Intestinal Histological Type Research Articles

Does clear cell carcinoma of stomach exist? Clinicopathological and prognostic significance of clear cell changes in gastric adenocarcinomas.

In contrast to clear cell carcinomas developing in other organs (e.g. ovary and uterus), gastric adenocarcinomas with clear cell features are not well characterized. We evaluated a series of 762 gastric adenocarcinomas for the presence of clear cell changes; and investigated the nature of the changes using several histochemical and immunohistochemical markers, their association with various clinicopathological features, and their prognostic significance. Clear cell changes were observed in 8.5% (n = 65) of gastric cancers. Cases with clear cell changes (GCC) were associated significantly with older age, intestinal type histology, body/fundic location, greater depth of invasion, lymph node metastases and lymphovascular invasion. An increasing proportion of clear cell changes indicated a worsening prognosis, and was identified as an independent marker of poor prognosis using the Cox proportional hazard model (hazard ratio, 0.462; P = 0.003). Of 62 GCCs subjected to special staining, 35 cases (55.6%) displayed cytoplasmic accumulation of glycogen, while 21 (33.3%) contained mucin. GCCs showing glycogen accumulation expressed AFP, glypican-3 and CD10 more commonly than those with mucin, which commonly expressed Muc5AC and Muc6. Clear cell gastric adenocarcinoma is a unique subgroup of gastric cancer which, although heterogeneous, has a poor prognosis.

Decreased expression of ten-eleven translocation 1 protein is associated with some clinicopathological features in gastric cancer

A decrease in ten-eleven translocation 1 (TET1) transcript and 5-Hydroxymethylcytosine (5hmC) levels has recently been demonstrated in primary gastric cancer (GC). However, little is known about TET1 protein levels in gastric tumoral and nontumoral tissue. Therefore, using reverse transcription, real-time quantitative polymerase chain reaction and western blotting analysis, we determined the TET1 transcript and protein levels in tumoral and nontumoral tissue from 38 patients with GC. We also assessed the association between the decrease in TET1 transcript and protein levels and some clinicopathological features in primary GC. We found significantly decreased levels of TET1 transcript (P=0.0023) and protein (P=0.00024) in primary tumoral tissues as compared to nontumoral tissues in patients with GC. Moreover, we also observed significantly lower amounts of TET1 transcript (P=0.03) and protein (P=0.00018) in tumoral tissues in patients aged>60. We also found significant lowered TET1 protein levels in male patients (P=0.0014), stomach (P=0.044) and cardia (P=0.013) tumor localization, T3 depth of invasion (P=0.019), N1 (P=0.012) and N3 lymph node metastasis (P=0.013) and G3 histological grade (P=0.0012). There were also significant decreases in TET1 transcript levels in female patients (P=0.042), intestinal histological types (P=0.0079) and T4 depth of invasion (P=0.037). Our results demonstrated that a decrease in TET1 transcript and protein levels is associated with some clinicopathological features in GC.

Combined HER2 analysis of biopsies and surgical specimens to optimize detection of trastuzumab-eligible patients in eso-gastric adenocarcinoma: a GERCOR study

BackgroundHER2 is overexpressed in 10 to 20% of gastro-esophageal adenocarcinoma (GE-ADK), and is a target for trastuzumab in metastatic patients. We conducted a study to compare HER2 expression between diagnostic biopsies (DBs) and surgical specimens (SSs) of GE-ADK, and to determine the influence of non-trastuzumab containing neoadjuvant chemotherapy (NAC) on this expression. Patients and methodsPathological specimens from biopsies of 228 patients operated on between 2004 and 2011 were collected. Two cohorts treated (n = 141) or not (n = 87) with a NAC were constituted. Two blind independent pathological HER2 analyses on DB and on SS were carried out using immunohistochemistry (IHC) and colorimetric in situ hybridization (CISH). HER-2 overexpression (HER2+) was defined by a score 3+ in IHC, or 2+ with a positive CISH test, according to the specific HER2 scoring guidelines for GE-ADK. ResultsPaired HER2 status could be determined for 218 out of the 228 patients (95.6%). HER2+ rates were 13.3% on DB (29/218) and 14.7% on SS (32/218). HER2+ tumors were mainly cardial or esophageal adenocarcinomas, with a well-differentiated, intestinal histological type. HER2 status differed between DB and SS in 6% of cases. When DB analyses were added to SS analyses, the relative increase in HER2+ cases was 13.5% (17.1% for patients with NAC and 23.5% for patients with histological response to NAC, versus 7.1% for patients without NAC, P = 0.4, NS). Differences between DB and SS HER2 expression could be explained by intratumoral heterogeneity and by a HER2 expression decrease in SS after NAC in responding patients possibly due to a higher chemosensitivity of HER2-positive clones. ConclusionThe determination of HER2 status on DB provides results that complete those obtained with SS. Combining the analysis of DB and of SS enables to optimize the selection of trastuzumab-eligible patients in case of metastatic relapse, and particularly in previously NAC-responding patients.

