Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium.

BACKGROUND: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. METHODS: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. RESULTS: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant. CONCLUSIONS: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.

Breast-feeding and risk of epithelial ovarian cancer.

PURPOSE: Evidence suggests that breast-feeding may decrease the risk of epithelial ovarian cancer but it is not clear whether there is a relationship with duration of breast-feeding, patterns of breast-feeding, or particular histological subtypes of ovarian cancer. We sought to investigate these issues in detail. METHODS: Data from participants in a population-based study of ovarian cancer in western Washington State, USA (2002-2007) who had had at least one birth (881 cases and 1,345 controls) were used to assess relations between patterns of breast-feeding and ovarian cancer. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Women who ever breast-fed had a 22 % reduction in risk of ovarian cancer compared with those who never breast-fed (OR = 0.78, 95% CI 0.64-0.96) and risk reduction appeared greater with longer durations of feeding per child breast-fed (OR = 0.56, 95% CI 0.32-0.98 for 18 months average duration breast-feeding versus none). Introduction of supplementary feeds did not substantially alter these effects. The overall risk reduction appeared greatest for the endometrioid and clear cell subtypes (OR per month of average breast-feeding per child breast-fed = 0.944, 95% CI 0.903-0.987). CONCLUSIONS: Among women who have had the opportunity to breast-feed, ever breast-feeding and increasing durations of episodes of breast-feeding for each breast-fed child are associated with a decrease in the risk of ovarian cancer independent of numbers of births, which may be strongest for the endometrioid subtype.

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer.

Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Use of antidepressant medications in relation to the incidence of breast cancer.

Although associations have been reported between antidepressant use and risk of breast cancer, the findings have been inconsistent. We conducted a population-based case-control study among women enrolled in Group Health Cooperative (GHC), a health maintenance organization in Washington State. Women with a first primary breast cancer diagnosed between 1990 and 2001 were identified (N = 2904) and five controls were selected for each case (N = 14396). Information on antidepressant use was ascertained through the GHC pharmacy database and on breast cancer risk factors and screening mammograms from GHC records. Prior to one year before diagnosis of breast cancer, about 20% of cases and controls had used tricyclic antidepressants (adjusted odds ratio = 1.06, 95% CI 0.94-1.19) and 6% of each group had used selective serotonin reuptake inhibitors (OR = 0.98, 95% CI 0.80-1.18). There also were no differences between cases and controls with regard to the number of prescriptions filled or the timing of use. Taken as a whole, the results from this and other studies to date do not indicate an altered risk of breast cancer associated with the use of antidepressants overall, by class, or for individual antidepressants.

Breast cancer risk in women who have had children with different partners.

The fetal antigen hypothesis suggests that the lowered risk of breast cancer in parous women may be afforded by the development of antibodies to fetal antigens that are structurally similar to mammary cancer antigens. It has previously been hypothesized that the likelihood of developing such antibodies may be higher among women who have had children with more than 1 partner. Utilizing information on parenthood and breast cancer available in nationwide Swedish registers, we undertook a case-control study nested within a nation-wide cohort to address this issue. Number of partners fathering a child was categorized as 1, 2 and 3 or more. All analyses were restricted to subjects with 2 or more births and encompassed a total of 20,881 women with breast cancer and 111,989 control women. In an unadjusted analysis, the risk of breast cancer was somewhat lower (odds ratio [OR] = 0.94, 95% confidence interval [CI] 0.89-0.99) in women who had had children with 2 different partners compared with women who had had children conceived with the same partner. After adjustment for parity, age at first birth and educational level, however, the risk of breast cancer was slightly elevated (OR = 1.09, 95% CI: 1.03-1.15). Among women who had had children with 3 or more different men, the pattern was similar. The present results provide no support for the hypothesis that greater antigenic exposure afforded by having children with more than 1 man may reduce the risk of breast cancer. It remains possible, however, that pregnancy may influence breast cancer risk through some immunologic mechanism; further testing of the fetal antigen hypothesis may require development of relevant laboratory measures.

Localization of a susceptibility gene for familial nonmedullary thyroid carcinoma to chromosome 2q21.

