Energy-Related Indicators and Breast Cancer Risk among White and Black Women

Energy-related indicators, including physical activity, energy intake, body mass index (BMI) and adult weight change, have been linked to breast cancer risk. Very few studies of these associations have been conducted among black women, therefore we used the Nashville Breast Health Study (NBHS) to determine whether similar effects were seen in black and white women. The NBHS is a population-based case-control study of breast cancer among women age 25 to 75 years conducted between 2001 and 2010 in and around the Nashville Metropolitan area. Telephone interviews and self-administered food frequency questionnaires were completed with 2,614 incident breast cancer cases ascertained through hospitals and the statewide cancer registry, and 2,306 controls selected using random digit dialing. Among premenopausal white and black women, there was little effect of adult exercise or other energy-related indicators on breast cancer risk, regardless of tumor estrogen receptor (ER) status. The beneficial effect of adult exercise on postmenopausal breast cancer appeared to be comparable between white and black women (highest tertile relative to none - white odds ratio [OR] 0.8, 95% confidence interval [CI] 0.6-1.0, p for trend=0.05; black OR 0.7, 95% CI 0.4-1.1, p for trend=0.07); however, among black women the reduction was limited to those with ER-positive disease. White and black women should be encouraged to engage in more physical activity to reduce their risk of postmenopausal breast cancer.     

Evaluating Genome-Wide Association Study-Identified Breast Cancer Risk Variants in African-American Women

Genome-wide association studies (GWAS), conducted mostly in European or Asian descendants, have identified approximately 67 genetic susceptibility loci for breast cancer. Given the large differences in genetic architecture between the African-ancestry genome and genomes of Asians and Europeans, it is important to investigate these loci in African-ancestry populations. We evaluated index SNPs in all 67 breast cancer susceptibility loci identified to date in our study including up to 3,300 African-American women (1,231 cases and 2,069 controls), recruited in the Southern Community Cohort Study (SCCS) and the Nashville Breast Health Study (NBHS). Seven SNPs were statistically significant (P≤0.05) with the risk of overall breast cancer in the same direction as previously reported: rs10069690 (5p15/TERT), rs999737 (14q24/RAD51L1), rs13387042 (2q35/TNP1), rs1219648 (10q26/FGFR2), rs8170 (19p13/BABAM1), rs17817449 (16q12/FTO), and rs13329835 (16q23/DYL2). A marginally significant association (P<0.10) was found for three additional SNPs: rs1045485 (2q33/CASP8), rs4849887 (2q14/INHBB), and rs4808801 (19p13/ELL). Three additional SNPs, including rs1011970 (9p21/CDKN2A/2B), rs941764 (14q32/CCDC88C), and rs17529111 (6q14/FAM46A), showed a significant association in analyses conducted by breast cancer subtype. The risk of breast cancer was elevated with an increasing number of risk variants, as measured by quintile of the genetic risk score, from 1.00 (reference), to 1.75 (1.30–2.37), 1.56 (1.15–2.11), 2.02 (1.50–2.74) and 2.63 (1.96–3.52), respectively, (P = 7.8×10^–10). Results from this study highlight the need for large genetic studies in AAs to identify risk variants impacting this population.     

Risk of Breast Cancer by Type of Menopausal Hormone Therapy: a Case-Control Study among Post-Menopausal Women in France

Background

There is extensive epidemiological evidence that menopausal hormone therapy (MHT) increases breast cancer risk, particularly combinations of estrogen and progestagen (EP). We investigated the effects of the specific formulations and types of therapies used by French women. Progestagen constituents, regimen (continuous or sequential treatment by the progestagen), and time interval between onset of menopause and start of MHT were examined.

Methods

We conducted a population-based case-control study in France in 1555 menopausal women (739 cases and 816 controls). Detailed information on MHT use was obtained during in-person interviews. Odds ratios and 95% confidence interval adjusted for breast cancer risk factors were calculated.