Is Colonoscopic Screening Necessary for Patients with Gastric Adenoma or Cancer?

Since colorectal adenoma or cancer is commonly associated with gastric adenoma or cancer, early colorectal adenoma detection can affect the survival of gastric adenoma or cancer patients. The purpose here was to investigate the colorectal adenoma or cancer prevalence and evaluate the necessity for screening colonoscopy in gastric adenoma or cancer patients. From September 2005 through August 2010, 857 patients younger than 70 years who had gastric adenoma or cancer were enrolled. Healthy age- and sex-matched controls were selected from the general screening population. The prevalence and risk of colorectal adenoma or cancer were compared between the participants and the controls. Data from 416 patients in the gastric neoplasm group (123 with gastric adenoma and 293 with gastric cancer) and 416 healthy control group participants were included in the statistical analysis. The presence of gastric adenoma or cancer was an independent risk factor for colorectal neoplasm (OR = 1.348, 95 % CI = 1.001-1.815). Patients with diffuse type gastric cancer had a lower prevalence of colorectal adenoma or cancer than those with gastric adenoma or intestinal type cancer. In gastric cancer patients younger than 50 years, intestinal type histology was significantly associated with colorectal adenoma or cancer (OR = 3.838, 95 % CI = 1.077-13.677). The colorectal adenoma or cancer risk was significantly increased in patients with gastric adenoma or cancer. Therefore, screening colonoscopy should be considered for gastric adenoma or cancer patients including young patients, in the case of intestinal type gastric cancer.

Lymph node ratio is a critical prognostic predictor in gastric cancer treated with S-1 chemotherapy

S-1 is an oral anticancer drug widely used in postoperative adjuvant therapy for patients in Japan with stage II/III gastric cancer. Candidates for more intense adjuvant treatments need to be identified, particularly among patients with stage III cancer. Univariate and multivariate analyses were conducted for patients with stage II/III gastric cancer who underwent surgery and received S-1 postoperatively between 2000 and 2010. Factors indicating poor prognosis identified by univariate analysis include male sex (P = 0.022), age ≥67 years (P = 0.021), intestinal-type histology (P = 0.049), lymph node ratio ≥16.7 % (P < 0.0001), open surgery (P = 0.039), as well as the 13th JGCA stage (P < 0.0001) and the 14th JGCA/7th International Union Against Cancer (UICC) stage (P < 0.0001). Multivariate analysis revealed that lymph node ratio ≥16.7 % and intestinal-type histology were significant as predictors of prognosis, independent from the pathological stages. Based on these and other findings, stage IIIC cancer on the 14th JGCA/7th UICC stage system in combination with the lymph node ratio could identify patients with extremely high risk for recurrence Our current findings suggest that lymph node ratio ≥16.7 % in combination with the new staging system could be a useful prognostic indicator in advanced gastric cancer. Because these high-risk patients cannot be identified preoperatively by any diagnostic tool, further improvement in postoperative adjuvant therapy is warranted.

Evaluation of serum HER2 extracellular domain in in metastatic gastric or gastroesophageal junction cancer: Correlation with HER2 status by immunohistochemistry and fluorescence in situ hybridization and clinicopathologic parameters.

