Organochlorines and endometrial cancer risk.

There is concern that persistent environmental pollutants such as dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs) increase breast cancer risk, at least partially through estrogenic effects. Because the endometrium is more sensitive to estrogenic stimulation than the breast, such a carcinogenic effect should be more pronounced in the endometrium than the breast. In a population-based case-control study in Sweden, we measured serum concentrations of 10 chlorinated pesticides and 10 PCB congeners in 154 endometrial cancer cases and 205 population controls. Information on potential confounders was obtained by mailed questionnaires. We used logistic regression to calculate odds ratios (ORs) as measures of relative risk. We performed analyses for lipid-adjusted concentrations of each individual substance and after grouping substances according to putative hormonal effects. We found no significant associations of increasing levels of pesticide or PCB exposure with endometrial cancer risk. The multivariate OR was 1.0 (95% confidence interval, 0.6-2.0; P for trend, 0.78) for the highest compared with the lowest quartile of dichlorodiphenyldichloroethylene (DDE), the predominant dichlorodiphenyltrichloroethane metabolite. Corresponding ORs were 1.0 for hexachlorobenzene, 0.9 for beta-hexachlorocyclohexane, 1.4 for oxychlordane, and 1.2 for trans-nonachlor. Analyses of substances grouped by putative hormonal effect also showed no associations with endometrial cancer risk. For all estrogenic compounds, the OR for the highest compared with the lowest quartile was 1.1 (95% confidence interval, 0.6-2.2; P for trend, 0.90). Our data do not support the hypothesis that the organochlorine exposure studied increases the risk for endometrial cancer.     

Organochlorines and breast cancer risk by receptor status, tumor size, and grade (Canada)

Objective: We evaluated the association between organochlorines and breast cancer subtype defined by the tumor characteristics: estrogen receptor status, progesterone receptor status, tumor size, and grade. Methods: A case–control study was conducted from 1995 to 1997 in Kingston and Toronto, Canada. Breast adipose tissue, taken from 217 cases and 213 biopsy controls frequency-matched on age, was analysed for 14 polychlorinated biphenyl (PCB) congeners and 10 pesticides. Results: Adjusting for age, geometric means of several organochlorines differed by estrogen receptor status and tumor grade (p < 0.05). Odds ratios (ORs) for each organochlorine relative to the common control group for breast cancers of differing subtype were compared using polytomous logistic regression. Although the ORs did not differ significantly by subtype, the ORs of PCBs and p, p-1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) were higher with risk of estrogen receptor-negative breast cancer than estrogen receptor-positive breast cancer. One of the most extreme differences was with DDE, where the OR for the association with risk of estrogen receptor-negative breast cancer was 2.4 (95% confidence interval (CI) 1.0–5.4) in the uppermost tertile relative to the lowest, whereas the corresponding OR for risk of estrogen receptor-positive breast cancer was 1.1 (95% CI 0.6–1.9). PCBs also tended to be more strongly positively associated with risk of larger and higher-grade tumors. Conclusions: The association between organochlorines and breast cancer risk did not significantly differ by subtype, but many PCBs were more strongly associated with tumors of poor prognosis.     

Organochlorines and breast cancer: a case-control study in Brazil.

Breast cancer is an important cause of morbidity and mortality in Brazil. Some studies have analyzed the potential role of organochlorine compounds in breast cancer etiology. These chemical compounds have been widely used in agriculture and in vector-control programs in Brazil. A case-control study was carried out in the main cancer hospital of the Instituto Nacional de Cancer in Rio de Janeiro to investigate exposure to organochlorinated pesticides as a risk factor for breast cancer. We investigated 177 cases of invasive breast cancer at the hospital, between May 1995 and July 1996, and 350 controls selected among female visitors at the same hospital. In addition to information obtained from interviews, blood samples were taken, to analyze residual amounts of organochlorine by gas chromatography using an electron capture detector. [1,1-Dichloro-2, 2-bis(p-chlorophenyl)ethylene] (DDE) was determined in sera of 457 women from a total of 493 participants who had serum samples available. Residues of hexachlorobenzene were found in 11 women only. No statistically significant association was found between breast cancer risk and serum level of DDE or history of exposure to pesticides. Serum levels of DDE (ng/ml) were similar in patients (median = 3.1, mean = 5.1) and controls (median = 3.1, mean = 4.8) (p = 0.93). The age-adjusted odds ratio of breast cancer for women in the upper quintile compared with those in the lowest quintile was 0.90 (95% confidence interval 0.47-1.73). When adjusted for other variables, the risk remained not statistically significant (upper quintile odds ratio = 0.79, 95% confidence interval 0.39-1.60). In our hands, exposure to organochlorinated pesticides measured by history or serum analysis was thus not a risk factor for breast cancer.     

