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Women who carry a deleterious mutation in BRCA1 or BRCA2 have high lifetime risks of breast and ovarian cancers. However, the influence of a family history of these cancers on these risks in women with BRCA mutations is unclear. We calculated cancer incidence rates for a multinational cohort comprising 3011 women with BRCA1 or BRCA2 mutations who were followed up for a mean of 3.9 years, during which time 243 incident breast or ovarian cancers were recorded. The 10-year cumulative risks of breast cancer were 18.1% (95% confidence interval [CI] = 13.3% to 22.8%) for women with a BRCA1 mutation and 15.2% (95% CI = 9.1% to 21.2%) for women with a BRCA2 mutation. Among women with a BRCA1 mutation, the risk of breast cancer increased by 1.2-fold for each first-degree relative with breast cancer before age 50 years (hazard ratio [HR] = 1.21; 95% confidence interval [CI] = 0.94 to 1.57) and the risk of ovarian cancer increased by 1.6 fold for each first- or second-degree relative with ovarian cancer (HR = 1.61; 95% CI = 1.21 to 2.14). Among women with a BRCA2 mutation, the risk of breast cancer increased by 1.7-fold for each first-degree relative younger than 50 years with breast cancer (HR = 1.67; 95% CI = 1.04 to 2.07) J Natl Cancer Inst 2010;102:1874-1878 DOI: 10.1093/jnci/djq443

Background Hormone therapy (HT) is commonly given to women to alleviate the climacteric symptoms associated with menopause. There is concern that this treatment may increase the risk of breast cancer. The potential association of HT and breast cancer risk is of particular interest to women who carry a mutation in BRCA1 because they face a high lifetime risk of breast cancer and because many of these women take HT after undergoing prophylactic surgical oophorectomy at a young age. Methods We conducted a matched case-control study of 472 postmenopausal women with a BRCA1 mutation to examine whether or not the use of HT is associated with subsequent risk of breast cancer. Breast cancer case patients and control subjects were matched with respect to age, age at menopause, and type of menopause (surgical or natural). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with conditional logistic regression. Statistical tests were two-sided. Results In this group of BRCA1 mutation carriers, the adjusted OR for breast cancer associated with ever use of HT compared with never use was 0.58 (95% CI = 0.35 to 0.96; P= .03). In analyses by type of HT, an inverse association with breast cancer risk was observed with use of estrogen only (OR = 0.51, 95% CI = 0.27 to 0.98; P = .04); the association with use of estrogen plus progesterone was not statistically significant (OR = 0.66, 95% CI = 0.34 to 1.27; P = .21). Conclusion Among postmenopausal women with a BRCA1 mutation, HT use was not associated with increased risk of breast cancer; indeed, in this population, it was associated with a decreased risk.

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for MSI testing.

Background: Oral contraceptive use has been associated with an increase in the risk of breast cancer in young women. We examined whether this association is seen in women at high risk of breast cancer because they carry a mutation in one of two breast cancer susceptibility genes, BRCA1 and BRCA2. Methods: We performed a matched case-control study on 1311 pairs of women with known deleterious BRCA1 and/or BRCA2 mutations recruited from 52 centers in 11 countries. Women who had been diagnosed with breast cancer were matched to control subjects by year of birth, country of residence, mutation (BRCA1 or BRCA2), and history of ovarian cancer. All study subjects completed a questionnaire about oral contraceptive use. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived by conditional logistic regression. All statistical tests were twosided. Results: Among BRCA2 mutation carriers, ever use of oral contraceptives was not associated with an increased risk of breast cancer (OR = 0.94, 95% CI = 0.72 to 1.24). For BRCA1 mutation carriers, ever use of oral contraceptives was associated with a modestly increased risk of breast cancer (OR = 1.20, 95% CI = 1.02 to 1.40). However, compared with BRCA1 mutation carriers who never used oral contraceptives, those who used oral contraceptives for at least 5 years had an increased risk of breast cancer (OR = 1.33, 95% CI = 1.11 to 1.60), as did those who used oral contraceptives before age 30 (OR = 1.29, 95% CI = 1.09 to 1.52), those who were diagnosed with breast cancer before age 40 (OR = 1.38, 95% CI = 1.11 to 1.72), and those who first used oral contraceptives before 1975 (OR = 1.42, 95% CI = 1.17 to 1.75). Conclusions: Among BRCA1 mutation carriers, women who first used oral contraceptives before 1975, who used them before age 30, or who used them for 5 or more years may have an increased risk of early-onset breast cancer. Oral contraceptives do not appear to be associated with risk of breast cancer in BRCA2 carriers, but data for BRCA2 carriers are limited. [J Natl Cancer Inst 2002;94: 1773-9]

