Family history and breast cancer hormone receptor status in a Spanish cohort

Background

Breast cancer is a heterogenous disease that impacts racial/ethnic groups differently. Differences in genetic composition, lifestyles, reproductive factors, or environmental exposures may contribute to the differential presentation of breast cancer among Hispanic women.

Materials and Methods

A population-based study was conducted in the city of Santiago de Compostela, Spain. A total of 645 women diagnosed with operable invasive breast cancer between 1992 and 2005 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics of the tumors were collected. Hormone receptor negative tumors were compared with hormone receptor postive tumors on their clinico-pathological characteristics as well as risk factor profiles.

Results

Among the 645 breast cancer patients, 78% were estrogen receptor-positive (ER+) or progesterone receptor-positive (PR+), and 22% were ER−&PR−. Women with a family history of breast cancer were more likely to have ER−&PR− tumors than women without a family history (Odds ratio, 1.43; 95% confidence interval, 0.91–2.26). This association was limited to cancers diagnosed before age 50 (Odds ratio, 2.79; 95% confidence interval, 1.34–5.81).

Conclusions

An increased proportion of ER−&PR− breast cancer was observed among younger Spanish women with a family history of the disease.     

Genetic variation in telomere maintenance genes, telomere length and breast cancer risk

Background

Telomeres at the ends of eukaryotic chromosomes play a critical role in maintaining the integrity and stability of the genome and participate in the initiation of DNA damage/repair responses.

Methods

We performed a case-control study to evaluate the role of three SNPs (TERT-07, TERT-54 and POT1-03) in telomere maintenance genes previously found to be significantly associated with breast cancer risk. We used sister-sets obtained from the New York site of the Breast Cancer Family Registry (BCFR). Among the 313 sister-sets, there were 333 breast cancer cases and 409 unaffected sisters who were evaluated in the current study. We separately applied conditional logistic regression and generalized estimating equations (GEE) models to evaluate associations between the three SNPs and breast cancer risk within sister-sets. We examined the associations between genotype, covariates and telomere length among unaffected sisters using a GEE model.

Results

We found no significant associations between the three SNPs in telomere maintenance genes and breast cancer risk by both conditional logistic regression and GEE models, nor were these SNPs significantly related to telomere length. Among unaffected sisters, shortened telomeres were statistically significantly correlated with never hormone replacement therapy (HRT) use. Increased duration of HRT use was significantly associated with reduced telomere length. The means of telomere length were 0.77 (SD = 0.35) for never HRT use, 0.67 (SD = 0.29) for HRT use <5yrs and 0.59 (SD = 0.24) for HRT use ≥5yrs after adjusting for age of blood donation and race and ethnicity.

Conclusions

We found that exogenous hormonal exposure was inversely associated with telomere length. No significant associations between genetic variants and telomere length or breast cancer risk were observed. These findings provide initial evidence to understand hormonal exposure in the regulation of telomere length and breast cancer risk but need replication in prospective studies.     

Effect of soy isoflavones on breast cancer recurrence and death for patients receiving adjuvant endocrine therapy

Background

The intake of soy isoflavones among women with breast cancer has become a public health concern, because these compounds have weak estrogenic effects. There is little clinical evidence about their safety for patients with breast cancer who are receiving adjuvant endocrine therapy.

Methods

For patients who underwent surgery for breast cancer between August 2002 and July 2003 and who were receiving adjuvant endocrine therapy, we examined associations between dietary intake of soy isoflavones and recurrence of breast cancer and death. We measured dietary intake of soy isoflavones at baseline using a validated food frequency questionnaire. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) by means of multivariable Cox proportional hazards regression models. We further stratified the analyses by hormonal receptor status and endocrine therapy.

