Localized Gastric Cancer Research Articles

Association of AREG exon 1 polymorphism with worse prognosis in Japanese and U.S. patients with gastric cancer.

e15022 Background: Recent data suggest that Amphiregulin (AREG) and Epiregulin (EREG), ligand of EGFR pathway, is possibly a prognostic and predictive marker in gastrointestinal cancer. Previous data have shown that higher AREG and EREG gene expression levels are associated with better survival in metastatic colorectal cancer as well as gastric cancer (GC). Since polymorphisms in AREG and EREG may affect their gene expression levels or change their functions, we tested the hypothesis whether these polymorphisms could predict outcome in two ethnically and epidemiologically different GC cohorts from Japan and the US. Methods: One-hundred and sixty-nine Japanese (n=169), as a training set, and one-hundred and thirty-seven (n=137) the US patients, as a validation set, with histopathologically-confirmed localized (stage Ib to IV; AJCC-6th) GC were enrolled between 2002 and 2010. Four functional SNPs in AREG and five SNPs in EREG were selected. Genomic DNA was extracted from blood or tissue, and all samples were analyzed by PCR-based direct DNA-sequencing. Results: The median follow-up periods were 4.0 years in the Japanese cohort and 3.3 years in the US cohort, respectively. The median DFS and OS in the Japanese cohort were 4.8 and 5.8 years, whereas the median TTR and OS in the US cohort were 2.8 and 4.7 years, respectively. Only exon 1 polymorphism rs1615111 G/A was associated with outcome in Japanese cohort. Patients heterozygous G/A (n=23) showed a median OS of 2.7 years vs. 20.1 years for patients homozygous G/G (n=146) (HR: 1.83 [95%CI: 1.02-3.30], p=0.039). This result was successfully validated in the US cohort. Patients harboring at least one-A allele (n=14) showed a median OS of 2.8 years vs. 5.4 years for patients homozygous G/G (n=111) (HR: 2.54 [95%CI: 1.09-5.89], p=0.018). In the pooled multivariate analysis, these results were still conserved (HR=2.24 [95%CI: 1.36- 3.67], p=0.0015). Conclusions: AREG exon 1 polymorphism rs161511 may be negative prognostic factor in GC regardless ethnicity and regional differences in gastric cancer. Further clinical validation of SNPs in EGFR ligands are warranted.

Clinicopathologic features predicting HER2 overexpression in gastric cancer.

e15098 Background: HER2-based therapy was found to improve survival outcome of patients with HER2-positive advanced gastric cancer. In gastric cancer, HER2 overexpression is commonly defined as IHC 3+ or IHC 2+/FISH amplification. Because positivity of HER2 overexpression is reported in below 20%, identifying the predictive clinical factors for the HER2 overexpression before the pathologic analysis may be helpful and cost-effective. Methods: From JAN 2005 to DEC 2010, 517 gastric cancer patients performed with HER2 IHC and/or FISH tests at Yonsei University College of Medicine were enrolled. Results: Among the 517 patients, 61 patients (11.8%) were confirmed as HER2 overexpression. Forty three out of stage IV, 258 patients (16.7%) and 18 out of 259 (6.9%) localized gastric cancer patients had HER2 overexpression (p <0.001). HER2 overexpression was more common in male (14.2% vs. 7.5% in female, p-value 0.024), moderately differentiated (26.4% vs. 11.1%, 8.9%, 4.9% and 5.9% in well differentiated, poorly differentiated, signet ring cell, and mucinous, retrospectively, p <0.001). Patients with elevated CEA (> 5.0 ng/mL vs. ≤ 5.0 ng/mL: 24.3% vs. 8.4%, p <0.001), metastasis to distant lymph node (with vs. without: 28.6% vs. 14.8%, p-value 0.042), without carcinomatosis (without vs. with: 21.2% vs. 11.6%, p-value 0.039) and pulmonary metastasis (with vs. without: 47.4% vs. 14.2%, p <0.001) also frequently had HER2-positive disease. In addition, high risk patients with 4 or more of the 7 features (metastatic disease, male, moderate differentiated adenocarcinoma, elevated CEA level, metastasis to distant lymph node, pulmonary metastasis, and without carcinomatosis) had 32.9% of HER2 positivity. (p <0.001). Conclusions: Those clinicopathologic factors may be helpful to predict the high likelihood of HER2 positive cases prior to pathologic confirmation in gastric cancer. Further molecular study for the HER2 overexpression is needed to clarify and explain this clinical phenomenon.