Results

We found that breast cancer risk differed by type of progestagen among current users of EP therapies. No increased risk was apparent among EP therapy users treated with natural micronized progesterone. Among users of EP therapy containing a synthetic progestin, the odds ratio was 1.57 (0.99-2.49) for progesterone-derived and 3.35 (1.07-10.4) for testosterone-derived progestagen. Women with continuous regimen were at greater risk than women treated sequentially, but regimen and type of progestagen could not be investigated independently, as almost all EP combinations containing a testosterone-derivative were administered continuously and vice-versa. Tibolone was also associated with an increased risk of breast cancer. Early users of MHT after onset of menopause were at greater risk than users who delayed treatment.

Conclusion

This study confirms differential effects on breast cancer risk of progestagens and regimens specifically used in France. Formulation of EP therapies containing natural progesterone, frequently prescribed in France, was not associated with increased risk of breast cancer but may poorly protect against endometrial cancer.     

Alcohol Consumption and Breast Cancer Risk among Women in Three Sub-Saharan African Countries

Background

Alcohol drinking is linked to the development of breast cancer. However, there is little knowledge about the impact of alcohol consumption on breast cancer risk among African women.

Methods

We conducted a case-control study among 2,138 women with invasive breast cancer and 2,589 controls in Nigeria, Cameroon, and Uganda from 1998 to 2013. A structured questionnaire was used to collect information on alcohol consumption, defined as consuming alcoholic beverages at least once a week for six months or more. Logistic regression was used to estimate adjusted odds ratio (aOR) and 95% confidence interval (CI).

Results

Among healthy controls, the overall alcohol consumption prevalence was 10.4%, and the prevalence in Nigeria, Cameroon, and Uganda were 5.0%, 34.6%, and 50.0%, respectively. Cases were more likely to have consumed alcohol (aOR = 1.62, 95% CI: 1.33–1.97). Both past (aOR = 1.54; 95% CI: 1.19–2.00) and current drinking (aOR = 1.71; 95% CI: 1.30–2.23) were associated with breast cancer risk. A dose-response relationship was observed for duration of alcohol drinking (P-trend <0.001), with 10-year increase of drinking associated with a 54% increased risk (95% CI: 1.29–1.84).

Conclusion

We found a positive relationship between alcohol consumption and breast cancer risk, suggesting that this modifiable risk factor should be addressed in breast cancer prevention programs in Africa.     

Therapy of Primary Breast Cancer

Most breast cancers are multicentric in origin. They drain into two primary lymphatic depots—the axilla and internal mammary chain of nodes. The incidence of metastasis to the internal mammary nodes rises as the location of the primary tumor approaches to the sternal margin of the breast.One hundred and thirty-seven patients primarily with in situ and non-infiltrating intraductal carcinoma were treated adequately by simple mastectomy and axillary dissection with preservation of the pectoral muscles.All have remained free of disease. Infiltrating cancers arising in the lateral portion of the breast are best treated by radical mastectomy since they spread mainly to the axillary nodes. Medial and central infiltrating cancers have been treated by radical mastectomy with internal mammary resection, since they show a higher incidence of internal mammary metastasis. Seventy-two percent of 500 patients treated in this fashion survived at five years and 65 percent were clinically free of disease. A five-year salvage rate of 60 percent and a ten-year salvage rate of 50 percent were obtained in patients with only internal mammary node metastasis or in those with only axillary involvement. When both nodal areas were involved 43 percent remained free of disease at five years and 20 percent at ten years.Mammography and biopsy of the contralateral breast at the time of radical mastectomy contributed to the detection of early localized breast cancer.     

Breast Tissue Composition and Immunophenotype and Its Relationship with Mammographic Density in Women at High Risk of Breast Cancer

Aim

To investigate the cellular and immunophenotypic basis of mammographic density in women at high risk of breast cancer.

