Risk Of Breast Cancer In Women Research Articles

Monoallelic MUTYH carrier status is not associated with increased breast cancer risk in a multigene panel cohort

Whether monoallelic MUTYH mutations increase female breast cancer risk remains controversial. This study aimed to determine if monoallelic MUTYH mutations are associated with increased breast cancer risk in women undergoing multigene panel testing (MGPT). The prevalence of monoallelic MUTYH mutations was compared between Non-Hispanic white female breast cancer cases (n = 30,456) and cancer-free controls (n = 12,289), all of whom underwent MGPT that included MUTYH. We tested breast cancer associations with MUTYH alleles using Fisher's exact test, followed by multivariate logistic regression adjusted for age at testing and MGPT type ordered. Frequencies of the two most common MUTYH founder mutations, p.G396D and p.Y179C, were compared independently between the breast cancer cases and MGPT controls, as well as the healthy UK10K control population (n = 2640). Comparing cases to MGPT controls, no association was observed between female breast cancer and any monoallelic MUTYH carrier status (OR 0.86-1.36, p = 0.21-0.96). Similarly, comparisons to UK10K controls revealed no significant increase in breast cancer risk associated with p.G396D (OR 1.20, p = 0.44) or p.Y179C (OR 1.71, p = 0.24). This study did not find a significant increase in breast cancer risk associated with monoallelic MUTYH mutations.

Association of Body Fat and Risk of Breast Cancer in Postmenopausal Women With Normal Body Mass Index

Obesity is associated with an increased risk of breast cancer, including the estrogen receptor (ER)-positive subtype in postmenopausal women. Whether excess adiposity is associated with increased risk in women with a normal body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown. To investigate the association between body fat and breast cancer risk in women with normal BMI. This ad hoc secondary analysis of the Women's Health Initiative (WHI) clinical trial and observational study cohorts was restricted to postmenopausal participants with a BMI ranging from 18.5 to 24.9. Women aged 50 to 79 years were enrolled from October 1, 1993, through December 31, 1998. Of these, 3460 participants underwent body fat measurement with dual-energy x-ray absorptiometry (DXA) at 3 US designated centers with follow-up. At a median follow-up of 16 years (range, 9-20 years), 182 incident breast cancers had been ascertained, and 146 were ER positive. Follow-up was complete on September 30, 2016, and data from October 1, 1993, through September 30, 2016, was analyzed August 2, 2017, through August 21, 2018. Body fat levels were measured at baseline and years 1, 3, 6, and 9 using DXA. Information on demographic data, medical history, and lifestyle factors was collected at baseline. Invasive breast cancers were confirmed via central review of medical records by physician adjudicators. Blood analyte levels were measured in subsets of participants. Among the 3460 women included in the analysis (mean [SD] age, 63.6 [7.6] years), multivariable-adjusted hazard ratios for the risk of invasive breast cancer were 1.89 (95% CI, 1.21-2.95) for the highest quartile of whole-body fat and 1.88 (95% CI, 1.18-2.98) for the highest quartile of trunk fat mass. The corresponding adjusted hazard ratios for ER-positive breast cancer were 2.21 (95% CI, 1.23-3.67) and 1.98 (95% CI, 1.18-3.31), respectively. Similar positive associations were observed for serial DXA measurements in time-dependent covariate analyses. Circulating levels of insulin, C-reactive protein, interleukin 6, leptin, and triglycerides were higher, whereas levels of high-density lipoprotein cholesterol and sex hormone-binding globulin were lower in those in the uppermost vs lowest quartiles of trunk fat mass. In postmenopausal women with normal BMI, relatively high body fat levels were associated with an elevated risk of invasive breast cancer and altered levels of circulating metabolic and inflammatory factors. Normal BMI categorization may be an inadequate proxy for the risk of breast cancer in postmenopausal women. ClinicalTrials.gov identifier: NCT00000611.

Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy.

