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1.  Outcome of triple-negative breast cancer in patients with or without deleterious BRCA mutations 
More than 75% of breast cancers that develop in BRCA1 mutation carriers are triple-negative breast cancers (TNBC). The aim of this study was to compare the recurrence-free survival (RFS) and overall survival (OS) in high-risk patients with TNBC with and without deleterious BRCA1/2 mutations. A total of 227 women with TNBC who were referred for genetic counseling and underwent BRCA genetic testing between 1997 and 2010 were included in the study. The relationships between clinical variables and outcomes were evaluated using univariate and multivariate Cox proportional hazard regression models. Of 227 high-risk women with TNBC, 50% (n = 114) tested positive for BRCA1/2 mutations. Age, race, and tumor characteristics did not differ between BRCA non-carriers and carriers. At a median follow-up of 3.4 years, the 5-year RFS rates were 74 and 81% (P = 0.21), and 5-year OS rates were 85 and 93% in BRCA non-carriers and BRCA carriers, respectively (P = 0.11). In a multivariate model, after adjusting for age and disease stage, BRCA carriers tended to have a decreased risk of recurrence (HR = 0.67; 95% CI: 0.38–1.19; P = 0.17) or death (HR = 0.51; 95% CI:0.23–1.17; P = 0.11) compared to non-carriers. Our data indicate a 50% prevalence of deleterious BRCA1/2 mutations in high-risk women diagnosed with TNBC. Overall prognosis of TNBC in BRCA carriers and non-carriers is not significantly different within the first 5 years following an initial diagnosis. Further studies need to evaluate whether different therapies will change the outcome in these subgroups of TNBC.
PMCID: PMC4334122  PMID: 21830012
Triple receptor-negative breast cancer; BRCA mutation; Survival; Recurrence; Chemotherapy
2.  Biologic markers determine both the risk and the timing of recurrence in breast cancer 
Breast cancer has a long natural history. Established and emerging biologic markers address overall risk but not necessarily timing of recurrence. 346 adjuvant naïve breast cancer cases from Guy’s Hospital with 23 years minimum follow-up and archival blocks were recut and reassessed for hormone-receptors (HR), HER2-receptor and grade. Disease-specific survival (DSS) was analyzed by recursive partitioning. To validate insights from this analysis, gene-signatures (proliferative and HR-negative) were evaluated for their ability to predict early versus late metastatic risk in 683 node-negative, adjuvant naïve breast cancers annotated with expression microarray data. Risk partitioning showed that adjuvant naïve node-negative outcome risk was primarily partitioned by tumor receptor status and grade but not tumor size. HR-positive and HER2-negative (HRpos) risk was partitioned by tumor grade; low grade cases have very low early risk but a 20% fall-off in DSS 10 or more years after diagnosis. Higher grade HRpos cases have risk over >20 years. Triple-negative (Tneg) and HER2-positive (HER2pos) cases DSS events occurred primarily within the first 5 years. Among node-positive cases, only low grade conferred late risk, suggesting that proliferative gene signatures that identify proliferation would be important for predicting early but not late recurrence. Using pooled data from four publicly available data sets for node-negative tumors annotated with gene expression and outcome data, we evaluated four prognostic gene signatures: two proliferation-based and two immune function-based. Tumor proliferative capacity predicted early but not late metastatic risk for HRpos cases. The immune function or HRneg specific signatures predicted only early metastatic risk in Tneg and HER2pos cases. Breast cancer prognostic signatures need to inform both risk and timing of metastatic events and may best be applied within subsets. Current signatures predict for outcome risk within 5 years of diagnosis. Predictors of late risk for HR positive disease are needed.
