GI Adenocarcinomas Research Articles

Navigating the HER2 Frontier: Advancing Gastrointestinal Adenocarcinoma Diagnosis through Updated NCCN Guidelines

Abstract Introduction/Objective HER2-status is routinely tested in breast and upper-gastrointestinal (GI) cancers. Studies have shown the importance of anti-HER2 therapy with HER2 being a negative predictive marker in advanced colorectal cancer (CRC). Thus, recent NCCN-guidelines recommend screening for HER2-status in such cases. To increase compliance with the NCCN recommendations, we performed a quality assurance project to screen for HER2 status by immunohistochemistry (IHC) in GI adenocarcinomas. Methods/Case Report We conducted a validation of HER2 IHC for GI adenocarcinomas. Surgical pathologists were informed via email discussing the criteria and significance of HER2 IHC in GI adenocarcinomas. A total of 50 GI adenocarcinoma cases were evaluated in our surgical-pathology service, from June to December 2023. Pathologists were periodically reminded, either through email or in-person meetings, to ensure HER2 IHC assessment, especially for cases initially missed. Results (if a Case Study enter NA) Out of 50 GI adenocarcinomas, HER2 IHC was performed on 27 out of 50 cases (54%) without any reminder. The pathologists were reminded to perform HER2 IHC on the remaining 23 cases, resulting in the IHC performance on an additional 22 cases, giving a yield of 98%. Of 49 cases, HER2 was negative in 46 cases and was positive (3+) in one case, and equivocal (2+) in two cases. Subsequent HER2 FISH analysis of equivocal cases showed HER2 amplification in one case. Thus, HER2 expression/amplification was present in 2 out of 50 cases (4%) including one case each in upper and lower GI tracts. Conclusion While we have long recognized importance of HER2 Status in upper GI adenocarcinomas, it’s now clear that understanding HER2 status is crucial in CRC too. New evidence highlights how anti-HER2 therapy can make a difference, especially for advanced cases. By screening for HER2 early, clinicians can enroll such patients in appropriate clinical trials and also guide them on the appropriate treatment options, offering hope and targeted care.

605. MITOCHONDRIAL METABOLISM IN UPPER GI ADENOCARCINOMA DETERMINES PATIENT SURVIVAL

Abstract Background Mitochondrial oxidative phosphorylation (OXPHOS) is responsible for meeting the vast majority of cellular energy demands. Ever since the description of aerobic glycolysis by Warburg in 1927, it has been recognised that cancers have dysfunctional metabolism. Clinically, this Warburg effect is the basis of FDG-PET imaging, increased FDG uptake represents increased tumour glycolysis and translates to worse upper GI adenocarcinoma outcomes. The cause of OXPHOS disruption in upper GI adenocarcinoma is poorly understood, its impact on potential therapeutic strategies is yet to be explored. This is particularly pertinent in upper GI adenocarcinomas as despite recent improvements, 5-year survival remains alarmingly low. Method Oesophageal and gastric adenocarcinoma samples collected in the UK from 175 patients (89 oesophageal adenocarcinoma, 86 gastric adenocarcinoma, 131 male, 44 female, median age=65, IQR=12) who underwent radical resection with curative intent between 1995 and 2009. Quantitative immunofluorescence were used to determine expressions of OXPHOS Complex I and IV at a single cell level. Patients were divided into high vs. low expressors of Complex I and IV using K-means clustering to allow for subsequent subgroup analysis. Result Survival analysis demonstrated significantly worse outcomes for low expressors as compared to high expressors of Complex I at 5 years post-op (5-year survival probability low expressors=0.440, 95%CI=0.358-0.539, high expressors=0.629, 95%CI=0.515-0.769, P-value=0.048). Similarly comparison of Complex IV expression also demonstrates disadvantageous survival for Complex IV low expressors (5-year survival probability low expressors=0.432, 95%CI=0.346-0.538, high expressors=0.603, 95%CI=0.499-0.729, P-value=0.042). The low expressors of Complex I and IV encompassed significantly more Stage III disease as per AJCC 7th edition. The low vs. high expression Complex I and IV groups are similarly matched for baseline patient characteristics. Conclusion These results demonstrate reduced capacity to carry out OXPHOS in oesophageal and gastric adenocarcinoma is characteristic of more advanced cancer and results in worse patient outcomes. Further work is needed to determine if OXPHOS status impacts on neo-adjuvant therapy response and how to exploit OXPHOS deficiency therapeutically in oesophageal and gastric adenocarcinomas. The limitations of this preliminary work include small sample size and tissue derived from historic patients over a long period of time, during which treatment and outcomes for upper GI cancer have significantly changed.

