Lipid metabolism genes in contralateral unaffected breast and estrogen receptor status of breast cancer
ABSTRACT: The contralateral unaffected breast of women with unilateral breast cancer (cases) is a good model for defining subtype-specific risk since women with ER-negative index primaries are at high risk for subsequent ER-negative primary cancers. We performed random fine needle aspiration (rFNA) of the unaffected breasts of cases; samples from 30 subjects (15 ER-positive and 15 ER-negative cases matched for age, race and menopausal status), were used for Illumina expression array analysis. In this study, we have examined gene expression profiles in random fine needle aspirate (rFNA) samples from the contralateral breasts of women with new unilateral breast cancer (cases) to seek candidate panels of ER-specific risk biomarkers. On a discovery set of 30 women, we have identified gene expression differences in the contralateral breast that associate with ER+ or ER- index primary tumors.
Project description:Gene and protein expression in the breast varies relative to menopausal status (MS) and menstrual phase (MP), but cancer risk biomarker research using archived benign breast samples is usually uninformed by MS-MP data. We hypothesized that gene expression variation relative to ambient hormones can be exploited to develop markers of MS-MP that can be measured directly in breast tissue. Random fine needle aspiration samples from the unaffected breasts of 18 women were utilized for Illumina microarray analysis. Gene expression was correlated with simultaneous serum levels of estradiol, progesterone, and follicle stimulating hormone (FSH). True MS-MP states were defined by age and serum hormones. Genes highly correlated to serum hormones were used to classify samples into 2 MS groups: premenopause or postmenopause. The premenopausal samples were further classified into 3 MP groups: early follicular, late follicular or luteal.
Project description:Genome-wide association studies, focusing primarily on unilateral breast cancer, have identified single nucleotide polymorphisms (SNPs) in a number of genomic regions that have alleles associated with a significantly increased risk of breast cancer. In the current study we evaluate the contributions of these previously identified regions to the risk of developing contralateral breast cancer. The most strongly disease-associated SNPs from prior studies were tested for association with contralateral breast cancer. A subset of these SNPs, selected upon their main effects on contralateral breast cancer risk was further evaluated for interaction with treatment modalities and estrogen receptor (ER) status.We genotyped 21 SNPs in 708 women with contralateral breast cancer and 1394 women with unilateral breast cancer who serve as the cases and controls in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study. Records of treatment and ER status were available for most of WECARE Study participants. Associations of SNP genotypes and risk for contralateral breast cancer were calculated with multivariable adjusted conditional logistic regression methods.Multiple SNPs in the FGFR2 locus were significantly associated with contralateral breast cancer, including rs1219648 (per allele rate ratio (RR) = 1.25, 95%CI = 1.08-1.45). Statistically significant associations with contralateral breast cancer were also observed at rs7313833, near the PTHLH gene (per allele RR = 1.26, 95%CI = 1.08-1.47), rs13387042 (2q35) (per allele RR = 1.19, 95%CI = 1.02-1.37), rs13281615 (8q24) (per allele RR = 1.21, 95%CI = 1.04-1.40), and rs11235127 near TMEM135 (per allele RR = 1.26, 95%CI = 1.04-1.53). The A allele of rs13387042 (2q35) was significantly associated with contralateral breast cancer in ER negative first tumors while the A allele of rs11235127 (near TMEM135) was significantly associated with contralateral breast cancer in ER positive first tumors. Although some SNP genotypes appeared to modify contralateral breast cancer risk with respect to tamoxifen treatment or particular radiation doses, trend tests for such effects were not significant.Our results indicate that some common risk variants associated with primary breast cancer also increase risk for contralateral breast cancer, and that these risks vary with the ER status of the first tumor.
Project description:Previously, we found that gene expression in histologically normal breast epithelium (NlEpi) from women at high breast cancer risk can resemble gene expression in NlEpi from cancer-containing breasts. Therefore, we hypothesized that gene expression characteristic of a cancer subtype might be seen in NlEpi of breasts containing that subtype.We examined gene expression in 46 cases of microdissected NlEpi from untreated women undergoing breast cancer surgery. From 30 age-matched cases [15 estrogen receptor (ER)+, 15 ER-] we used Affymetryix U133A arrays. From 16 independent cases (9 ER+, 7 ER-), we validated selected genes using quantitative real-time PCR (qPCR). We then compared gene expression between NlEpi and invasive breast cancer using four publicly available data sets.We identified 198 genes that are differentially expressed between NlEpi from breasts with ER+ (NlEpiER+) compared with ER- cancers (NlEpiER-). These include genes characteristic of ER+ and ER- cancers (e.g., ESR1, GATA3, and CX3CL1, FABP7). qPCR validated the microarray results in both the 30 original cases and the 16 independent cases. Gene expression in NlEpiER+ and NlEpiER- resembled gene expression in ER+ and ER- cancers, respectively: 25% to 53% of the genes or probes examined in four external data sets overlapped between NlEpi and the corresponding cancer subtype.Gene expression differs in NlEpi of breasts containing ER+ compared with ER- breast cancers. These differences echo differences in ER+ and ER- invasive cancers. NlEpi gene expression may help elucidate subtype-specific risk signatures, identify early genomic events in cancer development, and locate targets for prevention and therapy.
