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Women with a BRCA1 or BRCA2 mutation face a high lifetime risk of breast cancer.1 It is important to identify risk factors for breast cancer among genetically predisposed women, to devise strategies to minimize the risk. Several lines of evidence link diabetes and breast cancer.2,3 Insulin resistance and hyperinsulinemia, which predispose to diabetes, may increase the risk of breast cancer in the general population,4 and hyperinsulinemia may promote the growth of pre-existing breast neoplasms.5 Furthermore, a high body mass index (BMI) is a risk factor for both breast cancer recurrence and for insulin resistance.6–8 It is also of interest to establish whether diabetes (or any of the drugs used to treat diabetes) influences the risk of breast cancer in BRCA carriers. The risk of future diabetes may also be increased in women after a diagnosis of breast cancer.9 This risk may be mediated by common risk factors, such as high BMI or insulin resistance, or diabetes may be a late effect of breast cancer treatment. It is important to explore the impact of these factors on the risk of diabetes in women with BRCA mutations. In this cohort of BRCA carriers, we sought to determine whether diabetes increases the risk of breast cancer in BRCA carriers, and to identify risk factors for diabetes in this high-risk population.

Background: Germline mutation screening of BRCA1 and BRCA2 genes is performed in suspected familial breast cancer cases, but a causative mutation is found in only 30% of patients. The development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would therefore increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1—or BRCA2—mutated breast cancers. Materials and Methods: Array-cgh (comparative genomic hybridization) and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the basis of at least 3 affected first-degree relatives or at least 2 affected first-degree relatives with breast cancer at an average age of 45 years. Array-cgh analyses were performed on a 4407 BAC-array (CIT-V8) manufactured by IntegraGen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Results: Using supervised clustering analyses we identified two transcriptomic signatures: one for BRCA1-mutated breast cancers consisting of 600 probe sets and another for BRCA2-mutated breast cancers also consisting of 600 probes sets. We also defined cgh-array signatures, based on the presence of specific genomic rearrangements, one for BRCA1-mutated breast cancers and one for BRCA2-mutated breast cancers. Conclusions: This study identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. We also identified specific genomic rearrangements in these breast cancers, which could be screened for in a diagnostic setting using fluorescence in situ hybridization, thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis.

Physicians are often approached by young women with a BRCA mutation and a recent history of breast cancer who wish to have a baby. They wish to know if pregnancy impacts upon their future risks of cancer recurrence and survival. To date, there is little information on the survival experience of women who carry a mutation in one of the BRCA genes and who become pregnant. From an international multi-center cohort study of 12,084 women with a BRCA1 or BRCA2 mutation, we identified 128 case subjects who were diagnosed with breast cancer while pregnant or who became pregnant after a diagnosis of breast cancer. These women were age-matched to 269 mutation carriers with breast cancer who did not become pregnant (controls). Subjects were followed from the date of breast cancer diagnosis until the date of last follow-up or death from breast cancer. The Kaplan–Meier method was used to estimate 15-year survival rates. The hazard ratio for survival associated with pregnancy was calculated using a left-truncated Cox proportional hazard model, adjusting for other prognostic factors. Among women who were diagnosed with breast cancer when pregnant or who became pregnant thereafter, the 15-year survival rate was 91.5 %, compared to a survival of 88.6 % for women who did not become pregnant (adjusted hazard ratio = 0.76; 95 % CI 0.31–1.91; p = 0.56). Pregnancy concurrent with or after a diagnosis of breast cancer does not appear to adversely affect survival among BRCA1/2 mutation carriers.

PURPOSE: To determine the likelihood of long-term amenorrhea after treatment with chemotherapy in women with breast cancer who carry a BRCA1 or BRCA2 mutation. PATIENTS AND METHODS: We conducted a multicenter survey of 1,954 young women with a BRCA1 or BRCA2 mutation who were treated for breast cancer. We included premenopausal women who were diagnosed with invasive breast cancer between 26 and 47 years of age. We determined the age of onset of amenorrhea after breast cancer for women who were and were not treated with chemotherapy, alone or with tamoxifen. We considered chemotherapy-induced amenorrhea to have occurred when the patient experienced ≥ 2 years of amenorrhea, commencing within 2 years of initiating chemotherapy, with no resumption of menses. RESULTS: Of the 1,426 women who received chemotherapy, 35% experienced long-term amenorrhea. Of the 528 women who did not receive chemotherapy, 5.3% developed long-term amenorrhea. The probabilities of chemotherapy-induced amenorrhea were 7.2% for women diagnosed before age 30 years, 33% for women age 31 to 44 years, and 79% for women diagnosed after age 45 years (P trend < .001). The probability of induced amenorrhea was higher for women who received tamoxifen than for those who did not (52% v 29%; P < .001). CONCLUSION: Age at treatment and use of tamoxifen are important predictors of chemotherapy-induced amenorrhea in women who carry a BRCA1 or BRCA2 mutation. The risk of induced long-term amenorrhea does not seem to be greater among mutation carriers than among women who do not carry a mutation., published_or_final_version