PMCID: PMC4324750  PMID: 21597921
Breast cancer; Hormone therapy; Risk partitioning; Risk; Recurrence; Gene signatures
3.  A combination treatment with DNA methyltransferase inhibitors and suramin decreases invasiveness of breast cancer cells 
The treatment of patients with invasive breast cancer remains a major issue because of the acquisition of drug resistance to conventional chemotherapy. Here we propose a new therapeutic strategy by combining DNA methyltransferase inhibitors (DMTIs) with suramin. Cytotoxic effects of suramin or combination treatment with DMTIs were determined in highly invasive breast cancer cell lines MDA-MB-231, BT-20 and HCC1954, or control cells. In addition, effects on cell invasion were determined in 3-dimensional cell culture assays. DMTI-mediated upregulation of Protein Kinase D1 (PKD1) expression was shown by Western blotting. Effects of suramin on PKD1 activity was determined in vitro and in cells. The importance of PKD1 in mediating the effects of such combination treatment in cell invasion was demonstrated using 3D cell culture assays. A proof of principal animal experiment was performed showing that PKD1 is critical for breast cancer growth. We show that when used in combination, suramin and DMTIs impair the invasive phenotype of breast cancer cells. We show that PKD1, a kinase that previously has been described as a suppressor of tumor cell invasion, is an interface for both FDA-approved drugs, since the additive effects observed are due to DMTI-mediated re-expression and suramin-induced activation of PKD1. Our data reveal a mechanism of how a combination treatment with non-toxic doses of suramin and DMTIs may be of therapeutic benefit for patients with aggressive, multi-drug resistant breast cancer.
PMCID: PMC3982927  PMID: 24510012
Breast cancer; Suramin; Methyltransferase inhibitors; Invasive phenotype; MDA-MB-231
4.  DC-SCRIPT is a novel regulator of the tumor suppressor gene CDKN2B and induces cell cycle arrest in ERα-positive breast cancer cells 
Breast cancer is one of the most common causes of cancer-related deaths in women. The estrogen receptor (ERα) is well known for having growth promoting effects in breast cancer. Recently, we have identified DC-SCRIPT (ZNF366) as a co-suppressor of ERα and as a strong and independent prognostic marker in ESR1 (ERα gene)-positive breast cancer patients. In this study, we further investigated the molecular mechanism on how DC-SCRIPT inhibits breast cancer cell growth. DC-SCRIPT mRNA levels from 190 primary ESR1-positive breast tumors were related to global gene expression, followed by gene ontology and pathway analysis. The effect of DC-SCRIPT on breast cancer cell growth and cell cycle arrest was investigated using novel DC-SCRIPT-inducible MCF7 breast cancer cell lines. Genome-wide expression profiling of DC-SCRIPT-expressing MCF7 cells was performed to investigate the effect of DC-SCRIPT on cell cycle-related gene expression. Findings were validated by real-time PCR in a cohort of 1,132 ESR1-positive breast cancer patients. In the primary ESR1-positive breast tumors, DC-SCRIPT expression negatively correlated with several cell cycle gene ontologies and pathways. DC-SCRIPT expression strongly reduced breast cancer cell growth in vitro, breast tumor growth in vivo, and induced cell cycle arrest. In addition, in the presence of DC-SCRIPT, multiple cell cycles related genes were differentially expressed including the tumor suppressor gene CDKN2B. Moreover, in 1,132 primary ESR1-positive breast tumors, DC-SCRIPT expression also correlated with CDKN2B expression. Collectively, these data show that DC-SCRIPT acts as a novel regulator of CDKN2B and induces cell cycle arrest in ESR1-positive breast cancer cells.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-015-3281-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4326655  PMID: 25663546
DC-SCRIPT; ZNF366; CDKN2B; Breast cancer; Cell cycle; G1 arrest
5.  Risk of lymphedema after mastectomy – potential benefit of applying ACOSOG Z0011 protocol to mastectomy patients 
Axillary lymph node dissection (ALND) and radiation therapy (RT) are commonly recommended for mastectomy patients with positive sentinel lymph node biopsy (SLNB). Effective alternatives to ALND that reduce lymphedema risk are needed. We evaluated rates of lymphedema in mastectomy patients who received SLNB with RT, compared to ALND with or without RT.
