Mammographic density and estrogen receptor status of breast cancer.

BACKGROUND: The density of breast tissue on a mammogram is a strong predictor of breast cancer risk and may reflect cumulative estrogen effect on breast tissue. Endogenous and exogenous estrogen exposure increases the risk of estrogen receptor (ER)-positive breast cancer. We determined if mammographic density is associated more strongly with ER-positive breast cancer than with ER-negative breast cancer.METHODS: We analyzed data from 44,811 participants in the San Francisco Mammography Registry of whom 701 developed invasive breast cancer. Mammographic density was measured using the Breast Imaging Reporting and Data System (BI-RADS) classification system (1 = almost entirely fat, 2 = scattered fibroglandular, 3 = heterogeneously dense, 4 = extremely dense). We tested for associations between mammographic density and ER-positive and ER-negative breast cancer separately. Analyses were adjusted for age, body mass index, postmenopausal hormone use, family history of breast cancer, menopausal status, parity, and race/ethnicity.RESULTS: Mammographic density was strongly associated with both ER-positive and ER-negative breast cancers. Compared with women with BI-RADS 2, women with BI-RADS 1 (lowest density) had a lower risk of ER-positive cancer [adjusted hazard ratio (HR), 0.28; 95% confidence interval (95% CI), 0.16-0.50] and ER-negative cancer (adjusted HR, 0.17; 95% CI, 0.04-0.70). Women with BI-RADS 4 (highest density) had an increased risk of ER-positive breast cancer (adjusted HR, 2.21; 95% CI, 1.64-3.04) and an increased risk of ER-negative breast cancer (adjusted HR, 2.21; 95% CI, 1.16-4.18).CONCLUSION: Surprisingly, women with high mammographic density have an increased risk of both ER-positive and ER-negative breast cancers. The association between mammographic density and breast cancer may be due to factors besides estrogen exposure.     

Flame-broiled food, NAT2acetylator phenotype, and breast cancer risk among women with benign breast disease

Purpose The objective of this study was to examine the association between flame-broiled food consumption, a source of heterocyclic amine exposure, and the development of breast cancer among cohort of women with benign breast disease (BBD). The variation of the association by acetylation phenotype, as determined by the genotypes of selected N-acetyltransferase 2 (NAT2) enzymes, was also examined.Methods Among participants in an ongoing cohort study, 1187 women reported having a breast biopsy for BBD and completed a food frequency questionnaire. NAT2 G857A, NAT2 T341C, and NAT2 G590A genotypes were determined using DNA extracted from blood specimens collected in 1989. Incident cases of breast cancer were identified through linkage of the cohort participants with the Washington County Cancer Registry and the Maryland State Cancer Registry. Follow-up for the BBD cohort began at study entry in 1989 and ended on April 28, 2003.Results Of the women in this study, 77 subsequently developed breast cancer. Results showed that, among rapid acetylators, flame-broiled food intake was associated with a statistically significant increase in the risk of breast cancer (odds ratio (OR) 2.62; 95% confidence interval (CI) 1.06, 6.46). No association was observed between flame-broiled food intake and breast cancer among slow acetylators (OR 0.75; 95% CI 0.39, 1.43).Conclusions These findings suggest that flame-broiled food may be a modifiable risk factor for the progression of BBD to invasive breast cancer among women who have genotypes consistent with rapid acetylation.     

Risk of second breast cancer according to estrogen receptor status and family history

A recent study reported an increased risk of contralateral estrogen-negative breast cancer after a first primary estrogen-negative breast cancer. Our study aims to confirm this result and to evaluate how the risk of second breast cancer occurrence is affected by family history of breast cancer and anti-estrogen treatment. We included all 4,152 women diagnosed with breast cancer between 1995 and 2007, using data from the population-based Geneva Cancer Registry. We compared the incidence of second breast cancer among patients according to estrogen receptor (ER) status with that expected in the general population by age-period Standardized Incidence Ratios (SIRs). Among the cohort, 63 women developed second breast cancer. Patients with ER-positive first tumors had a decreased risk of second breast cancer occurrence (SIR: 0.67, 95% CI: 0.48–0.90), whereas patients with ER-negative primary tumors had an increased risk (SIR: 1.98, 95% CI: 1.19–3.09) limited to ER-negative second tumors (SIR: 7.94, 95% CI: 3.81–14.60). Patients with positive family history had a tenfold (SIR: 9.74, 95% CI: 3.57–21.12) higher risk of ER-negative second tumor which increased to nearly 50-fold (SIR: 46.18, 95% CI: 12.58–118.22) when the first tumor was ER-negative. Treatment with anti-estrogen decreased the risk of second ER-positive tumors but not ER-negative tumors. The risk of second ER-negative breast cancer is very high after a first ER-negative tumor, in particular among women with strong family history. Surveillance and prevention of second cancer occurrence should consider both ER status of the first tumor and family history.     