Results

The median follow-up period for the 524 patients in this study was 5.1 years. Among premenopausal patients, the overall death rate (30.6%) was not related to intake of soy isoflavones (HR = 1.05, 95% CI 0.78–1.71 for the highest quartile [> 42.3 mg/day] v. the lowest quartile [< 15.2 mg/day], p for trend = 0.87). Relative to post-menopausal patients in the lowest quartile of soy isoflavone intake, the risk of recurrence for post-menopausal patients in the highest quartile was significantly lower (HR = 0.67, 95% CI 0.54–0.85, p for trend = 0.02). Inverse associations were observed in patients with estrogen and progesterone receptor positive disease and those receiving anastrozole therapy.

Interpretation

High dietary intake of soy isoflavones was associated with lower risk of recurrence among post-menopausal patients with breast cancer positive for estrogen and progesterone receptor and those who were receiving anastrozole as endocrine therapy.A variety of health benefits in terms of cancer and cardiovascular disease have been attributed to the consumption of soy foods, primarily because of soy isoflavones.¹ Three primary isoflavones account for virtually all of the isoflavones in soy beans: genistein (about 50%), daidzein (about 40%) and glycitein (about 10%). The chemical structure of soy isoflavones is similar to that of estrogens. The isoflavones are therefore considered to be possible selective estrogen receptor modulators, which may bind to estrogen receptors and selectively stimulate or inhibit estrogen-like action in various tissues.² Given that soy-based foods are now more frequently consumed than was previously the case, both as an alternative approach to treating the symptoms of menopause and for promoting cardiovascular health,^3,4 concerns have arisen about the intake of these compounds by patients with hormone-sensitive breast cancer, in whom tumour growth depends largely on estrogen. Tamoxifen and anastrozole are commonly used as adjuvant endocrine therapy for hormone-sensitive breast cancer, and these drugs are effective in preventing recurrence and prolonging survival.^5,6 In some experimental studies the inhibitory effects of tamoxifen on growth of implanted mammary tumours were negated by dietary administration of soy isoflavones,^7,8 but in other rodent cancer models, soy food appeared to enhance the beneficial effects of tamoxifen.⁹ Little is known about the potential effects of consuming soy isoflavones for patients with breast cancer who are receiving adjuvant endocrine therapy. We used data for a cohort of postoperative patients with breast cancer who were receiving adjuvant endocrine therapy to examine the relation between intake of soy isoflavones and recurrence of breast cancer and death.     

Trends in breast cancer mortality in Sweden before and after implementation of mammography screening

Background

Incidence-based mortality modelling comparing the risk of breast cancer death in screened and unscreened women in nine Swedish counties has suggested a 39% risk reduction in women 40 to 69 years old after introduction of mammography screening in the 1980s and 1990s.

Objective

We evaluated changes in breast cancer mortality in the same nine Swedish counties using a model approach based on official Swedish breast cancer mortality statistics, robust to effects of over-diagnosis and treatment changes. Using mortality data from the NordCan database from 1974 until 2003, we estimated the change in breast cancer mortality before and after introduction of mammography screening in at least the 13 years that followed screening start.

Results

Breast mortality decreased by 16% (95% CI: 9 to 22%) in women 40 to 69, and by 11% (95% CI: 2 to 20%) in women 40 to 79 years of age.

Discussion

Without individual data it is impossible to completely separate the effects of improved treatment and health service organisation from that of screening, which would bias our results in favour of screening. There will also be some contamination of post-screening mortality from breast cancer diagnosed prior to screening, beyond our attempts to adjust for delayed benefit. This would bias against screening. However, our estimates from publicly available data suggest considerably lower benefits than estimates based on comparison of screened versus non-screened women.     

Radiation-induced breast cancer in women with Hodgkin's disease

Aim and background

The aim of this study is to analyze the main clinical and pathologic characteristics of radiation-induced breast carcinomas (BC) following treatment for Hodgkin''s disease (HD) and to identify the risk factors for their induction. To create a mathematical model for the prediction of expected age at which a BC might develop based on the age at treatment for HD.

Materials and methods

Thirty-nine cases of women with BC that developed after treatment for HD in puberty or adolescence were analyzed retrospectively. The median age at initiation of treatment for HD was 12.9 years (9–21). The median age at diagnosis of the second malignancy – breast carcinoma was 32.4 years (22.9–39).