Incidence of malignancies after lung transplantation and their effect on the outcome. 26 years' experience

BackgroundMalignancy is a significant, life-limiting complication after lung transplantation (LuTx) and the second common long-term cause of death. We aimed to investigate its incidence and effect on the outcome. MethodsThis is a retrospective observational study. Between 1996 and 2022, n = 627 lung transplantations (LuTx) were performed in our department. We used our institutional database to identify recipients with malignancies after LuTx and examined the malignancies’ incidence and mortality. ResultsN = 59 malignancies occurred in n = 55 (8.8%) LuTx recipients. The post-LTx malignancies incidence was 9.4% (59/627). We report the following rates based on their location: n = 17/55 (28,8% of all recipients diagnosed with malignancies) skin, n = 10/55 (16,95%) gastrointestinal, n = 9/55 (15,3%) respiratory, n = 5/55 (8,48%) lymphatic, n = 13/55 (23,6%) other, n = 5 (8,48%) multiple synchronous.During this study period, a total of n = 328 deaths after LuTx was determined. N = 29 (8,84% of all deaths) were malignancy induced, corresponding to a total malignancy-induced mortality of 4.6% (n = 29/627). The majority of deaths were attributed to GI adenocarcinoma and PTLD. Malignancies’ origin, primary COPD diagnosis, type, and specific age group were significantly survival-related (p-values <0.05). The most affected organ was skin and showed the best prognosis. PTLD had the fastest and pancreatic the latest onset. ConclusionsThis is the first report of its kind in a large cohort of german LuTx recipients. The prevalence ranking of the three commonest malignancy were skin > colorectal > PTLD. Post-LTx malignancy was the second commonest cause of death. Further studies are needed, while post-LuTx malignomas remain a serious impairment of long-term LuTx survival.

O12-1 Ramucirumab-containing chemotherapy for gastrointestinal neuroendocrine carcinoma: RAM-NEC study (WJOG13420G)

Second-line chemotherapy (CTx) for advanced gastrointestinal neuroendocrine carcinoma (GI-NEC) after platinum-based CTx is adopted according to the guidelines of GI adenocarcinoma or small cell lung cancer in daily practice. Recently, some reports suggested that vascular endothelial growth factor receptor-2 highly expressed in tumor vessels of GI-NEC. In this study, we evaluated the efficacy of ramucirumab (RAM)-containing CTx.

Multicenter retrospective study of ramucirumab-containing chemotherapy for gastrointestinal neuroendocrine carcinoma patients previously treated with platinum-based chemotherapy: RAM-NEC study (WJOG13420G).