NSAIDs and breast cancer recurrence in a prospective cohort study

Objective We examined the association between NSAID use and breast cancer recurrence in a prospective cohort of 2,292 early-stage breast cancer survivors diagnosed from 1997 to 2000 participating in the Life After Cancer Epidemiology (LACE) Study. Methods From 2000 to 2002, mailed questionnaires were used to obtain information on aspirin, ibuprofen, and other NSAID use and subsequent breast cancer events. A total of 270 recurrences (local, regional, and distant disease and new primary breast cancers) were reported and verified by medical record review. Cox proportional hazard models were used to estimate rate ratios (RR) and 95% confidence intervals (CI), adjusting for age at diagnosis, race, cancer stage, tamoxifen treatment, chemotherapy use, body mass index, and cyclooxygenase-2 (COX2) inhibitor use. Results Current, regular use (at least three days per week at time of questionnaire administration) of ibuprofen (RR, 0.56; 95% CI, 0.32–0.98), but not aspirin (RR, 1.09; 95% CI, 0.74–1.61), was associated with a statistically significant decreased risk of breast cancer recurrence. The combination of ibuprofen and other non-aspirin NSAIDs such as naproxen and sulindac reflected a similar reduction in risk (RR, 0.56; 95% CI, 0.33–0.95). No association was found for the non-NSAID analgesic acetaminophen. Conclusion Our findings provide support for an inverse association between current, regular ibuprofen use and breast cancer recurrence.     

Aspirin and other nonsteroidal anti-inflammatory drugs and breast cancer incidence in a large U.S. cohort.

Use of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, has consistently been associated with reduced risk of breast cancer in case-control studies. However, results from prospective studies have been less consistent. We examined the association between NSAID use and breast cancer incidence, adjusting for multiple breast cancer risk factors among 77,413 women in the Cancer Prevention Study II Nutrition Cohort. During follow-up from 1992 to 2001, we observed 3,008 cases of incident breast cancer. Information on NSAID use was obtained from a questionnaire completed at enrollment in 1992 or 1993 and was updated using follow-up questionnaires in 1997 and 1999. NSAID use was modeled using time-dependent variables to update exposure status. Neither current total NSAID use (aspirin and other NSAIDs combined) nor current aspirin use were associated with breast cancer incidence even at relatively high levels of use [rate ratio (RR), 1.07; 95% confidence interval (95% CI), 0.96-1.21 for > or =60 NSAID pills per month compared with no reported use of NSAIDs; RR, 1.01; 95% CI, 0.84-1.20 for > or =60 aspirin per month compared with no reported use of aspirin]. Even long-duration regular use (> or =30 pills per month for > or =5 years) was not associated with breast cancer incidence (RR, 1.05; 95% CI, 0.88-1.26 for total NSAIDs; RR, 0.88; 95% CI, 0.69-1.12 for aspirin). Although we cannot exclude a small reduction in breast cancer risk associated with NSAID use, the results of this study provide evidence against a large reduction in risk.     

Tamoxifen therapy for primary breast cancer and risk of contralateral breast cancer.