627 breast cancer patients who underwent 664 mastectomies between 2005–2013 were prospectively screened for lymphedema, median 22.8 months follow-up (range 3.0–86.9). Each mastectomy was categorized as: SLNB-no RT, SLNB+RT, ALND-no RT, or ALND+RT. RT included chest wall +/− nodal radiation. Perometer arm volume measurements were obtained pre- and post-operatively. Lymphedema was defined as ≥10% arm volume increase. Kaplan-Meier and Cox regression analyses were performed to determine lymphedema rates and risk factors.
Of 664 mastectomies, 52% (343/664) were SLNB-no RT, 5% (34/664) SLNB+RT, 9% (58/664) ALND-no RT, and 34% (229/664) ALND+RT. The two-year cumulative lymphedema incidence was 10.0% (95% CI: 2.6–34.4%) for SLNB+RT compared with 19.3% (95% CI: 10.8–33.1%) for ALND-no RT, and 30.1% (95% CI: 23.7–37.8%) for ALND+RT. The lowest cumulative incidence was 2.19% (95% CI: 0.88%–5.40%) for SLNB-no RT. By multivariate analysis, factors significantly associated with increased lymphedema risk included RT (p=0.0017), ALND (p=0.0001), greater number of lymph nodes removed (p=0.0006), no reconstruction (p=0.0418), higher BMI (p<0.0001) and older age (p=0.0021).
Avoiding completion ALND and instead receiving SLNB with RT may decrease lymphedema risk in patients requiring mastectomy. Future trials should investigate the safety of applying the ACOSOG Z0011 protocol to mastectomy patients.
PMCID: PMC4011490  PMID: 24500108
Mastectomy; Lymphedema; Quality of Life; Radiation Therapy; Sentinel Lymph Node Biopsy
6.  Barriers to physical activity and healthy eating in young breast cancer survivors: modifiable risk factors and associations with body mass index 
Physical activity (PA) and healthy eating (HE) are important behaviors to encourage in breast cancer survivors (BCS). We examined associations between various factors and barriers to PA (BPA) and barriers to HE (BHE), as well as relationships between barriers and body mass index (BMI) in younger BCS.
Self-reported data from 162 BCS (mean age 48 years) were used. BPA were assessed with a 21-item scale and BHE with a 19-item scale. Participants were classified as high or low on each scale. Sociodemographic, medical, and psychosocial characteristics were compared by high/low barriers. Correlates of continuous BPA and BHE were assessed as were associations between BHE, BPA and BMI.
61% of participants were characterized as having low BHE and low BPA; 12% were high for both. High BHE/High BPA participants had the least favorable scores for depression, perceived stress, social support, fatigue, bladder control, and weight problems. Factors associated with BHE were lower education, higher perceived stress, and more severe weight problems. Factors associated with BPA were more severe bladder control problems and lower physical well-being. Higher BHE and BPA were significantly and uniquely associated with higher BMI, controlling for covariates.
Several biopsychosocial factors (e.g., depression, stress, fatigue) characterize young BCS who experience barriers to both HE and PA. The correlates of BHE and BPA are distinct. Both BHE and BPA are associated with BMI. These results should be considered in designing interventions for younger women with breast cancer.
PMCID: PMC4318837  PMID: 24177756
breast cancer; survivorship; diet; physical activity; obesity
7.  Cost-effectiveness analysis of everolimus plus exemestane versus exemestane alone for treatment of hormone receptor positive metastatic breast cancer 
Everolimus in combination with exemestane significantly improved progression-free survival compared to exemestane alone in patients previously treated with non-steroidal aromatase inhibitors in the BOLERO-2 trial. As a result, this combination has been approved by the food and drug administration to treat postmenopausal women with hormone receptor positive and HER2 negative metastatic breast cancer. A cost-effectiveness analysis was conducted to determine whether everolimus represents good value for money, utilizing data from BOLERO-2. A decision-analytic model was used to estimate the incremental cost-effectiveness ratio between treatment arms of the BOLERO-2 trial. Costs were obtained from the Center for Medicare Services drug payment table and physician fee schedule. Benefits were expressed as quality-adjusted progression-free survival weeks (QAPFW) and quality-adjusted progression-free years (QAPFY), with utilities/disutilities derived from the literature. Deterministic and probabilistic sensitivity analyses were performed. A willingness to pay threshold of 1–3 times the per capita gross domestic product was adopted, as per the definition of the World Health Organization. The U.S. per capita gross domestic product in 2013 was $49,965; thus, a threshold varying between $49,965 and $149,895 was considered. Everolimus/exemestane had an incremental benefit of 11.88 QAPFW (0.22 QAPFY) compared to exemestane and an incremental cost of $60,574. This translated into an ICER of $265,498.5/QAPFY. Univariate sensitivity analyses showed important variations of the ICER, ranging between $189,836.4 and $530,947/QAPFY. A tornado analysis suggested that the key drivers of our model, by order of importance, included health utility value for stable disease, everolimus acquisition costs, and transition probabilities from the stable to the progression states. The Monte-Carlo simulation showed results that were similar to the base-case analysis. This cost-effectiveness analysis showed that everolimus plus exemestane is not cost-effective compared to exemestane alone. Further research is needed to investigate the cost-effectiveness of the drug combination within sub-groups of the population studied in BOLERO-2.