Results

The distribution of patients according to the clinical T stage of breast cancer was as follows: 11 patients with T1 stage BC (28%), 22 with T2 stage (56%) and 6 with stage T3 (16%). Prevalent were tumors localized in the lateral breast quadrants. The observed 5 year survival was 95%.

Conclusion

The risk of solid tumors, especially breast cancer, is high among women with HD disease who were treated with radiotherapy in their childhood. In this article, we propose a specific mathematical age formula which could be used as predictive equation when the age of the treatment for HD is in the range between 9 and 21 years. Systematic screening for breast cancer in these patients would be significantly important for their health and could improve their survival.     

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.     

Socioeconomic Disparity in Breast Cancer Detection in Hong Kong – A High Income City: Retrospective Epidemiological Study Using the Breast Cancer Registry

Background

It is not known whether socioeconomic disparities affect the detection of breast cancer in Asian countries where the incidence of breast cancer is a rising trend. In this study, we explore the socioeconomic profiles of women and the stage of the disease at the time of diagnosis in breast cancer patients aged 40 or over in Hong Kong.

Method

During the period 2008 to 2011, 5393 breast cancer patients registered with the Hong Kong Breast Cancer Registry. Participants and their clinicians were asked to complete standardised questionnaires including patient socio-demographics, health history and risk factors, the course of the disease, post-treatment physical discomfort and psychosocial impact, follow-up recurrence and survival status.

Results

Monthly household incomes, educational levels and the practice of regular screening are independently associated with the stage of the disease at diagnosis. Higher socioeconomic status and a higher educational level were associated with an earlier stage of the disease at the time of diagnosis. Yearly clinical examinations, ultrasound and mammographic screening every 2 to 3 years were significantly associated with the earlier detection of breast cancer.

Conclusion

There were socioeconomic disparities among Hong Kong women who were found to have breast cancer. Population-based screening policies, including raising awareness among women at risk, should be implemented.     

Passive Smoking Exposure from Partners as a Risk Factor for ER+/PR+ Double Positive Breast Cancer in Never-Smoking Chinese Urban Women: A Hospital-Based Matched Case Control Study

Background

The relationship between passive smoking exposure (PSE) and breast cancer risk is of major interest.

Objective

To evaluate the relationship between PSE from partners and breast cancer risk stratified by hormone-receptor (HR) status in Chinese urban women population.

Design

Hospital-based matched case control study.

Setting

Chinese urban breast cancer patients without current or previous active smoking history in China Medical University 1st Hospital, Liaoning Province, China between Jan 2009 and Nov 2009.

Patients

Each breast cancer patient was matched 1∶1 with healthy controls by gender and age (±2 years) from the same hospital.

Measurements

The authors used unconditional logistic regression analyses to estimate odds ratio for women with PSE from partners and breast cancer risk.

Results

312 pairs were included in the study. Women who endured PSE had significantly increased risk of breast cancer (adjusted OR: 1.46; 95% CI: 1.05–2.03; P = 0.027), comparing with unexposed women. Women who exposed to >5 cigarettes/day also had significant increased risk (adjusted OR: 1.99; 95% CI: 1.28–3.10; P = 0.002), as were women exposed to passive smoke for 16–25 years (adjusted OR: 1.87 95% CI: 1.22–2.86; P = 0.004), and those exposed to > 4 pack-years (adjusted OR: 1.71 95% CI: 1.17–2.50; P = 0.004). Similar trends were significant for estrogen receptor (ER)/progesterone receptor (PR) double positive subgroup(adjusted OR: 1.71; 2.20; 1.99; 1.92, respectively), but not for ER+/PR−, ER−/PR+, or ER−/PR− subgroups.

Limitations

limitations of the hospital-based retrospective study, lack of information on entire lifetime PSE and low statistical power.

Conclusions

Our findings provide further evidence that PSE from partners contributes to increased risk of breast cancer, especially for ER/PR double positive breast cancer, in Chinese urban women.     