The objective is to estimate the risk of breast cancer in women who carry a deleterious BRCA1 or BRCA2 mutation, according to parental origin of mutation. We conducted a cohort study of women with a BRCA1 mutation (n = 1523) or BRCA2 mutation (n = 369) who had not been diagnosed with breast or ovarian cancer. For each woman, the pedigree was reviewed and the origin of the mutation was assigned as probable paternal or maternal. The hazard ratio (HR) for developing breast cancer in the follow-up period was estimated for women with a paternal mutation compared to a maternal mutation. The risk of breast cancer was modestly higher in women with a paternal BRCA1 mutation compared to women with a maternal BRCA1 mutation (HR = 1.46; 95% CI = 0.99-2.16) but the difference was not significant (p = 0.06). The parental mutation origin did not affect the risk in women with a BRCA2 mutation. Our results are consistent with the hypothesis that there is an increased risk of breast cancer among women with a paternally inherited BRCA1 mutation compared to a maternally inherited mutation. However, the data are not sufficiently compelling to justify different screening recommendations for the two subgroups.

BRCA1 and BRCA2 mutation carriers have elevated risks of breast and ovarian cancers. The risks for cancers at other sites remain unclear. Melanoma has been associated with BRCA2 mutations in some studies, however, few surveys have included non-melanoma skin cancer. We followed 2729 women with a BRCA1 or BRCA2 mutation for an average of 5.0 years. These women were asked to report new cases of cancer diagnosed in themselves or in their family. The risks of skin cancer were compared for probands with BRCA1 and BRCA2 mutations. Of 1779 women with a BRCA1 mutation, 29 developed skin cancer in the follow-up period (1.6%). Of the 950 women with a BRCA2 mutation, 28 developed skin cancer (3.0%) (OR = 1.83 for BRCA2 versus BRCA1; 95% CI 1.08-3.10; P = 0.02). The odds ratio for basal cell carcinoma was higher (OR = 3.8; 95% CI 1.5-9.4; P = 0.002). BRCA2 mutation carriers are at increased risk for skin cancer, compared with BRCA1 carriers, in particular for basal cell carcinoma.

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.

Men with BRCA2 mutations have been found to be at increased risk of developing prostate cancer. There is a recent report that BRCA2 carriers with prostate cancer have poorer survival than noncarrier prostate cancer patients. In this study, we compared survival of men with a BRCA2 mutation and prostate cancer with that of men with a BRCA1 mutation and prostate cancer. We obtained the age at diagnosis, age at death or current age from 182 men with prostate cancer from families with a BRCA2 mutation and from 119 men with prostate cancer from families with a BRCA1 mutation. The median survival from diagnosis was 4.0 years for men with a BRCA2 mutation vs 8.0 years for men with a BRCA1 mutation, and the difference was highly significant (P

Among women with a mutation in BRCA1 or BRCA2, the risk of breast cancer is high, but it may be modified by exogenous and endogenous factors. There is concern that exposure to carcinogens in cigarette smoke may increase the risk of cancer in mutation carriers. We conducted a matched case-control study of 2,538 cases of breast cancer among women with a BRCA1 (n = 1,920) or a BRCA2 (n = 618) mutation. One non-affected mutation carrier control was selected for each case, matched on mutation, country of birth, and year of birth. Odds ratios were calculated using conditional logistic regression, adjusted for oral contraceptive use and parity. Ever-smoking was not associated with an increased breast cancer risk among BRCA1 carriers (OR = 1.09; 95% CI 0.95-1.24) or among BRCA2 carriers (OR = 0.81; 95% CI 0.63-1.05). The result did not differ when cases were restricted to women who completed the questionnaire within two years of diagnosis. A modest, but significant increase in risk was seen among BRCA1 carriers with a past history of smoking (OR = 1.27; 95% CI 1.06-1.50), but not among current smokers (OR = 0.95; 0.81-1.12). There appears to be no increase in the risk of breast cancer associated with current smoking in BRCA1 or BRCA2 carriers. There is a possibility of an increased risk of breast cancer among BRCA1 carriers associated with past smoking. There may be different effects of carcinogens in BRCA mutation carriers, depending upon the timing of exposure.