Inherited mutations in BRCA1, and, mainly, BRCA2 genes are associated with increased risk of male breast cancer (MBC). Mutations in PALB2 and CHEK2 genes may also increase MBC risk. Overall, these genes are functionally linked to DNA repair pathways, highlighting the central role of genome maintenance in MBC genetic predisposition. MUTYH is a DNA repair gene whose biallelic germline variants cause MUTYH-associated polyposis (MAP) syndrome. Monoallelic MUTYH variants have been reported in families with both colorectal and breast cancer and there is some evidence on increased breast cancer risk in women with monoallelic variants. In this study, we aimed to investigate whether MUTYH germline variants may contribute to MBC susceptibility. To this aim, we screened the entire coding region of MUTYH in 503 BRCA1/2 mutation negative MBC cases by multigene panel analysis. Moreover, we genotyped selected variants, including p.Tyr179Cys, p.Gly396Asp, p.Arg245His, p.Gly264Trpfs*7, and p.Gln338His, in a total of 560 MBC cases and 1,540 male controls. Biallelic MUTYH pathogenic variants (p.Tyr179Cys/p.Arg241Trp) were identified in one MBC patient with phenotypic manifestation of adenomatous polyposis. Monoallelic pathogenic variants were identified in 14 (2.5%) MBC patients, in particular, p.Tyr179Cys was detected in seven cases, p.Gly396Asp in five cases, p.Arg245His and p.Gly264Trpfs*7 in one case each. The majority of MBC cases with MUTYH pathogenic variants had family history of cancer including breast, colorectal, and gastric cancers. In the case-control study, an association between the variant p.Tyr179Cys and increased MBC risk emerged by multivariate analysis [odds ratio (OR) = 4.54; 95% confidence interval (CI): 1.17–17.58; p = 0.028]. Overall, our study suggests that MUTYH pathogenic variants may have a role in MBC and, in particular, the p.Tyr179Cys variant may be a low/moderate penetrance risk allele for MBC. Moreover, our results suggest that MBC may be part of the tumor spectrum associated with MAP syndrome, with implication in the clinical management of patients and their relatives. Large-scale collaborative studies are needed to validate these findings.

Green Tea Consumption and Risk of Breast Cancer and Recurrence-A Systematic Review and Meta-Analysis of Observational Studies.

Breast cancer (BC) is the most common cancer in women and several factors are involved in its onset. Green tea (GT) has been shown to have potential beneficial effects on different types of cancer. The aim of this review was to evaluate the association between GT regular consumption and risk of BC in women. The risk of BC recurrence and risk of BC in relation to menopausal status were also evaluated. A literature search of PubMed, Scopus, and Web of Science was conducted. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed to perform the systematic review and meta-analysis. Full texts were downloaded for 40 studies; however, only 13 records were included in the meta-analysis. Eight were cohort studies and five were case-control studies. The pooled sample consisted of 163,810 people. An inverse statistically significant relationship between GT and BC risk, with an Odds Ratio (OR) = 0.85 ((95% CI = 0.80–0.92), p = 0.000)), was found. Egger’s linear regression test did not show a potential publication bias (intercept 0.33, t = 0.40, p = 0.695), which was also confirmed by the symmetry of the funnel plot. Moreover, no high statistical heterogeneity (Chi2 = 31.55, df = 13, I2 = 58.79%, p = 0.003) was found. The results of this meta-analysis showed a potential protective effect of GT consumption on BC, especially for BC recurrence.

Estrogen metabolism in menopausal hormone users in the women's health initiative observational study: Does it differ between estrogen plus progestin and estrogen alone?

The WHI found an unexpected reduced breast cancer risk in women using CEE alone. We hypothesized CEE alone induces estrogen hydroxylation along the 2-pathway rather than the competing 16-pathway, a pattern linked to reduced postmenopausal breast cancer risk. One thousand eight hundred and sixty-four women in a WHIOS case-control study of estrogen metabolism and ovarian and endometrial cancer were studied of whom 609 were current E + P users (351 used CEE + MPA), while 272 used E alone (162 used CEE). Fifteen EM were measured, and analyses were conducted for each metabolite, hydroxylation pathway (2-, 4-, or 16-pathway) and ratios of pathway concentrations using inverse probability weighted linear regression. Compared to E + P users, all EM were higher in E alone users (significant for unconjugated estrone, total/conjugated estradiol, total/unconjugated 2-methoxyestrone, 4-methoxyestrone and unconjugated estriol). The relative concentrations of 2- and 4-pathway EM did not differ between the MHT users (2-pathway EM comprised 15% and 4-pathway EM <2% of the total), but 16-pathway EM were lower in E alone users (p = 0.036). Ratios of 2- and 4-pathway EM compared to 16-pathway EM were significantly higher in E alone compared to E + P users. Similar but not significant patterns were observed in CEE-alone and CEE + MPA users. Our data suggest that compared to E + P users, women using E alone have more extensive metabolism via the 2- vs. the competing 16-pathway. This is consistent with epidemiologic evidence of reduced postmenopausal breast cancer risk associated with this metabolic profile and may provide a clue to the breast cancer risk reduction in CEE alone users during the WHI.