Organochlorines, p53 mutations in relation to breast cancer risk and survival. A Danish cohort-nested case-controls study

Epidemiological studies integrating genetic susceptibility with biological measurements of organochlorine exposure may provide new clues regarding these substances influence on breast cancer etiology. Initial attempts pursuing this avenue has dealt with polymorphisms in the carcinogen-metabolizing enzymes cytochrome P450 (CYPlAl). This study examined if mutations in the tumor suppressor gene p53 affected organochlorine exposure related breast cancer risk and survival. The material consisted of 162 breast cancer cases and 316 matched controls, who had participated, in the Copenhagen City Heart Study (CCHS) between 1976 and 1978. Cases diagnosed between study initiation and 1993 were identified by linkage to the Danish Cancer Registry. The case group served as a cohort in the survival analyses. Information on known and suspected breast cancer risk factors was obtained from CCHS, and the Danish Breast Cancer Cooperative Group provided information on tumor characteristics. Lipid adjusted serum concentrations of selected organochlorines were compared between cases and controls while stratifing by p53 mutation status. A non-significant increased risk of breast cancer was observed in the highest exposure level of dieldrin and polychlorinated biphenyls among women who developed a tumor with mutant p53 (odds ratio (OR)=3.53, 95% confidence interval (CI)=0.79–15.79 and OR=3.00, 95% CI=0.66–13.62). There was no clear difference in overall survival between breast cancer cases with 'wild-type' and mutant p53, although a significant dose-response relationship appeared for dieldrin exposure in tumors with 'wild-type' p53. These preliminary results suggest that p53 mutations may have a modifying effect on at least the breast cancer risk associated with exposures to organochlorines.     

Organochlorines and risk of non-Hodgkin lymphoma

Organochlorine chemicals and polychlorinated biphenyls (PCBs) have been suspected as possible risk factors for non-Hodgkin lymphoma (NHL). We investigated PCBs and organochlorine pesticides and risk of NHL in a population-based case-control study in British Columbia, Canada. Congeners of PCBs (including dioxinlike congeners) and pesticides or pesticide metabolites were measured in plasma of 422 pretreatment cases and 460 control subjects. This is so far the largest study to examine organochlorines in plasma to date. Several dioxin-like PCB congeners were associated with increased risk of NHL, including dioxin-like PCB nos. 118 and 156 with odds ratios (OR) for the highest versus lowest quartile between 1.6 and 1.8. Several non-dioxin-like congeners also showed significant associations. The PCB congener with the strongest association was no. 180 with an OR for the highest versus the lowest quartile of 1.83 (95% confidence interval = 1.18-2.84). Six pesticide analytes also showed a significant association with NHL; beta-hexachlorocyclohexane, p,p'-DDE, hexachlorobenzene, mirex, oxychlordane and trans-nonachlor. The strongest association was found for oxychlordane, a metabolite of the pesticide chlordane (highest vs. lowest quartile OR = 2.68, 95% confidence interval = 1.69-4.24). Our results provide further evidence that organochlorines contribute to NHL risk.     

Novel breast cancer risk alleles and endometrial cancer risk

Genome-wide association studies have identified several novel risk alleles for breast cancer. We hypothesized that genetic variants that are associated with breast cancer, a hormone-related disease, would also be associated with endometrial cancer, another hormone-related disease. We conducted a case-control study nested within the Nurses' Health Study and the Women's Health Study to investigate the associations between these 7 newly identified risk alleles for breast cancer and endometrial cancer risk using 692 invasive endometrial cancer cases and 1,723 matched controls. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the risk of endometrial cancer. In contrast to the breast cancer findings, we did not observe an increased risk of endometrial cancer. We observed an inverse association among rs2981582 (FGFR2) variant carriers [OR= 0.75 (95% CI: 0.60-0.95)]. We also observed a nonsignificant inverse association with rs889312 (MAP3K1) variant carriers [OR = 0.85 (95% CI: 0.68-1.05)] and rs1219648 (FGFR2) variant carriers [OR= 0.86 (95% CI: 0.69-1.06) and endometrial cancer risk. We did not observe associations with the other single nucleotide polymorphisms (SNPs) and endometrial cancer risk. Replication studies investigating these polymorphisms and endometrial cancer risk are warranted. However, our findings do suggest the potential importance of biological differences between endometrial and breast cancer with respect to the genes identified in the scans. The molecular mechanisms underlying these differences remain to be defined.     