Association of transcription factor 7-like 2 (TCF7L2) polymorphisms with worse survival in three independent cohorts from the United States, Austria, and Japan in patients with gastric cancer.

4111 Background: The Wnt/β-catenin signaling pathwaycontrols cell proliferation and differentiation. Disruption of this pathway has been shown in the majority of colorectal (CRC) and gastric cancer (GC). The TCF7L2 complex plays a critical role in this pathway. Interaction of TCF7L2 and β-catenin results in translocation to the nucleus and leads to up-regulation of target genes, including c-myc and cyclin D1. Previous reports have shown that TCF7L2 polymorphism rs7903146 C/T is associated with CRC risk and outcome; however, the prognostic role of this polymorphism in GC is unknown. Therefore, we tested the hypothesis of whether this polymorphism could predict outcome in GC in three independent cohorts. Methods: A total of 369 patients (pts) with histopathologically-confirmed localized GC were enrolled from Japan (n=169), the US (n=137), and Austria (n=63) between 2002 and 2010. Results: In the US cohort, pts with at least one-T allele ((T/T or C/T; n=46) showed a median TTR of 1.7 yrs vs. 4.4 yrs compared to pts homozygous C/C (n=76) (HR: 2.09 95%CI: 1.21- 3.59, p=0.0053). A similar trend was shown in the Austrian cohort, where pts harboring at least one-T allele (n=25) showed a median DFS of 2.08 yrs vs. 5.42 yrs for pts homozygous C/C (n=38) (HR: 1.79 [95%CI: 0.90-3.55], p=0.092). Moreover, in the Japanese cohort, pts homozygous for T/T demonstrated (n=2) a median DFS of 0.15 yrs vs. 4.82 yrs for pts harboring at least one-C allele (n=165) (HR: 10.5 [95%CI: 2.46-45.5], p=0.001). These results were confirmed in the OS in the US and Japanese cohorts. Pts at least one-T allele (n=46) showed a median OS of 3.3 yrs vs. 5.5 yrs for pts homozygous C/C (n=76) (HR: 2.41 95%CI: 1.28-4.53, p=0.0043) in the US cohort, while pts homozygous T/T showed (n=2) a median OS of 0.22 yrs vs 5.76 yrs for pts harboring at least one-C allele (n=165) (HR: 15.2 [95%CI: 3.50-66.7], p<0.001). Conclusions: TCF7L2 polymorphism was associated with worse prognosis in recurrence in pts with GC in three independently global cohorts. This polymorphism may be negative prognostic factor in GC regardless of ethnicity and etiology, suggesting the importance role of Wnt/β-Catenin signaling in GC.

Association between genetic variations involved in tumor dormancy related genes and clinical outcomes in Japanese patients with gastric cancer.