Adherence to Mediterranean diet and the risk of breast cancer: a meta-analysis

Background: For a long period of time, the Mediterranean diet (MD) has been regarded by many as a very healthy and balanced daily diet that may be related to the incidences of many types of cancer. However, the association between an MD and breast cancer risk remains inconsistent even though many studies about the topic have been conducted. Hence, we performed a meta-analysis to evaluate the relationship between an MD and breast cancer risk. Methods: We searched PubMed, Medline, and EMBASE for relevant articles published earlier than May 2017. “Mediterranean diet” combined with “breast cancer” and “breast carcinoma” were used as search terms. The combined relative risk (RR) and corresponding 95% confidence interval (CI) were used to evaluate the association between an MD and breast cancer risk. Results: A total of 18 articles were included in our meta-analysis; the studies spanned 11 years, ranging from 2006 to May 2017. Ten cohort and 8 case-control studies were included. Seven studies analyzed breast cancer incidence separately in premenopausal and postmenopausal women, whereas 6 studies were performed only in postmenopausal women, for a total of 13 analyses in postmenopausal women and 7 analyses among premenopausal women. Our meta-analysis revealed a significant and inverse association of the MD and breast cancer risk (RR: 0.92, 95% CI: 0.86, 0.99). Stratification analysis by study design and menopause status revealed a significant inverse association between the MD and breast cancer risk in case-control studies (RR: 0.85, 95% CI: 0.73, 0.99) and postmenopausal women (RR: 0.91, 95% CI: 0.85, 0.97) but not in cohort studies and premenopausal women. Conclusions: Our meta-analysis revealed that an MD is significantly associated with a reduction of breast cancer risk in women, especially postmenopausal women. The MD can be suggested to women, especially postmenopausal women, as a healthy diet to reduce breast cancer risk.

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations.

BackgroundFull-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.MethodsUsing weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.ResultsFor BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, Ptrend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort Ptrend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).ConclusionsThese findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers.

Genetic Evidence for the Association between Schizophrenia and Breast Cancer.

Objective:To estimate the potential effect of schizophrenia on breast cancer risk in women, we performed a two-sample Mendelian randomization (MR) study.Methods:The instrumental variables comprised 170 uncorrelated and non-pleiotropic single nucleotide polymorphisms (SNPs) that are significantly associated with schizophrenia risk in genome-wide association studies in 105,000 European descent individuals of the Psychiatric Genomics Consortium (http://www.med.unc.edu/pgc/) and the United Kingdom Clozapine Clinic. The association between these SNPs determined schizophrenia and breast cancer risk was estimated in approximately 229,000 European descent females from the Breast Cancer Association Consortium using the inverse-variance weighted and the weighted median MR methods.Results:We found that the genetically-predicted risk of schizophrenia was associated with increased breast cancer risk (under a random-effects model: odds ratio per 1 unit increase in log odds of schizophrenia = 1.04, 95% confidence interval: 1.02–1.06, p = 5.6 × 10−5). Similar significant associations were observed in analyses using a weighted median model and sensitivity analysis excluding six SNPs with genotype imputation score of less than 0.8, as well as analyses stratified by estrogen receptor status of breast cancer.Conclusion:Our findings implicate a modest increased risk for breast cancer in genetically determined schizophrenic females.

Randomized Trial of Personalized Breast Density and Breast Cancer Risk Notification.