Menopause and breast cancer risk

Age at menopause and type of menopause from hospital records of breast cancer patients were compared with similar information reported by a national probability sample of women. The national sample comprised 3581 women who responded to the 1960-1962 National Health Examination Survey. The cancer series consisted of 3887 patients selected from those reported to the Connecticut Cancer Registry between 1950 and 1959. No substantial bias was identified when the validity of the comparison and the effect of the relatively large number of breast cancer patients whose menopause histories were deficient were evaluated. Overall, surgically induced menopause was associated with a reduction in breast cancer risk to about 60% of that experienced by women having natural menopause induced before age 35, but induction up to age 50 was protective. There was little effect in the 10 years following the surgical procedure, but substantial reduction occurred in all subsequent periods. Among women with menopause induced before age 35, breast cancer risk stayed as low as 1/3 that expected 30 and more years later. Relative risk of breast cancer increased with age at natural menopause. Women with natural menopause at age 55 or older had twice the breast cancer risk experienced by those whose menopause occurred before age 45. The relative risk of breast cancer associated with late natural menopause was greatest after age 70.     

Breastfeeding and breast cancer risk

A population-based case-control study of breast cancer with a focus on premenopausal women under 45 years of age, conducted in three geographic regions of the United States, enabled the evaluation of risk in relation to varying breastfeeding practices. Among premenopausal parous women (1,211 cases, 1,120 random-digit-dialing controls), a history of breastfeeding for two or more weeks was associated with a relative risk (RR) of 0.87 (95 percent confidence interval [CI]=0.7–1.0). This relationship was not altered substantially by removing from the reference group women who had problems with breastfeeding in the first two weeks, including those with insufficient milk production. Risk was not related substantially to number of children breastfed or length of breastfeeding, although a relatively low risk was observed among those breastfeeding for the longest duration examined (RR=0.67, CI=0.4–1.1 for an average period per child of 72 or more weeks). Women who began to breastfeed at a young age (<22 years) experienced the greatest reduction in risk, but other timing parameters (e.g., interval since first or last breastfeeding) were not predictive of risk. Risks were not modified substantially by age or menopause status, although the number of menopausal subjects examined was limited. Use of medications to stop breast milk was unrelated to risk (RR=1.04). The results of this study do not support the notion that breastfeeding substantially reduces breast cancer risk; however, this may reflect the fact that most of our study subjects breastfed only for limited periods of time (average breastfeeding per child of 30 weeks). Further studies are needed to clarify the relationship of breastfeeding to breast cancer risk, and to determine possible etiologic mechanisms underlying any observed associations.Drs Brinton, Potischman, and Swanson are with the Environmental Epidemiology Branch, National Cancer Institute, Betbesda, MD, USA. Authors also are affiliated with the Special Epidemiology Program, New Jersey State Department of Health, Trenton, NJ, USA (Ms Schoenberg); Rollins School of Public Health, Emory University, Atlanta, GA, USA (Dr Coates); the Division of Epidemiology, Columbia University School of Public Health, New York, NY, USA (Dr Gammon); and the Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA (Drs Malone, Stanford, Daling). Address correspondence to Dr Brinton, Environmental Epidemiology Branch, National Cancer Institute, Executive Plaza North, Room 443, Bethesda, MS 20892, USA.     