4107 Background: To explore the association between serum human epidermal growth factor receptor-2 (HER2) extracellular domain (ECD) and tissue HER2 status, their relationship with clinicopathological parameters and impact on overall survival (OS) in metastatic gastric or gastro-oesophageal junction (GEJ) adenocarcinoma. Methods: A total of 219 histologically confirmed inoperable locally advanced, recurrent, or metastatic gastric or GEJ adenocarcinoma were included. Serum HER2 ECD was measured by chemiluminescent assay. Tissue HER2 status was accessed by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) assay. Results: The median serum ECD level was 9.3 ng/ml (range 3.0 to &gt;350). Tissue HER2 status was positive (IHC3+ or 2+ with FISH amplification) in 37 patients (16.9%) and negative in 182 patients (83.1%). Statistically significant associations were found between serum HER2 ECD level and HER2 status assessed by IHC and FISH. The ROC-analysis suggested the cutoff of 16.35 ng/ml (24 of 219 patients had HER2 ECD &gt;16.35 ng/ml ) could produce a sensitivity of 51.4% and a specificity of 97.3% to predict tissue HER2 status. If the cutoff value was increaseed to 22 ng/ml, then all 12 patients with serum HER2 ECD &gt;22 ng/ml were HER 2 positive in primary tumor, corresponding to a specificity of 100% and a sensitivity of 32.4%. High serum HER2 ECD levels were strongly associated with liver metastasis (P &lt; 0.001), the intestinal histologic type (Lauren's classification) (P =0.003), large number of metastais (&gt;2) (P=0.012) and increased LDH level (P &lt; 0.001) . High serum HER2 ECD levels were more common in GEJ adenocarcinoma although the difference had no stastical significance. HER2 ECD levels did not show a significant impact on OS. Conclusions: A significant association was observed between serum HER2 ECD levels and tissue HER2 status in metastasis gastric or GEJ adenocarcinoma. The high specificity of serum HER2 ECD assay to predict tissue HER2 status suggests its potential use as a surrogate marker of the HER2 status in gastric cancer.

Comparison of HER2 expression in paired biopsies and surgical specimen of gastric and esophageal adenocarcinoma: Impact of neoadjuvant chemotherapy.

4069 Background: HER2 is overexpressed in 10 to 20% of gastro-esophageal adenocarcinoma (GE-ADK), and is a target for trastuzumab in metastatic patients. We conducted a study to compare HER2 expression between diagnostic biopsies (DB) and surgical specimens (SS) of GE-ADK, and to determine the influence of non-trastuzumab containing neoadjuvant chemotherapy (NAC) on this expression. Methods: Pathological specimens from biopsies of 228 patients operated on with a curative aim in two French hospitals between 2004 and 2011 were collected. Two cohorts treated (n=141) or not (n=87) with a NAC were constituted. Two blind independent pathological HER2 analyses on DB and on SS were performed using IHC and CISH. HER-2 overexpression (HER2 +) was defined by a score 3+ in IHC, or 2+ with a positive CISH test, and according to the specific HER2 scoring guidelines for GE-ADK. Results: Paired HER2 status could be determined for 218 out of the 228 patients (95.6%). HER2 + rates were 13.3% on DB (29/218) and 14.7% on SS (32/218). HER2 + tumors were mainly cardial or esophageal adenocarcinomas, with a well-differentiated, intestinal histological type. HER2 status differed between DB and SS in 13 patients (6%). When DB analyses were added to SS analyses, 5 additional patients were HER2 +, the relative increase in HER2 + cases being 13.5% (17.1% for patients with NAC versus 7.1% for patients without NAC, p=0.4, NS). Differences between DB and SS HER2 expression could be explained by the intratumoral heterogeneity and also by a possible HER2 expression decrease in SS after NAC. Conclusions: The determination of HER2 status on DB provides results that complete those obtained with SS. Combining the analysis of DB and of SS enables to optimize the selection of trastuzumab-eligible patients in case of metastatic relapse, especially in patients previously treated with NAC. [Table: see text]

Defective mismatch repair proteins and microsatellite instability in young Mexican patients with colorectal cancer.