Despite widespread implementation of mammographic breast density (MBD) notification laws, the impact of these laws on knowledge of MBD and knowledge of breast cancer risk is limited by the lack of tools to promote informed decision-making in practice. To develop and evaluate whether brief, personalized informational videos following a normal mammogram in addition to a legislatively required letter about MBD result can improve knowledge of MBD and breast cancer risk compared to standard care (i.e., legislatively required letter about MBD included with the mammogram result). Prospective randomized controlled trial of English-speaking women, age 40-74years, without prior history of breast cancer, receiving a screening mammogram with a normal or benign finding (intervention group n = 235, control group n = 224). brief (3-5min) video, personalized to a woman's MBD result and breast cancer risk. Primary outcomes were a woman's knowledge of her MBD and risk of breast cancer. Secondary outcomes included whether a woman reported that she discussed the results of her mammogram with her primary care provider (PCP). Relative to women in the control arm, women in the intervention arm had greater improvement in their knowledge of both their personal MBD (intervention pre/post 39.2%/ 77.5%; control pre/post 36.2%/ 37.5%; odds ratio (OR) 5.34 for change for intervention vs. control, 95% confidence interval (CI) 3.87-7.36; p < 0.001) and risk of breast cancer (intervention pre/post: 66.8%/74.0%; control pre/post 67.9%/ 65.2%; OR 1.42, 95% confidence interval (CI) 1.09-1.84; p = 0.01). Women in the intervention group were more likely than those in the control group to report discussing the results of their mammogram with their PCP (p = 0.05). Brief, personalized videos following mammography can improve knowledge of MBD and personal risk of breast cancer compared to a legislatively mandated informational letter. Trial Registration Clinicaltrials.gov (NCT02986360).

Abstract B29: An allelic series of rat mutations reveal a role of TOX3 in mammary gland development, obesity, and breast cancer susceptibility

Abstract With the rising incidence of breast cancer cases in the population, it is imperative to understand mechanisms of susceptibility. Genome-wide association studies (GWAS) have identified many variants associated with breast cancer susceptibility. These loci have low penetrance and are common in the population. Some of the alleles are associated with specific subtypes of breast cancer and/or associate specifically within ancestral populations. Variants in the TOX3/LOC643714 locus on human chromosomal band 16q12.1 are strongly associated with risk to estrogen receptor-positive (ER+) breast cancer in cohorts of women of European ancestry. Remarkably, replication of the association of these same variants with breast cancer risk in women of African American ancestry failed, but other variants in a more distal area of the locus were found to be associated with risk. The correlated polymorphisms comprising these variants exist in noncoding regions, providing the possibility that these polymorphisms alter gene expression. The most likely causal gene, TOX3, encodes a transcription factor that has previously been found to regulate estrogen receptor alpha (ERα)-responsive genes in breast cancer cells. We hypothesize that noncoding breast cancer-associated polymorphisms on 16q12.1 regulate TOX3, subsequently modifying risk of developing ER+ breast cancer. To genetically dissect this locus, we implemented the CRISPR-Cas9 genetic engineering system in the rat model organism. The rat is the preferred rodent model for ER+ breast cancer. We engineered an allelic series of mutations generating rats with deletions in the portion of the Tox3 locus orthologous to the human risk-associated regions. We obtained viable mutants across all genotypes, despite partial embryonic lethality in homozygous Tox3 knockouts. The mutants in the allelic series display variable levels of Tox3 downregulation in the mammary gland, suggesting the presence of multiple Tox3-regulatory elements. Mutants showing altered Tox3 expression also show significant effects on mammary gland development, implicating a role for Tox3 in mammary stem/progenitor cell biology potentially through ERα gene regulation. In accordance with the association of the human risk-increasing allele with lower TOX3 transcript level, preliminary data from mammary carcinogenesis experiments in our rat model indicate that lower Tox3 levels result in increased mammary carcinoma multiplicity. This result suggests that Tox3 is a breast cancer susceptibility gene. Interestingly, Tox3 knockout rats present an obesity phenotype, male and female sterility, and a behavioral phenotype (increased anxiety), indicating pleiotropic effects of TOX3 loss-of-function mutations. Ongoing studies are focused on Tox3 in rat mammary gland biology and carcinogenesis to elucidate the mechanism of Tox3 regulation in susceptibility to ER+ breast cancer. Understanding mechanisms of susceptibility genes will ultimately lead to innovative strategies aimed at preventing breast cancer. Citation Format: Lauren B. Shunkwiler, Royal Pipaliya, Cody C. Ashy, Benjamine Van Peel, Yang Zhao, Jan Guz, Alexander Awgulewitsch, Michael J. Kern, Bart M.G. Smits. An allelic series of rat mutations reveal a role of TOX3 in mammary gland development, obesity, and breast cancer susceptibility [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B29.