Project description:BACKGROUND:Mastitis and abscess in HIV-infected women increase the risk of breastfeeding transmission of HIV. Guidelines encourage women to stop breastfeeding on the affected breast and feed on the contralateral breast. However, impact of breast pathology on breast milk HIV dynamics is unknown. METHODS:HIV RNA was quantified in 211 breast milk samples collected before, during, and after a clinical mastitis or an abscess diagnosis from 38 HIV-infected women participating in a Zambian breastfeeding study. HIV RNA quantity was compared between affected and unaffected breasts over time using generalized estimating equation models. A sample of 115 women without breast pathology was selected as a control group. RESULTS:In the affected breast, breast milk HIV RNA quantity increased from the pre- to during-pathology period by log(10) 0.45 copies per milliliter [95% confidence interval (CI): 0.16 to 0.74], and after symptom resolution, HIV RNA levels were no different from prepathology levels (log10 -0.04 copies per milliliter 95% CI: -0.33 to 0.25). In the contralateral, unaffected breast, HIV RNA quantity did not significantly increase (log(10) 0.15 copies per milliliter, 95% CI: -0.41 to 0.10). Increase was more marked in women with abscess or with a greater number of mastitis symptoms. HIV RNA was not significantly different between affected and unaffected women, except at the time of diagnosis. CONCLUSIONS:Breast milk HIV RNA increased modestly in the affected breast with unilateral mastitis or abscess and returned to prepathology levels with symptom resolution. Contralateral HIV RNA was not affected. Results support guidelines encouraging feeding from the contralateral breast to minimize the risk of HIV transmission associated with unilateral breast pathology.
Project description:BACKGROUND:?One aim of unilateral postmastectomy breast reconstruction (BR) is to restore symmetry with the contralateral breast. As such, unilateral prosthetic reconstruction often requires a contralateral symmetry procedure (CSP). There is sparse literature on the impact of CSPs on long-term patient-reported outcomes (PROs) such as satisfaction and health-related quality of life (HRQoL). This study aims to describe PROs following CSPs, using a validated PRO tool, BREAST-Q. The hypothesis is that CSPs are associated with greater patient-reported satisfaction and HRQoL. METHODS:?This study is a single institutional analysis of prospectively collected BREAST-Q scores of patients who underwent unilateral prosthetic BR during 2011 to 2015. Women 18 years and older with BREAST-Q scores measured ? 9months after BR with or without CSP(s) at the time of expander replacement were included. Patients were classified into four subcohorts: augmentation, mastopexy, reduction, and no symmetry procedure (controls). Sociodemographic, clinical characteristics, and BREAST-Q scores were analyzed. Multivariable linear regression was performed. RESULTS:?Of 553 patients, 67 (12%) underwent contralateral augmentation, 68 (12%) mastopexy, 93(17%) reduction, and 325 (59%) were controls. Mean follow-up time was 52 months. Satisfaction with breast and outcomes were higher in the augmentation compared with the control groups (p?=?0.01). On multivariable analysis, augmentation remained an independent predictor of satisfaction with breast (p?=?0.04). Physical well-being scores were lower for contralateral mastopexy and reduction compared with the controls with a trend toward statistical significance on multivariable models. Psychological and sexual well-being was similar across groups. CONCLUSION:?Prosthetic reconstruction with contralateral breast augmentation was associated with greater satisfaction with breast and reconstructive outcome. In contrast, breast reduction and mastopexy procedures demonstrated equivalent satisfaction with breasts compared with controls but may be associated with lower physical well-being. Such information can be used to improve the shared decision-making process for women who choose unilateral prosthetic BR.
Project description:Nipple fluid aspiration provides direct non-invasive sampling of fluid from the mammary ductal system, where the majority of breast cancers originate. DNA promoter hypermethylation ("methylation") occurs early and at high frequency in breast carcinogenesis, bearing the potential as a biomarker for cancer detection at its earliest stages. We assessed methylation in nipple fluid from breasts of healthy women, of women with sporadic breast cancer and of their contralateral breasts. Our goal was to investigate whether nipple fluid can be used as a reliable methylation biomarker source.Methylation levels of 13 genes were analysed by quantitative multiplex-methylation specific PCR (QM-MSP) in nipple fluid samples from breasts of healthy women, and from the affected and contralateral breasts of breast cancer patients.Methylation analysis of the low-volume nipple fluid samples was feasible. Despite the generally low methylation levels, cancerous and healthy breasts nipple fluid could be discriminated with an area under the receiver operating characteristic curve (AUC) of 0.64 (p<0.01) based on a multivariate model including AKR1B1, ALX1, RASSF1A and TM6SF1. Within-patient differences between cancerous and contralateral nipple fluid samples were less prominent.Cancerous nipple fluid contains increased levels of methylation of tumor suppressor genes that potentially could serve as a biomarker for early breast cancer detection.