Pretreatment serum concentrations of 25-hydroxyvitamin D and breast cancer prognostic characteristics: a case-control and a case-series study

Background

Results from epidemiologic studies on the relationship between vitamin D and breast cancer risk are inconclusive. It is possible that vitamin D may be effective in reducing risk only of specific subtypes due to disease heterogeneity.

Methods and Findings

In case-control and case-series analyses, we examined serum concentrations of 25-hydroxyvitamin D (25OHD) in relation to breast cancer prognostic characteristics, including histologic grade, estrogen receptor (ER), and molecular subtypes defined by ER, progesterone receptor (PR) and HER2, among 579 women with incident breast cancer and 574 controls matched on age and time of blood draw enrolled in the Roswell Park Cancer Institute from 2003 to 2008. We found that breast cancer cases had significantly lower 25OHD concentrations than controls (adjusted mean, 22.8 versus 26.2 ng/mL, p<0.001). Among premenopausal women, 25OHD concentrations were lower in those with high- versus low-grade tumors, and ER negative versus ER positive tumors (p≤0.03). Levels were lowest among women with triple-negative cancer (17.5 ng/mL), significantly different from those with luminal A cancer (24.5 ng/mL, p = 0.002). In case-control analyses, premenopausal women with 25OHD concentrations above the median had significantly lower odds of having triple-negative cancer (OR = 0.21, 95% CI = 0.08–0.53) than those with levels below the median; and every 10 ng/mL increase in serum 25OHD concentrations was associated with a 64% lower odds of having triple-negative cancer (OR = 0.36, 95% CI = 0.22–0.56). The differential associations by tumor subtypes among premenopausal women were confirmed in case-series analyses.

Conclusion

In our analyses, higher serum levels of 25OHD were associated with reduced risk of breast cancer, with associations strongest for high grade, ER negative or triple negative cancers in premenopausal women. With further confirmation in large prospective studies, these findings could warrant vitamin D supplementation for reducing breast cancer risk, particularly those with poor prognostic characteristics among premenopausal women.     

HIV tropism and decreased risk of breast cancer

Background

During the first two decades of the U.S. AIDS epidemic, and unlike some malignancies, breast cancer risk was significantly lower for women with human immunodeficiency virus (HIV) infection compared to the general population. This deficit in HIV-associated breast cancer could not be attributed to differences in survival, immune deficiency, childbearing or other breast cancer risk factors. HIV infects mononuclear immune cells by binding to the CD4 molecule and to CCR5 or CXCR4 chemokine coreceptors. Neoplastic breast cells commonly express CXCR4 but not CCR5. In vitro, binding HIV envelope protein to CXCR4 has been shown to induce apoptosis of neoplastic breast cells. Based on these observations, we hypothesized that breast cancer risk would be lower among women with CXCR4-tropic HIV infection.

Methods and Findings

We conducted a breast cancer nested case-control study among women who participated in the WIHS and HERS HIV cohort studies with longitudinally collected risk factor data and plasma. Cases were HIV-infected women (mean age 46 years) who had stored plasma collected within 24 months of breast cancer diagnosis and an HIV viral load ≥500 copies/mL. Three HIV-infected control women, without breast cancer, were matched to each case based on age and plasma collection date. CXCR4-tropism was determined by a phenotypic tropism assay. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer were estimated by exact conditional logistic regression. Two (9%) of 23 breast cancer cases had CXCR4-tropic HIV, compared to 19 (28%) of 69 matched controls. Breast cancer risk was significantly and independently reduced with CXCR4 tropism (adjusted odds ratio, 0.10, 95% CI 0.002–0.84) and with menopause (adjusted odds ratio, 0.08, 95% CI 0.001–0.83). Adjustment for CD4⁺ cell count, HIV viral load, and use of antiretroviral therapy did not attenuate the association between infection with CXCR4-tropic HIV and breast cancer.