Biological and clinical impact of imbalanced progesterone receptor isoform ratios in breast cancer.

There is a consensus that progestins and thus their cognate receptor molecules, the progesterone receptors (PR), are essential in the development of the adult mammary gland and regulators of proliferation and lactation. However, a role for natural progestins in breast carcinogenesis remains poorly understood. A hint to that possible role came from studies in which the synthetic progestin medroxyprogesterone acetate was associated with an increased breast cancer risk in women under hormone replacement therapy. However, progestins have been also used for breast cancer treatment and to inhibit the growth of several experimental breast cancer models. More recently, PR have been shown to be regulators of estrogen receptor signaling. With all this information, the question is how can we target PR, and if so, which patients may benefit from such an approach? PR are not single unique molecules. Two main PR isoforms have been characterized, PRA and PRB, that exert different functions and the relative abundance of one isoform respect to the other determines the response of PR agonists and antagonists. Immunohistochemistry with standard antibodies against PR do not discriminate between isoforms. In this review, we summarize the current knowledge on the expression of both PR isoforms in mammary glands, in experimental models of breast cancer and in breast cancer patients, to better understand how the PRA/PRB ratio can be exploited therapeutically to design personalized therapeutic strategies.

Adipose tissue levels of polybrominated diphenyl ethers and breast cancer risk in Chinese women: A case–control study

Polybrominated diphenyl ethers (PBDEs) are suspected to be associated with breast cancer risk because of their estrogenic potencies. Epidemiological studies of PBDEs and breast cancer are scarce. Our study aimed to estimate the association between adipose-tissue PBDE concentrations and breast cancer risk. A total of 209 breast cancer cases and 165 controls were recruited from hospitals between January 2014 and May 2016 in Shantou, Chaoshan area, China. Concentrations of 14 PBDE congeners were measured in adipose tissues obtained from the breast for cases and the abdomen/breast for controls during surgery. Demographic and clinicopathologic characteristics were obtained from medical records. Breast cancer risk as well as clinicopathologic characteristics were evaluated by adipose-tissue PBDE level. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for breast cancer risk associated with levels of PBDE congeners were estimated from logistic regression models for all cases and stratified by estrogen receptor (ER) status. Level of total PBDEs (∑PBDE) and most individual PBDE congeners were higher in breast cancer cases than controls (median ∑PBDE, 94.99 vs 73.72 ng/g lipid). In the adjusted univariate model for all cases, breast cancer risk was increased with both 2nd and 3rd tertiles versus the 1st tertile of BDE-47 level (OR 2.05 [95% CI 1.08–3.92]; 5.47 [2.96–10.11]) and BDE-209 level (2.48 [1.30–4.73]; 4.72 [2.52–8.83]) with trend (both P < 0.001) and with the 3rd tertile of BDE-28 level (2.83 [1.63–4.92]), BDE-99 (3.22 [1.85–5.60]), BDE-100 (5.45 [2.90–10.23]), BDE-138 (2.40 [1.37–4.20]), BDE-153 (1.74 [1.02–2.97]), BDE-154 (1.84 [1.05–3.22]), and ∑PBDE levels (1.83 [1.07–3.14]) but decreased with the 3rd tertile of BDE-71 level (0.38 [0.22–0.65]) with trend (all P < 0.01). After stratifying by ER-positive or -negative status, the adjusted results were similar for ER-positive patients except for BDE-153 and BDE-154, with no statistical significance. In the multivariate model for all cases, age, menarche age, BDE-47, 71, 99, 100, 183 and 209 were independent factors associated with breast-cancer risk. ∑PBDE and most individual PBDE congeners investigated were positively associated with breast cancer risk in women from the Chaoshan area, China. PBDE may play a role in the occurrence and development of breast cancer.

Association between serum leptin levels and breast cancer risk: An updated systematic review and meta-analysis.