511 Background: Platinum-based systemic chemotherapy (CTx) is recommended for poorly differentiated advanced gastrointestinal neuroendocrine carcinoma (GI-NEC). As second-line CTx various regimens are adopted according to the guidelines of GI adenocarcinoma or small cell lung cancer in daily practice. Recently, some clinical and preclinical reports suggest that vascular endothelial growth factor (VEGF) inhibitors are effective against NEC. In this study, we evaluated the efficacy of ramucirumab (RAM, anti-VEGF receptor 2 antibody)-containing CTx. Methods: We retrospectively evaluated gastric (G-) or colorectal (C-) NEC patients previously treated with first-line platinum-based CTx followed by second-line CTx between March 2015 and June 2020 (G-NEC) or between May 2016 and June 2020 (C-NEC). The main inclusion criteria were ECOG performance status (PS) of 0–2, pathologically diagnosed as G or C- NEC or mixed adenoneuroendocrine carcinoma. We compared the efficacy of RAM-containing CTx as second- or later-line treatment (Group A) with that of CTx without RAM as second-line treatment (Group B). A Cox proportional hazard model and inverse probability weighting of propensity scores were used to adjust the background factors between the two groups. Results: From 25 facilities, 139 patients were included in this study. Group A and B contained 50 (G/C, 43/7 patients) and 89 (G/C, 58/31 patients) patients, respectively. Patient characteristics were as follows (Group A/Group B): median age (range), 70 (28–83)/68 (39–86); ECOG PS 1–2, 66/69%, more than two prior regimens, 46/0%; response to previous platinum-based CTx, 46/38%. The regimen in combination with RAM in Group A was paclitaxel/nab-paclitaxel/FOLFIRI (62/26/12%). Second-line CTx in Group B were commonly amrubicin (58%) and irinotecan (11%). The efficacy (Group A/Group B) after a median follow-up time of 7.5/5.5 months were as follows: median overall survival (mOS), 8.6/5.8 months (HR, 0.68; 95% CI, 0.45–1.01; p = 0.058); median progression-free survival, 4.3/1.9 months (HR, 0.57; 95% CI, 0.39–0.84; p = 0.004); objective response rate, 50/8% ( p &lt; 0.0001); disease control rate, 70/24% ( p &lt; 0.0001); mOS in G-NEC, 8.6/5.3 months (HR, 0.62; 95% CI, 0.39–0.99; p = 0.047); and mOS in C-NEC, 5.4/6.8 months (HR, 0.66; 95% CI, 0.26–1.66; p = 0.378). The most common grade 3 or higher treatment-related adverse event that occurred in more than 5% of patients in Group A was neutropenia (32%). Conclusions: This study suggests that RAM-containing CTx as second- or later-line treatment is effective for GI-NEC patients, especially for G-NEC. Central pathological review and biomarker analyses using pretreated tissue specimens are ongoing. We will present updated data in the congress. Clinical trial information: UMIN000043200.

Functional plasticity of putative TP53 gain of function mutations in human gastrointestinal tract adenocarcinomas.

e15530 Background: The TP53 gene product is a multifunctional protein and prototypical tumor suppressor. Certain missense mutations occurring in hotspots in the TP53 gene may confer gain of function (GOF) oncogenic properties. A recent mouse model (Kadosh et. al., Nature, 2020) demonstrated that secreted factors in the gut microbiome permit GOF p53 to be oncogenic in lower GI tract cancers (LT). By contrast, the GOF p53 mutants in the upper tract cancers (UT) retained tumor suppressor functions. We aimed to provide evidence of the plasticity of TP53 GOF mutants in human GI cancers. We hypothesized that UT should have a lower rate of TP53 GOF than the LT, and UT cancers with putative GOF TP53 mutations should display a higher degree of co-occurring oncogenic alterations such as dysregulation of CCND1, MYCS, or WNT. We also explored outcome differences for TP53 GOF variants. Methods: Tumors of UT (stomach, esophagus, small intestine) and LT (colorectum, anus) were tested at Caris Life Sciences (Phoenix, AZ) by NGS (NextSeq, 592 or NovoSeq, whole exome). MSI/MMRP status was determined by IHC and NGS. Real-world overall survival (OS) was obtained from payor claims data and Kaplan-Meier estimates were calculated. P values adjusted for multiple correction (q) of &lt; 0.05 was considered significant. Six p53 variants were classified as GOF (p.R175, p.G245, p.R248, p.R249, p.R273, and p.R282). Results: Of the 5311 UT and 14810 LT tumors sequenced, 4799 harbored a TP53 GOF variant. UT had TP53 GOF in 22.9% of cases compared to 27.0% of LT (q &lt; 0.05). 67 genes were enriched for amplification (q &lt; 0.05) in the UT TP53 GOF cancers compared to the LT TP53 GOF, including cell cycle regulators( CCND1, CCNE1, CDK6, CDK12), and oncogenes ( KRAS, ERBB2, EGFR). LT TP53 GOF cancers were enriched for eight gene amplifications, including CDX2, FLT3, and SRC. Differences in SNV/InDel patterns were not remarkable. OS analysis revealed TP53 GOF in UT had shorter OS when compared to TP53 wild-type (WT) (Median OS: 418 vs 515 days; HR: 0.864; 95%CI [0.772-0.966]; p = 0.011), but not when MSI/MMRP status was considered separately. LT TP53 GOF did not show OS difference in aggregate, however, MSI-High TP53 GOF cancers showed a shorter OS (Median OS: 762 vs 1479 days; HR: 1.522; [1.068 - 2.171]; p = 0.019). Sub-analysis of LT MSI-High cancers treated by immune checkpoint blockade showed a non-significant trend toward shorter OS of TP53 GOF versus TP53 wild type cancers (HR: 2.55; [0.90-7.19], p: 0.067), but no such trend was seen in UT (HR: 1.434; [0.304-6.758], p:0.646). Conclusions: Our study is the first to compare putative TP53 GOF variants across UT and LT GI adenocarcinoma. TP53 GOF variants are associated with decreased OS in both UT cancers and MSI-High LT cancers. Our findings support the functional plasticity of TP53 GOF variants in human GI cancers. Therefore, the purported effects of secreted microbiome factors on TP53 GOF variants cannot be ruled out.