PMCID: PMC4318525  PMID: 25012857
Metastatic breast cancer; Aromatase inhibitor therapy; Everolimus; Exemestane; Health-related quality of life; Progression-free survival; BOLERO-2; Cost-effectiveness; Analysis
8.  mTORC1/C2 and pan-HDAC inhibitors synergistically impair breast cancer growth by convergent AKT and polysome inhibiting mechanisms 
Resistance of breast cancers to targeted hormone receptor (HR) or human epidermal growth factor receptor 2 (HER2) inhibitors often occurs through dysregulation of the phosphoinositide 3-kinase, protein kinase B/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Presently, no targeted therapies exist for breast cancers lacking HR and HER2 overexpression, many of which also exhibit PI3K/AKT/mTOR hyper-activation. Resistance of breast cancers to current therapeutics also results, in part, from aberrant epigenetic modifications including protein acetylation regulated by histone deacetylases (HDACs). We show that the investigational drug MLN0128, which inhibits both complexes of mTOR (mTORC 1 and mTORC2), and the hydroxamic acid pan-HDAC inhibitor TSA synergistically inhibit the viability of a phenotypically diverse panel of five breast cancer cell lines (HR−/+, HER2−/+). The combination of MLN0128 and TSA induces apoptosis in most breast cancer cell lines tested, but not in the non-malignant MCF-10A mammary epithelial cells. In parallel, the MLN0128/TSA combination reduces phosphorylation of AKT at S473 more than single agents alone and more so in the 5 malignant breast cancer cell lines than in the nonmalignant mammary epithelial cells. Examining polysome profiles from one of the most sensitive breast cancer cell lines (SKBR3), we demonstrate that this MLN0128/TSA treatment combination synergistically impairs polysome assembly in conjunction with enhanced inhibition of 4eBP1 phosphorylation at S65. Taken together, these data indicate that the synergistic growth inhibiting consequence of combining a mTORC1/C2 inhibitor like MLN0128 with a pan-HDAC inhibitor like TSA results from their mechanistic convergence onto the PI3K/AKT/mTOR pathway, profoundly inhibiting both AKT S473 and 4eBP1 S65 phosphorylation, reducing polysome formation and cancer cell viability.
PMCID: PMC4318538  PMID: 24562770
mTOR; HDAC; MLN0128; INK128; Trichostatin A; TSA; Breast cancer; AKT; Polysomes; Ribosomes
9.  [No title available] 
PMCID: PMC3935518  PMID: 24407530
10.  [No title available] 
PMCID: PMC3941172  PMID: 24487688
11.  [No title available] 
PMCID: PMC3955055  PMID: 24442642
12.  [No title available] 
PMCID: PMC4026199  PMID: 24477977
13.  [No title available] 
PMCID: PMC4039190  PMID: 24395109
14.  [No title available] 
PMCID: PMC4059774  PMID: 24481681
15.  Estrogen Receptor (ER) Mutations in Breast Cancer: Hidden in Plain Sight 
The idea that somatic ER mutations could play an important role in the evolution of hormone dependent breast cancers was proposed some years ago [1,2], but has remained controversial until recently. A significant amount of new data has confirmed these initial observations and shown their significance, along with much additional work relevant to the treatment of breast cancer. Thus, it is the purpose of this review to summarize the research to date on the existence and clinical consequences of ER mutations in primary and metastatic breast cancer.