Breakthroughs in the development of reliable cancer biomarkers may be imminent because of advances in genomics and computer technology that allow the analysis of vast quantities of data. How can [...]

Background: Smoking has carcinogenic effects, and possibly antiestrogenic effects as well, but it has not been found to be a risk factor for breast cancer in women in the general population. However, hereditary breast cancer is primarily a disease of premenopausal women, and interactions between genes and hormonal and environmental risk factors may be particularly important in this subgroup. Methods: We conducted a matched case-control study of breast cancer among women who have been identified to be carriers of a deleterious mutation in either the BRCA1 or the BRCA2 gene. These women were assessed for genetic risk at one of several genetic counseling programs for cancer in North America. Information about lifetime smoking history was derived from a questionnaire routinely administered to women who were found to carry a mutation in either gene. Smoking histories of case subjects with breast cancer and age-matched healthy control subjects were compared. Odds ratios for developing breast cancer were determined for smokers versus nonsmokers by use of conditional logistic regression for matched sets after adjustment for other known risk factors. Results: Subjects with RRCA1 or BRCA2 gene mutations and breast cancer were significantly more likely to have been nonsmokers than were subjects with mutations and without breast cancer (two-sided P = .007). In a multivariate analysis, subjects with BRCA1 or BRCA2 mutations who had smoked cigarettes for more than 4 pack-years (i.e., number of packs per day multiplied by the number of years of smoking) were found to have a lower breast cancer risk (odds ratio 0.46, 95% confidence interval = 0.274.80; two-sided P = .006) than subjects with mutations who never smoked. Conclusions: This study raises the possibility that smoking reduces the risk of breast cancer in carriers of BRCA1 or BRCA2 gene mutations. [J Natl Cancer Inst 1998;90:761-6]

Background: The occurrence of approximately 5% of common epithelial malignant tumors of the ovary can be traced to inheritance of risk. One prophylactic strategy to decrease the probability of development of disease in individuals within families where this mendelian-dominant pattern of occurrence is apparent is to remove the ovaries of individuals at risk for ovarian cancer. The procedure, when done for this purpose, is recommended soon after completion of childbearing. Purpose: Our goal was to compare the histologic features of the ovaries of women at increased risk for ovarian cancer to those at no known increased risk for the disease. Methods: Ovaries removed for prophylaxis from 20 women considered to be at increased risk for developing ovarian cancer were examined histologically. During the course of this work, it seemed apparent that these ovaries contained numerous atypical features compared with the expected appearance of normal ovaries. Hence, we expanded the study to include a control group whose ovaries were removed for reasons unrelated to cancer. The study, therefore, was not blinded. The increased risk in the cancer-prone individuals was determined by family history, specifically the presence of at least one first-degree relative and one second-degree relative with ovarian and/or breast cancer and positive linkage or mutational analysis of BRCA1 in some. The difference in mean ages of patients in the control and high-risk groups was not statistically significant. The difference among both groups with respect to the number of atypical features as well as the intensity of those features was ascertained by computing probabilities using Fisher's exact test (two-sided) for rows x columns contingency tables. Results: Two unanticipated microscopic or near-microscopic malignant neoplasms and other benign and borderline tumors were discovered in the ovaries of the high-risk individuals. Of substantial interest was the finding that among the ovaries of high-risk women, 85% presented two or more and 75% presented three or more of the following histologic features: surface epithelial pseudostratification; surface papillomatosis; deep cortical invaginations of the surface epithelium, frequently with multiple papillary projections within small cystic spaces (microscopic papillary cystadenomas); epithelial inclusion cysts, frequently with epithelial hyperplasia and papillary formations; cortical stromal hyperplasia and hyperthecosis; increased follicular activity; corpus luteum hyperplasia; or hilar cell hyperplasia. Two or more or three or more such changes were observed in a lesser percentage (30% or 10%, respectively) of ovaries obtained from the control individuals, with a statistically significant difference (P = .001 or P = .00007, respectively), particularly considering that a detailed determination of a family history of cancer in the control group was not possible. Conclusions: The frequency of these changes in the high-risk ovaries compared with control ovaries suggests a characteristic histologin preneoplastic phenotype defined by an increased frequency and intensity of the above-described histologic features in the high-risk ovaries. Limited access to numerous small (stage I) ovarian cancers or cancer-prone ovaries by any one pathologist may explain the failure to identify the phenotype in the past. Implications: We suggest that the ovaries removed from ovarian cancer-prone individuals as a preventative measure should be thoroughly examined histologically to identify or rule out microscopic or near-microscopic invasive neoplasms. [J Natl Cancer Inst 1996; 88:1810-20]