43 Background: The major cause of cancer-related death is metastatic growth of disseminated tumor cells (DTCs) from the primary tumor despite approximate resection and adjuvant chemotherapy. Tumor dormancy is a stage in cancer progression in which micrometastases or residual tumor remains occult and asymptomatic until clinical appearance. The regulation of whether DTCs keep to a quiescent state or transit into a proliferative state can be explained through the interaction of the DTCs with the microenvironment, blood supply, and immunosurveillance. This suggests that host genetic background may impact this process. We tested our hypothesis whether polymorphisms involved in tumor dormancy related genes could predict clinical outcomes in gastric cancer (GC). Methods: One-hundred and sixty-nine Japanese patients with histolopathologically confirmed localized GC (stage Ib to IV; AJCC-6th) were enrolled from Kitasato East University Hospital and Fukushima Red Cross Hospital between 2002 and 2010. Twenty-four polymorphisms were selected from VEGF pathway genes, microenvironment related genes, and metastasis suppressor genes. Genomic DNA was extracted from blood or tissue, and all samples were analyzed by PCR-based direct DNA-sequencing. Results: The median age was 68 (31-88) years-old, and 64% of patients were males in this cohort. Pathological stages were 17% in stage Ib, 31% in stage II, 36% in stage III, and 17% in stage IV,. Almost all patients received D2 lymphadectomy based surgery and 65% patients received S-1 based adjuvant chemotherapy. The median follow-up periods were 4.0 years. NME1 rs2302254 was associated with significantly shorter disease-free survival (HR 1.555; 95%CI, 1.026-2.359; p=0.032). NME1 rs34214448 (HR 1.732; 95%CI, 1.082-2.770; p=0.036), PAI1 rs1799889 (HR 1.855; 95%CI, 1.032-3.333; p=0.02), and VEGF-A rs699946 (HR 1.678; 95%CI, 1.014-2.778; P=0.042) were associated with significantly shorter overall survival. Conclusions: NME1 rs2302254 may predict early recurrence of Japanese patients with GC. Additionally, survival after recurrence could be influenced by angiogenic factors in a synergic manner.

Adjuvant Therapy in Gastric Cancer: What Is The Optimal Approach?

Gastric cancer confers a poor prognosis even when diagnosed as localized disease. Multimodality therapy improves the cure rate of patients with localized cancer. However, adjunctive therapeutic approaches differ in different regions of the world. This review focuses on the current standards and unresolved issues based on updated literature on therapy for localized gastric cancer. In the USA, the Intergroup 0116 trial established the use of postoperative chemoradiotherapy as a standard for patients who have surgery first for treatment of gastric cancer. In Europe, the MAGIC trial investigating perioperative chemotherapy demonstrated a survival benefit for gastric cancer patients. Finally, in Asia, the ACTS-GC and CLASSIC trials investigating postoperative chemotherapy established this as the standard of care after primary surgery that included D2 dissection. It is clear, however, that surgery alone is insufficient to achieve the highest possible cure rates.

Management of localized gastric cancer

Gastric cancer continues to be a fatal disease with majority of cases presenting in late stages. For patients with advanced disease, we can only recommend palliative therapy. For localized gastric cancer, the approaches vary in various regions of the world. In western countries, preoperative chemotherapy or adjuvant chemo-radiation is preferred; however in Asia, surgery followed by adjuvant chemotherapy is favored. The extent of the lymph node dissection also varies by region. D2 gastrectomy is difficult to implement in most western countries while it is standardized and is a routine in Asia. We recommend multidisciplinary evaluation of each patient before starting any therapy. The prognosis after resection depends of the pathologic stage. Long-term survivors are often <50% in the West and <70% in many Asian countries. Regional and systemic recurrences are common. Improved systemic treatments are needed. Detailed studies of molecular biology might uncover novel therapeutic targets and prognostic subgroups.

Neoadjuvant Treatment for Gastric Cancer

Surgery is still considered to be the mainstay for the treatment of localized gastric cancer with negative margins (R0-resection) and an adequate lymph-node-dissection (D2-lymphadenectomy). Unfortunately, most cases of gastric cancer are only diagnosed at an advanced stage due to frequent recurrences after primary resection in curative intent. In order to improve prognosis after curative resection, in the recent past, patients with locally advanced tumors were subjected to a pre-, peri-, or postoperative treatment. Interestingly, postoperative chemotherapy has significantly improved survival after gastric resection in Asia, adjuvant radiochemotherapy is favored in North America and perioperative chemotherapy is considered as a treatment of choice in Europe indicating region specific approach towards the treatment. Recently there has also been growing evidence of positive outcomes of neoadjuvant radiochemotherapy on patient survival. In the present article, we discuss the concepts of neoadjuvant treatment approach and provide recommendations to surgeons based on current evidence.