PMCID: PMC4123761  PMID: 24487689
estrogen receptor; metastasis; tumor evolution; mutation; resistance
16.  Patterns of nodal staging during breast conservation surgery in the medicare patient: will the ACOSOG Z0011 trial change the pattern of care? 
ACOSOG Z0011 spares axillary dissection (AD) in breast conservation surgery (BCS) patients with T1/T2 tumors and 1–2 positive nodes. Current patterns of care and the impact of Z0011 on AD versus additional surgery rates for Medicare patients undergoing BCS are unknown. SEER data linked to Medicare claims for 1999–2005 were reviewed for women with invasive non-metastatic breast cancer who underwent nodal staging on the same day as BCS. There were 3,280 women with T1/T2 tumors and positive nodes who underwent same-day nodal staging; 2,532 (77.2 %) of these women had 1–2 positive nodes. Assuming 25.7 % have extracapsular extension, 651 women would require AD. However, 1,881 women, or 57.4 % of those with T1/T2 tumors and positive nodes, would be spared AD. Meanwhile, among the 748 women having ≥3 positive nodes, 579 underwent same-day AD, but under Z0011, would now wait for permanent section. A total of 160 of these women underwent re-excision or completion mastectomy at a later date anyway, when delayed AD could be performed. The remaining 419 women with ≥3 positive nodes would require an additional surgery date for the sole purpose of completion AD. The Z0011 paradigm would consequently necessitate an additional surgery date for 1,070 (651 + 419) women, or 32.6 % of those with T1/T2 tumors and positive nodes. The Z0011 paradigm appears to increase the number of Medicare patients undergoing BCS who require an additional surgery date but decrease the number requiring AD to a greater extent. Future changes in the use of AD or axillary irradiation may yet modify that impact substantially.
PMCID: PMC4161134  PMID: 24442687
Clinical trials; ACOSOG Z0011; Lymph node metastases; Sentinel lymphadenectomy; Sentinel node biopsy; Axillary lymphadenectomy; Axillary lymph node dissection; Patterns of care; Surveillance, epidemiology and end results; Medicare; Medicare claims
17.  Reproductive factors and histologic subtype in relation to mortality after a breast cancer diagnosis 
Evidence suggests that certain reproductive factors are more strongly associated with the incidence of lobular than of ductal breast cancer. The mechanisms influencing breast cancer incidence histology may also affect survival. Women with invasive breast cancer (N = 22,302) diagnosed during 1986–2005 were enrolled in a series of population-based studies in three US states. Participants completed telephone interviews regarding reproductive exposures and other breast cancer risk factors. Histologic subtype was obtained from state cancer registries. Vital status and cause of death were determined through December 2006 using the National Death Index. Women were followed for 9.8 years on average with 3,050 breast cancer deaths documented. Adjusted hazard rate ratios (HR) and 95% confidence intervals (95% CI) were calculated using Cox proportional hazards regression models for breast cancer-specific and all-cause mortality. Parity was inversely associated with breast cancer-specific mortality (PTrend = 0.002). Associations were similar though attenuated for all-cause mortality. In women diagnosed with ductal breast cancer, a 15% reduction in breast cancer-specific mortality was observed in women with five or more children when compared to those with no children (HR = 0.85, 95% CI: 0.73–1.00). A similar inverse though non-significant association was observed in women with lobular subtype (HR = 0.70, 95% CI: 0.43–1.14). The trend did not extend to mixed ductal–lobular breast cancer. Age at first birth had no consistent relationship with breast cancer-specific or all-cause mortality. We found increasing parity reduced mortality in ductal and lobular breast cancer. The number of full-term births, rather than age at first birth, has an effect on both breast cancer-specific and overall mortality.
