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Prespecified exploratory biomarker analyses of the phase II/III GATSBY study (NCT01641939) assessed whether patient subgroups experienced a survival benefit from trastuzumab emtansine (T-DM1) versus taxane therapy, and to advance understanding of HER2-positive advanced gastric/gastroesophageal junction cancer (AGC) disease biology. Adults with HER2-positive AGC whose disease progressed during/after first-line therapy were enrolled and randomized to receive T-DM1 [Stage 1: 3.6 mg/kg q3w, 2.4 mg/kg qw, or taxane (docetaxel/paclitaxel); Stage 2: 2.4 mg/kg qw or taxane]. Primary efficacy endpoint was overall survival (OS). Prespecified exploratory biomarkers included HER2, HER3, PTEN, PIK3CA mutation status, FcγR, and cMET. Tumor samples from patients who received 2.4 mg/kg T-DM1 (n = 228) or taxane (n = 117) were included. Median OS was longer in subgroups with HER2 immunohistochemistry (IHC) 3+ [9.5 versus 8.3 months for T-DM1 versus taxane; hazard ratio (HR) 0.99 (95% CI 0.68–1.43)] versus HER2 IHC 2+/in situ hybridization-positive [5.2 versus 9.2 months for T-DM1 versus taxane; HR 1.53 (95% CI 0.94–2.50)] tumors. Trends towards increased median OS were also observed in subgroups with > versus ≤ median HER2 mRNA expression, higher versus lower HER2 gene copy number, HER2 gene ratio and H score, and homogenous or nonfocal HER2 IHC staining. T-DM1 was not associated with superior OS versus taxane in any subgroup. Patients with previously treated HER2-positive AGC with higher HER2 expression experienced a better treatment effect from T-DM1 than those with lower HER2 expression and may derive comparable survival benefits from T-DM1 and taxane therapy. NCT01641939 ( https://clinicaltrials.gov/ct2/show/NCT01641939 ).

BACKGROUND: The benefit of preoperative chemoradiation (CXRT) over preoperative chemotherapy alone (“chemotherapy” hereafter) is unknown. By analyzing the National Cancer Database (NCDB), we investigated whether preoperative CXRT improves the incidence of primary tumor pathologic complete response (ypT0) and overall survival (OS) compared with preoperative chemotherapy in patients with gastric cancer. METHODS: Patients with non-metastatic gastric adenocarcinoma who underwent CXRT or chemotherapy followed by gastrectomy were included. Propensity score matching with a ratio of 1:1 was implemented to reduce selection bias. A conditional logistic regression model was used to compare incidences of ypT0 between groups, and Cox proportional hazards model was used to compare OS. RESULTS: We identified 8,464 patients. Median patient age was 63 years; 76% were male and 79% were white. ypT0 was observed in 16.1% of patients in the CXRT group and 6.6% in the chemotherapy group (p < 0.001). After propensity score matching, a total of 2,408 patients were matched. CXRT was associated with a higher incidence of ypT0 (OR 2.28, 95% CI 1.76–2.95; p < 0.0001) and higher frequency of R0 resection (92% vs. 86%; p < 0.001). However, CXRT was not associated with longer OS (HR 1.03, 95% CI 0.92–1.15; p = 0.63). Safety profiles (30-day mortality, 30-day readmission, and length of hospital stay) were equivalent between groups. CONCLUSIONS: In this study of gastric cancer patients from the NCDB, CXRT was associated with a higher incidence of ypT0 and R0 resection compared with chemotherapy, although it was not associated with a longer OS.

Background: In Western countries, the overall incidence of gastric cancer is declining, while the incidence of proximal gastric cancer is rising. We evaluated the effect of sex, racial/ethnic group, and age on the localization of gastric cancer. Methods: The records of all gastric cancer patients who registered at The University of Texas M. D. Anderson Cancer Center from January 1, 1985, to May 31, 1998, were reviewed. Tissue diagnosis and established tumor location were required. Results: The case records of 1242 eligible patients, consisting of 821 non-Hispanic white, 230 Hispanic, 125 African American, 63 Asian, and 3 Native American patients, were analyzed. Among the 459 women, racial/ethnic group did not have a significant impact on gastric cancer localization ( P = 0.57). However, among the 783 men, proximal cancers were significantly more frequent in the non-Hispanic white patients (57% vs 38% Hispanic, 41% African American, 17% Asian; P < 0.0001). Symptoms at diagnosis significantly varied for proximal vs non-proximal cancers. Conclusion: Proximal gastric cancer localization was more frequent among non-Hispanic white men, while non-Hispanic white women had a localization pattern similar to those of other racial/ethnic groups. Proximal gastric cancer represents a distinct subtype of gastric cancer that may have different biology, risk factors, and clinical behavior.

Laparoscopy has become a useful adjunct for the staging of gastric cancer; yet, other than standard TNM staging, few additional variables can be used to predict survival. This study evaluated the utility of serum and peritoneal tumor markers (carcinoembryonic antigen [CEA] and carbohydrate antigen [CA]-125) as predictors of locoregional recurrence and distant disease-free survival in patients with gastric cancer. Methods. During the period June 1990 to February 1994, 86 patients with gastric cancer were evaluated and deemed resectable by preoperative imaging studies. Serum levels of CEA and CA-125 were determined, and all patients underwent laparoscopic staging. Peritoneal washings were obtained from all patients, and 56 of these samples were evaluated for levels of CEA and CA-125. Results. Sixteen (19%) of the 86 patients were found to have metastatic disease at laparoscopy; 67 of the remaining 70 patients underwent potentially curative gastrectomy. Serum CEA and CA-125 levels were predictive of survival in the entire group of patients. In patients who underwent curative gastrectomy, serum CEA predicted survival, whereas peritoneal CA-125 predicted peritoneal recurrence. Conclusions. Elevated serum levels of CEA and CA-125 are predictive of decreased survival in patients with gastric cancer. Furthermore, determination of peritoneal CA-125 helps to identify those patients at an increased risk for recurrent peritoneal disease.

Gastric cancer is one of the leading causes of cancer death worldwide. Because of its heterogeneity, gastric cancer has been an interesting model for studying carcinogenesis and tumorigenesis. Various genetic and molecular alterations are found in gastric cancer that underlie the malignant transformation of gastric mucosa during the multistep process of gastric cancer pathogenesis. Although the detailed mechanisms of gastric cancer development remain uncertain, the enhancement in understanding of its molecular biology in recent years has led to a better perspective on the molecular epidemiology, carcinogenesis, and pathogenesis of gastric cancer. More importantly, it is becoming possible to use molecular markers in differential diagnosis, prognostic evaluation, and specific clinical interventions. Because multiple molecular alterations are frequently noted in gastric cancer and because its histology is complex, new technologies for studying its molecular biology are important to further evaluate gastric carcinogenesis. This review describes our current knowledge of the molecular basis of gastric cancer as it relates to molecular epidemiology, multiple molecular alterations in pathogenesis, and molecular determinants of invasion and metastasis, as well as their potential clinical applications.