Conclusions

Low breast cancer risk with HIV is specifically linked to CXCR4-using variants of HIV. These variants are thought to exclusively bind to and signal through a receptor that is commonly expressed on hyperplastic and neoplastic breast duct cells. Additional studies are needed to confirm these observations and to understand how CXCR4 might reduce breast cancer risk.     

External validation of Adjuvant! Online breast cancer prognosis tool. Prioritising recommendations for improvement

Background

Adjuvant! Online is a web-based application designed to provide 10 years survival probability of patients with breast cancer. Several predictors have not been assessed in the original Adjuvant! Online study. We provide the validation of Adjuvant! Online algorithm on two breast cancer datasets, and we determined whether the accuracy of Adjuvant! Online is improved with other well-known prognostic factors.

Patients and Methods

The French data set is composed of 456 women with early breast cancer. The Dutch data set is composed of 295 women less than 52 years of age. Agreement between observation and Adjuvant! Online prediction was checked, and logistic models were performed to estimate the prognostic information added by risk factors to Adjuvant! Online prediction.

Results

Adjuvant! Online prediction was overall well-calibrated in the French data set but failed in some subgroups of such high grade and HER2 positive patients. HER2 status, Mitotic Index and Ki67 added significant information to Adjuvant! Online prediction. In the Dutch data set, the overall 10-year survival was overestimated by Adjuvant! Online, particularly in patients less than 40 years old.

Conclusion

Adjuvant! Online needs to be updated to adjust overoptimistic results in young and high grade patients, and should consider new predictors such as Ki67, HER2 and Mitotic Index.     

Clinicopathological features and prognosis of triple negative breast cancer in Kuwait: A comparative/perspective analysis

Aim

The aim of this study was to determine the incidence of TNBC in Kuwait, to analyze the clinicopathologic features and prognosis of this type of breast cancer, and compare it with reports from other regions of the world.

Background

Triple negative breast cancer (TNBC) is defined as a subtype that is negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). There is a growing evidence of the heterogeneity of such entity on the molecular level that may cause discrete outcomes.

Methods

We analyzed the clinicopathologic features of 363 TNBC cases which were diagnosed in Kuwait from July 1999 to June 2009. The disease-free survival (DFS) and overall survival (OS) were analyzed by Kaplan–Meier method. Comparison was done with reports from USA, Europe, Middle and Far East.

Results

Among 2986 patients diagnosed with breast cancer in Kuwait, 363 patients (12.2%) were TNBC. The median age was 48 years, 57.2% had lymph nodes (LN) metastasis, 56.9% were of grade III tumor and 41.9% had stage II disease. 81% developed recurrences and 75% of deaths occurred by 2.5 years after treatment. There is marked variation of clinicopathologic features according to country of patients’ cohort.

Conclusion

The incidence of TNBC in our study is similar to other studies. TNBC patients showed an early major recurrence surge peaking at approximately year 2.5. Regional variation of clinicopathologic features indicates a need for molecular studies to define underlying molecular features and its impact on survival.     

Birth weight, breast cancer and the potential mediating hormonal environment

Background

Previous studies have shown that woman’s risk of breast cancer in later life is associated with her infants birth weights. The objective of this study was to determine if this association is independent of breast cancer risk factors, mother’s own birth weight and to evaluate association between infants birth weight and hormonal environment during pregnancy. Independent association would have implications for understanding the mechanism, but also for prediction and prevention of breast cancer.

Methods and Findings

Risk of breast cancer in relation to a first infant’s birth weight, mother’s own birth weight and breast cancer risk factors were evaluated in a prospective cohort of 410 women in the Framingham Study. Serum concentrations of estriol (E3), anti-estrogen alpha-fetoprotein (AFP), and pregnancy-associated plasma protein-A (PAPP-A) were measured in 23,824 pregnant women from a separate prospective cohort, the FASTER trial. During follow-up (median, 14 years) 31 women (7.6 %) were diagnosed with breast cancer. Women with large birth weight infants (in the top quintile) had a higher breast cancer risk compared to other women (hazard ratio (HR), 2.5; 95% confidence interval (CI), 1.2–5.2; P = 0.012). The finding was not affected by adjustment for birth weight of the mother and traditional breast cancer risk factors (adjusted HR, 2.5; 95% CI, 1.2–5.6; P = 0.021). An infant’s birth weight had a strong positive relationship with the mother’s serum E3/AFP ratio and PAPP-A concentration during pregnancy. Adjustment for breast cancer risk factors did not have a material effect on these relationships.