The familial form of nonmedullary thyroid carcinoma (NMTC) is a complex genetic disorder characterized by multifocal neoplasia and a higher degree of aggressiveness than its sporadic counterpart. In a large Tasmanian pedigree (Tas1) with recurrence of papillary thyroid carcinoma (PTC), the most common form of NMTC, an extensive genomewide scan revealed a common haplotype on chromosome 2q21 in seven of the eight patients with PTC. To verify the significance of the 2q21 locus, we performed linkage analysis in an independent sample set of 80 pedigrees, yielding a multipoint heterogeneity LOD score (HLOD) of 3.07 (alpha=0.42), nonparametric linkage (NPL) 3.19, (P=.001) at marker D2S2271. Stratification based on the presence of at least one case of the follicular variant of PTC, the phenotype observed in the Tas1 family, identified 17 such pedigrees, yielding a maximal HLOD score of 4.17 (alpha=0.80) and NPL=4.99 (P=.00002) at markers AFMa272zg9 and D2S2271, respectively. These results indicate the existence of a susceptibility locus for familial NMTC on chromosome 2q21.

Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality.

BACKGROUND: Hormone replacement therapy (HRT) is typically avoided for women with a history of breast cancer because of concerns that estrogen will stimulate recurrence. In this study, we sought to evaluate the impact of HRT on recurrence and mortality after a diagnosis of breast cancer. METHODS: Data were assembled from 2755 women aged 35-74 years who were diagnosed with incident invasive breast cancer while they were enrolled in a large health maintenance organization from 1977 through 1994. Pharmacy data identified 174 users of HRT after diagnosis. Each HRT user was matched to four randomly selected nonusers of HRT with similar age, disease stage, and year of diagnosis. Women in the analysis were recurrence free at HRT initiation or the equivalent time since diagnosis. Rates of recurrence and death through 1996 were calculated. Adjusted relative risks were estimated by use of the Cox regression model. All statistical tests were two-sided. RESULTS: The rate of breast cancer recurrence was 17 per 1000 person-years in women who used HRT after diagnosis and 30 per 1000 person-years in nonusers (adjusted relative risk for users compared with nonusers = 0.50; 95% confidence interval [CI] = 0.30 to 0.85). Breast cancer mortality rates were five per 1000 person-years in HRT users and 15 per 1000 person-years in nonusers (adjusted relative risk = 0.34; 95% CI = 0.13 to 0.91). Total mortality rates were 16 per 1000 person-years in HRT users and 30 per 1000 person-years in nonusers (adjusted relative risk = 0.48; 95% CI = 0.29 to 0.78). The relatively low rates of recurrence and death were observed in women who used any type of HRT (oral only = 41% of HRT users; vaginal only = 43%; both oral and vaginal = 16%). No trend toward lower relative risks was observed with increased dose. CONCLUSION: We observed lower risks of recurrence and mortality in women who used HRT after breast cancer diagnosis than in women who did not. Although residual confounding may exist, the results suggest that HRT after breast cancer has no adverse impact on recurrence and mortality.

Breast cancer risk and "delayed" primary Epstein-Barr virus infection.

Parallel to its established causal association with both infectious mononucleosis (IM) and young adulthood Hodgkin disease (YAHD), we propose a hypothesis that "delayed" primary EBV infection (i.e., primary infection occurring during adolescence or adulthood) is associated with elevated breast cancer risk. We evaluated this hypothesis with two investigations, one descriptive and the other analytic. The descriptive study used international/United States cancer registry data to assess the association between incidence rates of breast cancer and those of YAHD. The incidence rates of the seemingly unrelated neoplasms were strongly correlated (correlation coefficients of 0.74 and 0.88 for international and United States data, respectively; these were higher than the correlation coefficients of YAHD with two other cancers that we considered). Populations with higher incidence rates corresponded to those with higher likelihood of delayed primary EBV infection. The analytical study was based on a population-based case-control study of breast cancer in middle-aged women. Age-adjusted odds ratios of breast cancer in women who reported a history of IM, relative to women who did not, increased monotonically from 0.55 [95% confidence interval (CI), 0.05-6.17] for women with 0-9 years of age at IM onset to 2.67 (CI, 1.04-6.89) for women with > or =25 years of age at IM onset (P = 0.016). An older age at tonsillectomy, another surrogate of delayed EBV exposure, was also associated with increased risk of breast cancer: odds ratios, 0.92 (CI, 0.57-1.48) and 1.76 (CI, 1.15-2.69) for women with tonsillectomy at 0-4 years of age and > or =15 years of age, respectively (P = 0.018). Adjusting for additional potential confounders did not modify the associations appreciably. The implications of the findings and a potential biological mechanism are presented.

Recreational physical activity and risk of papillary thyroid cancer (United States).