Abortion and breast cancer risk

The relationship between spontaneous and induced abortions and breast cancer risk was analyzed using data from a case-control study conducted between June 1991 and February 1994 in 6 Italian centers on 2,569 histologically confirmed incident breast cancer cases and 2,588 controls admitted to hospital for a wide range of acute, non-neoplastic, non-hormone-related diseases. One or more abortions were reported by 31% of cases and 32% of controls, corresponding to a multivariate odds ratio (OR) of 1.0 (95% confidence interval [CI], 0.8–1.1). No trend in risk was observed with increasing number of total abortions or spontaneous and induced abortions separately. No significant relationship was found between the risk of breast cancer and history of spontaneous or induced or total abortions in separate strata of age at diagnosis, number of children, time of abortion in relation to first birth and family history of breast cancer. When abortion was the outcome of the first pregnancy, the OR was 1.2 for spontaneous and 1.3 for induced abortion, in relation to women with birth as outcome of the first pregnancy, and 1.0 and 1.1, respectively, when the reference category was nulligravidae. Thus, our results indicate a lack of association between induced and spontaneous abortions and breast cancer risk. © 1996 Wiley-Liss, Inc.     

Prolactin and breast cancer risk

Prolactin, a hormone involved in normal breast development and lactation, has been hypothesized to be important in the etiology of breast cancer. This review summarizes in vitro, animal, and epidemiologic data supporting this hypothesis. Experimental evidence indicates that prolactin can promote cell proliferation and survival, increase cell motility, and support tumor vascularization. Animal data suggest that prolactin can increase tumor growth rates and the number of metastases, as well as induce both estrogen receptor +(ER) and ER--tumors in a transgenic mouse model in which ER+ tumors are very rare. Epidemiologic data for premenopausal women are sparse; however a recent study with 235 cases reported a significant positive association between plasma prolactin levels and breast cancer risk. Studies in postmenopausal women have reported a positive association as well, and in the largest study (n=851 cases) the association was strongest for ER+ tumors. Overall, the available data support the hypothesis that prolactin increases risk of breast cancer. Future research directions include better characterizing the potential interplay between prolactin and estrogen and determining whether genetic variability in prolactin-related genes is associated with breast cancer risk.     

Catechol-O-methyltransferase and breast cancer risk

Recent studies suggest that a polymorphism in catechol-O- methyltransferase (COMT) is associated with increased risk of breast cancer. Methylation by COMT is the principal pathway for inactivation of catechol estrogens, which are hypothesized to participate in estrogen-induced carcinogenesis. We examined the association of COMT genotype and breast cancer risk in a population-based, case-control study of invasive breast cancer in North Carolina. The study population consisted of 654 cases and 642 controls, with approximately equal numbers of African-American and white women and women under the age of 50 and aged 50 or over. Contrary to previous reports, we did not observe an association between one or more copies of the low activity COMT allele (COMT-L) and breast cancer risk. Multivariate relative risks (RRs) were 0.8 (95% confidence interval: 0.6-1.1) for COMT-HL and 0.8 (0.6-1.1) for COMT-LL, compared with the COMT-HH genotype. RRs for COMT did not differ among African-American and white women and we did not observe strong modification of RR estimates by menopausal status, body mass index, physical activity or other covariates. Our results suggest that COMT genotype is not related to breast cancer risk.      

Contralateral breast cancer risk

The use of breast-conserving treatment approaches for breast cancer has now become a standard option for early stage disease. Numerous randomized studies have shown medical equivalence when mastectomy is compared to lumpectomy followed by radiotherapy for the local management of this common problem. With an increased emphasis on patient involvement in the therapeutic decision making process, it is important to identify and quantify any unforeseen risks of the conservation approach. One concern that has been raised is the question of radiation- related contralateral breast cancer after breast radiotherapy. Although most studies do not show statistically significant evidence that patients treated with breast radiotherapy are at increased risk of developing contralateral breast cancer when compared to control groups treated with mastectomy alone, there are clear data showing the amount of scattered radiation absorbed by the contralateral breast during a routine course of breast radiotherapy is considerable (several Gy) and is therefore within the range where one might be concerned about radiogenic contralateral tumors. While radiation related risks of contralateral breast cancer appear to be small enough to be statistically insignificant for the majority of patients, there may exist a smaller subset which, for genetic or environmental reasons, is at special risk for scatter related second tumors. If such a group could be predicted, it would seem appropriate to offer either special counseling or special prevention procedures aimed at mitigating this second tumor risk. The use of genetic testing, detailed analysis of breast cancer family history, and the identification of patients who acquired their first breast cancer at a very early age may all be candidate screening procedures useful in identifying such at- risk groups. Since some risk mitigation strategies are convenient and easy to utilize, it makes sense to follow the classic ‘ALARA’ (as low as reasonably achievable) principles and to minimize scattered radiation for these special risk groups and perhaps for all patients undergoing breast radiotherapy. This paper reviews the literature on the risk of radiation- related second contralateral breast cancers.     