Methods

Mammograms and targeted breast biopsies were accrued from 24 women at high risk of breast cancer. Mammographic density was classified into Wolfe categories and ranked by increasing density. The histological composition and immunophenotypic profile were quantified from digitized haematoxylin and eosin-stained and immunohistochemically-stained (ERα, ERβ, PgR, HER2, Ki-67, and CD31) slides and correlated to mammographic density.

Results

Increasing mammographic density was significantly correlated with increased fibrous stroma proportion (rs (22) = 0.5226, p = 0.0088) and significantly inversely associated with adipose tissue proportion (rs (22) = -0.5409, p = 0.0064). Contrary to previous reports, stromal expression of ERα was common (19/20 cases, 95%). There was significantly higher stromal PgR expression in mammographically-dense breasts (p=0.026).

Conclusions

The proportion of stroma and fat underlies mammographic density in women at high risk of breast cancer. Increased expression of PgR in the stroma of mammographically dense breasts and frequent and unexpected presence of stromal ERα expression raises the possibility that hormone receptor expression in breast stroma may have a role in mediating the effects of exogenous hormonal therapy on mammographic density.     

A Genome-Wide Scan for Breast Cancer Risk Haplotypes among African American Women

Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.     

The Effects of a Novel Hormonal Breast Cancer Therapy,Endoxifen, on the Mouse Skeleton

Endoxifen has recently been identified as the predominant active metabolite of tamoxifen and is currently being developed as a novel hormonal therapy for the treatment of endocrine sensitive breast cancer. Based on past studies in breast cancer cells and model systems, endoxifen classically functions as an anti-estrogenic compound. Since estrogen and estrogen receptors play critical roles in mediating bone homeostasis, and endoxifen is currently being implemented as a novel breast cancer therapy, we sought to comprehensively characterize the in vivo effects of endoxifen on the mouse skeleton. Two month old ovariectomized C57BL/6 mice were treated with vehicle or 50 mg/kg/day endoxifen hydrochloride via oral gavage for 45 days. Animals were analyzed by dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, micro-computed tomography and histomorphometry. Serum from control and endoxifen treated mice was evaluated for bone resorption and bone formation markers. Gene expression changes were monitored in osteoblasts, osteoclasts and the cortical shells of long bones from endoxifen treated mice and in a human fetal osteoblast cell line. Endoxifen treatment led to significantly higher bone mineral density and bone mineral content throughout the skeleton relative to control animals. Endoxifen treatment also resulted in increased numbers of osteoblasts and osteoclasts per tissue area, which was corroborated by increased serum levels of bone formation and resorption markers. Finally, endoxifen induced the expression of osteoblast, osteoclast and osteocyte marker genes. These studies are the first to examine the in vivo and in vitro impacts of endoxifen on bone and our results demonstrate that endoxifen increases cancellous as well as cortical bone mass in ovariectomized mice, effects that may have implications for postmenopausal breast cancer patients.     

Passive Smoking and Breast Cancer Risk among Non-Smoking Women: A Case-Control Study in China

Background

The role of passive smoking on breast cancer risk was unclear. This study aimed to evaluate the association between passive smoking and breast cancer risk among Chinese women.

Methods/Principal Findings

A hospital-based case-control study, including 877 breast cancer cases and 890 controls, frequency-matched by age and residence, was conducted. A structured questionnaire was used to collect information on passive smoking history through face-to-face interview by trained interviewers. Unconditional logistic regression models were used to estimate the association between passive smoking and breast cancer risk. A positive association between any passive smoking exposure and breast cancer risk was observed. Compared with women who were never exposed to passive smoking, women who were ever exposed had a higher breast cancer risk, with the adjusted odds ratio (OR) and 95% confidence interval (CI) of 1.35 (1.11-1.65). Similar result was found on home passive smoking exposure and breast cancer risk, but not on workplace passive smoking exposure. Women who were ever exposed to tobacco smoke at home had a higher risk of breast cancer compared with never exposed women, with the adjusted OR (95% CI) of 1.30 (1.05-1.61). Home passive smoking exposure showed significant dose-response relationships with breast cancer risk in smoker-years, cigarettes/day and total pack-years (P _trend=0.003, 0.006 and 0.009, respectively). An increased total smoker-years of any passive exposure significantly elevated the risk of breast cancer (P _trend<0.001). Positive associations and dose-response relationships were found among postmenopausal women and all subtypes of estrogen receptor (ER) and progesterone receptor (PR) status of breast cancer.

