Family History As a Positive Prognostic Factor in Gastric Cancer

Abstract

Conflicting reports have created controversy with respect to the effects of a positive family history on the survival of patients who are diagnosed with gastric cancer. Previously, Yatsuya et al reported that a positive family history of gastric cancer was negatively associated with patient survival. Other studies have reported that family history either reduces or has no effect on the risk of death from gastric cancer. In the article that accompanies this editorial, Han et al report on a study that seeks to clarify the relationship between a positive family history and survival of gastric cancer in a large, retrospective review of surgical cases from Korea. The authors retrospectively evaluated 1,273 Korean patients with gastric cancer for the presence of firstor second-degree relatives with any cancer. Results were reported for percentage of patients with first-degree relatives with any cancer (38.6%) or cancer type, including gastric cancer (20.6%). The authors reported a statistically significant improvement in disease-free survival, recurrence-free survival, and overall survival at 5 years for patients with a first-degree family history of gastric cancer compared with those without a positive family history of gastric cancer. These findings are similar to reports in other cancer types (ie, breast and colon) in which a positive family history is associated with improved prognosis. In addition, these results are most consistent with those previously reported by Yatsuya et al wherein a family history of gastric cancer was associated with improved patient survival. This study confirms that a positive family history of gastric cancer is clinically significant and prognostically favorable. These conclusions carry important implications for the families of individuals who are diagnosed with gastric cancer because it affects the mode of screening in first-degree family members, particularly in Asia where individuals with a first-degree family history of gastric cancer undergo more strict screening programs. This study also serves as a reminder of the importance of obtaining a detailed family history, which continues to be something of a lost art. Indeed, a history of cancer in firstor second-degree relatives has important implications for patients and for their family members who would potentially be candidates for more aggressive screening measures, particularly in cases of familial colon, breast, gastric, and other cancers. Despite the new insights about the significance of family history in gastric cancer that are provided by this study, we are left to wonder about the mechanism by which a positive history affects prognosis. Several potential explanations exist, including the possibility that individuals with a family history of gastric cancer share a genetic predisposition for their improved survival. For example, the presence of microsatellite instability (MSI) is a hallmark of all patients with hereditary nonpolyposis colon cancer and is present in 15% of sporadic colon cancers. Furthermore, MSI in colorectal cancer is positively associated with patient survival. MSI also serves as a negative predictive marker for response to treatment in patients with colorectal cancer. The role of MSI has been investigated in gastric cancer and is identified in 13% to 44% of sporadic tumors. Although a trend toward improved survival in MSI-high gastric cancer has been noted in several studies, these observations have not consistently reached statistical significance, and thus it is unclear whether the presence of MSI in gastric tumors serves as a prognostic or predictive indicator as it does in colon cancer. Additional studies are required to definitively determine whether the superior prognosis that has been observed in patients with a positive family history of gastric cancer is attributable to underlying genetic differences such as MSI or other genetic characteristics yet to be identified. The risk of developing gastric cancer is influenced by both genetic and environmental factors. Gastric adenocarcinoma is observed as part of inherited cancer syndromes that include Li-Fraumeni, hereditary nonpolyposis colon cancer, familial adenomatous polyposis, Peutz-Jeghers, and hereditary diffuse gastric cancer. Hereditary diffuse gastric cancer is an inherited gastric cancer predisposition syndrome that is associated with germline transmission of a CDH1 mutation and confers an approximate 75% lifetime risk of developing diffuse-type gastric cancer. Women with CDH1 germline mutations also carry an approximate 40% lifetime risk of developing lobular breast cancer. In contrast, environmental factors such as Helicobacter pylori (H pylori) infection, which confers an approximate five-fold increased risk of developing gastric cancer (primarily intestinal type), significantly affect gastric cancer risk. However, the role of H pylori infection in gastric cancer does not seem to be strictly environmental. Some evidence suggests that genetic factors contribute to an individual’s risk of developing gastric cancer after infection with H pylori. It will be important to determine whether a family history of H pylori infection and gastric cancer influences patient survival in a similar fashion. Additional explanations for the observed differences in prognosis for patients with a family history of gastric adenocarcinoma compared with those without such a history include behavioral differences and variable adherence to screening. A history of tobacco or alcohol use, as noted by the authors, is associated with a poorer prognosis in patients with gastric cancer. The study by Han et al identified a higher rate of smoking cessation and alcoholic consumption in patients with a firstdegree family history, which suggests that this health-related behavioral difference might influence the reported results. In contrast, the rate of adherence to screening recommendations was not observed to be different among those with a first-degree family history of gastric cancer (although this observation did not achieve statistical significance), which suggests that differential adherence to screening cannot account for the observed survival benefit. Editorials