BACKGROUND: Women diagnosed with breast cancer have a twofold to sixfold greater risk of developing contralateral breast cancer than women in the general population have of developing a first breast cancer. Tamoxifen therapy reduces this risk, but it is unclear if this benefit exists for both estrogen receptor (ER)-positive and ER-negative contralateral tumors. METHODS: Using data from a population-based tumor registry that collects information on the ER status of breast tumors, we followed 8981 women residing in western Washington State who were diagnosed with a primary unilateral invasive breast cancer during the period from 1990 through 1998 to identify cases of contralateral breast cancer. We restricted our analyses to women who were at least 50 years old and whose first breast cancer had a localized or regional stage; women who received adjuvant hormonal therapy but not chemotherapy (n = 4654) were classified as tamoxifen users, while those who received neither adjuvant hormonal therapy nor chemotherapy (n = 4327) were classified as nonusers of tamoxifen. By reviewing selected patient abstracts, we estimated that 94% of the subjects were classified correctly with respect to tamoxifen use. The risk of contralateral breast cancer associated with tamoxifen use was estimated with the use of Cox regression. All statistical tests were two-sided. RESULTS: Of the 89 tamoxifen users and 100 nonusers of tamoxifen diagnosed with contralateral breast cancer, 112 had ER-positive tumors, 20 had ER-negative tumors, and 57 had tumors with an ER status that was unknown or had not been determined by an immunohistochemical assay. The risk of developing an ER-positive and an ER-negative contralateral tumor among tamoxifen users was 0.8 (95% confidence interval [CI] = 0.5 to 1.1) and 4.9 (95% CI = 1.4 to 17.4), respectively, times that of nonusers of tamoxifen. This difference in risk by ER status was statistically significant (P<.0001). CONCLUSIONS: Tamoxifen use appears to decrease the risk of ER-positive contralateral breast tumors, but it appears to increase the risk of ER-negative contralateral tumors.     

Association of hormone replacement therapy to estrogen and progesterone receptor status in invasive breast carcinoma

BACKGROUND: Observational studies and randomized trials have demonstrated that hormone replacement therapy (HRT) increases the recipient's risk of developing breast carcinoma. Because it is known that some breast malignancies are hormonally responsive and that others are not, it has been hypothesized that HRT may be associated with the development of estrogen receptor (ER)-positive/progesterone receptor (PR)-positive breast carcinoma more so than with the development of ER-negative/PR-negative breast carcinoma. METHODS: The Nurses' Health Study is a prospective cohort study that enrolled 121,700 female registered nurses ages 30-55 years in 1976. In the current study, the authors analyzed 2548 malignancies that developed among eligible postmenopausal women in that cohort between 1980 and 2000 and for which data on ER and PR status were available. RESULTS: Compared with women who had never used HRT, current long-term users of HRT were more likely to develop ER-positive/PR-positive breast carcinoma (multivariate risk ratio [RR], 1.80; 95% confidence interval [CI], 1.52-2.12) but were not any more likely to develop ER-negative/PR-negative disease (multivariate RR, 1.00; 95% CI, 0.72-1.39). This effect grew stronger with increasing duration of current HRT use and was also more pronounced among women with body mass index < 25 kg/m2. Furthermore, the association between HRT use and ER-positive/PR-positive disease was stronger among patients receiving combined HRT (CHRT) regimens, which included estrogen and progesterone, than among users of estrogen alone (ERT). In addition, tumors tended to develop more quickly in current users of CHRT than in ERT users. CONCLUSIONS: The finding that current users of HRT were more likely to develop ER-positive/PR-positive tumors than they were to develop ER-negative/PR-negative ones suggests that both endogenous and exogenous hormonal factors may influence breast tumor characteristics. In analyses of the effects of hormonal factors on breast tumor development, ER-positive/PR-positive tumors and ER-negative/PR-negative tumors should be considered separately from each other.     

Post-diagnosis statin use and breast cancer recurrence in a prospective cohort study of early stage breast cancer survivors

PURPOSE: We examined the association between post-diagnosis statin use (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] inhibitors) and risk of breast cancer recurrence. MATERIALS AND METHODS: The study included 1945 early stage breast cancer survivors participating in the Life After Cancer Epidemiology (LACE) Study. Women who were diagnosed from 1997 to 2000 and identified from the Kaiser Permanente Northern California (KPNC) Cancer Registry entered the cohort on average 2 years post-diagnosis. Information on statin use was obtained from the KPNC pharmacy database. A total of 210 breast cancer recurrences were reported and verified by medical record review. Cox proportional hazard models were used to estimate rate ratios (RR) and 95% confidence intervals (CI). RESULTS: The mean duration of statin use in the cohort among those who initiated use post-diagnosis was 1.96 years, and lipophilic statins were mainly used (97.8%). Starting statins after diagnosis was suggestive of a decreased risk of breast cancer recurrence (RR = 0.67; 95% CI: 0.39-1.13). Risk of recurrence decreased with increasing duration of statin use after diagnosis (p linear trend = 0.02). CONCLUSION: Our findings provide initial support for an inverse association between post-diagnosis, lipophilic statin use and risk of breast cancer recurrence.     

Nonsteroidal anti-inflammatory drug use and breast cancer risk.