OBJECTIVE: Exercise has been hypothesized to influence cancer risk through a variety of mechanisms including hormonal, metabolic and immunologic effects, yet its relation with the risk of thyroid cancer has not been examined. We conducted a population-based case-control study in women aged 18-64 in three counties of western Washington State to assess the relation of recreational physical activity with risk of papillary thyroid cancer. METHODS: Of 558 women with thyroid cancer of the follicular epithelium diagnosed during 1988-1994 who were identified as eligible, 468 (83.9%) were interviewed; this analysis was restricted to women with papillary histology (n = 410). Controls (n = 574) were identified by random digit dialing, with a response proportion of 73.6%. Logistic regression was used to calculate odds ratios (OR) and associated confidence intervals (CI) estimating the relative risk of papillary thyroid cancer associated with various aspects of recreational exercise. RESULTS: Risk of thyroid cancer was reduced among women who reported that they engaged in regular recreational exercise during the 2 years before diagnosis relative to women who did not report exercise during that time period (OR = 0.76, 95% CI 0.59-0.98). A similar risk reduction was noted among women who reported having exercised regularly between ages 12 and 21 (OR = 0.83, 95% CI 0.64-1.1). However, no clear associations with aspects of recreational activity, including average hours exercised per week or weekly energy expenditure, were observed. CONCLUSIONS: These results provide some initial support for the hypothesis that physical activity may reduce risk of thyroid cancer.

Multiple primary breast and thyroid cancers: role of age at diagnosis and cancer treatments (United States).

BACKGROUND: Breast and thyroid cancer have been observed to occur more frequently than expected as multiple primary tumors in women. The study presented herein focuses on the effects of age at diagnosis and treatment for the first cancer on the development of the second cancer. METHODS: This retrospective cohort study used a study population consisting of 38,632 women diagnosed with primary invasive breast cancer and 2189 women diagnosed with primary invasive thyroid cancer between 1974 and 1994. Cases were identified from records of the Cancer Surveillance System of western Washington and followed for subsequent cancer development through 1995. RESULTS: Seventy-one women were diagnosed during their lives with both breast and thyroid cancers. Including cancers diagnosed during the same month as or after the initial cancer, the relative risk (RR) of breast cancer among women with thyroid cancer was 1.5 (95% confidence interval [CI] 1.1-2.0), and the RR of thyroid cancer among women with breast cancer was 1.5 (95% CI 1.1-2.2). Among women with thyroid cancer, risk of breast cancer was greatest when the latter cancer was diagnosed under 45 years of age (RR = 2.3, 95% CI 1.1-4.4). First course of treatment, including radiation or hormonal therapy to treat thyroid cancer, and radiation, chemotherapy, or hormonal therapy to treat breast cancer, did not alter a woman's risk of developing the second cancer. CONCLUSIONS: The data suggest that the incidence of breast and thyroid cancer may be related, and that in particular women with thyroid cancer may be at a moderately increased risk of developing breast cancer before age 45.

Evaluation of dietary and environmental risk factors for hyperthyroidism in cats.

OBJECTIVE: To identify dietary and environmental risk factors for hyperthyroidism in cats. DESIGN: Case-control study. ANIMALS: 100 cats with hyperthyroidism and 163 control cats. PROCEDURE: Medical records were examined, and owners completed a mailed questionnaire. Data collected included information regarding demographic variables, environmental exposures, and diet, including preferred flavors of canned cat food. RESULTS: Case cats were significantly less likely to have been born recently than control cats. Housing; exposure to fertilizers, herbicides, or plant pesticides; regular use of flea products; and presence of a smoker in the home were not significantly associated with an increased risk of disease, but cats that preferred fish or liver and giblets flavors of canned cat food had an increased risk. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that cats that prefer to eat certain flavors of canned cat food may have a significantly increased risk of hyperthyroidism.

Reproductive factors and risk of papillary thyroid cancer in women.

The authors conducted a population-based case-control study of 410 women residing in three counties in western Washington State who were aged 18-64 years when diagnosed with papillary thyroid cancer in 1988-1994 and 574 controls to assess the effects of pregnancy history and other aspects of reproductive life on risk of this disease. Among women aged 45-64, the authors observed no associations with number of live births, age at first live birth, or age at last live birth. Risk was somewhat increased in women <45 years who had given birth within the previous 5 years; this association was most evident among women who reported that cancer symptoms had led to diagnosis. Among women who had given birth within the last 5 years, risk was greatest among those with two or more births during that time period (relative risk (RR) = 4.2, 95% confidence interval (CI): 2.0, 8.9, relative to parous women whose last birth was >5 years before the reference date). Risk of thyroid cancer was also associated with lactation during the previous 5 years (e.g., RR = 2.9, 95% CI: 1.5, 5.5, among parous women who had breastfed > or =12 months, vs. 0-1 months, during that interval). Our results suggest that thyroid stimulation during both pregnancy and lactation may result in a transient increase in risk of papillary thyroid cancer.

Cimetidine use and risk of prostate and breast cancer.

