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Case 22-2007: A Woman with a Family History of Gastric and Breast Cancer
Daniel C. Chung, M.D., Sam S. Yoon, M.D., Gregory Y. Lauwers, M.D., and Devanshi Patel, M.S., C.G.C.

Pr e sen tat ion of C a se

A 38-year-old woman was seen in the Gastrointestinal Cancer Genetics Clinic of this hospital because of a family history of breast and gastric cancer. Approximately 15 months earlier, mild chronic gastrointestinal symptoms, including dyspepsia, heartburn, and midabdominal discomfort, increased in severity and began to occur daily. The symptoms did not resolve with antacid therapy. She had lost approximately 2.3 kg (5 lb) during this time, which she attributed to the stress of caring for her maternal aunt, who was dying of gastric cancer. Seven months before admission, an endoscopic examination of the upper gastrointestinal tract, performed at another hospital, was normal. Thiazine staining of the biopsy specimen disclosed no Helicobacter pylori, and a pathological examination of multiple gastric biopsy specimens was negative for cancer. A test for blood in the stool was negative. Protonpump inhibitor therapy, calcium carbonate tablets, and clonazepam were administered; her symptoms improved. Two weeks before evaluation, a repeat upper endoscopic examination with biopsies at the other hospital was normal. One week later, she came to the Gastrointestinal Cancer Genetics Clinic of this hospital. The patient had a family history of multiple malignant tumors (Fig. 1). The patients mother had died of gastric cancer at 33 years of age. Invasive ductal cancer of the right breast had developed in the patients maternal aunt at 58 years of age, and invasive lobular cancer had developed at 66 years of age. When the second breast cancer developed, her aunt was referred for genetic counseling because of the family history of breast and ovarian cancer; testing for mutations in the BRCA1 and BRCA2 genes had shown no abnormality of BRCA1 and a variant of uncertain significance in BRCA2. Diffuse gastric cancer developed in the maternal aunt at 67 years of age, and a well-differentiated pancreatic endocrine cancer was detected at the time of gastrectomy; she died less than 1 year later. The patient had had an eating disorder as a teenager, and she had anxiety and panic attacks. She was gravida 3, para 3, had most recently delivered an infant 14 months earlier, and was still breast-feeding her youngest child. She had had bilateral arthroscopic knee procedures in the past. She had no allergies, drank alcohol rarely, and did not smoke or use illicit drugs. She was married and lived with her husband and children, and she worked as a homemaker. Medications included
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From the Gastroenterology Unit (D.C.C.), the Division of Surgical Oncology and Department of Surgery (S.S.Y.), the Department of Pathology (G.Y.L.), and the Center for Cancer Risk Analysis (D.C.C., D.P.), Massachusetts General Hospital; and the Departments of Medicine (D.C.C.), Surgery (S.S.Y.), and Pathology (G.Y.L.), Harvard Medical School. N Engl J Med 2007;357:283-91.
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Breast cancer Miscellaneous cancer Gastrointestinal cancer Genitourinary cancer 75 Yr 86 Yr Breast cancer, 75 yr 65 Yr Ovarian cancer