Conclusions

Giving birth to an infant with high birth weight was associated with increased breast cancer risk in later life, independently of mother’s own birth weight and breast cancer risk factors and was also associated with a hormonal environment during pregnancy favoring future breast cancer development and progression.     

A signature inferred from Drosophila mitotic genes predicts survival of breast cancer patients

Introduction

The classification of breast cancer patients into risk groups provides a powerful tool for the identification of patients who will benefit from aggressive systemic therapy. The analysis of microarray data has generated several gene expression signatures that improve diagnosis and allow risk assessment. There is also evidence that cell proliferation-related genes have a high predictive power within these signatures.

Methods

We thus constructed a gene expression signature (the DM signature) using the human orthologues of 108 Drosophila melanogaster genes required for either the maintenance of chromosome integrity (36 genes) or mitotic division (72 genes).

Results

The DM signature has minimal overlap with the extant signatures and is highly predictive of survival in 5 large breast cancer datasets. In addition, we show that the DM signature outperforms many widely used breast cancer signatures in predictive power, and performs comparably to other proliferation-based signatures. For most genes of the DM signature, an increased expression is negatively correlated with patient survival. The genes that provide the highest contribution to the predictive power of the DM signature are those involved in cytokinesis.

Conclusion

This finding highlights cytokinesis as an important marker in breast cancer prognosis and as a possible target for antimitotic therapies.     

Case-control study of fetal microchimerism and breast cancer

Background

Prior pregnancy is known to protect against development of breast cancer. Recent studies have demonstrated that pregnancy has the capacity to establish small numbers of immunologically active fetal-derived cells in the mother, a phenomenon known as fetal microchimerism (FMc). We asked whether presence of FMc, routinely acquired during pregnancy, is a protective factor for breast cancer.

Methodology/Principal Findings

DNA extracts from peripheral blood specimens were obtained from a population-based case-control study of risk factors for breast cancer in women 21 to 45 years old. Specimens were tested with quantitative PCR for presence and concentrations of male DNA presumed to derive from prior pregnancies with a male fetus. Odds ratios (OR) and 95% confidence intervals (CI) were estimated with consideration of multiple established reproductive and environmental risk factors for breast cancer. FMc results were generated on 99 parous women, 54 with primary invasive breast cancer and 45 general population controls. FMc prevalence was 56% (25/45) and 26% (14/54) in controls and cases, respectively. Women harboring FMc were less likely to have had breast cancer (OR = 0.29, 95% CI 0.11–0.83; p = 0.02, adjusting for age, number of children, birth of a son, history of miscarriage, and total DNA tested). In addition, FMc concentrations were higher in controls versus cases (p = 0.01). Median concentrations were 2 (0–78) and 0 (0–374) fetal genomes/10⁶ maternal genomes in controls and cases, respectively.

Conclusions

Results suggest that the enigma of why some parous women are not afforded protection from breast cancer by pregnancy might in part be explained by differences in FMc. Mechanistic studies of FMc-derived protection against breast cancer are warranted.     

Combining gene signatures improves prediction of breast cancer survival

Background

Several gene sets for prediction of breast cancer survival have been derived from whole-genome mRNA expression profiles. Here, we develop a statistical framework to explore whether combination of the information from such sets may improve prediction of recurrence and breast cancer specific death in early-stage breast cancers. Microarray data from two clinically similar cohorts of breast cancer patients are used as training (n = 123) and test set (n = 81), respectively. Gene sets from eleven previously published gene signatures are included in the study.