Histamine (H2) receptor antagonists, such as cimetidine and ranitidine, became available in the late 1970s and presently number among the most commonly used drugs. Cimetidine has been hypothesized to exert a cancer preventive effect on the prostate due to its ability to inhibit the binding of dihydrotestosterone to androgen receptors. Other hormonal effects of this drug include increases in serum prolactin levels and inhibition of 2-hydroxylation of estradiol. We assessed risk of prostate and breast cancers in a cohort of 48,512 members of the Group Health Cooperative of Puget Sound prescribed cimetidine or another H2 blocker between 1977 and 1995. Standardized incidence ratios were calculated comparing the observed numbers of cancers to those expected based on population rates in western Washington State. Because cimetidine, but not other H2 blockers, influences hormonal activity and metabolism, we conducted nested case-control studies comparing cancer risk among individuals treated with cimetidine to individuals who used other H2 blockers. Risks of breast and prostate cancers were identical among users of cimetidine and users of other H2 blockers (relative risk, 1.0 for both cancers). We observed no trend in risk of breast cancer according to time since first or last cimetidine prescription or number of cimetidine prescriptions filled. For prostate cancer, our findings were similar save for a modest increase in risk among men who had filled > or =21 cimetidine prescriptions (relative risk, 1.4; 95% confidence interval, 1.0-1.9). Our results suggest that use of cimetidine does not influence risk of female breast cancer. Further, these data provide little evidence to support the previously hypothesized preventive effect of cimetidine on risk of prostate cancer.

Risk of papillary thyroid cancer in women in relation to smoking and alcohol consumption.

Both smoking and alcohol consumption may influence thyroid function, although the nature of these relations is not well understood. We examined the influence of tobacco and alcohol use on risk of papillary thyroid cancer in a population-based case-control study. Of 558 women with thyroid cancer diagnosed during 1988-1994 identified as eligible, 468 (83.9%) were interviewed; this analysis was restricted to women with papillary histology (N = 410). Controls (N = 574) were identified by random digit dialing, with a response proportion of 73.6%. We used logistic regression to calculate odds ratios (OR) and associated confidence intervals (CI) estimating the relative risk of papillary thyroid cancer associated with cigarette smoking and alcohol consumption. A history of ever having smoked more than 100 cigarettes was associated with a reduced risk of disease (OR = 0.7, 95% CI = 0.5-0.9). This reduction in risk was most evident in current smokers (OR = 0.5, 95% CI = 0.4-0.7). Women who reported that they had ever consumed 12 or more alcohol-containing drinks within a year were also at reduced risk (OR 0.7, 95% CI = 0.5-1.0). Similar to the association noted with smoking, the reduction in risk was primarily present among current alcohol consumers. The associations we observed, if not due to chance, may be related to actions of cigarette smoking and alcohol consumption that reduce thyroid cell proliferation through effects on thyroid stimulating hormone, estrogen, or other mechanisms.

Fetal antigen hypothesis and ovarian cancer: is there an immunogenic explanation for the reduction in risk associated with parity?

The hypothesis that a woman's immunologic response to fetal antigens arising from paternal genes may explain some of the reduction in risk of ovarian cancer associated with parity has not, to our knowledge, been examined. We analyzed data from a case-control study to evaluate the risk of epithelial ovarian cancer among women of similar parity associated with proposed indices of paternally derived fetal antigen exposure. Cases included white women 20-79 years of age diagnosed with epithelial ovarian cancer in three counties in Washington State between January 1, 1986, and December 31, 1988 (N = 322). Controls (N = 426) were selected by random-digit dialing and were broadly similar to cases in age and county of residence. After excluding women who had fewer than two pregnancies (or, in some analyses, fewer than two livebirths) and adjusting for age and number of livebirths, we observed no reduction in risk associated with number of marriages or number of partners with whom a study participant conceived a pregnancy and/or had a child. Nevertheless, these relatively crude indices of exposure to paternally derived fetal antigens do not preclude the possibility that a woman's response to other fetal or pregnancy-related antigens may antagonize the development of ovarian cancer.

Reproductive risk factors for mucinous and non-mucinous epithelial ovarian cancer.

We evaluated reproductive risk factors for mucinous and non-mucinous tumors in a population-based case-control study of epithelial ovarian cancer among women ages 20-79 years. We observed a reduction in risk of tumors of both types in association with one or more full-term pregnancies and with use of oral contraceptives for 5 or more years. While findings of some previous studies support the hypothesis that certain aspects of a woman's reproductive life have a different impact on the risk of these subtypes of ovarian epithelial cancer, our data suggest that this issue is not yet resolved.