Findings from previous epidemiological studies are inconclusive, though they suggest nonsteroidal anti-inflammatory drug (NSAID) use is associated with a reduction in breast cancer risk. In addition, animal studies report that NSAIDs inhibit mammary tumor development. The association between NSAID use and breast cancer risk was evaluated using a case-control study design. Cases were a random sample of women diagnosed with a first primary cancer of the breast, aged 25-74 years, identified through the Ontario Cancer Registry, and diagnosed between July 1996 and September 1998. Controls were an age-matched random sample of the female population of Ontario. Cases (n = 3133) and controls (n = 3062) completed a mailed questionnaire with information on their past use of NSAID and other medications, as well as many risk factors thought to be associated with breast cancer. Multivariate logistic regression analysis was used to obtain adjusted odds ratio (OR) estimates. Use of any NSAID medication (daily use for > or =2 months) was found to be associated with a significant 24% reduction in breast cancer risk (OR = 0.76; 95% confidence interval: 0.66, 0.88). The reduced risk was strongest for use lasting > 8 years, compared with nonusers (OR = 0.68; 95% confidence interval: 0.54, 0.86). No marked trends were observed for time since first use or last use or age at first use. Our results suggest a reduction in breast cancer risk associated with any regular NSAID use. NSAID use is a modifiable factor, and any protective effect attributed to its use could be of great public health importance.     

Adult weight gain and histopathologic characteristics of breast cancer among postmenopausal women

BACKGROUND: Although the link between postmenopausal breast cancer and adiposity is well established, the association between weight gain and specific histopathologic characteristics of breast carcinoma has not been studied carefully. METHODS: Using 1200 incident invasive breast cancers among 44,161 postmenopausal women who were not taking hormone therapy in the American Cancer Society's Cancer Prevention Study II Nutrition Cohort, the authors computed age-adjusted rates and rate ratios (RR) for breast cancer by histology, stage, grade, and estrogen receptor (ER) and progesterone receptor (PR) status by categories of adult weight gain. RESULTS: Age-adjusted rates of breast cancer were highest for women who reported the most weight gain, regardless of histologic type. For weight gain >60 pounds, compared with weight gain < or =20 pounds the RR for ductal carcinoma was 1.89 (95% confidence interval [95%CI], 1.53-2.34), and the RR for lobular carcinoma was 1.54 (95%CI. 1.01-2.33). Weight gain was associated with increased risk at every tumor stage and grade. The risk for regional or distant stage was elevated significantly in every category of weight gain and was 3 times higher among women who had the greatest weight gain (RR, 3.15; 95%CI, 2.21-4.48). Weight gain was associated with increased risk of ER-positive/PR-positive tumors (P for trend <.0001) but not ER-negative/PR-negative tumors (P for trend = .09). The results essentially remained unchanged when the analysis was restricted to women who had regular screening mammograms. CONCLUSIONS: Excess adiposity is an important contributor to breast cancer risk among postmenopausal women, regardless of histologic type, and especially for tumors of advanced stage and high grade.     

NSAID use and survival after breast cancer diagnosis in post-menopausal women

Many epidemiologic studies, although not all, have shown an inverse relation between non-steroidal anti-inflammatory drug (NSAID) use and risk of incident breast cancer, but the possible influence of NSAID use on breast cancer survival has not been evaluated. We examined the association between self-reported NSAID use and survival after invasive breast cancer diagnosis among 591 postmenopausal women in a prospective study. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer death as well as all-cause mortality associated with NSAID use. There was an indication of reduced risk of breast cancer mortality and all-cause mortality for women reporting any versus no use of NSAIDs, with multivariate-adjusted HRs of 0.64 (95% CI 0.39–1.05) and 0.57 (95% CI 0.40–0.81), respectively. There was no trend of decreasing risk of death with increasing frequency of NSAID use per week. While the results from this exploratory analysis are preliminary, there is biological plausibility for such an association. Further studies should consider whether NSAIDs, which have biological activity affecting tumor promotion and progression and appear to protect against breast cancer incidence, may be associated with better prognosis after a diagnosis of invasive breast cancer. This study was supported by NIH grant National Cancer Institute RO1CA39742     

