6%), GEJ 3(9.4%); intestinal histotype 21(65.6%), non-intestinal 11(34.4%); locally advanced disease 4(12.5%), metastatic disease 28(87.5%). The OR were: 15 CR+PR, 15 SD, 2 PD. No relationship was observed between Ki67, p53, TS and EGFR expression and OR (Chi-squared test/Fisher’s Exact Test). In the multivariate analysis adjusted for the impact of intestinal/non-intestinal histotype and locally advanced/metastatic disease, the low TS expression was associated with an improved TTP ( Table 1 ). Conclusions: This results suggest that TS, EGFR, p53 and Ki67 expressions are not significantly correlated with OR. Low TS expression is predictive of better TTP. [Table: see text] No significant financial relationships to disclose.

18FDG-PET in targeted therapy with cetuximab in gastric or gastroesophageal junction (GEJ) adenocarcinoma: First results of the Italian FOLCETUX Study

4061 Background: The aim of the study was to evaluate 18FDG-PET impact in gastric or GEJ cancer patients (pts) treated with cetuximab plus chemotherapy. Methods: Pts with stomach or GEJ unresectable/metastatic adenocarcinoma, not yet treated, EGFR+, were enrolled in the FOLCETUX study. Pts received cetuximab weekly at 400 mg/m2 iv loading dose, and then at 250 mg/m2 iv maintenance dose, weekly at 400 mg/m2 iv loading dose, and then at 250 mg/m2 iv maintenance dose, CPT11 180 mg/m2 iv d1, LFA 100 mg/m2 iv followed by 5FU 400 mg/m2 iv bolus and 600 mg/m2 iv continuous infusion 22h d1–2 (FOLFIRI) every 2 weeks, for a maximum of 24 weeks, then cetuximab alone was allowed in pts with CR/PR/SD. Anti-tumor activity was assessed by CT and PET scan at baseline and then every 6 weeks. A decrease in tumor FDG-uptake (metabolic response) was evaluated according to EORTC recommendations; objective response (OR) was evaluated with CT scan according to the RECIST criteria. Results: From November 2004 to December 2005, 22 pts (16M, 6F) performed at least 2 consecutive PET scans (at baseline and after 6 weeks), with a total of 91 PET scans (median per pts 4; range 2–8). PET was positive in 20 pts (90.9%); no FDG uptake was seen in 2 pts (9.1%) with signet ring cell carcinoma. A metabolic response correctly predicted: CR/PR in 10/12 pts (83%) after 6 weeks of therapy and in 11/12 (91.7%) after 12 weeks; SD in 4/8 pts (50%) after both 6 and 12 weeks. On the whole, response to therapy was predicted by PET after 6 weeks in 14/20 pts (70%). No correlation was demonstrated between median Standardized Uptake Value (SUV) at baseline PET and OR: 10.9 (3–29) in CR/PR pts and 9.6 (6.4–29.8) in SD pts. In the PET scan after 6, 12 and 18 weeks, the median SUV value respectively decreased to 4.4, 2.6 and &lt;2.0 in CR/PR pts and to 7.5, 7.4 and 3.6 in SD pts. The percentage of SUV reduction after 6 weeks was 54.2 in CR/PR pts vs 30.3 in SD pts (p = 0.36); no difference was observed between intestina (55%) and non-intestinal (45%) subtypes. No significant correlation was observed between the Ki-67 and SUV value. Conclusions: These preliminary results suggest that PET can make an early prediction of the response to cetuximab plus FOLFIRI therapy. No significant financial relationships to disclose.