Performance of Different Gastric Cancer Screening Methods in Korea: A Population-Based Study

BackgroundThere is a lack of agreement on which gastric cancer screening method is the most effective in the general population. The present study compared the relative performance of upper-gastrointestinal series (UGIS) and endoscopy screening for gastric cancer.MethodsA population-based study was conducted using the National Cancer Screening Program (NCSP) database. We analyzed data on 2,690,731 men and women in Korea who underwent either UGIS or endoscopy screening for gastric cancer between January 1, 2002 and December 31, 2005. Final gastric cancer diagnosis was ascertained through linkage with the Korean Central Cancer Registry. We calculated positivity rate, gastric cancer detection rate, interval cancer rate, sensitivity, specificity, and positive predictive value of UGIS and endoscopy screening.ResultsThe positivity rates for UGIS and endoscopy screening were 39.7 and 42.1 per 1,000 screenings, respectively. Gastric cancer detection rates were 0.68 and 2.61 per 1,000 screenings, respectively. In total, 2,067 interval cancers occurred within 1 year of a negative UGIS screening result (rate, 1.17/1,000) and 1,083 after a negative endoscopy screening result (rate, 1.17/1,000). The sensitivity of UGIS and endoscopy screening to detect gastric cancer was 36.7 and 69.0%, respectively, and specificity was 96.1 and 96.0%. The sensitivity of endoscopy screening to detect localized gastric cancer was 65.7%, which was statistically significantly higher than that of UGIS screening.ConclusionOverall, endoscopy performed better than UGIS in the NCSP for gastric cancer. Further evaluation of the impact of these screening methods should take into account the corresponding costs and reduction in mortality.

An update of adjuvant treatments for localized advanced gastric cancer

Although adjuvant therapy has become the standard of care worldwide for resectable localized gastric cancer, geographic differences exist in standard adjuvant treatments: postoperative chemoradiation in North America, perioperative chemotherapy in Europe, and postoperative chemotherapy in East Asia. Global differences in standard surgical methods or study populations may influence the discrepancies in adjuvant therapy. However, now that D2 gastrectomy has been recognized as the optimal surgery for localized gastric cancer in the West, the standard adjuvant treatments used may need to be reconsidered. One of the most pertinent issues surrounding adjuvant therapy is how to improve the outcomes of current standard treatments. Negative results of recent Phase III trials suggest that simply intensifying the adjuvant chemotherapy is insufficient to enhance its efficacy in patients with localized gastric cancer. However, the AMC 0101 study showed that new strategies, such as the early initiation of chemotherapy ...

Malignant gastric cancer cured by short-term chemotherapy and long-term use of combined chinese medicine: A case report

Introduction Gastric cancer is still a major health problem and a leading cause of cancer mortality despite the worldwide decline in incidence.Surgery is the only potentially curative treatment for localized gastric cancer and radical gastrectomy with extended lymphadenectomy is now recognized as a reasonably safe procedure in experienced centers.Adenocarcinoma(ADC) represents 95%of the total number of gastric malignancies.Two histologic classifications are

Localized Gastric Cancer Treated with Chemoradation without Surgery: UTMD Anderson Cancer Center Experience