Gastrointestinal neoplasia in patients with inflammatory bowel disease: Opportunities to enhance preventative strategies.

Background and AimsGastrointestinal (GI) adenocarcinoma, especially colorectal cancer (CRC), is a devastating complication of inflammatory bowel disease (IBD). We sought to examine the role of chronic inflammation and other possible predictors of the development of CRC, as well as assess as yet unexamined factors such as psychological comorbidity and engagement in care.MethodsThis study included all patients involved in a tertiary hospital IBD service diagnosed with CRC between 2007 and 2017. Reports from histological specimens were assessed, and all those with adenocarcinoma, high‐grade dysplasia (HGD), or multifocal low‐grade dysplasia (LGD) originating within IBD‐affected mucosa were included in the study.ResultsA total of 32 patients were included in the study (17 with adenocarcinoma and 15 with HGD/multifocal LGD). The majority had a duration of disease >20 years. Eleven patients (34%, CI 20–52%) had previous disease‐related surgery, and 16 (50%, CI 34–66%) had multiple previous disease‐related admissions. Thirteen patients (62%, CI 41–79%) had >50% of CRP results higher than 8 mg/L. Psychiatric comorbidities were common, with 19 patients (59%, CI 42–74%) having a psychiatric comorbidity or poor engagement in treatment.ConclusionIn this cohort, we have highlighted poor engagement, hesitation to up‐titrate therapy when indicated, and psychological comorbidities as likely contributors to poor disease control and development of GI adenocarcinoma. Based on our data, these easily identifiable clinical care factors should not be overlooked when addressing IBD‐related GI malignancy prevention. Additional research is required to assess a direct causal relationship, but this study would support the incorporation of psychology services into IBD clinics.

Phase 1 dose escalation study of MEDI-565, a bispecific T-cell engager that targets human carcinoembryonic antigen (CEA), in patients with advanced gastrointestinal (GI) adenocarcinomas.

320 Background: MEDI-565, a bispecific single-chain antibody, targets human CEA on tumor cells and the CD3 epsilon subunit of the human T-cell receptor complex. In murine models, MEDI-565 showed antitumor activity in CEA-expressing tumors (J Immunother 2009;34:341-52). Methods: This phase 1, multicenter, open-label, dose-escalation study enrolled adults with GI adenocarcinomas (including esophageal, gastric, small intestine, colorectal, biliary tract, and pancreatic). MEDI-565 was given intravenously over 3 h on days 1–5 in 28-day cycles, with 4 single-patient (pt) (0.75–20 μg) and 5 standard 3+3 escalation (60 μg–3 mg; 1.5–7.5 mg with dexamethasone [dex]) cohorts. Primary objective was to determine the maximum tolerated dose (MTD); secondary objectives were to evaluate pharmacokinetics (PK), antidrug antibody (ADA), and antitumor activity. Results: Study enrolled39 pts: mean age 59 y; 56% male; 28 (72%) colorectal, 6 (15%) pancreatic, 5 (13%) other. Dose-limiting toxicities (grade ≥ 3 nonhematologic) were seen in 4 pts (2 at 3-mg; 2 at 7.5-mg + dex): hypoxia (n = 2), diarrhea, and cytokine release syndrome (CRS). Grade 3 treatment-related adverse events (AEs) seen in 5 pts: diarrhea, CRS, increased alanine aminotransferase, hypertension (all n = 1), and hypoxia (n = 2). Treatment-related serious AEs seen in 6 pts: diarrhea, vomiting, pyrexia, CRS (all n = 1), and hypoxia (n = 2). Five pts discontinued treatment due to AEs: diarrhea, CRS, central nervous system metastases, and hypoxia (n = 2). MEDI-565 exposures increased in approximately dose-proportional manner, with clearance (35–77 L/d) and half-life (2–7 h) typical of drug class. ADA had minor impact; 19 pts (48.7%) had ADAs, 5/39 (12.8%) with high titer, with decreased MEDI-565 concentrations in 2 pts. Plasma inflammatory cytokines were elevated posttreatment in several pts at 1.5- and 3-mg (no dex) dose levels. No objective responses were observed; 11 (28%) pts had stable disease as best response. Conclusions: The MTD of MEDI-565 in pts with GI adenocarcinomas was 5 mg with dex. PK was linear, with fast clearance and short half-life. No objective responses were observed. Clinical trial information: NCT01284231.