Principal Findings

To investigate the relationship between breast cancer survival and gene expression on a particular gene set, a Cox proportional hazards model is applied using partial likelihood regression with an L2 penalty to avoid overfitting and using cross-validation to determine the penalty weight. The fitted models are applied to an independent test set to obtain a predicted risk for each individual and each gene set. Hierarchical clustering of the test individuals on the basis of the vector of predicted risks results in two clusters with distinct clinical characteristics in terms of the distribution of molecular subtypes, ER, PR status, TP53 mutation status and histological grade category, and associated with significantly different survival probabilities (recurrence: p = 0.005; breast cancer death: p = 0.014). Finally, principal components analysis of the gene signatures is used to derive combined predictors used to fit a new Cox model. This model classifies test individuals into two risk groups with distinct survival characteristics (recurrence: p = 0.003; breast cancer death: p = 0.001). The latter classifier outperforms all the individual gene signatures, as well as Cox models based on traditional clinical parameters and the Adjuvant! Online for survival prediction.

Conclusion

Combining the predictive strength of multiple gene signatures improves prediction of breast cancer survival. The presented methodology is broadly applicable to breast cancer risk assessment using any new identified gene set.     

Extra-nuclear signalling of estrogen receptor to breast cancer cytoskeletal remodelling, migration and invasion

Background

Estrogen is an established enhancer of breast cancer development, but less is known on its effect on local progression or metastasis. We studied the effect of estrogen receptor recruitment on actin cytoskeleton remodeling and breast cancer cell movement and invasion. Moreover, we characterized the signaling steps through which these actions are enacted.

Methodology/Principal Findings

In estrogen receptor (ER) positive T47-D breast cancer cells ER activation with 17β-estradiol induces rapid and dynamic actin cytoskeleton remodeling with the formation of specialized cell membrane structures like ruffles and pseudopodia. These effects depend on the rapid recruitment of the actin-binding protein moesin. Moesin activation by estradiol depends on the interaction of ERα with the G protein Gα₁₃, which results in the recruitment of the small GTPase RhoA and in the subsequent activation of its downstream effector Rho-associated kinase-2 (ROCK-2). ROCK-2 is responsible for moesin phosphorylation. The Gα₁₃/RhoA/ROCK/moesin cascade is necessary for the cytoskeletal remodeling and for the enhancement of breast cancer cell horizontal migration and invasion of three-dimensional matrices induced by estrogen. In addition, human samples of normal breast tissue, fibroadenomas and invasive ductal carcinomas show that the expression of wild-type moesin as well as of its active form is deranged in cancers, with increased protein amounts and a loss of association with the cell membrane.

Conclusions/Significance

These results provide an original mechanism through which estrogen can facilitate breast cancer local and distant progression, identifying the extra-nuclear Gα₁₃/RhoA/ROCK/moesin signaling cascade as a target of ERα in breast cancer cells. This information helps to understand the effects of estrogen on breast cancer metastasis and may provide new targets for therapeutic interventions.     

Prognostic role of c-met expression in breast cancer patients

Background

Hepatocyte growth factor plays an important role in tumor growth, metastasis and angiogenesis. C-met is HGF''s high affinity receptor.

Aim

The aim of the study was to assess the correlations between c-met expression and clinic-pathological factors in breast cancer tissues. Furthermore, the purpose of the study was to evaluate the prognostic value of the hepatocyte growth factor receptor (HGFR, c-met) expressions in homogenous group of breast cancer patients.

Materials and methods

Tumor samples were collected from 302 patients with breast carcinoma treated with primary surgery. We have assessed the percentage of tumor cells with c-met expression, the intensity of reaction and the ratio of these two factors—immunoreactivity according to the Remmele score.

Results

We have observed no correlations between HGFR immunoreactivities and clinical parameters (tumor size, grade, axillary lymph node status, age). In 5-year observation we have found prognostic value of assessing c-met immunoreactivity in primary tumor.

Conclusion

Our study has revealed prognostic value of c-met. Unlike in other authors’ studies, our patients’ group is very homogenous which might contribute to obtained results.