Background:Many studies have indicated that leptin is correlated with breast cancer occurrence and tumor behavior. However, this issue remains controversial. Therefore, we conducted an updated meta-analysis to investigate the role of leptin in breast cancer.Methods:We performed a systematic literature search and identified relevant papers up to 1 September 2017. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were used to evaluate effect sizes.Results:Thirty-five eligible studies were included in the current meta-analysis. Serum leptin levels were related to breast cancer risk as demonstrated by calculations of the overall SMD = 0.46 (95% CI = 0.31-0.60, I2 = 93.5%). A subgroup analysis of BMI identified an association between breast cancer and serum leptin levels in patients who are overweight and obese (overweight: SMD = 0.35, 95% CI = 0.13–0.57, I2 = 88.1%; obesity: SMD = 1.38, 95% CI = 0.64–2.12, I2 = 89.6%). Additionally, menopausal status subgroup analysis revealed a significant association in postmenopausal women (SMD = 0.26, 95% CI = 0.12–0.40, I2 = 77.9%). Furthermore, we identified a significant association between breast cancer and serum leptin levels in Chinese women (SMD = 0.61, 95% CI = 0.44–0.79, I2 = 40.6%).Conclusion:The results of this meta-analysis suggested that leptin could be a potential biomarker for breast cancer risk in women, especially overweight/obese or postmenopausal women. Therefore, it may be useful for identifying subjects with a high risk for breast cancer who may benefit from preventive treatments.

Abstract 4216: Adiponectin, leptin and breast cancer in high risk postmenopausal women: Results from a nested case-control study

Abstract Introduction: Obesity is a risk factor for postmenopausal breast cancer (BC) and evidence supports the pivotal role of adipokines in the association between obesity and BC. In the present study, we aim to investigate the role of adiponectin and leptin as independent risk markers for postmenopausal BC in a prospective nested case-control study within the cohort of women from the International Breast cancer Intervention prevention Study II (IBIS-II). Methods and Results: In the IBIS-II Prevention trial, 3864 healthy postmenopausal women at increased risk for BC were randomized to receive 1 mg/day oral anastrozole or matching placebo for 5 years. We measured serum adiponectin and leptin at baseline and 12-months in 119 cases and 336 controls in the placebo arm, and 57 cases and 165 controls in the anastrozole arm. We performed the adipokines measurements on the automated immunoassay platform ELLA (ProteinSimple, Biotechne). Baseline characteristics (age, body mass index (BMI), smoking status, and oophorectomy) were not different between cases and controls in both trial arms, except for hormone replacement therapy (HRT) use (38.7% of cases vs 51.5% of controls) and hysterectomy (25.2% of cases vs 37.5% of controls) in the placebo arm. We did not observe any statistically significant difference in adiponectin and leptin at baseline between cases and controls in both trial arms. When we considered the change in adiponectin levels between baseline and 12-months of follow-up, we observed a borderline significant higher proportion of BC cases in subjects with a decrease in adiponectin (36.4%) compared to subjects with an increase in adiponectin (25.7%). The multivariate Cox model indicated that women on placebo with a decrease in adiponectin between baseline and 12-months had a 36% significant increased risk in BC (HR=0.64; CI 0.42-0.98; adjusted for age, BMI, previous HRT use, smoking, oophorectomy, hysterectomy). Changes in leptin were not significantly associated with BC incidence overall. However, the multivariate Cox model for the anastrozole arm, indicated a significant higher BC risk for women with the highest increase (&amp;gt;10 ng/ml) vs the lowest decrease (&amp;lt;-10 ng/ml) in leptin: HR=4.45; CI 1.08-18.30; adjusted for age, BMI, previous HRT use, smoking, oophorectomy, hysterectomy. Conclusion: Our results did not support a prognostic role of baseline adiponectin and leptin levels in postmenopausal BC development. However, we observed an increased BC risk in women with a 12-month adiponectin decrease and leptin increase. These data suggest further investigations of changes of adiponectin and leptin levels as attractive targets for BC prevention in postmenopausal women at high risk for BC. Citation Format: Debora Macis, Ivana Sestak, Valentina Aristarco, Harriet Johansson, Aliana Guerrieri-Gonzaga, Andrea Decensi, Bernardo Bonanni, Jack Cuzick, Sara Gandini. Adiponectin, leptin and breast cancer in high risk postmenopausal women: Results from a nested case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4216.

