Tracy Slanger

Risk of different histological types of postmenopausal breast cancer by type and regimen of menopausal hormone therapy.

In a large population‐based case–control study in Germany, including 3,464 breast cancer cases aged 50–74 at diagnosis and 6,657 population based and frequency matched controls, we investigated the effects of menopausal hormone therapy (HT) by type, regimen, timing and progestagenic constituent on postmenopausal breast cancer risk overall and according to histological type. Data were collected by face‐to‐face interviews. Logistic and polytomous logistic regression analysis were used to estimate odds ratios (OR) and 95%‐confidence intervals (95% CI). Risk of invasive breast cancer was significantly elevated in current users (OR, 1.73, 95% CI, 1.55–1.94) and heterogeneous by histological type (p < 0.01), being more than 2‐fold higher for lobular and tubular than for ductal cancer. Risks for current users varied significantly by type and regimen of HT, with ORs per year of use of 1.05 (95% CI, 1.04–1.06) for continuous combined estrogen–progestagen, 1.03 (95% CI, 1.02–1.04) for cyclical EP and 1.01 (95% CI, 1.00–1.03) for estrogen‐only therapy. No statistically significant increase in risk was observed after 5 years of cessation of HT use for any histological type. Analyses of progestagenic content by regimen revealed a significantly higher risk for continuously administered norethisterone‐ or levonorgestrel‐derived progestagens than for continuously administered progesterone‐derived progestagens (OR, 2.27, 95% CI, 1.98–2.62 vs. 1.47, 95% CI, 1.12–1.93, respectively, p = 0.003), which may be explained by dose rather than type of progestagen. These data suggest that the risks associated with menopausal HT differ by type and regimen of HT and histological type of breast cancer and may vary by progestagenic component, depending on the effective dose.

The Gc2 Allele of the Vitamin D Binding Protein Is Associated with a Decreased Postmenopausal Breast Cancer Risk, Independent of the Vitamin D Status

Vitamin D pathway gene polymorphisms may influence breast cancer risk by altering potential anticarcinogenic effects of vitamin D. The association between polymorphisms in the vitamin D binding protein (Gc) and postmenopausal breast cancer risk, with additional focus on the influence of serum 25-hydroxyvitamin D [25(OH)D], the biomarker for vitamin D status in humans, has not been examined thus far. We assessed the combined effects of two known functional polymorphisms in the Gc gene (rs4588 and rs7041), composing the phenotypic alleles Gc1s, Gc1f (combined: Gc1), and Gc2, on postmenopausal breast cancer risk and potential effect modification by 25(OH)D status in a population-based case-control study including 1,402 cases and 2,608 matched controls. Odds ratios (OR) for breast cancer risk adjusted for potential confounders were calculated for Gc genotypes. ANOVA was used to compare geometric means of serum 25(OH)D across Gc genotypes. Serum 25(OH)D concentrations in the control group significantly differed by Gc genotype, being lowest in Gc2 allele carriers. The geometric means of 25(OH)D were 53.0, 47.8, and 40.4 nmol/L for Gc1-1, Gc2-1, and Gc2-2 genotypes, respectively (Ptrend < 0.0001). Gc2-2 genotype was associated with a significantly decreased risk of postmenopausal breast cancer with an odds ratio (95% confidence interval) of 0.72 (0.54-0.96), compared with homozygote Gc1s allele carriers. No interaction between 25(OH)D status and Gc genotype was observed, nor did the association change considerably after adjustment for 25(OH)D status. Our results provide evidence for a serum 25(OH)D-independent effect of Gc2 allele carrier status in postmenopausal breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1339–43)

Physical Activity and Postmenopausal Breast Cancer: Effect Modification by Breast Cancer Subtypes and Effective Periods in Life

