Timing of oral contraceptive use and the risk of breast cancer in BRCA1 mutation carriers.

It is not clear if early oral contraceptive use increases the risk of breast cancer among young women with a breast cancer susceptibility gene 1 (BRCA1) mutation. Given the benefit of oral contraceptives for the prevention of ovarian cancer, estimating age-specific risk ratios for oral contraceptive use and breast cancer is important. We conducted a case-control study of 2,492 matched pairs of women with a deleterious BRCA1 mutation. Breast cancer cases and unaffected controls were matched on year of birth and country of residence. Detailed information about oral contraceptive use was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the odds ratios (OR) and 95 % confidence intervals (CI) for the association between oral contraceptive and breast cancer, by age at first use and by age at diagnosis. Among BRCA1 mutation carriers, oral contraceptive use was significantly associated with an increased risk of breast cancer for women who started the pill prior to age 20 (OR 1.45; 95 % CI 1.20-1.75; P = 0.0001) and possibly between ages 20 and 25 as well (OR 1.19; 95 % CI 0.99-1.42; P = 0.06). The effect was limited to breast cancers diagnosed before age 40 (OR 1.40; 95 % CI 1.14-1.70; P = 0.001); the risk of early-onset breast cancer increased by 11 % with each additional year of pill use when initiated prior to age 20 (OR 1.11; 95 % CI 1.03-1.20; P = 0.008). There was no observed increase for women diagnosed at or after the age of 40 (OR 0.97; 95 % CI 0.79-1.20; P = 0.81). Oral contraceptive use before age 25 increases the risk of early-onset breast cancer among women with a BRCA1 mutation and the risk increases with duration of use. Caution should be taken when advising women with a BRCA1 mutation to take an oral contraceptive prior to age 25.

Should all BRCA1 mutation carriers with stage I breast cancer receive chemotherapy?

To estimate the 15-year survival following a diagnosis of stage I breast cancer among women who carry a BRCA1 mutation and to determine predictors of mortality, including the use of chemotherapy. Patients were 379 women with stage I breast cancer for whom a BRCA1 mutation had been identified, in herself or in a close family member. Patients were followed for up to 15 years from the initial diagnosis of breast cancer. Survival rates were estimated for women by age, tumor size (≤ 1 cm; > 1 cm), ER status (±), and by chemotherapy (yes/no). 42 women died of breast cancer in the follow-up period (11.2 %). Survival rates were similar for women with cancers of size 0-1.0 cm and size 1.1-2.0 cm. Of the 267 women in the study who used chemotherapy, 21 had died (7.9 %) compared to 21 deaths among 112 women who did not receive chemotherapy (18.8 %; p = 0.002). The 15-year survival was 89.4 % for women who received chemotherapy and was 73.1 % for women who did not receive chemotherapy (p = 0.08; log rank). The adjusted hazard ratio for death following a diagnosis of stage I breast cancer associated with chemotherapy was 0.53 (95 % CI 0.28-1.07; p value 0.06) after adjusting for age of diagnosis, tumor size, and estrogen receptor status. This was statistically significant only among women with ER-negative breast cancers (HR = 0.28; 95 % CI 0.10-0.79; p = 0.02). BRCA1 positive women who are treated for stage I breast cancer with chemotherapy have better survival than those who do not receive chemotherapy. The difference cannot be explained by other prognostic factors. All women with invasive breast cancer and a BRCA1 mutation should be considered to be candidates for chemotherapy.

The impact of pregnancy on breast cancer survival in women who carry a BRCA1 or BRCA2 mutation.

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.