PMCID: PMC4306414  PMID: 21769659
Epidemiology; reproduction; lobular breast cancer; ductal breast cancer; mortality
18.  The prognostic and predictive value of Tregs and tumor immune subtypes in postmenopausal, hormone receptor-positive breast cancer patients treated with adjuvant endocrine therapy: a Dutch TEAM study analysis 
Evidence exists for an immunomodulatory effect of endocrine therapy in hormone receptor-positive (HR+ve) breast cancer (BC). Therefore, the aim of this study was to define the prognostic and predictive value of tumor immune markers and the tumor immune profile in HR+ve BC, treated with different endocrine treatment regimens. 2,596 Dutch TEAM patients were treated with 5 years of adjuvant hormonal treatment, randomly assigned to different regimens: 5 years of exemestane or sequential treatment (2.5 years of tamoxifen–2.5 years of exemestane). Immunohistochemistry was performed for HLA class I, HLA-E, HLA-G, and FoxP3. Tumor immune subtypes (IS) (low, intermediate & high immune susceptible) were determined by the effect size of mono-immune markers on relapse rate. Patients on sequential treatment with high level of tumor-infiltrating FoxP3+ cells had significant (p = 0.019, HR 0.729, 95 % CI 0.560–0.949) better OS. Significant interaction for endocrine treatment and FoxP3+ presence was seen (OS p < 0.001). Tumor IS were only of prognostic value for the sequentially endocrine-treated patients (RFP: p = 0.035, HR intermediate IS 1.420, 95 % CI 0.878–2.297; HR low IS 1.657, 95 % CI 1.131–2.428; BCSS: p = 0.002, HR intermediate IS 2.486, 95 % CI 1.375–4.495; HR low IS 2.422, 95 % CI 1.439–4.076; and OS: p = 0.005, HR intermediate IS 1.509, 95 % CI 0.950–2.395; HR low IS 1.848, 95 % CI 1.277–2.675). Tregs and the tumor IS presented in this study harbor prognostic value for sequentially endocrine-treated HR+ve postmenopausal BC patients, but not for solely exemestane-treated patients. Therefore, these markers could be used as a clinical risk stratification tool to guide adjuvant treatment in this BC population.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-015-3269-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4326646  PMID: 25616355
Breast cancer; Adjuvant endocrine therapy; Tumor immune subtypes; Prognostic and predictive value
19.  In vivo antimetastatic effects of uPAR retargeted measles virus in syngeneic and xenograft models of mammary cancer 
The urokinase receptor (uPAR) plays a critical role in breast cancer (BC) progression and metastases, and is a validated target for novel therapies. The current study investigates the effects of MV-uPA, an oncolytic measles virus fully retargeted against uPAR in syngeneic and xenograft BC metastases models.
In vitro replication and cytotoxicity of MVs retargeted against human (MV-h-uPA) or mouse (MV-m-uPA) uPAR were assessed in human and murine cancer and non-cancer mammary epithelial cells. The in vivo effects of species-specific uPAR retargeted MVs were assessed in syngeneic and xenograft models of experimental metastases, established by intravenous administration of luciferase expressing 4T1 or MDA-MD-231 cells. Metastases progression was assessed by in vivo bioluminescence imaging. Tumor targeting was evaluated by qRT-PCR of MV-N, rescue of viable viral particles and immunostaining of MV particles in lungs from tumor bearing mice.
In vitro, MV-h-uPA and MV-m-uPA selectively infected, replicated and induced cytotoxicity in cancer compared to non-cancer cells in a species-specific manner. In vivo, MV-m-uPA delayed 4T1 lung metastases progression and prolonged survival. These effects were associated with identification of viable viral particles, viral RNA and detection of MV-N by immunostaining from lung tissues in treated mice. In the human MDA-MB-231 metastases model, intravenous administration of MV-h-uPA markedly inhibited metastases progression and significantly improved survival, compared to controls. No significant treatment related toxicity was observed in treated mice.
The above preclinical findings strongly suggest that uPAR retargeted measles virotherapy is a novel and feasible systemic therapy strategy against metastatic breast cancer.