65 Yr

80 Yr

45 Yr Cancer?

73 Yr Breast cancer, 66 yr

51 Yr Stomach cancer, 50 yr

81 Yr Breast cancer, 77 yr

78 Yr

24 Yr

58 Yr Breast cancer, 56 yr

68 Yr

33 Yr Stomach cancer, 32 yr

69 Yr

67 Yr Breast cancer, 58 yr Breast cancer, 66 yr Stomach cancer, 67 yr

59 Yr

56 Yr

33 Yr Thyroid cancer, 29 yr

38 Yr

39 Yr

2 5 Yr 3 Yr 1 Yr

Figure 1. Pedigree of the Patients Family. Circles represent female family members, and squares male family members. Slashes indicate persons who died, and the numbers beneath the circles or squares are age at death (if there is a slash) or, for those living, age at the time the pedigree was created. Yellow represents confirmed cancer. The diamond indicates that sex is unknown; the RETAKE 1st AUTHOR: Chung ICM the number of persons represented by the diamond. The patients (arrow) number inside the diamond indicates 2nd of 2 REG breast F FIGURE: maternal aunt had cancer of the right at 581years of age, cancer of the left breast at 66 years of age, and dif3rd CASEand she died at 67 years of age. The Revised fuse gastric cancer at 67 years of age, patients mother had gastric cancer at 32 Line grandmother 4-C EMail SIZE breast cancer at 77 years of age, years of age and died at 33 years of age. The patients maternal had ARTIST: ts H/T H/T 33p9 grandfather had gastric cancer at and the maternal great-grandmother died of ovarian cancer. The patients paternal Enon Combo 50 years of age and died at 51 years of age. The patients brother, 33 years of age, had papillary thyroid cancer at 29 AUTHOR, PLEASE NOTE: years of age. Her father was of German ancestry, and her mother was of German Figure has been redrawn and type has been reset. and English ancestry.
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omeprazole, clonazepam, famotidine, sucralfate, n3 fatty acids, Lactobacillus acidophilus, and vi tamins. On examination, the patient appeared well. The weight was 58 kg (128 lb), the temperature was 36.9C, the pulse was 76 beats per minute, the respirations were 16 breaths per minute, and the blood pressure was 120/60 mm Hg. A rectus diastasis of the abdomen was present, with some excess abdominal skin. The abdomen was soft, without tenderness, distention, or masses. The remainder of the examination was normal. A diagnostic test was performed.
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Differ en t i a l Di agnosis
Hereditary Breast Cancer Syndromes

Ms. Devanshi Patel: The most important step in the diagnosis of a hereditary cancer syndrome is the compilation of a thorough family history of cancer. This is done by identifying all persons in the patients family, all persons with cancer in the family, the types and sites of the cancer, the age of the family member at the time of diagnosis of each cancer, and other phenotypes that can help to delineate cancer syndromes.1 By the use of this method, the pedigree shown in Figure 1 was obtained

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when this 38-year-old woman came to the Cancer Genetics Clinic. The first person in this patients family to seek genetic counseling was her maternal aunt, who had two primary breast cancers. At the time of the diagnosis of the second breast cancer, the maternal aunt was referred to the Center for Medical Genetics at Evanston Northwestern Healthcare, Evanston, Illinois, for risk assessment. Because of the preponderance of breast cancer in the family, with an autosomal dominant pattern of inheritance, hereditary breast cancer syndromes were considered. It is estimated that approximately 7 to 10% of breast cancers have an identifiable heritable component.2,3 Several hereditary syndromes have breast cancer as component tumors; features of the autosomal dominant syndromes are summarized in Table 1. Cowdens disease is associated with both breast and thyroid cancers, both of which were seen in this family, but the family did not exhibit any of the other characteristics of this syndrome. Peutz Jeghers syndrome is associated with breast, ovarian, and gastric cancers, but the family did not have the characteristic mucocutaneous lesions or hamartomatous polyps. The average age of the patient at cancer diagnosis was older than is typical for the LiFraumeni syndrome and none of the other typical LiFraumeni syndrome tumors were present in the family. Hereditary diffuse gastric cancer syndrome was not considered at the time of the maternal aunts presentation, even though there were two gastric cancer diagnoses in the family, because there was no information as to whether the cancers were diffuse on histologic examination. The most common hereditary breast cancer syndrome is hereditary breast and ovarian cancer syndrome. In this family, the confirmed case of ovarian cancer provided support for this diagnosis. Reports have suggested an increased risk of gastric cancer in families with hereditary breast and ovarian cancer syndrome,4 but this link remains unclear. Thus, the family history at that time was most consistent with hereditary breast and ovarian cancer syndrome, and the patients aunt was offered genetic testing to detect mutations in the BRCA1 and BRCA2 genes. The change that was found in BRCA2 (E2175Q) had not been previously reported, and thus was of uncertain clinical significance; the family was advised to manage cancer risks on the basis of family history alone, and no testing to detect the BRCA2 variant was offered to unaffected

relatives. Less than 4 months after the maternal aunt received the results of the BRCA1/2 genetic test, the diagnosis of diffuse gastric cancer was made, and the differential diagnosis was changed.
Hereditary Gastric Cancer Syndromes

Dr. Daniel C. Chung: This 38-year-old woman came to us because of a strong family history of gastric cancer, with some of the cases occurring at a young age; this finding suggests that in addition to a hereditary breast cancer syndrome, the family has a hereditary gastric cancer syndrome. Gastric cancer is the second leading cause of cancer deaths worldwide, but it is less common in the West than in other parts of the world. In the United States, it is the seventh leading cause of cancer death, with about 22,000 cases diagnosed per year and about 11,000 deaths per year.5 There are two major histologic subtypes of gastric cancer: intestinal and diffuse. The intestinal subtype is associated with environmental risk factors including H. pylori infection, smoking, and diets high in salted and cured foods; this subtype has been decreasing in incidence.6 Only 1 to 3% of the cases are probably attributable to a high-penetrance genetic syndrome. Five entities confer a risk of gastric cancer (Table 1), all of which are inherited in an autosomal dominant manner.
Colorectal Cancer Syndromes

The Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer syndrome, is caused by a germ-line mutation in DNA mismatch-repair genes (MSH2, MLH1, or MSH6). It confers a 60 to 80% lifetime risk of colon cancer and a high risk of both uterine and gastric cancers. A 10% lifetime risk of gastric cancer predominantly the intestinal subtype7 is estimated in the Western world, but families of Asian ancestry with the Lynch syndrome have up to a 30% lifetime risk.8 Breast cancer is not a feature of this syndrome; this fact, coupled with the absence of colon cancers in the family, makes the diagnosis of the Lynch syndrome unlikely in this patient. Gastric cancer also occurs in the familial adenomatous polyposis syndrome, which is caused by germ-line mutations in the APC gene. This syndrome is characterized by thousands of colonic adenomatous polyps and a 100% risk of colon cancer unless the patient undergoes a prophylactic colectomy.9 Gastric fundic-gland polyps occur in at least 50% of affected persons.10 These polyps are generally thought to have no precancerous
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Table 1. Hereditary Cancer Syndromes That Include Breast Cancer, Gastric Cancer, or Both. Syndrome Hereditary breast and ovarian cancer Cowdens Gene BRCA1, BRCA2 PTEN Cancers Breast, ovarian Breast, thyroid (nonmedullary), uterine Other Features Pancreatic cancer Mucocutaneous lesions (trichilemmomas, papillomatous papules, facial acral keratoses, mucosal lesions), macrocephaly, LhermitteDuclos disease, hamartomatous gastrointestinal polyps, mental retardation, fibrocystic disease of the breast, lipomas, fibromas, genitourinary tumors

PeutzJeghers

STK11

Esophagus, stomach, small intesHamartomatous gastrointestinal tine, colon, pancreas, lung, breast, polyps, mucocutaneous pigendometrial, ovarian (sex cord), mentation adenoma malignum of the cervix, testicular Sertoli-cell tumors Breast, sarcoma, brain, adrenocortical, leukemia Colon, duodenal, and ampullary tumors Colon, uterine, gastric Childhood cancers Adenomatous polyps of colon, fundic-gland gastric polyps, thyroid cancer, gastric cancer (rare) Ovarian cancer, renal pelvis and ureteral tumors, glioblastoma, sebaceous-skin tumors, smallbowel tumors, biliary-tract tumors

LiFraumeni Familial adenomatous polyposis Lynch (hereditary nonpolyposis colorectal cancer)

TP53 APC

MSH2, MLH1, or MSH6

Hereditary diffuse gastric cancer

CDH1

Diffuse gastric, breast (typically lobular)

potential, but there are case reports of gastric cancer developing in some kindreds, predominantly in families in Asia (Japan or Korea). Again, breast cancer is not a feature of this syndrome, and colonic polyposis was not observed, so this diagnosis is unlikely in this patient. Both breast and gastric cancers can occur in the PeutzJeghers and LiFraumeni syndromes, but both are unlikely, for the reasons indicated by Ms. Patel.
Hereditary Diffuse Gastric Cancer Syndrome

The hereditary diffuse gastric cancer syndrome is caused by a germ-line mutation in the E-cadherin (CDH1) gene; only about 50 families with this syndrome have been reported.11 The gastric cancers in this syndrome are of the diffuse type, and the mean age at the diagnosis of gastric cancer is approximately 40 years. The lifetime risk of gastric cancer is estimated to be 83% in women and 67% in men.12 In contrast to other gastrointestinal cancer syndromes, there is also an important risk of

breast cancer (39% in women), particularly the lobular type. Thus, this syndrome could explain the cancers seen in this family. Before the genetic abnormality was identified, the International Gastric Cancer Linkage Consortium developed clinical criteria for the diagnosis of this syndrome.13 One of two criteria must be met: at least two cases of histologically confirmed diffuse gastric cancer in first- or seconddegree relatives, one of which must have developed before the relative was 50 years of age, or three or more cases of histologically confirmed diffuse gastric cancer in first- or second-degree relatives of any age. This patients family does not strictly fulfill these criteria, because the presence of diffuse gastric cancer was histologically confirmed only in the patients maternal aunt. Only 30 to 50% of families who do fulfill these criteria are found to have a CDH1 germ-line mutation,14 suggesting that in at least half the families, other genes are involved that have not been identified.

