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Most (but not all) individuals who are candidates for prophylactic surgery have a hereditary predisposition for cancer, and the wider use of genetic testing has identified greater numbers of these individuals. For individuals with a hereditary predisposition for cancer, it is important to emphasize that there are no randomized prospective studies that have addressed the impact of prophylactic surgery on outcomes. Thus, the efficacy of prophylactic surgery is not fully understood, and patients should be fully informed of its potential risks and benefits.

The multistage process of genetic alteration forms the basis of malignant transformation and results from either inherited (germline) or acquired (somatic) mutations in cellular genes. Germ line mutations are present within all cells, whereas somatic mutations affect only individual cells within a particular tissue. Hereditary cancers are attributable to inherited or germ line mutations and a better understanding of these cancers has led to improved knowledge about key genes involved in tumor formation.

Most human cancers are a consequence of somatic mutations, with only 1% due to preexistent germ line mutations. According to Knudson's “two-hit” hypothesis, individuals with an inherited cancer predisposition already possess a mutation in 1 allele and thus require only 1 further somatic mutation for tumor formation. Individuals who have a genetic predisposition for breast, gastric, thyroid, and colorectal cancers may now wish to consider prophylactic surgery to reduce their cancer risk. Indeed, the role of surgery as a potential means of preventing these cancers has expanded dramatically in recent years.

In the USA, a woman's lifetime risk of breast cancer is approximately 12.7%, and women with a substantially greater risk than this may wish to consider bilateral prophylactic mastectomy (BPM) to reduce their risk. Thus, women who carry gene mutations that increase breast cancer risk, those with a very strong family history of breast cancer but no identifiable mutation, and women with a very strong family history of breast cancer who refuse genetic testing may all wish to consider BPM. In the USA, approximately 5% to 10% of all breast cancers occur in women who carry gene mutations that increase their risk for the disease. The 2 genes most commonly responsible are the breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2). However, mutations in other genes have been associated with breast cancer as well, including those in the p53, PTEN, STK11/LKB1, CDH1, ATM, and CHEK 2 genes. The lifetime risk of breast cancer (penetrance) varies considerably among these mutation carriers. The high penetrance mutations (eg, BRCA1, BRCA2, p53, PTEN, STK 11, LKB 1, CDH 1) are generally associated with a breast cancer lifetime risk ranging from 40% to 85%, whereas the low penetrance mutations (eg, ATM, CHEK 2) are associated with a lifetime risk below 40%. It should be noted that these mutations not only increase a woman's risk for breast cancer, but other cancers and diseases as well. For example, BRCA mutation carriers are also at increased risk for ovarian cancer, and that risk is approximately 40% and 20% for the BRCA1 and BRCA2 mutation carriers, respectively.

Women who have a hereditary predisposition for breast cancer may consider 3 options to reduce their risk: screening, chemoprevention, and prophylactic surgery. No randomized prospective studies have assessed the efficacy of BPM. However, retrospective and nonrandomized prospective studies suggest that BPM reduces breast cancer risk by approximately 90%. Additionally, premenopausal BRCA mutation carriers may reduce their breast cancer risk by approximately 50% with prophylactic salpingo-ophorectomy. A few studies also seem to suggest that BPM substantially reduces breast cancer mortality.

Following diagnosis of unilateral breast cancer, the risk of a cancer diagnosis in the contralateral breast is greatly increased. For women with BRCA mutations, the risk of developing a contralateral breast cancer is extremely high, approximately 39% at 15 years. Thus, these women may wish to consider contralateral prophylactic mastectomy. Again, there are no randomized prospective studies that have assessed the efficacy of contralateral prophylactic mastectomy, but there are retrospective studies suggesting that it may reduce the risk of contralateral breast cancer, and the risk of death from breast cancer.

Although the incidence of gastric cancer has decreased steadily over the past 5 decades, it is still the second most common cause of cancer death worldwide. There are 2 major histologic types of gastric cancer: 1) intestinal, which is the more common variant and has a strong association with environmental factors; and 2) diffuse gastric cancer, which is characterized by multifocal signet ring cell infiltrates and is more likely to be attributed to host-factor effects. Approximately 10% of all gastric cancers have family clustering indicating a genetic predisposition.

Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant cancer syndrome with 70% to 80% penetrance attributed to mutations of the E-cadherin gene, CDH1. In 1999, the International Gastric Cancer Linkage Consortium defined HDGC as “(1) two or more documented cases of diffuse gastric cancer in first/second degree relatives, with at least one diagnosed before the age of 50, or (2) three or more cases of documented diffuse gastric cancer in first/second degree relatives, independently of age of onset.” Approximately 40% of well-defined HDGC families may be found to harbor CDH1 mutations. Women carrying the mutation also have an approximately 20% to 40% lifetime risk of developing lobular carcinoma of the breast.