Regulation of HDM2 E3-ubiquitin ligase in esophageal adenocarcinoma cells by AURKA.

35 Background: Esophageal adenocarcinomas (EAC) exhibit intrinsic resistance against chemotherapy. AURKA regulates cell cycle progression and its overexpression is associated with oncogenic transformation. We have recently reported that AURKA is significantly overexpressed in about 70% of human EAC tissue samples and EAC cell lines. We have previously shown that AURKA inhibits p53- and p73-mediated apoptotic pathways in GI adenocarcinomas. HDM2 is an E3-ubiquitin ligase which is closely involved in regulating p53 and p73 protein stability and activity. In this study we demonstrate that AURKA directly interacts with HDM2 and regulates HDM2 protein expression and phosphorylation in both FLO-1 and OE33 EAC cells. Methods and Results: Western blot analyses were done following AURKA overexpression with adenovirus, knockdown with si-RNA or inhibition with MLN 8237 (0.5µM) in FLO-1 and OE33 EAC cell lines. The data indicated that overexpression of AURKA induced both total and phospho-HDM2-(Ser166) protein levels. Knockdown or inhibition of AURKA significantly decreased expression of both total and phospho-HDM2-(Ser166) protein levels in FLO-1 and OE33 EAC cells. Additionally, following adenovirus mediated overexpression of AURKA, co-immunoprecipitaion (Co-IP) was done for AURKA and HDM2 in FLO-1 and OE33 EAC cells. The two-way Co-IP data indicated the presence of HDM2 in a complex associated with AURKA and vice-versa. The data from in vitro protein kinase assay indicated that recombinant AURKA directly phosphorylates recombinant HDM2 at Ser166 site. To confirm direct interaction between recombinant AURKA and HDM2 proteins we performed IP following the in vitro kinase assay. The in vitro kinase IP data indicates that kinase intact recombinant AURKA directly interacts and phosphorylates recombinant HDM2 protein. Conclusions: Our data indicate that AURKA regulates HDM2 expression and phosphorylation in both FLO-1 and OE33 EAC cells. Additionally, we also report for the first time that AURKA directly interacts with HDM2 and phosphorylates it at Ser166 site. Therefore, our study suggests that AURKA-mediated regulation of HDM2 could be the major underlying mechanism for induction of apoptosis in p53-negative EAC.

Interim results of a phase II study of the mTOR inhibitor everolimus in patients with pretreated metastatic gastric and esophageal adenocarcinoma.