Conclusions

Passive smoking was associated with an increased risk of breast cancer among non-smoking Chinese women. A stronger positive association with breast cancer risk was seen mainly among postmenopausal women.     

The Impact of Prostate Cancer and Hormonal Therapy on Bone

Large-scale studies agree that the observed decline in prostate cancer mortality that began in the early 1990s, shortly after prostate-specific antigen testing was introduced in the United States, is most likely explained by more widespread treatment of prostate cancer, including hormonal therapy. Practitioners should be aware of the risk of the development of osteoporosis and of skeletal side effects related to hormonal therapy to optimize the care of men with prostate cancer.Key words: Hormone deprivation therapy, Androgen deprivation therapy, Bone destruction, Osteoporosis, OsteopeniaProstate cancer is the most commonly diagnosed cancer among men in the United States, with approximately 192,280 cases anticipated in 2009.¹ It also remains a common cause of cancer death, with 27,360 deaths anticipated in 2009. Moreover, the declining US death rates from cardiovascular and smoking-related disease coupled with the aging of the population associated with the Baby Boom generation may beget an anticipated increase in prostate cancer diagnoses in the coming years. It has been estimated that about 10% of the US population was over the age of 65 years in 2000 and that this proportion will approximately double by 2030.² As a condition of aging men, prostate cancer is apt to remain a significant, if not growing, public health problem.Current efforts to reduce the mortality burden of prostate cancer have included prostate-specific antigen (PSA)-based screening, but its effect on mortality as assessed in randomized trials, particularly during the first 10 years of follow-up, is controversial.^3,4 But these large-scale studies agree that the observed decline in prostate cancer mortality that began in the early 1990s, shortly after PSA testing was introduced in the United States, is most likely explained by more widespread treatment of prostate cancer, including hormonal therapy.⁵ Given these considerations, it is quite likely that hormone deprivation therapy will remain an important treatment for men with prostate cancer. Therefore, a thorough understanding of its long-term side effects is necessary if we are to optimize the care of men with prostate cancer.     

乳腺癌SULT1A1、ICAM5基因单核苷酸多态性的研究

目的:探讨硫酸基转移酶(sulfotransferase,SULT)lA1、细胞间粘附分子(ICAM5)基因多态性与女性乳腺癌易感性的关系.方法:采外周血DNA后用等位基因特异性扩增法(allele specific amplification,ASA)检测青岛市200例正常对照者和160例乳腺癌患者的SULTIA1、ICAM5基因多态性分布,并进行统计学分析.结果:(1)SULTlA1 Arg/Arg、Arg/His、His/His三种基因型分布在对照组和病例组之间的差异无显著意义(P=0.103);病例组、对照组His等位基因频率分别为19.5%和9.2%(P=0.039),此差别有统计学意义;在淋巴结转移方面SULTIA1基因三种基因型在阴、阳性组间的差异有统计学意义(P=0.038).(2)ICAM5基因各基因型及等位基因分布频率在病例组和对照组间的差异无显著意义(P=0.245,P=0.294);从临床病例分型方面进一步分析,基因型GG与携带变异基因A的GA及AA基因型相比差异均无统计意义.结论:SULTlA1 His等位基因与汉族女性乳腺癌的发生可能相关.     