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Genetic Testing

When the patients maternal aunt received a diagnosis of gastric cancer, she was offered tests to detect the CDH1 gene. These tests were performed in the laboratory of Dr. David Huntsman15,16 and showed an R732Q mutation resulting in a substitution of glutamine for arginine at amino acid 732. This information was known to the patient and to us at the time of her evaluation in our clinic. We offered this patient germ-line testing for the R732Q mutation that had previously been identified in the family; these tests showed the same mutation in our patient. Mutations in E-cadherin, the protein encoded by the gene CDH1, result in a loss of normal adhesion and an increase in cellular migration and invasion. About 75% of the CDH1 mutations that have been described lead to a premature truncation, a shortened peptide, and a loss of function and immunoreactivity of the protein, which results in failure to identify the protein on immunohistochemical staining of the cancer. The mutation in this family is a missense mutation, rather than a truncating mutation. Missense mutations are not necessarily pathogenic, but the R732Q mutation has been described previously in the literature, and in vitro assays have shown that it is indeed pathogenic.14 This family is described in two reports that will be published elsewhere.15,16 Thus, in this patient with a family history of documented diffuse gastric cancer, a high prevalence of breast cancer, including lobular cancer, and a mutation in the CDH1 gene, the diagnosis of hereditary diffuse gastric cancer syndrome was confirmed. The patients mother was an obligate carrier of the same mutation, since she had gastric cancer at a very young age. It is likely that the patients maternal grandfather, who had gastric cancer, also carried the CDH1 mutation.

Dis cus sion of M a nage men t

Management of the Risk of Gastric Cancer

The care of persons such as our patient with hereditary diffuse gastric cancer syndrome focuses primarily on managing their risk of gastric cancer. The lifetime risks are high, and they are agedependent. By 30 years of age, the risk is approximately 4%, but by 50 years of age, the risk is 21% for men and 46% for women. At all ages, it appears that women have a higher risk of the development

of gastric cancer, and the reason for this remains unknown. As compared with the intestinal type of gastric cancer, environmental factors do not appear to have a major role in diffuse gastric cancers.10 There are two major options for screening for gastric cancer in this patient: surveillance upper endoscopy with random biopsies and prophylactic gastrectomy. No controlled data provide support for either approach, but the momentum has shifted toward prophylactic gastrectomy. In gastrectomy specimens from patients in whom gastrectomy had been performed without a preoperative diagnosis of cancer, histopathological analysis of the entire stomach revealed previously unrecognized cancer in more than 90% of the patients.11,17 These microscopic cancer foci are not visible with conventional white-light endoscopy, are often multifocal, with up to 500 foci per stomach, and can lie beneath a layer of normal epithelium. Thus, prophylactic gastrectomy may be the only way to detect these cancers at an early stage. The timing of gastrectomy in this patient is an important question. Gastric cancers have been reported in teenagers in affected families, so gastrectomy is often offered to patients before their early 20s. Although microscopic foci of cancer are seen in nearly all gastrectomy specimens, even in patients at an early age, the risk of a clinically significant cancer by 50 years of age is less than 50%. Thus, not all of these microscopic cancers pro gress, and the rate at which they do so is variable. Nonetheless, for the time being, the conservative route is to treat each microscopic focus as if it is potentially an invasive cancer. Are there alternatives to prophylactic gastrectomy? Chromoendoscopy is a procedure in which the gastric mucosa is coated with dyes such as methylene blue and Congo red. Methylene blue is taken up by cells in regions of intestinal metaplasia, which is a precursor to intestinal-type cancer, and Congo red stains areas that are acidic and contain parietal cells. Since gastric cancer is typically devoid of parietal cells, it should appear as a pale area on endoscopic examination. In the one published observational study,18 chromoendoscopy detected foci of early diffuse gastric cancer in 10 of 33 patients; only two of these foci were detected by means of routine endoscopy. 18 F-fluorodeoxyglucosepositron-emission tomographic scanning was reported to detect foci of early gastric cancer in a patient with a CDH1 mu-