International rates of breast reconstruction after prophylactic mastectomy in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: Breast reconstruction is an option for women with BRCA1 or BRCA2 mutations who elect to undergo prophylactic mastectomy to prevent breast cancer. We report on the uptake of breast reconstruction after prophylactic mastectomy in women with BRCA mutations from eight countries. METHODS: Women with a BRCA1 or BRCA2 mutation were questioned regarding their cancer preventive practices. Information was recorded on prophylactic mastectomy and breast reconstruction. RESULTS: A total of 1,635 women with a BRCA1 or BRCA2 mutation who elected to undergo prophylactic mastectomy from eight countries were included. A total of 1,137 women (69.5%) had breast reconstruction after prophylactic mastectomy. A total of 58.7% of women over the age of 45 years at the time of prophylactic mastectomy had breast reconstruction compared to 77.6% of women 35 years of age or younger [odds ratio (OR) 0.36, 95% confidence interval (CI) 0.26-0.50, p < 0.001]. In addition, 62.9% of women with a breast cancer diagnosis (contralateral prophylactic mastectomy) had breast reconstruction after prophylactic mastectomy compared to 79.7% of women without a previous breast cancer diagnosis (OR 0.48, 95% CI 0.38-0.61, p < 0.001). A total of 66.9% of women from Canada had breast reconstruction after mastectomy compared to 71.9% of American women (OR 0.75, 95% CI 0.59-0.96, p = 0.02). CONCLUSIONS: The majority of women elect for breast reconstruction after prophylactic mastectomy. However, younger women and those without a previous diagnosis of breast cancer are more likely to have breast reconstruction than older women or those with a previous diagnosis of cancer.

The incidence of endometrial cancer in women with BRCA1 and BRCA2 mutations: an international prospective cohort study.

OBJECTIVE: To evaluate the risk of endometrial cancer in women who carry a mutation in the BRCA1 or the BRCA2 gene. METHODS: We followed 4456 women with a BRCA1 or a BRCA2 mutation for incident cases of endometrial cancer. The incidence of endometrial cancer was estimated per 100,000 women per year. The hazard ratios for endometrial cancer were estimated by calculating standardized incidence ratios (SIRs) according to age group and country of residence. We estimated the impact of tamoxifen and hormone replacement therapy on the incidence of endometrial cancer in BRCA1 and BRCA2 carriers. RESULTS: After a mean follow-up of 5.7 years, we identified 17 endometrial cancers (13 cases in BRCA1 and 4 cases in BRCA2). The SIR for BRCA1 carriers was 1.91 (95% CI: 1.06-3.19, p=0.03) and for BRCA2 carriers was 1.75 (95% CI: 0.55-4.23, p=0.2). The SIR was 4.14 (95% CI: 1.92 to 7.87) for women who received tamoxifen and was 1.67 (95% CI: 0.81 to 3.07) for women who did not receive tamoxifen. The ten-year cumulative risk of endometrial cancer in women who were treated with tamoxifen was 2.0%. CONCLUSIONS: The risk of endometrial cancer is higher in BRCA1 mutation carriers than in the general population. The excessive risk is largely attributable to a history of tamoxifen use, but the actual risk of endometrial cancer associated with tamoxifen is small. It is important to discuss hysterectomy at the time of prophylactic bilateral salpingo-oophorectomy if tamoxifen is to be considered.

Exposure to environmental tobacco smoke (ETS) and risk of lung cancer in Montreal: a case-control study.

BACKGROUND: The objective of the present study was to examine the association between environmental tobacco smoke (ETS) and risk of lung cancer among never smokers, defined as subjects who smoked less than 100 cigarettes in their lifetime. METHODS: We conducted a population-based case-control study on lung cancer in Montreal, Canada (1996-2000) including 1,203 cases and 1513 controls. The present analysis is restricted to the 44 cases and 436 population controls who reported never smoking and completed the questionnaire on lifetime ETS exposure. Collected information included duration and intensity of exposure from multiple sources: inside home (parents, spouses, roommates and any other co-resident) and outside homes (in vehicles, social settings, and workplace). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated between ETS and lung cancer, adjusting for age, sex, socioeconomic status (SES), and proxy respondent. RESULTS: Overall there was no association between ETS cumulative exposure from all sources (measured in pack-years) and lung cancer: OR = 0.98 (95%CI: 0.40-2.38), comparing upper with lower tertiles of exposure. While there were no elevated ORs associated with ever having lived with parents who smoked (OR = 0.62; 95%CI: 0.32-1.21) or with spouses who smoked (OR = 0.39; 95%CI: 0.18-0.85), ETS exposure from sources outside homes was associated with a slight, although non-significant increased risk: OR = 2.30 (95%CI: 0.85-6.19) for the upper 50% exposed. There were no clear differences in ORs by age at exposure to ETS or by histologic type of tumour, though numbers of subjects in subgroup analyses were too small to provide reliable estimates. CONCLUSION: No clear association between lifetime ETS exposure from all sources and increased risk of lung cancer was found in the current study.

Breastfeeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

INTRODUCTION: Breastfeeding has been inversely related to breast cancer risk in the general population. Clarifying the role of breastfeeding among women with a BRCA1 or BRCA2 mutation may be helpful for risk assessment and for recommendations regarding prevention. We present an updated analysis of breastfeeding and risk of breast cancer using a large matched sample of BRCA mutation carriers. METHODS: We conducted a case-control study of 1,665 pairs of women with a deleterious mutation in either BRCA1 (n = 1,243 pairs) or BRCA2 (n = 422 pairs). Breast cancer cases and unaffected controls were matched on year of birth, mutation status, country of residence and parity. Information about reproductive factors, including breastfeeding for each live birth, was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the association between ever having breastfed, as well as total duration of breastfeeding, and the risk of breast cancer. RESULTS: Among BRCA1 mutation carriers, breastfeeding for at least one year was associated with a 32% reduction in risk (OR = 0.68; 95% CI 0.52 to 0.91; P = 0.008); breastfeeding for two or more years conferred a greater reduction in risk (OR = 0.51; 95% CI 0.35 to 0.74). Among BRCA2 mutation carriers, there was no significant association between breastfeeding for at least one year and breast cancer risk (OR = 0.83; 95% CI 0.53 to 1.31; P = 0.43). CONCLUSIONS: These data extend our previous findings that breastfeeding protects against BRCA1-, but not BRCA2-associated breast cancer. BRCA mutation carriers should be advised of the benefit of breastfeeding in terms of reducing breast cancer risk.

The risk of breast cancer in women with a BRCA1 mutation from North America and Poland.

Women with a BRCA1 mutation face a high lifetime risk of breast cancer. It is unknown to what extent environmental factors modify the inherent genetic risk. If women from different countries, but with similar mutations, experience different levels of cancer risk, nongenetic risk modifiers are likely to be present. Study subjects were a cohort of 1477 women with a BRCA1 mutation, from Canada (n = 358), the United States (n = 256) and Poland (n = 863). The women were followed for a mean of 4.3 years and 130 incident cases of breast cancer were recorded. Annual cancer incidence rates were calculated, and based on these, penetrance curves were constructed for women from North America and Poland. In a Cox proportional hazards model, residence in Poland, versus North America, was associated with an adjusted hazard ratio of 0.54 (95% CI 0.34-0.86; p = 0.01). The risk of breast cancer to age 70 was estimated to be 49% for women from Poland and 72% for women from North America. Among women with BRCA1 mutations, the risk of breast cancer in women who reside in Poland is less than that of women who reside in North America. The reasons for the difference are unknown, but this observation suggests that environmental factors or genetic modifiers are important in determining risk.

The BRCA2 c.9004G>A (E2002K) [corrected] variant is likely pathogenic and recurs in breast and/or ovarian cancer families of French Canadian descent.