Physical activity (PA) has been inversely associated with postmenopausal breast cancer risk. However, it is unclear how and in which life periods PA may be effective to reduce breast cancer risk. Moreover, the evidence is still not judged as ‘convincing’ as there is some heterogeneity among study results. Most studies regarded breast cancer as a single disease, at best separated by menopausal status. Yet, breast cancers are heterogeneous and likely have different etiologies. Therefore, we analyzed the association of PA with different breast cancer subtypes in 3,414 postmenopausal cases and 6,569 controls from a case-control study on breast cancer conducted 2002-2005 in Germany (MARIE study). PA in the age periods 30-49 and 50+ years was assessed, including leisure-time PA (sports, cycling, walking) and non-recreational PA (occupational and household activities). There was a significant protective effect of leisure-time PA for ER+/PR+ carcinomas (adjusted odds ratio = 0.71, 95% confidence interval: 0.60, 0.85; trend P = 0.0001), but no effect for ER-/PR- carcinomas. Moreover, looking at physical activity pattern over time, the effect of PA after menopause on reducing breast cancer risk was more pronounced than the effect of PA before menopause. Overall, effects of PA were independent from adult weight gain, body mass index, and energy intake. These findings suggest that leisure-time PA after menopause may reduce postmenopausal breast cancer risk at least in part via hormonal pathways and not solely by changing body composition. Inactive postmenopausal women should be encouraged to become physically active even later in life. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3402–10)

Vitamin D receptor gene polymorphisms and haplotypes and postmenopausal breast cancer risk.

IntroductionVitamin D receptor (VDR) genotypes may influence breast cancer risk by altering potential anticarcinogenic effects of vitamin D, but epidemiological studies have been inconsistent. Effect modification by serum 25-hydroxyvitamin D (25 [OH]D), the biomarker for vitamin D status in humans, has rarely been examined.MethodsWe assessed the effects of two frequently analyzed polymorphisms (FokI and TaqI) and two potentially functional variants (VDR-5132 and Cdx2) in the VDR gene, which thus far have not been analyzed with respect to breast cancer risk, on postmenopausal breast cancer risk in a population-based, case-control study including 1,408 patients (cases) and 2,612 control individuals (controls) matched for year of birth. Odds ratios (ORs) for breast cancer adjusted for potential confounders were calculated for genotypes and estimated haplotypes.ResultsNo differences in serum 25(OD)D concentrations by VDR genotype were observed. None of the analyzed polymorphisms was associated with overall risk for postmenopausal breast cancer. However, the TaqI polymorphism was associated with a significantly increased risk for oestrogen receptor positive tumours (OR = 1.18, 95% confidence interval [CI] = 1.00 to 1.38, comparing t allele carriers with noncarriers) but not for oestrogen receptor negative tumours (OR = 0.88, 95% CI = 0.69 to 1.13; P for interaction = 0.04). Haplotype analysis revealed the haplotype FtCA (FokI F, TaqI t, VDR-5132 C, Cdx2 A), which contains the TaqI t allele, to be associated with a significantly greater breast cancer risk as compared with the most frequent haplotype FTCG (OR = 1.43, 95% CI = 1.00 to 2.05). No significant interaction between VDR genotypes or haplotypes and 25(OH)D was observed.ConclusionOur results support potential effects of VDR polymorphisms on postmenopausal breast cancer risk and possible differential effects of receptor status of the tumour. However, further studies focusing on the influence of polymorphisms and haplotypes on VDR functionality, activity and concentration are needed.

The Role of HIV-Related Knowledge and Ethnicity in Determining HIV Risk Perception and Willingness to Undergo HIV Testing Among Rural Women in Burkina Faso

We conducted a random community based survey of 300 young (15–29 years) rural women in Nouna, Burkina Faso. Only one-third of women were aware that a person could have HIV without having symptoms and these women were significantly more likely to classify themselves to be at high risk for getting HIV. Furthermore, multiple partners, Bwaba ethnicity and having mentioned a health worker as a source of HIV information were significantly associated with perceived high personal risk. Perceived willingness to participate in VCT was high (69%). The dissemination of information on the asymptomatic nature of HIV infection could potentially be very important in forming risk perception, awareness, and their willingness to participate in HIV interventions.