PMCID: PMC4302411  PMID: 25519042
Urokinase receptor; measles virus; tumor targeting; metastasis
20.  The impact of cancer prevention guideline adherence on overall mortality in a high-risk cohort of women from the New York site of the Breast Cancer Family Registry 
The American Cancer Society (ACS) recommends at least 150 min of moderate intensity physical activity per week, alcohol intake of ≤1 drink per day, and maintaining a body mass index (BMI) of <25 kg/m2 for breast cancer prevention. Adherence to these guidelines has been linked to lower overall mortality in average-risk populations, it is not known if mortality reduction extends to women at higher risk given their family history of breast cancer. We followed 2,905 women from a high-risk Breast Cancer Family Registry in New York, of which 77 % were white non-Hispanic and 23 % were Hispanic. We collected information on BMI, physical activity, and alcohol intake at baseline and prospectively followed our cohort for outcomes based on questionnaires and National Death Index linkage. We used Cox regression to examine the relation between adherence to ACS guidelines and overall mortality and examined effect modification by race, age, and BRCA status. There were 312 deaths after an average of 9.2 ± 4.1 years of follow-up. Adherence to all three ACS recommendations was associated with 44–53 % lower mortality in women unaffected with breast cancer at baseline [Hazard Ratio (HR) 0.56, 95 % CI (0.33–0.93)] and in women affected with breast cancer at baseline [HR 0.47, 95 % CI (0.30–0.74)]. These associations remained after stratification by age, race, and BRCA status {e.g., BRCA1 and/or BRCA2 carriers [HR 0.39, 95 % CI (0.16–0.97)]}. These results support that women at high risk, similar to women at average risk, may also have substantial benefits from maintaining the ACS guidelines.
PMCID: PMC4308644  PMID: 25604794
Breast cancer risk; Lifestyle behaviors; Mortality; Racial/ethnic disparities; Prevention
21.  Differential anti-proliferative activities of poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer cells 
Despite recent advances in the clinical evaluation of various poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer (TNBC) patients, data defining potential anti-tumor mechanisms beyond PARP inhibition for these agents are lacking. To address this issue, we investigated the effects of four different PARP inhibitors (AG-014699, AZD-2281, ABT-888, and BSI-201) in three genetically distinct TNBC cell lines (MDA-MB-468, MDA-MB-231, and Cal-51). Assays of cell viability and colony formation and flow cytometric analysis were used to determine effects on cell growth and cell cycle progression. PARP-dependent and -independent signaling mechanisms of each PARP inhibitor were investigated by western blotting and shRNA approaches. Potential synergistic interactions between PARP inhibitors and cisplatin in suppressing TNBC cell viability were assessed. These PARP inhibitors exhibited differential anti-tumor activities, with the relative potencies of AG-014699 > AZD-2281 > ABT-888 > BSI-201. The higher potencies of AG-014699 and AZD-2281 were associated with their effects on G2/M arrest and DNA damage as manifested by γ-H2AX formation and, for AG-014699, its unique ability to suppress Stat3 phosphorylation. Abilities of individual PARP inhibitors to sensitize TNBC cells to cisplatin varied to a great extent in a cell context- and cell line-specific manner. Differential activation of signaling pathways suggests that the PARP inhibitors currently in clinical trials have different anti-tumor mechanisms beyond PARP inhibition and these PARP-independent mechanisms warrant further investigation.