Because the signet ring cancer cells in HDGC are located in gastric submucosa, surveillance endoscopy has an unacceptably high false negative rate. There is in fact no effective method for detection of cancer in this patient population. Therefore, prophylactic total gastrectomy is recommended for asymptomatic carriers of CDH1 mutations. Since the discovery of CDH1 gene mutations in 1998, many totally asymptomatic patients from different kindreds with varying CDH1 gene mutations and a family history of HDGC have been treated with prophylactic total gastrectomy. Occult signet ring cell carcinoma foci have been found in the stomach in most of those patients.

The multiple endocrine neoplasia type 2 syndromes (MEN 2) are rare hereditary cancer and endocrinopathy syndromes caused by germ line activating missense mutations in the RET oncogene, a transmembrane receptor tyrosine kinase. Transmission is autosomal-dominant. All of these syndromes share the clinical feature of medullary thyroid carcinoma (MTC), a malignancy of thyroid parafollicular C cells. In these patients, MTC occurs with nearly complete penetrance, is multifocal and bilateral, and occurs at an earlier age than sporadic cases. MTC is associated with multicentric C-cell hyperplasia, with an age-related progression to cancer. MTC arises from thyroid parafollicular C cells, which produce, store, and secrete calcitonin. Patients with locally advanced MTC present with a palpable mass and may have symptoms of dysphagia, shortness of breath, or hoarseness. Metastases to regional cervical lymph nodes are common in patients with palpable, clinically evident thyroid tumors. Other typical metastatic sites include the upper and anterior mediastinum, lungs, liver, and bone. The clinical features of MEN 2 are variably expressed and the presentation differs between the specific syndromes.

The lifetime penetrance of MTC is near 100% in carriers of RET mutations associated with MEN 2 syndromes. Therefore, all patients diagnosed with MEN 2 should undergo total thyroidectomy. Recommendations for the timing and extent of surgery differ based on the patient's age at diagnosis, clinical presentation, and the risk level of their RET mutation.

Colorectal cancer is the third leading cause of new cancer diagnosis and the second leading cause of cancer death in the USA. Most colorectal cancer is sporadic, without an obvious familial predisposition, but there is a portion, as many as 10%, that can be attributed to a heritable cause. Hereditary nonpolyposis colon cancer makes up the largest portion of the inherited colon cancers, followed by familial adenomatous polyposis. In addition to these conditions, nonhereditary diseases, including inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, are associated with increased risk of developing colorectal cancer. Although patients who are at high risk clearly warrant increased screening regimens with colonoscopy, prophylactic resection of the at-risk bowel for the prevention of cancer should be considered.

It has long been recognized that genetic factors play a role in the risk for developing cancer. The understanding has been furthered by the discovery of specific genes involved in certain cancer types. As the role of heritability is appreciated and patients/physicians have a better understanding of an individual's cancer risk, the role to prophylactic surgery increases. Specifically, 5 criteria have been described when considering the potential benefit of prophylactic resection of the colon or rectum: 1) penetrance of a genetic mutation; 2) reliability of genetic screening; 3) effectiveness of surgery with reasonable morbidity; 4) suitable organ replacement; and 5) follow-up screening to verify disease-free state.

Prophylactic surgery for hereditary colon cancer has been described as early as 1901 with the first colectomy being reported for a patient with familial form of polyposis. Since then, the understanding of the role of genetics has evolved as well as the ability to identify specific genetic mutations. With this, the role of prophylactic surgery has become a topic of increasing consideration. Genetic testing is now routinely recommended by the National Comprehensive Cancer Network for patients who meet established criteria for hereditary nonpolyposis colon cancer or familial adenomatous polyposis. Through increased awareness and recommendations such as these, compliance with colonoscopic screening has continued to increase. Moreover, aggressive screening and interventional colonoscopy programs in such high risk individuals have been shown to reduce risk for the development of colorectal cancer. Through regular biopsies and aggressive polypectomies, premalignant lesions can be identified and removed, reducing the risk of progression to colon cancer by as much as 40% to 80%.

Individuals with a hereditary predisposition for breast, gastric, thyroid, and colorectal cancers can now be identified and may wish to consider prophylactic surgery. Nevertheless, there are no randomized trials addressing the efficacy of prophylactic surgery in these individuals, so its full impact is not fully understood. All patients should be informed of the potential risks and benefits of prophylactic surgery, and alternatives (such as screening and chemoprevention) should be considered as well. In the years ahead, additional studies will be required to better elucidate the role of surgery in cancer prevention. In particular, these studies should also address the effect of prophylactic surgery on quality of life.