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tation and no macroscopic evidence of gastric cancer.19 Studies of large numbers of patients will be required to determine whether either of these techniques will be clinically useful. In this 38-year-old patient with a CDH1 mutation, we recommended prophylactic gastrectomy. If she declined, upper endoscopy every 6 months with random biopsies would have been recommended. She was initially hesitant to proceed with gastrectomy, so an upper endoscopy with methylene blue stain was performed. The examination was normal, and pathological examination of random biopsy specimens detected no cancer. After additional consultation with the surgeon, the patient elected to have a prophylactic gastrectomy.
Prophylactic Gastrectomy

Morbidity and Mortality

Dr. Sam S. Yoon: To make an educated decision regarding prophylactic surgery, patients with germline E-cadherin mutations must understand certain technical aspects of prophylactic total gastrectomy and outcomes after total gastrectomy.
Technical Considerations

In performing prophylactic total gastrectomy for patients with germ-line E-cadherin mutations, it is critically important to remove all gastric mucosa. Gastric cancer in residual gastric-cardia mucosa has been reported as long as 24 years after prophylactic gastrectomy.20 The distal division across the duodenum should be performed at least 1 to 2 cm beyond the pylorus, and the proximal division should be performed at least 2 cm above the squamocolumnar junction. Some authors recommend intraoperative endoscopy to ensure accurate identification of the squamocolumnar junction.20 The gastrectomy specimen should be sent for frozensection analysis of the proximal and distal margins to confirm that all gastric mucosa has been removed. Some perigastric lymph nodes, especially those along the lesser and greater curvatures, may be removed with the stomach, but no formal lymphnode dissection is required if no cancer has been detected preoperatively. Reconstruction by means of Roux-en-Y esophagojejunostomy is generally performed with at least a 50-cm Roux limb to prevent bile reflux.21 Creation of a jejunal pouch may result in better food intake in the early period after gastrectomy.22

Operative mortality after prophylactic total gastrectomy for a germ-line E-cadherin mutation has not been reported, but mortality after gastrectomy for diagnosed gastric cancer ranges from less than 1% at specialized, high-volume centers23 to 7% in a large survey of U.S. hospitals.24 Prophylactic operations also are associated with the risk of early complications such as ileus, wound and intraabdominal infections, and anastomotic leaks, as well as with late complications such as anastomotic stricture. These risks should be lower for prophylactic total gastrectomy than for total gastrectomies performed for invasive cancer, since the patient population is generally younger and healthier, and lymphadenectomy, which increases complications, is not required.25 Total gastrectomy has clear nutritional consequences. Nearly all patients lose weight, with a nadir after 3 to 6 months at about 75% of preoperative weight.26 Dumping syndrome and diarrhea are common.27 Patients are initially instructed to eat small amounts continuously over the course of the day and after several months can eat three to five meals per day. Patients should receive monthly intramuscular vitamin B12 and a daily oral multivitamin with ferrous sulfate. Since some patients have difficulty maintaining an adequate nutritional status after total gastrectomy, regular follow-up visits with the surgeon and nutritionist are essential. In an older person with germ-line E-cadherin mutations, it is not clear at what age the risks of prophylactic gastrectomy outweigh its potential benefits. Since no formal lymph-node dissection is required, laparoscopic total prophylactic gastrectomy28,29 with a surgeon experienced with this technique may be a reasonable option for patients with germ-line E-cadherin mutations. This patient was extremely well informed about the risks and benefits of prophylactic surgery through discussions with her physicians, nutritionist, and support groups. I performed a total gastrectomy and Roux-en-Y reconstruction consisting of a jejunal pouch and hand-sewn esophagojejunostomy. A study with diatrizoate meglumine and diatrizoate sodium on the fifth postoperative day showed no evidence of anastomotic leak, and she started a clear liquid diet. She was discharged

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Figure 2. Gastrectomy Specimen. Gross photograph (Panel A) shows normal gastric mucosa with a small central scar (arrowhead), which proved to be benign and of unknown cause. Glistening, gray esophageal mucosa is present at the proximal end (thin arrows), RETAKEwere 1st AUTHOR Chung and the pylorus is seen at the distalICM end (thick arrow). More than 200 sections obtained for microscopy; the 2nd specimen was submitted for REG F FIGURE overlay (Panel B) indicates the initial sections that were obtained. Eventually the entire 2a-d of 2 3rd CASE microscopy. A single focus (Panel C, arrows) of intramucosal signet-ringcell carcinoma was identified; it is shown TITLE Revised EMail at high magnification in Panel D. The location of the cancerLine is shown in the red circle on Panel B. 4-C
Enon FILL

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on the eighth postoperative day, tolerating a soft solid diet. Five months after the operation, her weight had stabilized at 52 kg (115 lb) (decreased from 58 kg [128 lb]), and she was eating six to eight meals per day.