Genetic variation in the Hippo pathway and breast cancer risk in women of African ancestry.

Gene expression changes within the Hippo pathway were found to be associated with large tumor size and metastasis in breast cancer. The combined effect of genetic variants in genes of this pathway may have a causal role in breast cancer development. We examined 7086 SNPs that were not highly correlated (r2 < 0.8) in 35 Hippo pathway genes using data from the genome-wide association study of breast cancer from the Root Consortium, which includes 3686 participants of African ancestry from Nigeria, United States of America, and Barbados: 1657 cases (403 estrogen receptor-positive [ER+], 374 ER-) and 2029 controls. Gene-level analyses were conducted using improved AdaJoint test for large-scale genetic association studies adjusting for age, study site and the first four eigenvectors from the principal component analysis. SNP-level analyses were conducted with logistic regression. The Hippo pathway was significantly associated with risk of ER+ breast cancer (pathway-level P = 0.019), with WWC1 (Padj = 0.04) being the leading gene. The pathway-level significance was lost without WWC1 (P = 0.12). rs147106204 in the WWC1 gene was the most statistically significant SNP after gene-level adjustment for multiple comparisons (OR = 0.53, 95%CI = 0.41-0.70, Padj = 0.025). We found evidence of an association between genetic variations in the Hippo pathway and ER+ breast cancer. Moreover, WWC1 was identified as the most important genetic susceptibility locus highlighting the importance of genetic epidemiology studies of breast cancer in understudied populations.

Effect of dairy products intake on breast cancer risk: A case-control study in Algeria

The aim of this hospital-based case-control study is to evaluate the association between dairy products consumption and breast cancer risk. This relationship has not previously been studied in Algeria. Our study was conducted on 184 breast cancer patients and equal number of age-matched controls. Data on sociodemographic characteristics, reproductive and menstrual history, medical history, lifestyle factors and anthropometric measurements were collected by interviewers. Dietary intake information was also obtained using a short food questionnaire. The Odds ratios [95% confidence interval (CI)] of breast cancer were estimated across categories of dairy intake using multivariable logistic regression. We observed an increased breast cancer risk in women with higher consumption of milk [OR = 2.61, 95% CI: 1.32–5.16, P = 0.027] comparing with those in lower category of intake. An inverse association with breast cancer risk was observed for total cheese intake when comparing highest with lowest quartiles. The protective effect of cheese was confirmed only for fresh cheese. No significant association was found for other types of dairy foods. Our study demonstrates the differential effect of dairy products types on breast cancer risk. Future studies are warranted to confirm these results. Le but de cette étude cas-témoin était d’évaluer l’association entre la consommation de produits laitiers et le risque de développer un cancer du sein. Cette association n’a pas été étudiée auparavant en Algérie. Notre étude a été menée sur 184 patientes atteintes d’un cancer du sein et un nombre égal de témoins appariés aux cas selon l’âge. Les données sur les caractéristiques sociodémographiques, l’histoire menstruelle, les antécédents médicaux, les antécédents familiaux, les facteurs liés au mode de vie, les mesures anthropométriques ainsi que les informations concernant l’apport alimentaire ont été recueillies par les intervieweurs. Les odd-ratios (intervalle de confiance à 95 % [IC]) du cancer du sein ont été estimés pour toutes les catégories de consommation de produits laitiers en utilisant une régression logistique multivariée. Nous avons observé un risque accru de cancer du sein chez les femmes ayant une consommation élevée de lait (OR = 2,61, IC 95 % : 1,32–5,16, p = 0,027) par rapport à celles appartenant à la catégorie inférieure de consommation. Une association inverse avec le risque de cancer du sein a été observée pour la consommation totale de fromage lorsqu’on compare le quatrième au premier quartile. L’effet protecteur du fromage n’a été confirmé que pour le fromage frais. Aucune association significative n’a été observée avec les autres types de produits laitiers. Notre étude démontre l’effet différentiel des types de produits laitiers sur le risque de développer un cancer du sein. De futures études sont nécessaires pour confirmer ces résultats.