Twinship and risk of postmenopausal breast cancer

BACKGROUND: Intrauterine exposure to high levels of endogenous estrogens has been hypothesized to increase the risk of breast cancer. Because estrogens and other pregnancy hormones are substantially elevated in twin pregnancies, and possibly more so in dizygotic twin pregnancies, we evaluated the association between aspects of twin membership (i.e., belonging to a twin pair) and the risk of breast cancer. METHODS: In a cohort of 29 197 postmenopausal Iowa women with no prior diagnosis of cancer (except for nonmelanoma skin cancer), breast cancer risk factors were determined by use of a mailed questionnaire in 1986 (baseline); twin membership, sex of the twin, and zygosity were determined by use of a follow-up questionnaire in 1992. RESULTS: Within the cohort, 1.8% (n = 538) of the women reported being a twin; of these, 24% (n = 130) were monozygotic twins, 63% (n = 337) were dizygotic twins, and 13% (n = 71) did not know their zygosity. From 1986 through 1996, 1230 breast cancers in the cohort were ascertained by linkage to the Iowa Cancer Registry. Compared with singletons, women who belonged to a twin pair were at elevated risk of breast cancer (multivariate-adjusted risk ratio [RR] = 1.72; 95% confidence interval [CI] = 1.22-2.42), with adjustment for educational level, family history of breast cancer, height, body mass index, body fat distribution, age at menarche, age at first live birth, use of hormone replacement therapy, and alcohol use. Multivariate-adjusted risk was elevated (in comparison with singletons) if the sex of the other twin was female (RR = 1.82; 95% CI = 1.20-2.75); however, this risk was limited to female dizygotic twins (RR = 2.14; 95% CI = 1. 21-3.79), since no excess risk was evident for monozygotic twins (RR = 1.04; 95% CI = 0.43-2.50). The risk to women with a male twin was also elevated (RR = 1.49; 95% CI = 0.80-2.78) in comparison with singletons, but this estimate was not statistically significant. CONCLUSIONS: This cohort study lends further support to the theory that there are important intrauterine influences on carcinogenesis of the breast.     

Polymorphisms in ER-alpha gene interact with estrogen receptor status in breast cancer survival.

PURPOSE: The effects of estrogens are mediated primarily through estrogen receptor (ER) in breast tissue, and polymorphisms in the ER genes may alter the functions of these receptors. Polymorphisms in the ER-alpha gene have been reported to be associated with breast cancer risk. However, to our knowledge, no study has been published on the relation between ER-alpha gene polymorphisms and breast cancer survival. EXPERIMENTAL DESIGN: To determine whether three common polymorphisms in the ER-alpha gene, PvuII, XbaI, and GT dinucleotide repeats are associated with breast cancer survival, we evaluated data from a cohort of 1,069 breast cancer patients who participated in the Shanghai Breast Cancer Study between 1996 and 1998. The median follow-up time for this cohort of women was 5.2 years. RESULTS: No overall association was observed between ER gene polymorphisms and breast cancer survival. The genotype associations, however, were modified by ER status in breast cancer tissues. Comparing those with the PP genotype to the pp genotype of the PvuII polymorphism, the hazard ratios (HR) of dying were 3.30 [95% confidence interval (95% CI), 1.42-7.69] and 0.54 (95% CI, 0.24-1.23), respectively, for participants with ER-negative breast cancer and ER-positive breast cancer. Similarly, compared with those with no (GT)(23) alleles, carrying one or two (GT)(23) alleles of the GT repeat polymorphism was related to a HR of 1.48 (95% CI, 0.77-2.87) for ER-negative breast cancer and a HR of 0.25 (95% CI, 0.09-0.69) for ER-positive cancer. The effect of ER on breast cancer survival was also modified by genotypes of ER-alpha gene. Tests for multiplicative interaction were highly significant. CONCLUSIONS: These data suggest that the ER-alpha gene polymorphisms and ER status may have an interactive effect on breast cancer survival.     

Patterns of alcohol consumption and breast cancer risk in the California Teachers Study cohort.