e14708 Background: Colorectal carcinoma (CRC) is prevalent malignancy and a third of the cases affect young patients. 15% of CRC have microsatellite instability (MSI) due to disruptions in mismatch repair (MMR) genes, like germline mutations (3%) and hypermethylation of the MLH1 gene promoter associated to the BRAF V600E mutation (12%). The aim of this work was to assess MMR abnormalities in tumors of Mexican CRC patients under 50 years old. Methods: CRC paraffin-embedded tissues of 47 patients with available demographic/clinical data were studied by immunohistochemistry (IHC) for MLH1/MSH2, qPCR with specific probes/sequencing for the BRAF V600E mutation, and conventional PCR (5 markers) for MSI analysis. Results: Female:Male ratio was 0.81:1. Most of the cases were classified as TNM Stage II, were located in the cecum, invaded the serous coat, and showed intestinal-type histology. 20 samples showed alterations in MMR protein expression. MLH1, MSH2, and combined deficiency of both proteins were detected in 17, 4, and 4 tumors, respectively. No BRAF mutations were detected. MSI analysis restricted to the 20 altered IHC samples showed MSI in 10 tumors (3 MSI-low and 7 MSI-high tumors). The four cases with MLH1/MSH2 deficiency, showed MSI-high pattern. Conclusions: We found 42.6% cases with defective MMR expression. No epigenetic abnormalities associated to BRAF V600E mutation were registered. The lack of MSI in ten tumors with deficient MMR may be due to alternate DNA repair mechanisms. Acknowledgments. Work supported by the CHIBCHA Project (European Commission7FP grant #223678).

Serum HER 2 Extracellular Domain Level Is Correlated with Tissue HER 2 Status in Metastatic Gastric or Gastro-Oesophageal Junction Adenocarcinoma

BackgroundTo explore the association between serum human epidermal growth factor receptor 2 (HER 2) extracellular domain (ECD) levels and tissue HER 2 status in metastatic gastric cancer.Patients and MethodsHER 2 status was retrospectively analyzed in 219 advanced gastric or gastroesophageal junction (GEJ) patients. Serum HER 2 ECD was measured by chemiluminescent assay and tissue HER 2 was assessed by fluorescent in situ hybridisation (FISH) and immunohistochemistry (IHC) assay.ResultsSignificant associations were found between serum HER 2 ECD levels and tissue HER 2 status. Twenty-four patients had HER 2 ECD levels >16.35 ng/mL, which has a sensitivity of 51.4% and a specificity of 97.3% to predict tissue HER 2 status. When the cut-off value was increased to 22 ng/mL, then all 12 patients with serum HER 2 ECD levels>22 ng/mL were tissue HER 2 positive, corresponding to a specificity of 100% and a sensitivity of 32.4%. High serum HER 2 ECD levels were strongly associated with the intestinal histological type (Lauren’s classification), liver metastasis, multiple metastasis (>2) and increased LDH levels, but not with overall survival.ConclusionsThe high specificity of the serum HER 2 ECD assay in predicting tissue HER 2 status suggests its potential as a surrogate marker of the HER 2 status in gastric cancer.

Sa1687 SPARC Modulates Autophagy via Caspase 8 in the Presence of 5-Fluorouracil in Colorectal Cancer

present in 53 cases (24%) and was significantly correlated with deeper invasion (p=0.02). IGF1R was positive in 62 cases (29%) and was significantly correlated with intestinal histological type (p=0.03) and MSI (p=0.01). Although pAkt expression was only correlated with HER2 overexpression (p=0.005), pAkt expression was more frequent in cases with PIK3CA exon 20 mutations (100%) than in those with other PIK3CA mutations (50%). In multivariable analysis of prognostic factors, male, Stage 3 or 4, PTEN inactivation and pAkt expression were significantly correlated with poor prognosis. Among themolecular alterations analyzed in this study, 90 cases (43%) showed a single alteration and 32 cases (15%) showed two or more alterations. With increase in the number of alterations, frequency of pAkt expression tended to increase and prognosis tended to be worse. p95HER2 expression was positive in 13 (34%) of 38 HER2-positive cases. The 3-year survival rate of patients with p95HER2 positive was shorter than that of other patients (48% vs 68%). Conclusions: The number of alterations in each patient was significantly correlated with poor prognosis and PI3K-Akt pathway activation. Our findings indicate that there are some interactions among alterations in the PI3K-Akt pathway and that they could affect prognosis. We characterized p95HER2 expression in GC for the first time. This result supports the use of p95HER2 expression as a biomarker in a future clinical trial of Tmab for GC.

Prognostic value of epidermal growth factor receptors in gastric cancer: a survival analysis by Weibull model incorporating long-term survivors.