Background: In patients with localized gastric cancer (LGC) who are unfit for surgery, decline surgery, or have unresectable cancer, chemoradiotherapy may provide palliation; however, data in the literature are sparse. Methods: We identified 66 LGC patients who had definitive chemoradiation but no surgery. All patients had baseline and postchemoradiation staging including an endoscopic biopsy. Multiple statistical methods were used to analyze outcomes. Results: Most patients were men and most had stage III or IV cancer. Five patients were surgery eligible but declined to have surgery. The median follow-up time was 33.9 months (95% CI 18.3–49.6). The median survival time (MST) for 66 patients was only 14.5 months (95% CI 10.8–19.7) and the median relapse-free survival (RFS) was 5.03 months (95% CI 4.67–6.40). The estimated overall survival (OS) and RFS rates at 3 years were 22.6% (95% CI 13.7–37.3) and 7.7% (95% CI 3.2–18.6), respectively. Twenty-three (35%) patients who achieved a clinical complete response (cCR; negative postchemoradiation biopsy and no progression by imaging) fared better than those who achieved less than cCR (<cCR) [cCR: MST 30.7 months (95% CI 20.4–NA); <cCR: MST 10.6 months (95% CI 8.43–14.9); p < 001]. In multivariate analysis, cCR was the only independent prognosticator for OS [hazard ratio (HR) = 0.32, p < 0.0012] and RFS (HR = 0.12, p < 0.0001). Conclusion: Our data demonstrate that in the absence of surgery, outcomes with definitive chemoradiation are only modest. A third of the patients achieved cCR and had a longer OS and RFS than those who achieved <cCR.

Adjuvant Treatments for Localized Advanced Gastric Cancer: Differences among Geographic Regions

After much debate, adjuvant therapy has become the standard of care worldwide for resected localized gastric cancer. However, geographic differences exist in standard adjuvant treatments: postoperative chemoradiation in North America, perioperative chemotherapy in the United Kingdom, and postoperative chemotherapy in East Asia. Now that D2 gastrectomy has been recognized as the optimal surgery for localized gastric cancer in the West as well as in Asia, the standard adjuvant treatments used in the West may need to be reconsidered. One of the most important issues in adjuvant therapy for localized gastric cancer is how to improve the clinical outcomes of current standard treatments. Recent Cancer and Leukemia Group B (CALGB) and AMC studies suggest that simply intensifying chemotherapy by adding more agents or prolonging treatment duration is insufficient. However, new strategies like early initiation of chemotherapy and/or intraperitoneal chemotherapy may further improve the current standard adjuvant therapy. In the era of targeted therapy, the role of biologic agents for gastric cancer should also be explored in the adjuvant setting. With a deeper understanding of the molecular biology of gastric cancer, adjuvant therapy for patients with localized gastric cancer can be optimized and individualized.

MEK/ERK pathway characterization and its prognostic implication in gastric cancer (GC).

e14552 Background: MEK/ERK pathway is considered one of the main controllers of cell proliferation and survival and its deregulation has been involved in several tumors. Different mechanisms have been described leading to ERK activation and nuclear translocation including mutations on genes encoding pathway constituents', or upstream factors overexpression. Little is known about the status of this pathway in GC. The aim of our study was to evaluate the expression of different factors of this pathway in GC and their correlation with patient outcome. Methods: Fifty-eight patients with localized stage Ib-III GC who underwent radical surgery followed by adjuvant chemoradiotherapy were selected. ERK and its activated form (pERK) expression were analyzed by IHC, and KRAS and BRAF mutations were determined by PCR. Additionally, expression of upstream factors such as EGFR, HER2, VEGFR and downstream factor such as MST2 was evaluated by IHC. Finally, EGFR and HER2 copy number alterations were analyzed by FISH. Association of these markers to overall survival was assessed using the log rank test, and survival curves were plotted with Kaplan-Meier methodology. Results: Among the 58 tumors analyzed, 7% arose from the cardias and 33% corresponded to signet ring cell carcinomas. ERK and pERK expression was observed in the majority of tumors (86 and 64%, respectively, p=0.002). Cytoplasmic pERK expression did not show any association with the clinico-pathological characteristics. Notably, nuclear pERK (pERKnc) expression was observed in 12% of the cases and it showed a significant correlation with patient survival (p=0.05), conferring a worse prognosis. Moreover, EGFR overexpression (p=0.03) correlated with pERKnc. Finally, multivariate Cox analysis for survival confirmed that stage (HR 0.31, p=0.01) and pERKnc (HR 2.7, p=0.04) are unique independent prognostic factors. Conclusions: MEK/ERK pathway is commonly activated in localized GC, backed up by ERK and pERK being highly expressed in these tumors. Moreover, EGFR expression correlates with nuclear ERK expression, suggesting that ERK translocation to the nucleus could be mediated by this factor. More importantly, nuclear ERK has appeared as an independent marker of poor prognosis.