Pathol o gic a l Dis cus sion

Dr. Gregory Y. Lauwers: On gross examination, the gastrectomy specimen contained normal-appearing gastric mucosa, with a single, well-defined, tan-white superficial scar, 1.0 by 0.8 cm, distant from all margins (Fig. 2A). The entire stomach was submitted for microscopical examination (Fig. 2B). A total of 206 slides were reviewed. One focus of intramucosal signet-ringcell adenocarcinoma, 2 mm in diameter, was identified on a single slide (Fig. 2C and 2D). In patients with a CDH1 mutation, intramucosal adenocarcinomas are difficult to detect on surveillance endoscopy and biopsy specimens.30,31 No in situ carcinomas or pagetoid spread of signet-ring cells beneath the preserved epithelial lining of preexisting foveolae, as reported by others, were observed.32,33 Thirteen lymph nodes removed with the stomach contained no cancer. The final staging of this cancer was stage pT1N0M0 (tumornodemetastasis stage IA). Ms. Patel: The lifetime risk of breast cancer in this patient is approximately 40%; the mean age at breast-cancer diagnosis is 53 years.12 The majority of breast cancers in patients with CDH1 mutations are of the infiltrating lobular type, which may be more difficult than ductal cancers to detect by means of screening and surveillance. Currently, there are no standard guidelines for the management of breast-cancer risk in carriers of A nat omic a l Di agnosis the CDH1 mutation. However, a referral to a program for patients at high risk for breast cancer is Hereditary diffuse gastric cancer syndrome due to warranted. This patient was referred to the Breast germ-line E-cadherin mutation, with gastric inand Ovarian Cancer Genetics Clinic at this hos- tramucosal signet-ringcell carcinoma. pital, and the options of screening and prophylacDr. Chung reports receiving consulting fees from Myriad Getic mastectomy were discussed. She elected to un- netics. Dr. Lauwers reports receiving consulting fees from Sanofi-Aventis. No other potential conflict of interest relevant to dergo screening (including magnetic resonance this article was reported. imaging [MRI], mammography, and clinical We thank Scott M. Weissman, M.S., C.G.C., and Wendy S. breast examination twice each year and a month- Rubinstein, M.D., Ph.D., from Evanston Northwestern Healthcare, Evanston, IL, and the Feinberg School of Medicine, ly breast self-examination) and is considering the Northwestern University, Chicago, for providing details of the option of prophylactic mastectomy. Breast MRI genetic evaluation of the patients maternal aunt and for helpperformed 2 months and 10 months after the ful comments on the manuscript; and Dr. David Huntsman, Department of Pathology and Laboratory Medicine, University gastrectomy showed no suspicious lesions. of British Columbia, Vancouver, Canada, for performing the Dr. Bruce Chabner (Hematology/Oncology): Is analysis of the CDH1 gene.

there any role for chemoprevention for patients like this who are at risk for breast cancer? Ms. Patel: There are no data on the efficacy of agents such as tamoxifen in the prevention of breast cancer in patients with CDH1 mutations. Dr. Nancy Lee Harris (Pathology): I invited the patient to comment on the effect of this diagnosis on herself and her family. The Patient: I always feared I would die young of stomach cancer, as my mother had, and the fear worsened after my three children were born. Learning that my aunt had the CDH1 mutation and helping care for her as she died, I became increasingly anxious. When I learned that I had the mutation, I was shocked to know that I was at great risk for the development of cancer, yet relieved I could do something about it but it would be a radical choice. My husband researched the issue and helped us both realize that gastrectomy was the best option. It helped me tremendously to talk with others who had had this operation, and a support group for families with this diagnosis is available (http://health.groups.yahoo.com/group/ HDGC/). I learned that recovery would be very difficult, but that I would be okay. My husband and I were honest with our children (1, 3, and 5 years of age), and reading a childrens book with them helped the older ones understand.34 It was a very difficult recovery, but a year later, I feel almost normal, with even a 5-lb weight gain! When I consider that each of our children has a 50% chance of having this mutation, I know they at least have the same option I did, and I hope to show them what a livable solution it is.

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