Potential Overestimation of Aspirin's Beneficial Effect on Breast Cancer by Study Design.

Potential Overestimation of Aspirin's Beneficial Effect on Breast Cancer by Study Design.

Associations between dietary inflammatory index and incidence of breast and prostate cancer: a systematic review and meta-analysis.

Dietary inflammatory index (DII) scores have been inconsistently linked to cancer risks. Therefore, a systematic review and meta-analysis was performed to examine the associations between the DII and the risks of breast and prostate cancer among men and women. Relevant studies were identified by searching PubMed and EMBASE databases up to March 2018. Data were available from 13 studies; of these, four studies used a prospective cohort design and nine studies were case-control studies. A total of 231 947 individuals from nine countries were included in these studies for the meta-analysis. The results were pooled using a random-effects model. A pooled, adjusted odds ratio (OR) analysis indicated that there was a direct relationship between the highest versus lowest DII scores and prostate cancer risk in men (OR: 1.31; 95% CI: 1.04-1.57) but not the breast cancer risk (BCR) in women (OR: 1.65; 95% CI: 0.96-2.33). In the subgroup analyses, a more significant association between DII score and increased BCR was noted in premenopausal (OR: 2.03; 95% CI: 1.06-3.00) than in postmenopausal women (OR: 1.52; 95% CI: 0.89-2.16). When the results were stratified by body mass index, a positive association was observed between DII score and increased BCR in women (OR: 1.83; 95% CI: 1.48-2.18). Furthermore, there was no significant association between the highest versus lowest DII score and BCR among women who received hormone therapy (OR: 1.29; 95% CI: 0.93-1.64). Men and premenopausal women who exhibit higher DII scores have increased prostate and breast cancer incidence risks, respectively. Moreover, body mass index had positive associations with the relationship between DII score and BCR in women. Further prospective cohort studies with longer follow-up periods are needed to support this possible association between DII score and cancer incidence.

Model for Predicting Breast Cancer Risk in Women With Atypical Hyperplasia

Purpose Women with atypical hyperplasia (AH) on breast biopsy have an aggregate increased risk of breast cancer (BC), but existing risk prediction models do not provide accurate individualized estimates of risk in this subset of high-risk women. Here, we used the Mayo benign breast disease cohort to develop and validate a model of BC risk prediction that is specifically for women with AH, which we have designated as AH-BC. Patients and Methods Retrospective cohorts of women age 18 to 85 years with pathologically confirmed benign AH from Rochester, MN, and Nashville, TN, were used for model development and external validation, respectively. Clinical risk factors and histologic features of the tissue biopsy were selected using L1-penalized Cox proportional hazards regression. Identified features were included in a Fine and Gray regression model to estimate BC risk, with death as a competing risk. Model discrimination and calibration were assessed in the model-building set and an external validation set. Results The model-building set consisted of 699 women with AH, 142 of whom developed BC (median follow-up, 8.1 years), and the external validation set consisted of 461 women with 114 later BC events (median follow-up, 11.4 years). The final AH-BC model included three covariates: age at biopsy, age at biopsy squared, and number of foci of AH. At 10 years, the AH-BC model demonstrated good discrimination (0.63 [95% CI, 0.57 to 0.70]) and calibration (0.87 [95% CI, 0.66 to 1.24]). In the external validation set, the model showed acceptable discrimination (0.59 [95% CI, 0.51 to 0.67]) and calibration (0.91 [95% CI, 0.65 to 1.42]). Conclusion We have created a new model with which to refine BC risk prediction for women with AH. The AH-BC model demonstrates good discrimination and calibration, and it validates in an external data set.

BRCA Previvors: Medical and Social Factors That Differentiate Them From Previvors With Other Hereditary Cancers

In this paper, I outline some of the reasons why BRCA “previvors” (i.e., “survivors of a predisposition to cancer”) are different from previvors with other hereditary cancers. I examine how the absence of a standard of care for breast cancer risk for women with a BRCA mutation, coupled with a broad range of genetic penetrance and lower mortality, makes BRCA different than other hereditary cancers that have clear and established guidelines. In addition to these medical differences, social factors like the cultural prominence of breast cancer and the social significance of breasts have engendered a more complicated individual previvor identity for and cultural response to women with a BRCA mutation.