80 Background: There is increased evidence that cancers of the upper GI tract are comprised of distinct epidemiological and molecular entities that may respond differently to anti-cancer therapy in Asian patients compared to North American patients. Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR) showed clinical promise in a phase II study in Japanese patients with pre-treated metastatic gastric cancer with a disease control rate of 56% (Doi et al, JCO, 2010). This study evaluates the efficacy and safety of everolimus in patients with pre-treated metastatic gastric and esophagus cancers in a US population. Methods: Patients with advanced upper GI adenocarcinomas who experienced disease progression despite 1-2 prior regimens were treated with everolimus 10 mg PO daily. The primary endpoint was disease control rate (DCR; CR+PR+SD). Secondary end points included progression free survival (PFS), toxicity, overall survival (OS) and translational correlatives of the mTOR pathway. Results: Of the 40 patients enrolled to date, 19 have gastric, 7 have esophagus and 14 have tumors from the GEJ. 32 patients are evaluable to date: median age of 59 (range 36-79), all patients had an ECOG of 0 or 1; 11 (34%) received 1 prior regimen and 21 (64%) received 2 prior regimens. We observed 0 responses with 44% of evaluable patients having stable disease. Median overall survival was 5.6 months (95% CI: 3.2-7.6) and PFS was 1.8 months (95% CI: 1.6-2.2). 89% of all adverse events were grade 1-2, and 11% were grade 3-4. Grade 3-4 related adverse events include: fatigue (24%), thrombocytopenia (22%), anemia (9%). Updated results of translational correlatives with the mTOR pathway will be presented. Conclusions: We did not achieve the same degree of overall survival or disease control as in the Japanese study which may reflect differences in the locations of the primary tumor or underlying geographic variation. However, OS is significantly better than best supportive care reported in a recent randomized European trial (Thuss-Patience PC et al, Eur J Cancer 2011). Results of the randomized Phase III trial of everolimus vs best supportive care in this patient population are pending.

Perioperative chemotherapy for upper gastrointestinal cancer: Correlation between response to treatment and outcome.

95 Background: Perioperative chemotherapy improves outcomes of surgery for upper GI cancer. Some patients have rapid recurrence. We hypothesized that any type of response to chemotherapy would predict better disease-free survival (DFS). Methods: From May 2007 to Sep 2009, 43 patients with operable adenocarcinoma of the esophagus, stomach or gastroesophageal junction went on a multicenter phase II trial. 3 cycles of docetaxel/cisplatin/5FU were given pre and post surgery. We compared DFS between responders and nonresponders after 3 cycles. Clinical response was defined as improvement of ≥ 2 points on a dysphagia score (0: normal swallowing, to 4: total obstruction), metabolic response as ≥ 35% reduction of maximum SUV by PET scan. Lack of nodal involvement or significant histologic regression (less than 50% viable tumor) was considered pathologic response. Log-rank test was used for univariate analysis, Cox regression model for multivariate analysis. All p values are double sided, median follow-up from surgery is 808 days. Results: Clinical response data for 29/40 patients: 26 responses (90%). Median DFS was 405 days for clinical responders vs. 210 days for nonresponders (p= 0.018). Metabolic response data for 28/40 patients : 22 responses (70%). Median DFS was 276 days in metabolic nonresponders, and has not been reached in responders (p = 0.009). 14 patients had no nodal involvement at resection (N0) and had longer DFS (median not reached) than the 26 with N+, who had median DFS of 562 days (p = 0.045). A nonsignificant trend (p = 0.192) was seen in favor of the 20 with significant tumor regression (DFS 565 days) compared to the 20se without it (median DFS not reached). All results were supported by multivariate analysis. Conclusions: These preliminary results indicate that clinical, metabolic and pathologic responses may be individually predictive of longer DFS in patients receiving perioperative chemotherapy for upper GI adenocarcinoma. This requires confirmation in larger datasets. The optimal management of nonresponders is unclear at present. Acknowledgements: Biostatistics Unit (McGill University Health Centre) and Cedars Cancer Institute (Henry R Shibata Fellowship to Dr Alcindor).

Male predominance of upper gastrointestinal adenocarcinoma cannot be explained by differences in tobacco smoking in men versus women