三阴乳腺癌的异质性及靶向治疗

三阴乳腺癌指雌激素受体(ER)、孕激素受体(PR)、人表皮生长因子受体2(HER-2)均为阴性的乳腺癌,占乳腺癌的15%~20%,具有侵袭转移率高、总生存率低、预后差等特点。三阴乳腺癌有很强的异质性,根据其基因表达特征,可分为基底细胞样1型、基底细胞样2型、间质型、间质干细胞型等7个亚类。由于其不表达ER、PR和HER-2,因此内分泌治疗和抗HER-2治疗无效,通常以化疗作为主要治疗方法。近年来,对其靶向治疗如EGFR、PARP、SRC等靶向治疗已有大量研究与应用报道,并显示了一定的治疗效果,提示靶向治疗是未来三阴乳腺癌的治疗方向。我们简要综述三阴乳腺癌的异质性、靶向治疗及预后诊断。     

SEPP1 Influences Breast Cancer Risk among Women with Greater Native American Ancestry: The Breast Cancer Health Disparities Study

Selenoproteins are a class of proteins containing a selenocysteine residue, many of which have been shown to have redox functions, acting as antioxidants to decrease oxidative stress. Selenoproteins have previously been associated with risk of various cancers and redox-related diseases. In this study we evaluated possible associations between breast cancer risk and survival and single nucleotide polymorphisms (SNPs) in the selenoprotein genes GPX1, GPX2, GPX3, GPX4, SELS, SEP15, SEPN1, SEPP1, SEPW1, TXNRD1, and TXNRD2 among Hispanic/Native American (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women in the Breast Cancer Health Disparities Study. Adaptive Rank Truncated Product (ARTP) analysis was used to determine both gene and pathway significance with these genes. The overall selenoprotein pathway P_ARTP was not significantly associated with breast cancer risk (P_ARTP = 0.69), and only one gene, GPX3, was of borderline significance for the overall population (P_ARTP =0.09) and marginally significant among women with 0-28% Native American (NA) ancestry (P_ARTP=0.06). The SEPP1 gene was statistically significantly associated with breast cancer risk among women with higher NA ancestry (P_ARTP=0.002) and contributed to a significant pathway among those women (P_ARTP=0.04). GPX1, GPX3, and SELS were associated with Estrogen Receptor-/Progesterone Receptor+ status (P_ARTP = 0.002, 0.05, and 0.01, respectively). Four SNPs (GPX3 rs2070593, rsGPX4 rs2074451, SELS rs9874, and TXNRD1 rs17202060) significantly interacted with dietary oxidative balance score after adjustment for multiple comparisons to alter breast cancer risk. GPX4 was significantly associated with breast cancer survival among those with the highest NA ancestry (P_ARTP = 0.05) only. Our data suggest that SEPP1 alters breast cancer risk among women with higher levels of NA ancestry.     

Mammographic Breast Density and Common Genetic Variants in Breast Cancer Risk Prediction

Introduction

Known prediction models for breast cancer can potentially by improved by the addition of mammographic density and common genetic variants identified in genome-wide associations studies known to be associated with risk of the disease. We evaluated the benefit of including mammographic density and the cumulative effect of genetic variants in breast cancer risk prediction among women in a Singapore population.

Methods

We estimated the risk of breast cancer using a prospective cohort of 24,161 women aged 50 to 64 from Singapore with available mammograms and known risk factors for breast cancer who were recruited between 1994 and 1997. We measured mammographic density using the medio-lateral oblique views of both breasts. Each woman’s genotype for 75 SNPs was simulated based on the genotype frequency obtained from the Breast Cancer Association Consortium data and the cumulative effect was summarized by a genetic risk score (GRS). Any improvement in the performance of our proposed prediction model versus one containing only variables from the Gail model was assessed by changes in receiver-operating characteristic and predictive values.