Correlation between classical prognostic factors and overexpression of HER2 and HER3 in localized gastric cancer.

e14589 Background: Although HER2 overexpression has been identified as a predictive factor for targeted therapy in advanced gastric cancer (GC), little is known about its role in localized GC. Recent studies suggest that not only HER2 but also HER3 might have a role in prognosis in GC. Our study aimed to identify the prevalence of HER2 and HER3 overexpression in a series of localized GC and to describe correlations of these with traditional prognostic factors Methods: We performed a retrospective analysis of HER2 and HER3 overexpression in archived tumour samples in pts diagnosed with GC at stage I-III. HER2 was assessed with herceptest, (negative if 0 or 1+, or positive with 2+ or 3+). Staining of HER3 was determined with the Rajkumar score (HER3+ when score &gt; or = 8). Correlation between the HER receptors expression and the clinicopathologic parameters was statistically analyzed. Statistical analysis of the correlation of HER2 and HER3 with other variables was performed with chi-square test or with the Mann Witney U for continuous variables. Impact on survival was analysed with Kaplan-Meier and log-rank tests. Results: From Jan 2003 to Sep 2011, 125 patients with clinical stage I-III GC were included. Median age was 73 years (35-91) and most frequent location was antrum (47.2%). Up to 43.2% of the patients were treated with preoperative chemotherapy. HER2 was + in 18 patients (14.4%) and HER3 in 38 (30.4%). HER2 was more likely to be overexpressed in older patients (median age: 78.4 vs 68.4; p&lt;0.0001) and in low grade adenocarcinomas (grade 1-2: 13.8% vs grade 3: 1.1%; p=0.006). HER3 was more frequently overexpressed at advanced stages (I and IIA: 10.3% vs IIB and III: 20.3%; p=0.004) and in adenocarcinoma with intestinal subtype (intestinal: 21.4% vs difuse/mixed: 8.5%; p=0.03) or without evidence of signet ring cells (absent: 26.8% vs present: 4.1%; p=0.03) . HER2 and HER3 were significantly related (p=0.0012) with an OR of 3,52 times more frequently HER3+, if HER2 was +. No significant impact was shown in survival for either HER2 or HER3. Conclusions: HER2 and HER3 overexpression seems to identify a particular subgroup of patients with favourable classical prognostic factors.

A prospective evaluation of the utility of 2‐deoxy‐2‐[18F]fluoro‐D‐glucose positron emission tomography and computed tomography in staging locally advanced gastric cancer

The aim of this study was to examine prospectively the utility of adding preoperative [(18) F]fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) to routine CT, endoscopic ultrasound (EUS), and laparoscopic staging of localized gastric cancer. Patients with locally advanced gastric/gastroesophageal cancer were screened for 2 institutional review board-approved Memorial Sloan-Kettering Cancer Center neoadjuvant chemotherapy protocols. Locally advanced disease was defined as T3 or T4, or lymph node-positive, based on EUS and high-resolution CT scan. All patients underwent both standard FDG-PET/CT and laparoscopy with cytological examination of washings. The sensitivity and specificity of FDG-PET/CT for the identification of metastatic disease not seen on CT was determined. An economic model using Medicare/Medicaid reimbursement charges was developed to assess the cost-effectiveness of these interventions. A total of 113 patients were enrolled from 2003 to 2010. All patients were assessed as having locally advanced disease by CT/EUS. FDG uptake in the primary tumor was associated with male sex, proximal tumors, and nondiffuse Lauren's subtype. 31 (27%) patients had occult metastatic disease detected by PET/CT (n = 11, 10%) and/or laparoscopy (n = 21, 19%), with a single overlap. Economic modeling suggests that the addition of FDG-PET/CT to the standard staging evaluation of patients with locally advanced gastric cancer resulted in an estimated cost savings of ∼US $13,000 per patient. FDG-PET/CT identifies occult metastatic lesions in approximately 10% of patients with locally advanced gastric cancer. Because of reduced morbidity from fewer futile surgeries and lower patient care costs, PET/CT should be considered as a component of the standard staging algorithm for localized gastric cancer.