Project description:PURPOSE:To report reconstructive outcomes of patients treated with post-mastectomy intensity modulated proton therapy (IMPT) following immediate breast reconstruction (IBR). MATERIALS AND METHODS:Consecutive women with breast cancer who underwent implant-based IBR and post-mastectomy IMPT were included. Clinical characteristics, dosimetry, and acute toxicity were collected prospectively and reconstruction complications retrospectively. RESULTS:Fifty-one women were treated between 2015 and 2017. Forty-two had bilateral reconstruction with unilateral IMPT. The non-irradiated contralateral breasts served as controls. Conventional fractionation (median 50?Gy/25?fractions) was administered in 37 (73%) and hypofractionation (median 40.5?Gy/15?fractions) in 14 (27%) patients. Median mean heart, ipsilateral lung V20Gy, and CTV-IMN V95% were 0.6?Gy, 13.9%, and 97.4%. Maximal acute dermatitis grade was 1 in 32 (63%), 2 in 17 (33%), and 3 in 2 (4%) patients. Surgical site infection (hazard ratio [HR] 13.19, 95% confidence interval [CI] 1.67-104.03, p?=?0.0012), and unplanned surgical intervention (HR 9.86, 95% CI 1.24-78.67, p?=?0.0068) were more common in irradiated breasts. Eight of 51 irradiated breasts and 2 of 42 non-irradiated breasts had reconstruction failure (HR 3.59, 95% CI 0.78-16.41, p?=?0.084). Among irradiated breasts, hypofractionation was significantly associated with reconstruction failure (HR 4.99, 95% CI 1.24-20.05, p?=?0.024), as was older patient age (HR 1.14, 95% CI 1.05-1.24, p?=?0.002). CONCLUSIONS:IMPT following IBR spared underlying organs and had low rates of acute toxicity. Reconstruction complications are more common in irradiated breasts, and reconstructive outcomes appear comparable with photon literature. Hypofractionation was associated with higher reconstruction failure rates. Further investigation of optimal dose-fractionation after IBR is needed.
Project description: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 (ER?, ER?, 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 ER? 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 ER? 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.
Project description:BACKGROUND:Given that breast cancer and normal dense fibroglandular tissue have similar radiographic attenuation, we examine whether automated volumetric density measures identify a differential change between breasts in women with cancer and compare to healthy controls. METHODS:Eligible cases (n = 1160) had unilateral invasive breast cancer and bilateral full-field digital mammograms (FFDMs) at two time points: within 2 months and 1-5 years before diagnosis. Controls (n = 2360) were matched to cases on age and date of FFDMs. Dense volume (DV) and volumetric percent density (VPD) for each breast were assessed using Volpara™. Differences in DV and VPD between mammograms (median 3 years apart) were calculated per breast separately for cases and controls and their difference evaluated by using the Wilcoxon signed-rank test. To simulate clinical practice where cancer laterality is unknown, we examined whether the absolute difference between breasts can discriminate cases from controls using area under the ROC curve (AUC) analysis, adjusting for age, BMI, and time. RESULTS:Among cases, the VPD and DV between mammograms of the cancerous breast decreased to a lesser degree (- 0.26% and - 2.10 cm3) than the normal breast (- 0.39% and - 2.74 cm3) for a difference of 0.13% (p value < 0.001) and 0.63 cm3 (p = 0.002), respectively. Among controls, the differences between breasts were nearly identical for VPD (- 0.02 [p = 0.92]) and DV (0.05 [p = 0.77]). The AUC for discriminating cases from controls using absolute difference between breasts was 0.54 (95% CI 0.52, 0.56) for VPD and 0.56 (95% CI, 0.54, 0.58) for DV. CONCLUSION:There is a small relative increase in volumetric density measures over time in the breast with cancer which is not found in the normal breast. However, the magnitude of this difference is small, and this measure alone does not appear to be a good discriminator between women with and without breast cancer.
Project description:Higher background parenchymal enhancement (BPE) could be used for stratification of MRI screening programs since it might be related to a higher breast cancer risk. Therefore, the purpose of this study is to correlate BPE to patient and tumor characteristics in women with unilateral MRI-screen detected breast cancer who participated in an intermediate and high risk screening program. As BPE in the affected breast may be difficult to discern from enhancing cancer, we assumed that BPE in the contralateral breast is a representative measure for BPE in women with unilateral breast cancer.This retrospective study was approved by our local institutional board and a waiver for consent was granted. MR-examinations of women with unilateral breast cancers screen-detected on breast MRI were evaluated by two readers. BPE in the contralateral breast was rated according to BI-RADS. Univariate analyses were performed to study associations. Observer variability was computed.Analysis included 77 breast cancers in 76 patients (age: 48±9.8 years), including 62 invasive and 15 pure ductal carcinoma in-situ cases. A negative association between BPE and tumor grade (p?0.016) and a positive association with progesterone status (p?0.021) was found. The correlation was stronger when only considering invasive disease. Inter-reader agreement was substantial.Lower BPE in the contralateral breast in women with unilateral breast cancer might be associated to higher tumor grade and progesterone receptor negativity. Great care should be taken using BPE for stratification of patients to tailored screening programs.