Risks and Benefits of Risk-Reducing Surgery in Inherited Breast and Gastric Cancer Susceptibility

rophylactic risk-reducing surgery has been earlier suggested effective to improve survival in individuals selected on the basis of a strong family history. Now, genetic increasing the accuracy of cancer risk estimates allows surgery to target individuals with CDH1 or BRCA1/BRCA2 mutations who are at high risk of developing gastric cancer and breast cancer respectively. Here, we discuss the reinvigorated role of prophylactic surgery in the management of hereditary diffuse gastric cancer (HDGC) and inherited breast cancer syndromes. Conventional surgery in the treatment of solid tumors suggests a recently declining trend. Endoscopic and laparoscopic techniques are increasingly replacing traditional surgery as both rates of early detection and minimally invasive treatment are steadily increasing. Premalignant lesions and early-stage small cancers confined to the mucosal layer along the whole gastrointestinal tract from esophagus and stomach to the colorectum can now curatively be resected by minimally invasive techniques substantially improving the quality of life of many patients. In contrast, traditional surgical resection of specific organs for the protection of individuals at very high risk of developing inherited cancer in the breast, colon, and stomach is increasingly receiving considerable attention. However, although surgery is the only preventive intervention able to eliminate the risk of cancer at a specific organ, surgical prophylaxis has been controversial for a numerous of reasons and questions have been raised. Here we discuss the benefits and obstacles of prophylactic surgery. Hereditary cancer syndromes are rare. They account for less than 5% of all cases because most breast, colon or gastric adenocarcinomas occur sporadically. These syndromes include hereditary nonpolyposis colon cancer syndrome (HNPCC), Peutz-Jeghers syndrome, Cowden's syndrome, and some kindreds affected with Li-Fraumeni syndrome and familial adenomatous polyposis. Germ-line mutations in BRCA1 and BRCA2 genes have been identified, 8 gears ago, to cause hereditary breast-ovarian cancer syndrome. Recently, the hereditary diffuse gastric cancer (HDGC) syndrome, which is an autosomal dominantly inherited gastric cancer susceptibility syndrome caused by germ-line mutations in CDH1, the gene encoding E-cadherin, has been added in the list of these syndromes. Surgery in the prophylaxis of multiple-cases family members is not an innovative approach. Prophylactic bilateral mastectomy in women with a family history of breast cancer has been previously performed and proposed as effective in reducing the risk of breast cancer. However, this preventive approach has been strongly criticized, particularly because surgery may be nontherapeutic and thus, unnecessarily performed in many women selected on the basis of family history and clinical criteria. By contrast, genetic testing provides a more accurate risk assessment allowing surgery to target individuals who are really at very high risk of cancer. Indeed, estimates indicate that only 25% among members of the families with hereditary breast-ovarian cancer or diffuse gastric cancer syndrome, are carriers of mutations in BRCA and CDH1 genes respectively. The knowledge of the probability that cancer will in fact develop in a carrier of a particular mutation -the penetrance of the mutationis essential in the clinical management of these high-risk persons. Women with mutations in BRCA1 and BRCA2 genes have a cumulative lifetime risk of 50% to 85% for breast cancer and a 10% to 40% risk of ovarian cancer. Carriers of a mutation in CDH1 gene are thought to have an approximately 70% lifetime risk of gastric cancer;' 67% for men and 83% for women who had an additional risk of 39% for breast cancer. This high risk of breast-ovarian cancer and gastric cancer in carriers of mutations in BRCA and CDH1 genes, the ineffectiveness of surveillance and the high lethality by late diagnosis are the main argues for the recommendation of prophylactic surgery as a reasonable strategy. Several current studies validate this prevention option. In a recent study of 119 women carrying BRCA mutations, breast cancer at three-year period developed in 8 Gastric Breast Cancer 2002; 1(3): 64-66