Localized gastric cancer—a CLASSIC shift in the paradigm?

The management of localized gastric cancer has evolved globally to region-specific approaches with little convergence. The unifying theme, however, is that surgery alone is insufficient for best outcomes, and adjunctive therapy must be offered. Multidisciplinary evaluation before therapy is highly recommended, but postoperative approaches are not conducive to this scenario.

Infectious complication and recurrence after surgery for gastric cancer.

85 Background: There are many known prognostic indicators following surgery for gastric cancer. However, the impact of infectious complication on prognosis is less clear. The aim of the present study was to evaluate the relationship between infectious complication and relapse-free survival in patients undergoing potentially curative resection of gastric cancer. Methods: A consecutive series of 657 patients who underwent macroscopically curative resection between 2000 and 2005 in Kanagawa Cancer Center were retrospectively studied. Five-year relapse-free survival rates in each stages (TNM7th) were calculated. Infectious complications (≥Grage2 by Clavien-Dindo classification) were classified as pneumonia, anastomotic leakage, intra-abdominal abscess, septicaemia, colitis, pancreatic-fistula, and wound infection. Results: Mean age was 61 years; male-female ration was 4:1; the number of patients in TNM7th stages were I :389, II :93, III :116, and IV :59. Infectious complications occurred in 57 patients (8.7%) including 8.5% in stage I, 3.2% in stage II, 12.1% in stage III, and 11.9% in stage IV, respectively. Five-year relapse-free survival rates in patients without infectious complications and with infectious complications were 93.1% vs 81.6% in stage I, 84.4% and 100% in stage II, 55.8% and 28.6% in stage III, and 9% and 0% in stage IV, respectively. In stage III, patients with infectious complication had significantly poorer outcome in relapse-free survival compared with those without one (p&lt;0.05). Conclusions: This study indicates a correlation between infectious complications and cancer recurrence in advanced but localized gastric cancer. Immunologic response of the host against postoperative infection could influence the viability of microscopic residual disease. Further clinical and basic study are needed to improve outcome for this category of patients.

Use of genetic variants of LMTK3 to predict tumor recurrence in female localized gastric adenocarcinoma.

63 Background: Previous study suggests that high basal Lemur Tyrosine Kinase 3 (LMTK3) expression was associated with advanced stage of primary breast cancers as well as decreased overall and disease-free survival. LMTK3 was also found overexpressed in gastric cancer. Our previous data showed the mutant variants of two single nucleotide polymorphisms (SNPs) in LMTK3 (rs8108419 and rs9989661) were independently associated with reduced time to tumor recurrence (TTR) in colon cancer (CC). We hypothesized that LMTK3 rs808419 and rs9989661 may predict TTR in a cohort of localized gastric cancer patients. Methods: Either blood or FFPE tissue specimens obtained from 137 localized (stage Ib-IV) GA patients (54 females and 83 males) were included in this study. All patients were treated with surgery alone or surgery and adjuvant (radio)-chemotherapy at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC), the Los Angeles County/University of Southern California Medical Center, or the Memorial Sloan-Kettering Cancer Center from 1992 to 2008. The median follow-up was 3.3 years. LMTK3 rs8108419 and rs9989661 were determined by PCR-RFLP. The primary endpoint of the study was TTR. Results: LMTK3 rs9989661 was significantly associated with TTR in females GA patients. Female patients with minor C allele (TC or CC) (n=25) of LMTK3 rs9989661 showed significantly longer median TTR=7.0 (95%CI: 2.1-8.3+) years compared to those harboring homozygous TT genotype. (n=28), TTR=1.7 (95%CI: 0.7-7.0+) years.( log-rank p=0.025; univariate analysis). After Cox proportional hazards model adjustment for stage and type of adjuvant chemotherapy, this result remained significant (HR: 0.14, 95%CI: 0.02-0.94, multivariate Wald p value = 0.043 in the dominant model). No significant association was found between TTR and LMTK3 rs9989661 in men and rs8108419 in both genders. Conclusions: This pilot study demonstrating LMTK3 rs9989661 may be potential molecular marker to predict TTR in female localized GA. Larger prospective trials are warranted to confirm these findings, and in vitro and in vivo studies are needed to identify the underlying biological mechanism.