PMCID: PMC4297209  PMID: 22678161
Poly(ADP-ribose) polymerase; PARP inhibitors; Triple-negative breast cancer
22.  [No title available] 
PMCID: PMC4291081  PMID: 22733221
23.  Luminal progenitor and fetal mammary stem cell expression features predict breast tumor response to neoadjuvant chemotherapy 
Mammary gland morphology and physiology are supported by an underlying cellular differentiation hierarchy. Molecular features associated with particular cell types along this hierarchy may contribute to the biological and clinical heterogeneity observed in human breast carcinomas. Investigating the normal cellular developmental phenotypes in breast tumors may provide new prognostic paradigms, identify new targetable pathways, and explain breast cancer subtype etiology. We used transcriptomic profiles coming from fluorescence-activated cell sorted (FACS) normal mammary epithelial cell types from several independent human and murine studies. Using a meta-analysis approach, we derived consensus gene signatures for both species and used these to relate tumors to normal mammary epithelial cell phenotypes. We then compiled a dataset of breast cancer patients treated with neoadjuvant anthracycline and taxane chemotherapy regimens to determine if normal cellular traits predict the likelihood of a pathological complete response (pCR) in a multivariate logistic regression analysis with clinical markers and genomic features such as cell proliferation. Most human and murine tumor subtypes shared some, but not all, features with a specific FACS-purified normal cell type; thus for most tumors a potential distinct cell type of ‘origin’ could be assigned. We found that both human luminal progenitor and mouse fetal mammary stem cell features predicted pCR sensitivity across all breast cancer patients even after controlling for intrinsic subtype, proliferation, and clinical variables. This work identifies new clinically relevant gene signatures and highlights the value of a developmental biology perspective for uncovering relationships between tumor subtypes and their potential normal cellular counterparts.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-014-3262-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4308649  PMID: 25575446
Breast cancer; Comparative genomics; Genetically engineered mouse models; Genomic signatures; Neoadjuvant chemotherapy; Normal mammary tissue
24.  Characterization of BRCA1 Ring Finger Variants of Uncertain Significance 
The majority of pathogenic mutations in BRCA1 result in a truncated protein. Although most missense changes in BRCA1 are of unknown functional significance, a handful of deleterious missense mutations have been identified. The majority of these occur in splice sites or highly conserved protein domains. Previously, we developed a predictive model, VUS Predict, to classify BRCA variants of uncertain significance as neutral or deleterious. It uses evolutionary prediction algorithms together with clinical information from cancer pathology reports and BRCA genetic testing results. Because of the higher probability that missense changes occurring in conserved BRCA1 domains are of pathogenic significance, we identified all individuals in our cohort who had been tested for BRCA1 and BRCA2 mutations who had missense changes in the BRCA1 ring finger domain and sought to classify those changes. We applied VUS Predict to three previously uncharacterized variants and four missense changes known to be deleterious. Two variants, L22S and T37K, were predicted to be deleterious and one variant, K45Q, was predicted to be neutral by VUS Predict. The mutations C39R, C44Y, C44S and C61G were confirmed as deleterious.
PMCID: PMC4283813  PMID: 19543972
BRCA1; variants of uncertain significance; ring finger domain; mutation characterization
25.  Thyroid function alters during neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01) 
This side study investigated the effect of chemotherapy on thyroid function and the extent to which it can predict pathological complete response (pCR) in patients with early breast cancer taking part in NEOZOTAC phase III trial, randomizing between neoadjuvant chemotherapy with or without additional zoledronic acid. Moreover, we examined the impact of thyroid function on toxicity. Serum samples of 38 patients were available for analyses. Free thyroxin (fT4) and thyroid stimulating hormone (TSH) levels were compared between baseline and before the 6th cycle and between subjects with and without pCR. The relation between toxicity and the variation in fT4 and TSH levels during chemotherapy was tested. Samples at baseline and before the 6th cycle were available for 31 and 21 patients, respectively. The mean baseline fT4 level was 16.0 pmol/L and TSH level 1.11 mU/L, and these did not differ between both arms at each time point. During six cycles of chemotherapy, fT4 levels decreased (p = 0.0001), and TSH levels increased significantly (p = 0.019). Interestingly, the decrease of fT4 was significantly greater in patients without nausea, vomiting, or neuropathy, than in patients with those side effects (p = 0.037, p = 0.043, and p = 0.050, respectively). Baseline TSH levels tended to be higher in patients with pCR (p = 0.035 univariate analysis and p = 0.074 multivariate analysis). Chemotherapy blunts thyroid function, which was associated with less side effects. These data urge further evaluation of the effects of thyroid function on toxicity and outcome of breast cancer therapy.
PMCID: PMC4308642  PMID: 25556355
Breast cancer; Thyroid hormones; Chemotherapy; Toxicity; pCR

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