Background Adenocarcinomas of the upper gastrointestinal tract (UGI) show remarkable male predominance. As smoking is a well-established risk factor, we investigated the role of tobacco smoking in the male predominance of UGI adenocarcinomas in the United States NIH-AARP Diet and Health Study. Method A questionnaire was completed by 281,422 men and 186,133 women in 1995–1996 who were followed until 31st December 2003. Incident UGI adenocarcinomas were identified by linkage to state cancer registries. We present age-standardised cancer incidence rates per 100,000-person years and male/female ratios (M/F) calculated from age-adjusted Cox proportional hazards models, both with 95% confidence intervals (CI). Results After 2013,142-person years follow-up, 338 adenocarcinomas of the oesophagus, 261 of gastric cardia and 222 of gastric non-cardia occurred in men. In women, 23 tumours of oesophagus, 36 of gastric cardia and 88 of gastric non-cardia occurred in 1351,958-person years follow-up. The age-standardised incidence rate of all adenocarcinoma sites was 40.5 (37.8–43.3) and 11.0 (9.2–12.8) in men and women, respectively. Among smokers, the M/F of all UGI adenocarcinomas was 3.4 (2.7–4.1), with a M/F of 7.3 (4.6–11.7) for tumours in oesophagus, 3.7 (2.5–5.4) for gastric cardia and 1.7 (1.2–2.3) for gastric non-cardia. In non-smokers, M/F ratios were 14.2 (5.1–39.5) for oesophagus, 6.1 (2.6–14.7) for gastric cardia and 1.3 (0.8–2.0) for gastric non-cardia. The overall M/F ratio was 3.0 (2.2–4.3). Conclusion The male predominance was similar in smokers and non-smokers for these cancer sites. These results suggest that the male predominance of upper GI adenocarcinomas cannot be explained by differences in smoking histories.

T2061 Male Predominance of Adenocarcinoma of Upper Gastrointestinal Tract Is Related to Intestinal Histological Subtype Not Tumour Location

Background: Upper gastrointestinal adenocarcinomas show an unexplained male predominance which is more apparent in the oesophagus than stomach. We have conducted a population-based study to determine whether the gender phenomenon is primarily related to the anatomical site or the histological subtype of the tumour. Method: The study was based upon 3270 gastric and oesophageal cancers recorded in West of Scotland cancer Registry, 1998-2002. 812 of these cases were randomly selected for detailed analysis. Their records were reviewed for histology and anatomical site of tumour using ICD-10 and ICD O-2. The Lauren histological subtype of adenocarcinoma was determined by reviewing 1204 original reports and 3241 biopsy and surgical slides. Results: 405 (51.5%) cancers originated from the non-cardia region of the stomach, 173 (22.0%) from the gastric cardia and 209 (26.6%) from the oesophagus. Regardless of anatomical subsite, the upper GI cancers were more common in males (502, 63.8%) than females (285, 36.2%). Regardless of anatomical site, the crude incidence rate of intestinal type upper GI adenocarcinoma was higher in males (23.86/ 105/y) versus females (9.00/ 105/y), giving M/F of 2.65. In contrast, the crude incidence rate of diffuse-type adenocarcinoma was similar in males and females (5.58 vs 5.20 /105/y) yielding M/F of 1.07. Male predominance was greatest in the oesophagus with M/F of 3.50, less in the cardia (M/F= 2.00) and least in the non-cardia cancer (M/F= 1.65). The relationship between tumour location and male predominance lost its significance in the multivariate analysis when histological subtype was added [OR (95%) = 1.37 (0.88 2.12)]. Multivariate analyses including histological subtype, tumour location and age indicated that the male predominance was related to the histological type rather than anatomical location. Intestinal type adenocarcinoma showed similar male predominance irrespective of its anatomical location (OR, 95% CI: 2.6, 1.78 3.9). Conclusion: Male predominance in upper GI adenocarcinomas is not a function of tumour location but rather related to histological subtype. The mechanism of the strong gender association with intestinal subtype requires elucidation.

S2060 Aberrant Expressions of Gastric Type Mucin and Claudin in Colorectal Serrated Polyps

F ratio of intestinal type cancer was 3.41 at age less than 50, reached a peak of 7.86 at age 50-59, and then showed a progressive decrease with a minimum of 2.29 at age group 80 years and over. In contrast, the crude incidence rate of diffuse-type adenocarcinoma was similar in males and females (5.58 vs. 5.20 /100, 000/ year) yielding M/F of 1.07. Curve modelling of the age-specific rates for diffuse subtypes showed similar equations, y = 0.016 x mean age 2.007 +32.98, R2 = 0.999 and y = 0.016 x mean age 1.954+35.97, R2 = 0.989, for male and females, respectively. For the intestinal histological type, the age-specific incidence rates were different for males and females. Curve modelling indicated the same kinetic equation for rise in incidence with age, in males (y = 0.016 x mean age 2.315+28.75, R2 = 0.990) and in females (y = 0.016 x mean age 2.316+46.07, R2 = 0.998). However, the female curve was displaced to the right indicating a delay in the cancer onset. The estimated cancer onset delay for females was 17.2 years (i.e. +46.07 minus +28.75= 17.22). Conclusion Male predominance in upper GI adenocarcinomas is a reflection of approximately 2 decades delay of development of intestinal subtype adenocarcinoma in females. The mechanism of the marked delay in development of intestinal subtype requires elucidation.