Association of a Common AKAP9 Variant With Breast Cancer Risk: A Collaborative Analysis

Data from several studies have suggested that polymorphisms in A-kinase anchoring proteins (AKAPs), which are key components of signal transduction, contribute to carcinogenesis. To evaluate the impact of AKAP variants on breast cancer risk, we genotyped six nonsynonymous single-nucleotide polymorphisms that were predicted to be deleterious and found two (M463I, 1389G>T and N2792S, 8375A>G) to be associated with an allele dose-dependent increase in risk of familial breast cancer in a German population. We extended the analysis of AKAP9 M463I, which is in strong linkage disequilibrium with AKAP9 N2792S, to 9523 breast cancer patients and 13770 healthy control subjects from seven independent European and Australian breast cancer studies. All statistical tests were two-sided. The collaborative analysis confirmed the association of M463I with increased breast cancer risk. Among all breast cancer patients, the combined adjusted odds ratio (OR) of breast cancer for individuals homozygous for the rare allele TT (frequency = 0.19) compared with GG homozygotes was 1.17 (95% confidence interval [CI] = 1.08 to 1.27, P = .0003), and the OR for TT homozygotes plus GT heterozygotes compared with GG homozygotes was 1.10 (95% CI = 1.04 to 1.17, P = .001). Among the combined subset of 2795 familial breast cancer patients, the respective ORs were 1.27 (95% CI = 1.12 to 1.45, P = .0003) and 1.16 (95% CI = 1.06 to 1.27, P = .001).

The Use of Herbal Preparations to Alleviate Climacteric Disorders and Risk of Postmenopausal Breast Cancer in a German Case-Control Study

Background:The use of herbal preparations (HEP) to alleviate climacteric disorders is expected to increase as women seek alternatives to menopausal hormone therapy to avoid the associated breast cancer risk. Data are sparse on the long-term effects of HEP containing phytoestrogens and black cohosh on breast cancer risk. Methods: Within a German case-control study, associations between patterns of HEP use and incident breast cancer were investigated in 10,121 postmenopausal women (3,464 cases, 6,657 controls). Information on HEP use was collected in face-to-face interviews supported by a list of brand names. Multivariate logistic and polytomous regression analyses were done. Findings: Ever use of HEP (9.9%) was inversely associated with invasive breast cancer [odds ratio (OR), 0.74; 95% confidence interval (CI), 0.63-0.87] in a dose-dependent manner (OR, 0.96 per year of use; P = 0.03). Classes of HEP did not differ significantly (Pheterogeneity = 0.81). Risks for invasive ductal (OR, 0.72; 95% CI, 0.60-0.87) and combined lobular/mixed/tubular tumors (OR, 0.76; 95% CI, 0.58-1.01) were similarly reduced by any HEP use but not for in situ carcinomas (1.34; 95% CI, 0.86-2.09). There were no substantial differences in associations of HEP use by estrogen receptor status (ER+ OR, 0.74; 95% CI, 0.62-0.89; ER− OR, 0.68, 95% CI, 0.50-0.93) and progesterone receptor status of the tumor. Interpretation: Our findings support the hypothesis that HEP use protects from invasive breast cancer in postmenopausal women. Among conceivable modes of action, those independent of estrogen receptor–mediated pathways seem to be involved (i.e., cytotoxicity, apoptosis). (Cancer Epidemiol Biomarkers Prev 2009;18(8):2207–13)