Specific BRCA1 and BRCA2 mutations recur in French Canadian breast and/or ovarian cancer families because of common ancestors, facilitating carrier detection in this population. We recently reported a BRCA2 c.9004G>A variant of unknown clinical significance in two French Canadian breast cancer families. It confers a E3002K alteration in the conserved C-terminus domain of BRCA2, and has been reported in non-French Canadian cancer families. Seven variant positive French Canadian families have since been identified by mutation screening of referrals to hereditary cancer clinics. In this article, we describe the cancer phenotypes of these families and further assess the contribution of this variant in the French Canadian population. We screened index breast cancer cases from 58 cancer families with at least three confirmed cases of breast and/or ovarian cancer and 960 breast cancer cases (48 years mean age) not selected for family history of cancer that were previously found not to carry the most common BRCA1 and BRCA2 mutations reported in this population. The index variant-positive cases from each family had breast cancer between the ages of 35-55 years (43 years mean age); and reported close relatives with breast cancer diagnoses between the ages of 28-84 years (57 years mean age). Three families had ovarian or peritoneal cancers. BRCA2-associated cancers, such as bladder, esophagus, pancreas, prostate, and thyroid cancers also occurred in these families. One c.9004G>A carrier also harbored the PALB2 c.2323C>T (Q775X) mutation found to recur in French Canadian breast cancer cases. No new BRCA2 variant carriers were identified in mutation screens. The absence of BRCA2 c.9004G>A carriers in the breast cancer cases not selected for family history contrasts with familial cases, supporting a pathogenic status for this variant and addition to the existing common BRCA1 and BRCA2 mutation-screening panel for French Canadian breast and/or ovarian cancer families.

Mutations in Fanconi anemia genes and the risk of esophageal cancer.

The incidence of esophageal squamous cell carcinoma (ESCC) is very high in northeastern Iran. Previously, we reported a strong familial component of ESCC among Turkmens, who constitute approximately one-half of the population of this region. We hypothesized that the genes which cause Fanconi anemia might be candidate genes for ESCC. We sequenced the entire coding regions of 12 Fanconi anemia genes in the germline DNA of 190 Turkmen cases of ESCC. We identified three heterozygous insertion/deletion mutations: one in FANCD2 (p.Val1233del), one in FANCE (p.Val311SerfsX2), and one in FANCL (p.Thr367AsnfsX13). All three patients had a strong family history of ESCC. In addition, four patients (out of 746 tested) were homozygous for the FANCA p.Ser858Arg mutation, compared to none of 1,373 matched controls (OR = 16.7, 95% CI = 6.2-44.2, P = 0.01). The p. Lys3326X mutation in BRCA2 (also known as Fanconi anemia gene FANCD1) was present in 27 of 746 ESCC cases and in 16 of 1,373 controls (OR = 3.38, 95% CI = 1.97-6.91, P = 0.0002). In summary, both heterozygous and homozygous mutations in several Fanconi anemia-predisposing genes are associated with an increased risk of ESCC in Iran.

Risk of ipsilateral breast cancer in BRCA1 and BRCA2 mutation carriers.

Women with a BRCA1 or BRCA2 mutation have an elevated risk of breast cancer and of contralateral breast cancer. In this study, we estimate the risk of non-synchronous ipsilateral breast cancer after a diagnosis of breast cancer in BRCA carriers and evaluate the effects of various treatments on this risk. Patients were 396 women with stage I or stage II breast cancer with an intact ipsilateral breast and for whom a BRCA1 or BRCA2 mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer until the first of ipsilateral mastectomy, ipsilateral breast cancer, death or last follow-up. The 5-year actuarial risk of ipsilateral breast cancer was 5.8% (95% CI 3.2-8.4%) and the 10-year risk was 12.9% (95% CI 8.7-17.1%). Subjects who received chemotherapy had a significantly lower risk of ipsilateral breast cancer compared to those who did not receive chemotherapy (RR 0.45; 95% CI 0.24-0.84; P = 0.01). Radiotherapy was associated with a reduced risk of ipsilateral breast cancer (RR 0.28; 95% CI 0.12-0.63; P = 0.002). Oophorectomy was associated with a significant reduction in the risk of ipsilateral breast cancer (RR 0.33; 95% CI; 0.13-0.81; P = 0.02). On average, following a diagnosis of breast cancer, the annual risk of ipsilateral breast cancer risk in BRCA mutation carriers is 1.2% per year. For women treated with chemotherapy, radiation therapy or oophorectomy the risk is low, compared to women who did not receive any of these treatments.