Alcohol consumption of approximately two drinks or more per day has been associated with elevated breast cancer risk in the California Teachers Study cohort as well as in many other populations. The objective of this analysis is to examine effects of age at drinking and drinking patterns and to identify effect modifiers. Of the 103,460 at-risk cohort members, age <85, who resided in California and completed the baseline alcohol assessment, 1,742 were diagnosed with invasive breast cancer after joining the cohort and before January 2001. Incident breast cancers were identified through the California Cancer Registry and follow-up for death and confirmation of continued California residence used various sources. Multivariate Cox proportional hazards regression models were used to estimate relative risks (RRs). Elevated breast cancer risk was most evident for recent drinking [RR = 1.28, 95% confidence interval (CI): 1.06-1.54 for >/=20 g/day versus nondrinkers], with no clear pattern for consumption during earlier periods of life. This elevation in risk was 32% among postmenopausal women (95% CI: 1.06-1.63) and 21% among pre/perimenopausal women (95% CI: 0.76-1.92). Highest risks associated with heavy alcohol consumption were observed among postmenopausal women with a history of biopsy-diagnosed benign breast disease (RR = 1.97, 95% CI: 1.39-2.79 compared to nondrinkers without benign breast disease) or who had used combination hormone replacement therapy (HRT) (RR = 2.24, 95% CI: 1.59-3.14 compared to nondrinkers who never used HRT). Recent alcohol consumption equivalent to two or more drinks per day increases the risk of invasive breast cancer, with the greatest RRs observed among heavy drinkers who are also postmenopausal and have a history of benign breast disease or who use HRT.     

Nonsteroidal anti‐inflammatory drug use and breast cancer risk in a European prospective cohort study

Experimental studies have shown a protective effect of nonsteroidal anti‐inflammatory drugs (NSAIDs) on breast cancer development. However, results from epidemiological cohort studies are less consistent. Our objective was to assess the association between NSAID use and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Self‐reported information on NSAID use at baseline has been collected in five EPIC countries. Multivariable Cox regression models were used to estimate hazard ratios for the association of NSAID use with breast cancer incidence with adjustment for potential confounders. We also assessed effect modification by breast cancer risk factors and examined the associations within specific breast cancer subtypes. Among the 140,981 women included in the analysis, 7% were regularly using NSAIDs at baseline. During a median follow‐up time period of 13 years, 7,379 incident breast cancer cases were diagnosed (816 in situ and 6,563 invasive). There were no statistically significant associations between NSAID use and breast cancer risk, overall and by subtypes. However, a statistically significant interaction was observed for invasive cases between NSAID use and ever use of menopausal hormonal therapy (MHT) among postmenopausal women [MHT users: HR_{NSAID use} = 0.84 (0.73–0.96); non MHT users: HR_{NSAID use} = 1.08 (0.93–1.25); p_interaction = 0.05]. Our results indicate potential effect modification of MHT use on the association between use of NSAIDs and breast cancer risk which deserves in‐depth investigation in studies with accurate data on both NSAID and MHT use.     

Risks of breast and endometrial cancer after estrogen and estrogen–progestin replacement

Objective: We studied the risk of breast and endometrial cancer in a cohort of 11,231 Swedish women prescribed different replacement hormone regimens.Methods: All 10,472 women at risk of developing breast cancer and 8,438 women at risk of endometrial cancer were followed up from the time of the questionnaire in 1987–88 through 1993, by record-linkages to the National Swedish Cancer Registry. Using data from a questionnaire we analyzed the relationships between hormone exposures and cancer risk, with non-compliers and users of less than 1 year as a reference group.Results: For breast cancer, women reporting use of estrogens combined with progestins had evidence of an increased risk relative to women denying intake or taking hormones for less than 1 year; relative risk (RR) = 1.4 (95% confidence interval 0.9–2.3) after 1–6 years of intake, and RR=1.7 (95% CI 1.1–2.6) after more than 6 years. This excess risk seemed confined to recent exposure. We found no association with intake of estrogens alone using non-compliers and short-term takers as the reference group. The risk of invasive endometrial cancer was increased four-fold in women using medium-potency estrogens alone for 6 years or longer, RR = 4.2 (95% CI 2.5–8.4). Women on such long-term progestin-combined treatment had a lower, non-significant, excess risk (RR = 1.4; 95% CI 0.6–3.3).Conclusions: We conclude that long-term recent use of estrogen–progestin combined replacement therapy may increase the risk of breast cancer. Exposure to estrogen alone substantially elevates the risk of endometrial cancer, an increase that can be reduced or perhaps avoided by adding progestins.     

Association of aspirin and nonsteroidal anti-inflammatory drug use with breast cancer.