Menopausal Hormone Therapy and Risk of Clinical Breast Cancer Subtypes

Background: Breast cancer is a heterogeneous disease with subtypes that may vary in their etiologies. Menopausal hormone therapy has been associated more strongly with lobular and tubular than ductal histologic types and with tumors that are smaller, hormone receptor–positive, and of lower grade. At the same time, correlations have been observed between histology and clinical characteristics. To identify those tumor subtypes most strongly associated with hormone therapy use, it is necessary to disentangle these interrelationships. Methods: Based on 3,464 postmenopausal breast cancer cases and 6,657 controls from the population-based Mammary carcinoma Risk factor Investigation study, we used polytomous logistic regression to evaluate associations between hormone therapy use and risk of invasive breast cancer subtypes. We assessed variations in risk for selected tumor characteristics among histologic and hormone receptor subtypes, both overall and for specific hormone therapy regimens. Results: Lobular and mixed types showed less variation by prognostic factors than did ductal tumors. Current hormone therapy use had the strongest associations with prognostic variables in estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive ductal tumors and in lobular tumors regardless of ER/PR status, with little effect on ER/PR-negative ductal tumors. The observed associations varied minimally by hormone therapy type or regimen. Conclusion: Current hormone therapy use was associated with more favorable breast cancer characteristics for ductal tumors but had less effect on prognostic characteristics in women with lobular tumors. Both histologic type and estrogen receptor/progesterone receptor status seem to be important in explaining the role of hormone therapy in the etiology of breast cancer subtypes. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1188–96)

Abstract PR-4: Physical activity and postmenopausal breast cancer: Effect modifications by hormone receptor status and breast cancer risk factors

Abstracts: Frontiers in Cancer Prevention Research 2008 PR-4 Background Physical activity (PA) has been inversely associated with postmenopausal breast cancer risk. Most studies regarded breast cancer as a single disease, at best separated by menopausal status. Yet, breast cancers are heterogeneous and likely to have different etiologies. Furthermore, little is known about the biological mechanisms by which physical activity reduces breast cancer risk and about potential modifying effects of other risk factors. Information on the association of PA with breast cancer according to hormone receptor and risk factor status may provide insight into mechanisms of action. Material and Methods We analyzed these associations in 3,414 postmenopausal cases and 6,569 controls from a population-based case-control study on breast cancer conducted 2002-2005 in two regions in Germany (MARIE study). Comprehensive data on risk factors were collected. PA in the age periods 30-49 and 50+ years was assessed, including leisure-time PA (sports, cycling, walking) and non-recreational PA (occupational and household activities). Polytomous logistic regression was used to model the association between the PA variables and breast cancer according to estrogen- and progesterone- receptor-status (ER/PR). Case-case comparisons were performed to evaluate heterogeneity between cancer subgroups (Pdiff). Effect modifications by other cancer risk factors were evaluated by including an interaction term with leisure-time PA as continuous variable into unconditional logistic regression models, separately for each ER/PR type. Results The effect of leisure-time PA since age 50 on ER+/PR+ differed significantly from the effects on ER+/PR- (Pdiff = 0.028), ER-/PR+ (Pdiff = 0.024), and ER-/PR- (Pdiff = 0.028), with more active women having reduced risk for ER+/PR+ carcinomas compared to less active women (OR = 0.71, 95% CI = (0.60 - 0.85) for the highest vs. lowest quintile; linear trend P = 0.0001), but no effects for the other receptor-types. Effects of PA during age 30-49 years were similar but less pronounced. The association between leisure-time PA and ER+/PR+ carcinoma risk was significantly modified by breastfeeding (pinteraction = 0.045) with a protective effect for women who ever breastfed (OR = 0.62 (0.50 - 0.77) highest vs. lowest PA 50+ quintile), while no risk reduction was observed for women who never breastfed, irrespectively whether they were parous or nulli-parous (OR= 0.95 (0.72 - 1.25)). Effect modification was also observed for benign breast diseases, but statistically significant only for PA during 30-49 years (pinteraction = 0.023). For women who ever had a benign breast disease a clear protective effect was observed (OR = 0.68 (0.52 - 0.89) for PA 30-49; OR = 0.56 (0.42 - 0.74) for PA 50+), but there was no effect for women without benign breast diseases. No effect modification was found for family history of breast cancer, BMI, and parity. Conclusions These findings suggest that leisure-time PA may reduce postmenopausal breast cancer risk at least in part via hormonal pathways. The protective effects of PA appear to be more pronounced for women who had ever breastfed or ever had a benign breast disease. However, these observed effect modifications need further confirmation. Citation Information: Cancer Prev Res 2008;1(7 Suppl):PR-4.