Breast cancer risk in relation to alcohol consumption and BRCA gene mutations--a case-only study of gene-environment interaction.

The variable penetrance of the BRCA1 and BRCA2 genes suggests that other genetic or environmental factors may interact with these mutations to modify breast cancer risk. The objective of this study was to measure departures from multiplicative effects of alcohol consumption and BRCA gene mutations. A cohort of French-Canadian breast cancer patients was tested for BRCA gene mutations and completed a food frequency questionnaire. The case-only odds ratio (COR) was calculated. A total of 857 women, including 10 BRCA1 and 33 BRCA2 mutation carriers, participated in the study. No significant interaction between alcohol consumption and BRCA1 mutations was detected, although the interaction with wine consumption suggested a sub-multiplicative effect (COR = 0.38, 95% CI: 0.08-1.81). Consumption of alcohol other than wine interacted significantly with BRCA2 mutations (COR = 2.15, 95% CI: 1.03-4.49). Consumption of wine may protect against BRCA1-associated tumors, while women with BRCA2 mutations may be at greater risk of alcohol-induced breast cancer.

Diet and prostate cancer risk with specific focus on dairy products and dietary calcium: a case-control study.

BACKGROUND: Despite the prevalence of prostate cancer worldwide, only a few risk factors have been well-established. The role of diet, especially of dairy products, in the etiology of prostate cancer is still controversial. METHODS: This study assessed the association of dietary components, particularly dairy products and dietary calcium, on prostate cancer risk in a case-control study of 197 cases and an equal number of individually matched controls recruited in Montreal, Canada. A semi-quantitative food frequency questionnaire was administered in which the usual consumption frequency and amounts consumed of more than 200 food items were recorded. RESULTS: We found a twofold increased risk of prostate cancer associated with an increased intake of dairy products {Odds Ratio (OR) = 2.19; 95% Confidence Intervals (CI) 1.22-3.94}. A significant trend of decreasing prostate cancer risk with higher intake was found for legumes, nuts, finfish/shellfish and for alpha-tocopherol after adjustment for calcium intake. Milk was the only dairy product significantly associated with prostate cancer risk, with OR = 2.27; 95% CI (1.25-4.09) for the highest versus lowest quartiles of consumption. Calcium, the main micronutrient contained in dairy products, showed only a borderline association with prostate cancer risk (P = 0.09), with slightly higher risk for higher calcium intake. In conclusion, this study supports the hypothesis that dairy products, especially milk, are involved in the etiology of prostate cancer. However, the mechanisms by which the various nutrients in dairy products and total diet may interact to influence this risk remain unknown.

Toenail selenium status and DNA repair capacity among female BRCA1 mutation carriers.

Selenium is an important cofactor of various antioxidant enzymes and has been shown to enhance DNA repair in normal human fibroblasts. Oral selenium supplementation has also been shown to decrease the number of chromosome breaks in BRCA1 mutation carriers. Because the predisposition to cancer among BRCA1 mutation carriers may be linked to high rates of DNA damage and chromosome breakage, we evaluated the association between toenail selenium concentrations and three measures of DNA repair capacity (the single-cell alkaline gel electrophoresis (comet) assay, the micronucleus test, and the enumeration of gamma-H2AX nuclear foci) in female BRCA1 mutation carriers and in non-carriers. Toenail selenium levels were inversely associated with levels of chromosomal damage following exposure to gamma-irradiation, as assessed by the micronucleus test. This association was limited to women with a BRCA1 mutation (p = 0.03). Toenail selenium was not a significant predictor of DNA repair capacity, as quantified by either the comet assay or the number of gamma-H2AX foci, in carriers or in non-carriers. These results provide evidence for a possible protective effect of selenium against BRCA1-associated breast cancers.

Breast cancer risk in relation to the joint effect of BRCA mutations and diet diversity.