Predictive V16alue of Thymidylate Synthase Expression in Gastric Cancer: A Systematic Review with Meta-analysis

The relationship between thymidylate synthase (TS) expression and outcomes in gastric cancer (GC) patients remains controversial, although most studies reported poor survival and reduced response to fluoropyrimidine were related to high TS in tumors. We carried out a systematic review of the literature with meta-analysis to estimate the predictive value of TS expression from published studies. We identified 24 studies analysing the outcome data in gastric cancer stratified by TS expression. Effect measures of outcome were hazard ratios (HRs) for overall survival (OS) and event-free survival (EFS), or the odds ratio (OR) for overall response rate (ORR). HRs and ORs from these eligible studies were pooled using random-effects meta- analysis. Fifteen studies investigated outcomes in a total of 844 patients with advanced GC, and nine studies investigated outcomes in a total of 1,235 patients with localized GC undergoing adjuvant therapy. Meta- analysis of estimates showed high TS expression was significantly associated with poor OS in the advanced setting (HR: 1.43, 95%CI: 1.08 - 1.90), and poor EFS in the adjuvant setting (HR: 1.53, 95%CI: 1.01 - 2.32). Subgroup analysis demonstrated TS expression to have even greater value in predicting OS, EFS and ORR in advanced GC patients treated with fluoropyrimidine monotherapy (HR for OS: 2.32, 95%CI: 1.53 - 3.50; HR for EFS: 1.76, 95%CI: 1.19 - 2.60; OR for ORR: 0.32, 95%CI: 0.11 - 0.95). High levels of TS expression were associated with a poorer OS for advanced GC patients compared with low levels. In the adjuvant setting, high TS expression was also associated with a worse EFS. Additional studies with consistent methodology are needed to define the precise predictive value of TS.

Adjuvant Chemotherapy in Gastric Cancer

Gastric cancer remains the second most common malignancy worldwide. Surgical resection with D2 lymph node dissection is the standard of care in localized gastric cancer. However about 40% of patients in East Asia and 70% of patients in Western countries experience recurrence after curative surgical resection of localized gastric cancer. Once recurrence occurs, the prognosis of patients is usually dismal, especially in case of distant metastases. Although many clinical trials of adjuvant treatment were conducted to reduce recurrence of gastric cancer after surgical resection, it was controversial until early 2000s whether adjuvant treatment could improve recurrence-free survival or overall survival in gastric cancer. In early 2000s, adjuvant chemoradiation became the standard of care in the US based on the results of SWOG 9008/INT 0116 trial, where only minor portion of patients underwent D2 lymph node dissection. However, adjuvant chemoradiation was considered not applicable to patients with gastric cancer in East Asia where D2 lymph node dissection is the standard surgical method. Recently, large scale phase III studies including ACTS-GC and CLASSIC trial were conducted in the East Asia. Based on those studies, adjuvant chemotherapy is currently accepted as standard treatment in gastric cancer in the East Asia. (Korean J Med 2012;83:291-296)