BackgroundThere is no consensus about the prognostic role of HER2 expression and that of other members of the EGFR family in gastric cancer patients. The aim of this study was to evaluate the prognostic value of the EGFR family in gastric cancer.MethodsThis retrospective study included 201 patients with gastric and esophagogastric junction adenocarcinoma stages 0–IV (AJCC 6th edition) who underwent primary tumor resection. Tissues from primary tumors were analyzed by tissue microarray technology and immunohistochemistry. Correlations between receptor expression and clinicopathological characteristics were performed according to the chi-square test. Survival analysis was calculated according to the Weibull model with a mixture model incorporating long-term survivors. Multivariate analysis of prognostic factors was performed by a regression model incorporating long-term survivors with the Weibull distribution.ResultsMembrane expression of HER1, HER2, and HER4 were 9, 17, and 15 %, respectively. No membrane expression of HER3 was observed. Cytoplasmic expression of HER1, HER3, and HER4 were 45, 62, and 24 %, respectively. HER2 and HER3 expression were correlated (p < 0.001) and associated with intestinal-type histology (p = 0.001 and p < 0.001, respectively) and advanced age (p = 0.011 and p = 0.008, respectively). According to a regression model adjusted for age, surgical radicality, surgical modality, Laurén histology, adjuvant therapy, TNM stage, and receptor expressions, only TNM stage showed prognostic influence.ConclusionsAccording to analysis by a parametric model, the EGFR family did not have prognostic influence in the gastric cancer population studied. The data presented showed a correlation between HER2 and HER3 expression, which might suggest a potential role for HER2–HER3 heterodimerization inhibitors.

Comparison of HER-2 expression in diagnostic biopsies and surgical specimens of gastric and esophageal adenocarcinoma: Influence of neoadjuvant chemotherapy.

18 Background: HER-2 is overexpressed in 15 to 20% of gastric and esophageal adenocarcinoma (ADK), and is a target for trastuzumab in metastatic patients (Bang YJ et al, Lancet 2010). The main objective of this study was to compare HER-2 expression between diagnostic biopsies and surgical specimens of gastric ADK, and to determine the influence of non-trastuzumab containing neoadjuvant chemotherapy (NAC) on this expression. Methods: Pathological specimens and biopsies of patients operated on with a curative aim in two French hospitals (Institut Mutualiste Montsouris and Saint-Antoine hospital) between 2004 and 2011 were collected; two cohorts treated or not with a NAC were constituted. Blind HER-2 analyses on biopsies and on surgical specimens were performed using IHC and ISH methods, with two independent pathological readings. HER-2 overexpression was defined by a score 3+ in IHC, or by a score 2+ in IHC with a positive ISH test. Results: Paired samples of 201 patients wereanalyzed. HER-2 overexpression rates were 16.4% on biopsies and 19.4% on surgical specimens. HER-2 positive tumors were mainly cardial or esophageal tumors, with a well-differentiated, intestinal histological type. Surgical specimens seemed to allow better identification of HER-2 positive tumors than diagnostic biopsies for patients that had not received NAC (13.5% of HER-2 positivity on biopsies versus 24.3% on surgical specimens), whereas this trend was reversed for patients with NAC (18.1% of HER-2 positivity on biopsies versus 16.5% on surgical specimens). HER-2 status differed between biopsies and surgical specimens in 10% of patients. Conclusions: The determination of HER-2 status on biopsies provides results that completed those obtained with the analysis of surgical specimens. Analyzed only on surgical specimens, HER-2 status is underestimated in particular after NAC. This study suggests the interest of repeating HER-2 evaluations to optimize the identification of patients that can benefit from trastuzumab treatment.

Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach

Microsatellite instability (MSI) has been observed in 8-39 % of sporadic gastric cancers. However, despite numerous reports indicating a significant relationship between intestinal-type histology and MSI, detailed correlation between histological subtypes and MSI remains obscure. The purpose of the present study is to clarify the relationship between histological subtype and microsatellite status in gastric carcinomas. Microsatellite status was examined for 464 consecutive gastric carcinomas from 420 patients as well as histological subtypes and other clinicopathological findings. MSI was observed in 82 carcinomas (17.7 %), and the greatest proportions were observed in solid-type, poorly differentiated adenocarcinoma (43.0 %) and papillary adenocarcinoma (32.5 %), both being significantly higher than those of other subtypes. The proportion increased with advancing age (0 % at 51-64 years, 8.5 % at 65-74 years, 18.4 % at 75-84 years, 35.3 % at 85-96 years). Compared with microsatellite-stable carcinomas, microsatellite-unstable carcinomas were significantly related with older age, female gender, antral location, and predominant papillary adenocarcinoma and solid-type, poorly differentiated adenocarcinoma. Poorly differentiated type carcinoma was significantly less frequent than differentiated type in microsatellite-unstable cancer at the early stage, whereas no significant difference existed at the advanced stage. These results suggest that there are specific histological subtypes with highly frequent MSI and that gastric carcinoma with MSI originates from differentiated-type carcinomas, indicating histological diversity during tumor growth.

The prognostic impact of epidermal growth factor receptor in patients with metastatic gastric cancer

BackgroundThe epidermal growth factor receptor (EGFR) is a potential target of anticancer therapy in gastric cancer. However, its prognostic role in metastatic gastric or gastroesophageal junction (GE) cancer has not been established yet.MethodsEGFR status was analyzed by immunohistochemistry (IHC) in paraffin-embedded samples from 357 patients who received chemotherapy in 4 first-line trials. Automated RNA extraction from paraffin and RT-quantitative PCR were additionally used to evaluate EGFR mRNA expression in 130 patients.ResultsEGFR protein expression (any grade) and overexpression (3+) were observed in 43% and 11% of patients, respectively. EGFR positivity correlated with intestinal type histology (p = 0.05), but not with other clinicopathologic characteristics. Median follow-up was 18.2 months. Median overall survival (OS) was similar in patients with EGFR positive vs. those with EGFR negative tumors, regardless whether positivity was defined as ≥1+ (10.6 vs. 10.9 months, p = 0.463) or as 3+ (8.6 vs. 10.8 months, p = 0.377). The multivariate analysis indicated that EGFR status is not an independent prognostic factor (hazard ratio 0.85, 0.56 to 1.12, p = 0.247). There were also no significant differences in overall survival when patients were categorized according to median (p = 0.116) or quartile (p = 0.767) distribution of EGFR mRNA gene expression. Similar distributions of progression-free survival according to EGFR status were observed.ConclusionsUnlike different cancer types where EGFR-positive disease is associated with an adverse prognostic value, EGFR positivity is not prognostic of patient outcome in metastatic gastric or GE cancer.

Genetic variation in C20orf54, PLCE1 and MUC1 and the risk of upper gastrointestinal cancers in Caucasian populations

Recently, two large genome-wide association studies, conducted in Chinese populations, have reported associations between upper gastrointestinal cancer and the rs2274223, rs13042395 and rs4072037 polymorphisms in PLCE1, C20orf54 and MUC1, respectively. We aimed to determine whether similar associations existed for Caucasian populations. We genotyped two population-based, case-control studies of upper gastrointestinal cancer; the first study included 290 gastric cancer (GC) cases and 376 controls and the second study included 306 GC cases, 107 oesophageal adenocarcinoma cancer cases, 52 oesphageal squamous cell cancer cases and 211 controls. Odds ratios (OR) and 95% confidence intervals (CIs) were computed from logistic models and adjusted for confounding variables. The rs4072037 polymorphism in MUC1 was associated with a reduced risk of GC of intestinal histological type (OR 0.4; 95% CI 0.2-0.9) and a reduced risk of oesophageal squamous cell cancer (OR 0.5; 95% CI 0.2-1.0), but not oesphageal adenocarcinoma. Similarly, rs2274223 in PLCE1 was associated with a reduced risk of oesophageal squamous cell cancer (OR 0.5; 95% CI 0.3-1.0), but not oesphageal adenocarcinoma. We observed no association between rs13042395 in Corf54 and the risk of gastric or oesphageal cancer in either of the two studies. Our findings for rs4072037 and the risk of GC are in agreement with one previous report for a Caucasian population. To the best of our knowledge, this is the first study to report an association between rs2274223 and rs4072037 and the risk of oesophageal squamous cell carcinoma in a Caucasian population.