It has been suggested that gene-environment interaction is related to the risk of cancer. To evaluate departure from multiplicative effects between BRCA mutations and diet diversity in breast cancer (BC), a case-only study was carried out in a French-Canadian population including 738 patients with incident primary BC comprising 38 BRCA mutation carriers. Diet diversity was assessed using a validated food frequency questionnaire. Unconditional logistic regression analysis was performed to assess case-only odds ratio (COR) and 95% confidence interval (CI) while adjusting for age, body mass index, smoking, hormonal replacement therapy, and total energy intake. Ours results reveal a strong and significant interaction between BRCA mutations and vegetable and fruit diversity (COR = 0.27; 95%CI = 0.10-0.80; P = 0.03) when comparing the upper to the lower quartiles. The estimates for departure from multiplicative effects between BRCA mutations and total or other food groups' diversity were not supportive of the idea of a gene-environment interaction. The results of this study suggest that the combination of BRCA mutations and vegetable and fruit diversity may be associated with a reduced risk of BC.

Germline RAP80 mutations and susceptibility to breast cancer.

Most of the breast cancer susceptibility genes identified to date are involved in DNA repair, including BRCA1, BRCA2, PALB2, CHEK2 and BRIP1. RAP80 works upstream of BRCA1 and is essential for the localization of BRCA1 to the site of damaged DNA. To investigate whether or not RAP80 is also a breast cancer susceptibility gene, we sequenced the entire exonic regions of RAP80 in the germline DNA of 152 women with familial breast cancer, who were previously found to be negative for BRCA1 and BRCA2 mutations. No truncating mutation was identified. Eleven potentially deleterious RAP80 variants were identified; these 11 variants were genotyped in 424 more familial cases and in 726 healthy controls. Three novel p.Ala342Thr, p.Met353Thr and p.Tyr575Asp rare missense variants and a novel haplotype composed of two variants in the CpG island (c.-24149G > T and c.-24001A > G) and a variant in the 5'UTR (c.-8A > G) and a variant in the 3'UTR (c.*27A > C) were detected in 26 of 571 (4.6%) individuals with familial breast cancer, compared to 14 of 725 (1.9%) controls (P = 0.01; OR = 2.4, 95% CI = 1.2-5.1). In summary, we did not find truncating mutations of the RAP80 gene to be a cause of familial breast cancer. A novel RAP80 haplotype or rare missense mutations may be associated with a modest increased risk of breast cancer, but this observation needs to be confirmed by additional studies.

Smoking and the risk of breast cancer in BRCA1 and BRCA2 carriers: an update.

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.

Menstrual and reproductive factors and pancreatic cancer in the SEARCH program of the IARC.

We conducted a population-based case-control study on the relation of menstrual and reproductive factors and hormone use with pancreatic cancer risk among female participants of the SEARCH program study. We evaluated 367 cases of ductal adenocarcinoma and 821 controls for associations between pancreatic cancer and age at menarche, age at menopause, number of pregnancies, exogenous hormone use, and history of gynaecologic surgery. Among directly interviewed and proxy participants, we found a statistically significant association for having age of menarche at 11 years or younger compared with menarche at ages 12-13 years (OR = 1.8, 95% CI = 1.1-3.1). This result was consistent, but not statistically significant, among three of the four studies analyzed, and when the data were analyzed separately by response status (direct vs. proxy interviews). No other menstrual or reproductive factors were associated with pancreatic cancer risk in this study. In conclusion, earlier age at menarche may be weakly associated with pancreatic cancer, but it seems unlikely that menstrual and reproductive factors play more than only a minor role in pancreatic cancer. Additional analyses in large prospective study populations and in pooled studies may help to clarify remaining inconsistencies.

Risk of breast cancer among French-Canadian women, noncarriers of more frequent BRCA1/2 mutations and consumption of total energy, coffee, and alcohol.