Family history of breast cancer and breast cancer risk in Japan

We studied 132 families with a family history of breast cancer (familial aggregation cases, FA cases) to assess the breast cancer risk presented by such a family history. For comparison with these FA cases, we randomly selected 132 control families of sporadic cases (SP controls) by adjusting for the age of the proband at surgery. Information on family history was collected for all first-degree female relatives and maternal and paternal grandmothers. Japanese women with a first-degree relative affected by breast cancer were found to have an increased risk of the disease. The odds ratio (OR) for women with a family history of breast cancer was 1.99 (95% confidence interval [ CI ], 1.48-2.66). The OR for FA-case doughters of women with breast cancer was 1.54 (95% CI, 0.91-2.63). A higher risk was not observed if a woman's mother had breast cancer. If the proband had a sister with breast cancer, a slightly increased risk of other cancers of the proband was observed (OR, 1.85 [ 0.87-3.92]). These results suggest that a family history of breast cancer in Japanese women may affect their risk of developing cancer of the breast and other organs.     

Knowledge about breast cancer risk factors and hereditary breast cancer among early-onset breast cancer survivors

Little is known about knowledge levels regarding hereditary breast cancer among breast cancer survivors. This study explored, among women with early-onset breast cancer (<50 years): 1) knowledge regarding breast cancer risk factors and hereditary breast cancer; and 2) differences in knowledge based on risk for hereditary disease. Participants recruited from 34 Virginia hospitals responded to two questionnaires. The Family History Questionnaire assessed risk for hereditary breast cancer. The Knowledge, Attitudes, and Beliefs Questionnaire evaluated knowledge of general breast cancer risk factors and hereditary breast cancer. Of 314 respondents, 273 (87%) returned both questionnaires. A total of 137 (52%) participants met the study's criteria for hereditary breast cancer risk. Most participants knew common breast cancer-associated risk factors, including family history of breast cancer. Only 35% recognized family history of non-breast malignancies as a risk factor for breast cancer. Most participants recognized that prophylactic mastectomy does not eliminate breast cancer risk (63%), that not all women carrying a mutation develop disease (73%), and that men can develop breast cancer (96%). The majority selected 'I don't know' for knowledge of several characteristics of hereditary breast cancer, including: early-onset disease (54%); multifocal or bilateral disease (62%); risk transmission through fathers (58%); association with other cancer types (61%); and male breast cancer (70%). Knowledge regarding hereditary breast cancer did not vary between women with suspected hereditary disease and those with presumed sporadic disease. These data highlight the need for information regarding hereditary breast cancer for early-onset breast cancer survivors.     

Antidepressant use and breast cancer risk

Summary Background Antidepressants are among the most commonly prescribed drugs in the United States. Laboratory studies suggest that because certain antidepressants increase prolactin levels that they may also increase breast cancer risk. However, human studies evaluating use of antidepressants in relation to breast cancer risk have yielded inconsistent results. Methods A population-based case-control study consisting of 975 breast cancer cases 65–79 years of age diagnosed from 1997–1999 and 1007 age and residence-matched controls was conducted in western Washington State. Detailed information on antidepressant use was obtained through structured in-person interviews. Logistic regression was performed to analyze the relationship between antidepressant use and breast cancer risk. Results Overall, there was no association between ever use of antidepressants and breast cancer risk (odds ratio [OR] = 1.2, 95% confidence interval [95% CI]: 0.9–1.6). When evaluated separately, tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), and triazolopyridines were each not associated with breast cancer risk. However, risk varied by hormone receptor status. Compared to never users, ever users of SSRIs had elevated risks of progesterone receptor (PR) negative and estrogen receptor (ER) positive/PR-negative breast cancers (OR = 1.8, 95% CI: 1.1–3.6 and OR = 2.0, 95% CI: 1.1–3.8, respectively), but not of tumors with other hormone receptor profiles. Conclusions Based on these results and those of previous studies, there is limited evidence that any type of antidepressant use is associated with breast cancer risk overall. SSRIs may elevate risks of PR- and ER+/PR- tumors, though further studies are needed to confirm these associations.