WS3-2 - Clinicopathological and Molecular Correlates of HER2 Expression, PIK3CA Mutations and EBV Infection Involved in the PI3K-AKT Pathway in Gastric Cancer

ABSTRACT Background We have characterized the molecular alterations in gastric cancers, especially those with MSI (Nature, Science, Nature Genetics 2006, 2009, Cancer Cell 2010). We have also reported the efficacy of molecular therapies targeting IGF1R in gastric cancer (Mol Cancer Ther 2008, Cancer 2010). Considerable attention has been given to the potential role of the PI3K-Akt signaling pathway in gastric cancer. This signal activation is thought to be one of the mechanisms underlying resistance to trastuzumab. Aims The aim of this study was to systematically characterize HER2 expression, PIK3CA mutations and EBV infection, all of which are involved in the PI3K-Akt-signaling pathway, in a large cohort of patients with gastric cancer to determine their prevalences with a high level of precision and to correlate them with clinicopathological and molecular features, such as MSI and pAkt expression. Methods We analyzed 231 T2–T4 gastric cancer tissues. Expression of HER2 and pAkt was analyzed by immunohistochemistry. PIK3CA mutations in exons 1, 9 and 20 were analyzed by pyrosequencing. EBV infection was analyzed by ISH. Results HER2 overexpression (IHC 3+) was present in 20 samples (8.4%) and it was significantly correlated with intestinal histological type (P = 0.05) and pAkt expression. PIK3CA mutations were present in 20 cases (8.4%) and it was significantly correlated with MSI (P Conclusions HER2 expression, PIK3CA mutations and EBV infection in gastric cancer were characterized in relation to Akt activation. pAkt expression was significantly correlated with poor prognosis and HER2 expression. The results have potential clinical implications since the mutational status of PIK3CA could stratify patients for genotype-based molecular therapy targeting the HERs-PI3K pathway. We will discuss the next-generation strategies including anti-IGF1R for molecular targeted therapy for gastric cancer.

1681P - The Role of Macrophages Polarization in Predicting Prognosis in Radically Resected Gastric Cancer

ABSTRACT Introduction Macrophages are one of the major populations of tumor-infiltrating immune cells. Tumor associated Macrophages (TAM) present two different phenotypes or polarizations: classical (M1) characterized by immunostimulation activity and tumor suppression; alternative (M2) characterized by angiogenesis, tumor promotion, and immune suppression. Despite these opposite properties, most of the previous studies focused merely on evaluating absolute TAM count. In this work, for the first time in literature, we evaluated the correlation between the two forms of TAM with survival time in patients affected by gastric cancer after radical surgery. Methods 52 chemo- and radio-naive gastric cancer patients undergone to resection for curative intent were included in this retrospective study. Two slides were prepared for each patients and double-stained for CD68/NOS2 (M1) or CD68/CD163 (M2) and five representative high-power fields (×400 magnification) per slide were evaluated for TAM count. The median value of the two macrophage populations density (M1 = 7.0; M2 = 6.4) and the median value of M1/M2 ratio (1.16) was used as cut-off. Results 27 patients with M1 density above the median had a significantly higher survival compared to those below the median (median OS of 25.6 months, CI95%:22.33-44.85 vs 17.1 months, CI95%:13.66-27.98; P = 0.041). 26 patients with M1/M2 ratio above the median showed median OS of 27.2 months (CI95%:25.45-47.51) compared to 15.5 months (CI95%:11.36-25.50) of the patients below the median (P = 0.001). No statistically significant difference in terms of M1/M2 ratio was observed between intestinal vs diffuse histological type. No association between M2 macrophage density and patients outcome (P= 0.724) was found. In multivariate analysis M1/M2 was a positive independent predictor of survival (P= 0.001; HR 0.420, CI95%: 0.22-0.78) whereas grading, histotype and TNM stage were not statistically significant. Conclusion The M1 macrophage density and in particular M1/M2 ratio, as confirmed in multivariate analysis, is an independent factor that can predict patients survival time in gastric cancer after radical surgery. The role of macrophage phenotype in influencing the gastric cancer prognosis warrant further investigation. Disclosure All authors have declared no conflicts of interest.