Although the connection between diet, lifestyle and hormones suggests that nutritional and lifestyle factors may exert an influence in the etiology of breast cancer, it is not clear whether these factors operate in the same way in women without BRCA gene mutations. A nested case-control study was conducted in a cohort of French-Canadian women, with 560 members involving 280 nongene carriers of mutated BRCA gene affected by breast cancer and 280 nonaffected and nongene carriers of mutated BRCA gene. A validated semi-quantitative food frequency questionnaire was used to ascertain dietary intake, and a core questionnaire, to gather information on lifestyle risk factors. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in logistic regression models. It was found that energy intake >2,057 Kcal/day was significantly and positively related to breast cancer risk (OR = 2.54; 95% CI: 1.67-3.84; p = 0.01). Women who drank more than eight cups of coffee per day had an increased risk of breast cancer: OR = 1.40 (95% CI: 1.09-2.24; p = 0.03). Subjects who drank >9 g of alcohol (ethanol) per day had an increased risk of breast cancer: OR = 1.55 (95% CI: 1.02-2.37; p = 0.04). In addition, a positive and significant association was noted between the consumption of beer, wine and spirits, and breast cancer risk. The ORs were 1.34 (95% CI: 1.28-2.11; p = 0.04) for more than two bottles of beer per week, OR = 1.16 (95% CI: 1.08-2.58; p = 0.05) for >10 oz of wine per week and OR = 1.09 (95% CI: 1.02-2.08; p = 0.05) for >6 oz of spirit per week, respectively. Intakes of other nutrients and dietary components were not significantly associated with nongene carrier breast cancer risk. This study provides evidence that total energy intake, coffee, and alcohol consumption may play a role in breast cancer risk.

Omega-3 fatty acid treatment of children with attention-deficit hyperactivity disorder: A randomized, double-blind, placebo-controlled study.

BACKGROUND: Although several clinical trials have evaluated the impact of n-3 polyunsaturated fatty acid (PUFA) on patients with attention-deficit hyperactivity disorder (ADHD), changes in plasma PUFA composition were not always assessed following n-3 supplementation. Furthermore, no reports are available on the efficacy of n-3 PUFA in Canadian youth with ADHD. OBJECTIVES: To determine fatty acid (FA) composition, and the efficacy and safety of n-3 PUFA supplementation on ADHD clinical symptoms in French Canadian primary school children. PATIENTS AND METHODS: The Strengths and Weaknesses in ADHD and Normal Behaviors (SWAN) and Conners' questionnaires were used to assess changes in ADHD symptoms in 37 children (only 26 children completed the study from zero to 16 weeks). They were divided into two groups (A and B), and participated in a 16-week, double-blind, one-way, crossover randomized study. In the first phase, group A received the n-3 PUFA supplement and group B received n-6 PUFA (sunflower oil) as a placebo. During the second phase, group B received the active n-3 PUFA supplement that was continued in group A. FA composition and lipid profile were assessed during the phases of the study. RESULTS: FA differences between groups were observed in the 26 patients. Supplementation with n-3 PUFA resulted in significant increases in eicosapentaenoic and docosahexaenoic acids in group A, while group B was enriched with alpha-linolenic, gamma-linolenic and homo-gamma-linolenic acids. The n-3 PUFA supplement was tolerated without any adverse effects. A statistically significant improvement in symptoms was noted based on the parent version of the Conners' questionnaire from baseline to the end of phase 1, and this amelioration continued from phases 1 to 2, although the latter changes from phases 1 and 2 were not statistically significant in any of the subscales except for the subscale measuring inattention in group B. The improvement was greater in patients from group A in phase 1 and in patients from group B in phase 2. A subgroup of eight patients (four in each group) displayed a statistically significant clinical improvement following the administration of the n-3 PUFA supplement, particularly for the inattention and global Diagnostic and Statistical Manual of Mental Disorders, Fourth edition, total Conners' subscales. CONCLUSIONS: A subgroup of children with ADHD who used n-3 PUFA supplements achieved and maintained symptom control. The data of the present study also supported n-3 PUFA safety and tolerability, but limited changes were noted in the FA profile in French Canadians with ADHD.