To study the possible role of dietary and supplementary selenium intake in the etiology of cancer, we carried out a case-control study of breast, colon, and prostate cancer in Montreal between 1989 and 1993. In this study, we were able to interview a total of 1,048 incidence cases of colon (402), breast (414) and prostate (232) cancer subjects and 688 population-based controls matched for age and gender. Of these, a total of 501 cancer cases and 202 controls produced toenail samples for their selenium concentrations, which were determined by neutron activation analysis. We found no association between toenail selenium and breast cancer (odds ratio [OR], 0.72; 95% confidence interval [CI], 0.4-1.31) or prostate cancer (OR, 1.14; 95% CI, 0.46-2.83), though we did observe a statistically significant inverse association between toenail selenium level and the risk of colon cancer for both genders combined (OR, 0.42; 95% CI, 0.19-0.93; P = .009) and for female subjects (P = .050). We also found that nonsmoker case and control subjects had higher selenium in their toenail samples. This could be due either to the nature of tobacco, which reduces selenium absorption, or to smokers' consumption of certain foods containing less selenium. Further epidemiologic studies are required to clarify the role of selenium in the etiology of certain cancers.

A prospective study of 149 unselected incident cases of pancreatic adenocarcinoma and 146 ethnically-matched controls found no associations between GSTM1 (adjusted odds ratio (AOR) 1.14), GSTT1 (AOR: 1.19) and CYP1A1 (AOR: 1.08) polymorphisms and pancreatic cancer susceptibility. Smoking and drinking status did not affect results. These polymorphisms do not appear to be important gene modifiers in pancreatic cancer. © 2000 Cancer Research Campaign

Lucenteforte, E La Vecchia, C Silverman, D Petersen, G M Bracci, P M Ji, B T Bosetti, C Li, D Gallinger, S Miller, A B Bueno-de-Mesquita, H B Talamini, R Polesel, J Ghadirian, P Baghurst, P A Zatonski, W Fontham, E Bamlet, W R Holly, E A Gao, Y T Negri, E Hassan, M Cotterchio, M Su, J Maisonneuve, P Boffetta, P Duell, E J eng CA098889/CA/NCI NIH HHS/ CA108370/CA/NCI NIH HHS/ CA109767/CA/NCI NIH HHS/ CA59706/CA/NCI NIH HHS/ CA89726/CA/NCI NIH HHS/ N01-CP-05225/CP/NCI NIH HHS/ N01-CP-05227/CP/NCI NIH HHS/ N01-CP-31022/CP/NCI NIH HHS/ N01-CP-51089/CP/NCI NIH HHS/ N01-CP-51090/CP/NCI NIH HHS/ N01-CP-51092/CP/NCI NIH HHS/ N01-PC-35136/PC/NCI NIH HHS/ Meta-Analysis Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't England 2011/05/04 06:00 Ann Oncol. 2012 Feb;23(2):374-82. doi: 10.1093/annonc/mdr120. Epub 2011 May 2.; International audience; BACKGROUND: Heavy alcohol drinking has been related to pancreatic cancer, but the issue is still unsolved. METHODS: To evaluate the role of alcohol consumption in relation to pancreatic cancer, we conducted a pooled analysis of 10 case-control studies (5585 cases and 11,827 controls) participating in the International Pancreatic Cancer Case-Control Consortium. We computed pooled odds ratios (ORs) by estimating study-specific ORs adjusted for selected covariates and pooling them using random effects models. RESULTS: Compared with abstainers and occasional drinkers (< 1 drink per day), we observed no association for light-to-moderate alcohol consumption (/= 9 drinks per day). Results did not change substantially when we evaluated associations by tobacco smoking status, or when we excluded participants who reported a history of pancreatitis, or participants whose data were based upon proxy responses. Further, no notable differences in pooled risk estimates emerged across strata of sex, age, race, study type, and study area. CONCLUSION: This collaborative-pooled analysis provides additional evidence for a positive association between heavy alcohol consumption and the risk of pancreatic cancer.

Purpose: To investigate risk factors that may be linked to pancreatic cancer. Methods: We designed a multicenter population-based case-control (823 cases, 1679 control patients) study with data collection by using a common protocol and questionnaire. Participating centers were located in Australia, Canada, the Netherlands, and Poland. Results: After adjustment for confounding factors, a positive history of pancreatitis was associated with pancreatic cancer (odds ratio [OR], 4.68; 95% confidence interval [95% CI], 2.23 - 9.84). The risk was especially high in heavy smokers (OR, 15.4; 95% CI, 3.18 - 74.9). Patients with diabetes had an increased risk of developing pancreatic cancer (OR, 2.16; 95% CI, 1.60 - 2.91). The risk was highest in the first year after the development of diabetes (OR, 6.68; 95% CI, 3.56 - 12.6) and decreased over time. A history of allergy was associated with a reduced risk of pancreas cancer (OR, 0.64; 95% CI, 0.50 - 0.82). Conclusions: Patients with newly diagnosed diabetes and patients with pancreatitis, particularly in heavy smokers, have an increased risk for developing pancreatic cancer. In addition to being risk factors, these conditions could be early manifestations of underlying pancreatic cancer. A history of allergy decreases the risk of pancreatic cancer. © 2010 Elsevier Inc. All rights reserved.