The prognostic impact of epidermal growth factor receptor (EGFR) in patients with metastatic gastric cancer.

e14557 Background: The prognostic role of the epidermal growth factor receptor (EGFR) in metastatic gastric cancer has not been established. Methods: EGFR was analyzed by immunohistochemistry (IHC) in a total of 357 patients (formalin-fixed, paraffin-embedded samples) and by real-time quantitative PCR (RTqPCR) in 130 patients with esophagogastric cancer. Staining intensity on IHC was scored in EGFR 0, 1+, 2+ and 3+. Staining intensity (alternatively intensity x % positive cells or the H-Score) and quantitative mRNA expression were correlated with progression-free (PFS) and overall survival (OS) and pathological and clinical characteristics. Results: On IHC, EGFR was negative, 1+, 2+, and 3+ in 205 (57%), 50 (14%), 62 (17%), and 40 (11%) patients, respectively. EGFR 3+ status correlated positively with intestinal type histology (p=.05) but no other correlations between baseline criteria such as age, sex, ECOG, tumor location, type of metastatic sites, and type of sampling and EGFR status were found. PFS and OS were similar in patients with EGFR-positive vs. those with EGFR negative gastric cancer, regardless whether positivity was defined as ≥1+ (PFS, 5.3 vs. 5.7 months, p=.185; OS, 10.6 vs. 10.9 months, p=.463) or as 3+ (PFS, 5.7 vs. 4.9 months, p=.159; OS, 8.6 vs. 10.8 months, p=.377) or when alternative scores were used such as the H-score. The multivariate overall survival analysis indicated that EGFR status is not an independent prognostic factor (hazard ratio 0.84, 0.56 to 1.12, p=.227). There were also no significant differences in progression-free or overall survival when patients were categorized according to median (PFS p=.173, OS p=.116) or quartile (PFS p=.634, OS p=.767) distribution of EGFR mRNA expression or when the cut-off with the highest predictive value was calculated (PFS p=.148, OS p=.189). Conclusions: EGFR status is not prognostic of patient’s outcome in metastatic gastric cancer.

Prognostic value of epidermal growth factor receptors (EGFR) on overall survival of gastric cancer patients.

e14599 Background: The human EGFR family is involved in the pathogenesis and progression of several solid tumors. However, there is no consensus about the prognostic role of HER2 expression and of other members of EGFR family in gastric cancer patients. The aim of this study was to evaluate the prognostic value of members of the EGFR family in gastric cancer. Methods: Retrospective study with 201 patients with gastric and esophagogastric junction (EGJ) adenocarcinoma stages 0 to IV (AJCC 6th edition) who underwent primary tumor resection between January 2006 and December 2008 at Barretos Cancer Hospital, Barretos, São Paulo, Brazil. Tissue from primary tumors were analyzed by tissue microarray technology. IHC scores 0 and 1+ were classified as negative and scores 2+ and 3+ as positive, both for membrane and cytoplasmic expression of HER1, HER2, HER3 and HER4. The HER2 scoring system for gastric cancer was used for classification. Correlations between receptor expression and clinicopathological characteristics were performed according to the chi-square test. Survival analysis was calculated according to a parametric Weibull model with a mixture model incorporating long-term survivors. Multivariate analysis of prognostic factors was performed by a regression model incorporating long-term survivors with the Weibull distribution. Results: Membrane expression of HER1, HER2 and HER4 were 9%, 17% and 15%, respectively. No membrane expression of HER3 was observed. Cytoplasmic expression of HER1, HER3 and HER4 were 45%, 62% and 24%, respectively. Expression of HER2 and HER3 correlated with intestinal-type histology (p: 0.001 and p &lt; 0.001, respectively) and advanced age (p: 0.011 and p: 0.008, respectively). According to a regression model adjusted for age, surgical radicality, surgical modality, Laurén histology, adjuvant therapy, TNM stage and receptors expressions, only TNM stage showed prognostic influence. Conclusions: Expression of HER2 and other members of EGFR family did not have influence on the overall survival in the gastric cancer population studied. The elaboration of a systematic review with meta-analysis or a prospective study could help elucidate this controversial issue.

HER2/neu testing for anti-HER2-based therapies in patients with unresectable and/or metastatic gastric cancer

AimTo study the HER2 gene amplification or overexpression in patients with advanced gastric cancer (GC) and their association with patient characteristics and patient survival.Patients and methodsTumour tissue samples from 148...