Ovarian cells from women with family histories of ovarian or breast cancer behave differently in culture compared with cells from women without such a history. Cell samples of the ovarian outer layer were obtained from women having gynecologic surgery for nonmalignant problems. Eighteen women had no parents, siblings, or children with breast or ovarian cancer, five women had a family history but were not believed to have hereditary cancer, and seven women had a strong family history of cancer. Cells were analyzed for the cancer marker CA 125 and examined under the microscope. CA 125 production declined markedly in successive generations of cells in women with no family history or a minor family history but remained the same in women with a family history. Cells from women with no family history transformed from skin-like cells to connective tissue-like cells, whereas cells from women with a strong history maintained their skin cell-like appearance and women with a weak family history fell in between.

We know cancer as an environmental disease primarily because of the evidence linking smoking and lung cancer. But we have also learned in the past decade that cancer arises from [...]

Background. There is a paucity of knowledge pertaining to the attitudes, feelings, and emotions of women who are at increased familial risk for breast cancer and how these concerns will affect their surveillance behavior. k review of the literature shows an unevenness in the conclusions about these matters, with some reports indicating that anxiety aroused in the familial cancer setting may abet surveillance behavior, whereas other data indicates a negative effect. Methods. The authors reported anecdotal accounts of such behavior in women from hereditary breast and hereditary breast-ovarian cancer prone families. Results. Although these responses of fear, anxiety, and apprehension about cancer risk are not unique to this hereditary cohort, they nevertheless must have been tempered by often life-long exposure of cancer occurrences that may have decimated their families. Conclusions. All accounts agree with the need to devote more research to the special needs--psychological, social, insurance, and general public health measures of these high risk women. Cancer 1994; 74:1184-92. Key words: genetics, psychological, fear, anxiety, high risk, surveillance.

Women at risk for endometrial carcinoma because of a hereditary cancer syndrome may need increased medical surveillance so that risk factors may be minimized and precancerous or early invasive lesions may be managed. Tracing one family's disease history identified five women in three consecutive generations who all had endometrial carcinoma. These women did not have the usual risk factors of obesity, high blood pressure and diabetes. Women who are the first-degree relatives of endometrial cancer patients have a much greater risk of developing the disease. Such women should be informed about the risks for developing endometrial cancer such as chronic lack of ovulation, estrogen replacement therapy without sufficient progesterone, obesity, and poorly control of illnesses such as diabetes, high blood pressure and liver disease. Young women at risk for endometrial cancer should receive yearly pelvic exams, Pap smears and, in cases of menstrual irregularity, endometrial sampling or ultrasonography. Hysterectomy may be indicated for older women or women who do not plan to have children.