Results

During 17 years of follow-up, 680 breast cancer cases were diagnosed. The multivariate-adjusted hazard ratios (95% confidence intervals) were 1.60 (1.22–2.10), 2.20 (1.65–2.92), 2.33 (1.71–3.20), 2.12 (1.43–3.14), and 3.27 (2.24–4.76) for the corresponding mammographic density categories: 11-20cm², 21-30cm², 31-40cm², 41-50cm², 51-60cm², and 1.10 (1.03–1.16) for GRS. At the predicted absolute 10-year risk thresholds of 2.5% and 3.0%, a model with mammographic density and GRS could correctly identify 0.9% and 0.5% more women who would develop the disease compared to a model using only the Gail variables, respectively.

Conclusion

Mammographic density and common genetic variants can improve the discriminatory power of an established breast cancer risk prediction model among females in Singapore.     

Mediterranean Dietary Pattern and Risk of Breast Cancer

Background

A Mediterranean diet has a recognized beneficial effect on health and longevity, with a protective influence on several cancers. However, its association with breast cancer risk remains unclear.

Objective

We aimed to investigate whether adherence to a Mediterranean dietary pattern influences breast cancer risk.

Design

The Swedish Women’s Lifestyle and Health cohort study includes 49,258 women aged 30 to 49 years at recruitment in 1991–1992. Consumption of foods and beverages was measured at enrollment using a food frequency questionnaire. A Mediterranean diet score was constructed based on the consumption of alcohol, vegetables, fruits, legumes, cereals, fish, the ratio of unsaturated to saturated fat, and dairy and meat products. Relative risks (RR) for breast cancer and specific tumor characteristics (invasiveness, histological type, estrogen/progesterone receptor status, malignancy grade and stage) associated with this score were estimated using Cox regression controlling for potential confounders.

Results

1,278 incident breast cancers were diagnosed. Adherence to a Mediterranean dietary pattern was not statistically significantly associated with reduced risk of breast cancer overall, or with specific breast tumor characteristics. A RR (95% confidence interval) for breast cancer associated with a two-point increment in the Mediterranean diet score was 1.08 (1.00–1.15) in all women, and 1.10 (1.01–1.21) and 1.02 (0.91–1.15) in premenopausal and postmenopausal women, respectively. When alcohol was excluded from the Mediterranean diet score, results became not statistically significant.

Conclusions

Adherence to a Mediterranean dietary pattern did not decrease breast cancer risk in this cohort of relatively young women.     

Korean Risk Assessment Model for Breast Cancer Risk Prediction

Purpose

We evaluated the performance of the Gail model for a Korean population and developed a Korean breast cancer risk assessment tool (KoBCRAT) based upon equations developed for the Gail model for predicting breast cancer risk.

Methods

Using 3,789 sets of cases and controls, risk factors for breast cancer among Koreans were identified. Individual probabilities were projected using Gail''s equations and Korean hazard data. We compared the 5-year and lifetime risk produced using the modified Gail model which applied Korean incidence and mortality data and the parameter estimators from the original Gail model with those produced using the KoBCRAT. We validated the KoBCRAT based on the expected/observed breast cancer incidence and area under the curve (AUC) using two Korean cohorts: the Korean Multicenter Cancer Cohort (KMCC) and National Cancer Center (NCC) cohort.

Results

The major risk factors under the age of 50 were family history, age at menarche, age at first full-term pregnancy, menopausal status, breastfeeding duration, oral contraceptive usage, and exercise, while those at and over the age of 50 were family history, age at menarche, age at menopause, pregnancy experience, body mass index, oral contraceptive usage, and exercise. The modified Gail model produced lower 5-year risk for the cases than for the controls (p = 0.017), while the KoBCRAT produced higher 5-year and lifetime risk for the cases than for the controls (p<0.001 and <0.001, respectively). The observed incidence of breast cancer in the two cohorts was similar to the expected incidence from the KoBCRAT (KMCC, p = 0.880; NCC, p = 0.878). The AUC using the KoBCRAT was 0.61 for the KMCC and 0.89 for the NCC cohort.

Conclusions

Our findings suggest that the KoBCRAT is a better tool for predicting the risk of breast cancer in Korean women, especially urban women.