OBJECTIVE: Previous epidemiological studies have suggested that use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with reduced risk of breast cancer, but some studies have been limited in their ability to separate the effects of aspirin from other NSAIDs or to account for breast cancer risk factors. METHODS: We examined the incidence of breast cancer in association with self-reported aspirin, as well as other nonaspirin NSAID use in a large prospective cohort of postmenopausal women (n = 27,616). Over 6 years of follow-up, 938 incident breast cancers were identified. RESULTS: After adjustment for other breast cancer risk factors, any current use of aspirin or other NSAIDs compared with no use was associated with a reduction in risk of breast cancer [relative risk (RR) = 0.80, 95% confidence interval (CI) 0.67-0.95]. There was a trend of decreasing risk of incident breast cancer with increasing frequency of aspirin use (P(trend) = 0.0011). The multivariate-adjusted RR of breast cancer was 0.71 (95% CI 0.58-0.87) for women who reported using aspirin six or more times per week compared with women who reported no use. These results did not depend on whether women had early or late stage breast cancer. No association was found between nonaspirin NSAID use and incident breast cancer. The adjusted RR of using other NSAIDs six or more times per week compared with no use was 1.01 (95% CI 0.83-1.25). CONCLUSION: This prospective study corroborates other reports that use of aspirin might reduce risk of breast cancer.     

Association of genetic polymorphisms in CYP19 and CYP1A1 with the oestrogen receptor-positive breast cancer risk

Since tamoxifen has been shown to reduce the risk of oestrogen receptor (ER)-positive, but not ER-negative, breast cancers in a chemoprevention trial (P-1), it is important to develop assays to assess risk factors for ER-positive breast cancer in order to appropriately select candidates for chemoprevention with tamoxifen. Thus, the significance of genetic polymorphisms of genes involved in oestrogen biosynthesis (CYP19) and metabolism (CYP1A1) as a risk factor for ER-positive breast cancers was evaluated. A case-control study was conducted with 257 breast cancer patients and 191 healthy female controls. Two polymorphisms, CYP19 (TTTA repeats) in intron 4 and CYP1A1 6235C/T in the 3' non-coding region, and their association with the breast cancer risk after adjustment for the other epidemiological risk factors were examined. CYP19 (TTTA)7(-3bp) allele carriers showed a significantly (P<0.05) increased risk of ER-positive breast cancers (Odds Ratio (OR)=1.72, 95% Confidence Interval (CI) 1.10-2.69), but not ER-negative breast cancers. CYP1A1 6235C allele carriers showed a non-significant (P=0.06) trend towards a decreased risk of ER-positive breast cancers (OR=0.65, 95% CI 0.42-1.02), but not ER-negative breast cancers. The combination of these two polymorphisms was found to be more useful in the assessment of the ER-positive breast cancer risk (OR=3.00, 95% CI=1.56-5.74) than the CYP19 (TTTA)7(-3bp) polymorphism alone. The combination of CYP19 (TTTA)7(-3bp) and CYP1A1 6235C/T polymorphisms is associated with an ER-positive, but not ER-negative, breast cancer risk, and, thus, would be useful in the selection of candidates for chemoprevention with tamoxifen.     

High breast cancer incidence rates among California teachers: results from the California Teachers Study (United States)

Objective: To determine risk factor profiles and cancer incidence rates among participants in the California Teachers Study (CTS), a study designed to document high breast cancer incidence rates of California teachers and to investigate emergent hypotheses in the etiology of breast and other cancers. Methods: The CTS is a prospective study of 133,479 California female teachers and administrators, established in 1995–1996 with members of the California State Teachers Retirement System completing a detailed mailed questionnaire regarding possible risk factors for breast and other cancers. Cancer outcomes were identified by linkage with the California Cancer Registry. Results: CTS participants have a 51% higher age-standardized invasive breast cancer incidence rate and a 67% higher in-situ breast cancer incidence rate than would be expected based on race-specific statewide rates after three years of follow-up. CTS participants also have substantially elevated rates of endometrial cancer (rate ratio, RR = 1.72), ovarian cancer (RR = 1.28), melanoma (RR = 1.59), non-Hodgkin's lymphoma (RR = 1.53), and leukemia (RR = 1.28), but low rates of invasive cervix cancer (RR = 0.53) and lung cancer (RR = 0.66). Conclusions: CTS members have high rates of several major cancers, particularly breast cancer, and low rates of lung and cervix cancer. Although late age at first birth can explain a portion of the observed excess risk of breast cancer in this cohort, the unique risk factor profile of CTS members may account for much of their higher risk of breast and selected other cancers. The CTS offers a rich resource for future studies of cancer risk and of women's health, in general.