Combination of gastric atrophy, reflux symptoms and histological subtype indicates two distinct aetiologies of gastric cardia cancer

Introduction:Atrophic gastritis is a risk factor for non-cardia gastric cancer, and gastro-oesophageal reflux disease (GORD) for oesophageal adenocarcinoma. The role of atrophic gastritis and GORD in the aetiology of adenocarcinoma...

Site-Specific Gene Expression Profiles and Novel Molecular Prognostic Factors in Patients with Lower Gastrointestinal Adenocarcinoma Diffusely Metastatic to Liver or Peritoneum

Generally, colorectal and high-grade appendiceal cancers are treated similarly; treatment approach is primarily based on tumor histology and stage of disease. Patients with adenocarcinoma of the lower gastrointestinal tract frequently experience diffuse metastases isolated to liver or peritoneum and have a poor survival. Identification of novel molecular pathways in metastases from these patients may identify novel targets and prognostic factors. Microarray analyses of 20 metastatic tumors from patients with colorectal adenocarcinoma isolated to liver or peritoneum and eight high-grade appendiceal adenocarcinoma metastatic to peritoneum were performed using oligonucleotide microarray. In an unsupervised hierarchical cluster analysis of 2-fold upregulated or downregulated genes, there was a clear site-specific segregation of liver versus peritoneal metastases. Genes primarily involved in metastasis, angiogenesis, cell cycle regulation, cell proliferation, and cell adhesion were distinctly altered between these two metastatic sites. Among the metastasis genes, the average expression levels of LI-cadherin, ALCAM, CD2, and CD14 were significantly higher in both metastatic sites. TIMP1 was overexpressed in both sites where as TIMP-2, IGF-1, and HIF-1alpha were upregulated only in peritoneal metastases demonstrating the potential benefit of metastasis site-specific treatments. Subsets of genes significantly associated with poor survival were defined, a RET proto-oncogene interacting gene, GOLGA5, was highly predictive for survival in patients with colorectal adenocarcinoma. These results demonstrate that liver and peritoneal metastases of lower GI adenocarcinoma have distinct gene expression patterns; these distinctions may help in the development of therapies based on site of metastases.

33. DO GASTRIC “ULCER-CANCERS” PRESENT DIFFERENTLY TO “MASS-CANCERS”?

Aims: The aim of this retrospective study is to identify whether there is a difference in the pattern of presentation of “ulcer-cancers” and “mass-cancers” and so identify any potential to...

Hospital procedure volume and hospital teaching status do not influence operative mortality or long-term survival for rectal cancer in a large general population: An outcomes study

The indications for the resection of noncolorectal/nonneuroendocrine hepatic metastases (NCNNE) have evolved as the safety of hepatic resection has increased. The prognostic features of NCNNE treated surgically were reviewed in order to better define the indications for resection. Methods: A retrospective review of patients undergoing liver resection for NCNNE between 1978 and 1997. Results: Thirty patients were identified. The mean age was 57 years with a median follow up of 18 months. Primary tumor sites included GI adenocarcinoma (bowel n=3, unknown n=2, pancreatic n=2, esophageal n=l), and other (renal cell n=5, testicular n=l, ovarian n=l, sarcoma n=6, adrenal n=3, melanoma n=3, thyroid n=2, and breast n=l). All patients were operated upon for cure. Synchronous metastases were treated in 9 patients. There was no operative mortality. Overall survival is shown in Figure 1. Survival was better in patients with non-GI origin metastases (Figure 2, p=0.04). Long term survivors were seen only in patients with non GI origin metastases. Neither the extent of resection (segmental n=l 1, lobe n---14, extended n=5) nor the presence of synchronous metastases was predictive of outcome.