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by increased risk for cancer, especially colorectal cancer. It has been recommended that colon cancer control programs for family members be expanded to include endometrial cancer, the commonest extracolonic cancer observed in HNPCC families. We estimated the age-specific and cumulative endometrial cancer risk for women at high risk for HNPCC. PATENTS AND METHODS: Family history data from three large HNPCC registries were combined for this study. High risk family members were identified without regard to extracolonic cancer. Life table methods were used to calculate estimates of risk. RESULTS: One thousand eighteen women from 86 families were included in the study. Cumulative incidence was 20% by age 70, compared to 3% in the general population. Risk was highest in women most likely to carry the HNPCC gene (P

Background. The hereditary flat adenoma syndrome (HFAS) is characterized by an autosomal dominantly inherited predisposition to multiple colonic adenomas (usually less than 100) with proximal predominance and flat as opposed to polypoid growth. Patients with the syndrome experience colorectal cancers in excess, and the lesions are distributed randomly in the colon. The polyps occur at a later age (median, 55 years) compared with age at onset of polyps in patients with familial adenomatous polyposis (FAP) and patients with the Lynch syndromes. FAP and HFAS are linked to the same locus on chromosome 5q21-q22. Methods. Upper endoscopic examination was performed on 22 relatives from four families with HFAS. Results. Fifteen patients from three of these families had multiple fundic gland polyps; four had duodenal or gastric adenomas. Periampullary carcinoma was present in two members from separate families. Conclusions. The authors conclude that the upper gastrointestinal tract pathologic characteristics of HFAS are similar to those described in FAP. Thus, those at risk for HFAS require upper endoscopic screening in addition to meticulous attention to the colon. Cancer 1993; 71:2709-14.

Background. It has been hypothesized that in some but not all families with hereditary nonpolyposis colorectal cancer (HNPCC) there is a high risk of certain cancers other than colon cancer. Methods. The authors compared the observed frequency of cancer at specific sites in more than 1300 high-risk members of 23 kindreds with HNPCC with expectations based on general population incidence and evaluated the hypothesis that there was heterogeneity in cancer frequency among families. Results. The authors observed significantly increased numbers of cancers of the stomach, small intestine, upper urologic tract (renal pelvis and ureter), and ovary. No excess was seen in other cancer types that have been associated previously with HNPCC, including cancer of the breast, pancreas, and urinary bladder. Significant heterogeneity among families was observed in the frequencies of endometrial, ovarian, and upper urologic system cancer. Conclusion. In addition to early onset cancers of the colorectum, HNPCC family members are at increased risk for cancers of other gastrointestinal tract organs, and, especially in some families, cancers of the upper urologic and female genital tract. Concer 1993; 71:677-85.

Background. Hereditary ovarian cancer (HOC) is heterogeneous, with at least three distinctive syndromes, namely, hereditary site-specific ovarian cancer, hereditary breast-ovarian cancer (HBOC) syndrome, and Lynch syndrome II. Ovarian cancer, in accord with virtually all varieties of adult onset cancer, displays an increasing incidence with advancing age; however, it shows an earlier age of onset in hereditary settings. Methods. Detailed medical and pathology studies were performed on extended ovarian cancer-prone pedigrees, with special attention given to age at ovarian cancer onset. Results. The age of onset of ovarian cancer is heterogeneous, wherein the average age of onset in HBOC is 52 years, in hereditary site-specific ovarian cancer it is 49 years, and in the Lynch syndrome II it is 45 years, in contrast to its occurrence in the general population, at an average age of 59 years. Conclusions. These differences are important for the initiation of surveillance and management strategies. Age of onset of ovarian cancer differences in these several hereditary subsets are less striking than they are in the case of other integral forms of cancer in the respective syndromes, such as the breast in the HBOC syndrome. In addition, the phenomenon of extremely early age of onset of ovarian cancer occurs infrequently in HOC when compared to other forms of cancer, such as the breast in HBOC or the colon in Lynch syndrome II. Knowledge about age of onset heterogeneity in HOC may harbor important clues about etiology, pathogenesis, and cancer control. Cancer 1993; 71:573-81.