bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-04-05: Pros and cons of breast cancer screening: Knowledge in lay women
Authors: Morère J-F , Pivot X , Touboul C , Viguier J , Blay J-Y , Coscas Y , Lhomel C , Eisinger F
Published: August 2014

Background: It has been more than 20 years since local initiatives were proposed and 8 years since national organized breast cancer screening (BCS) (nationwide coverage) was implemented in France. It was associated with mass media and professional information for women with the aim of increasing the participation rate. The current reported coverage rate for women aged 50-74 every other year is about 80%. However the fairness of the process had not yet been assessed. It appears that having information about the pros and cons of BCS is thus a critical issue for targeted women.

Methodology: A nationwide observational study, recorded in the EDIFICE iterative surveys, with a representative sample of 451 women living in France aged 40-75 years old, was carried out in January 2013, using the quota method. The survey questionnaire was conducted using a computer-assisted telephone interviewing technique (CATI) 3 months after the beginning of a worldwide controversy spread by the mass media on BCS.

Results: The vast majority of women are reassured by BCS (74% vs. 13%). However 39% reported that they were stressed by BCS, with the main reason being fear of the results (30%) rather than the examination itself (9%). The main-reported benefits consisted of early detection of BC (38%), increased cure rate (22%) and preventing breast cancer (10%). The main reported limitations are a long period between two examinations (21%), starting too late (19%) and not being reliable enough (14%). A few people spontaneously reported screening-related risks (14%); the main risk being radiation-induced cancer (6%) false positives, over diagnosis and over treatment (5%). 18% have already heard about over diagnosis. With early detection of BC, 79% of women think that they will have only loco regional treatment, 3% think they will avoid major surgery, and only 10% of them think they will still have systemic treatment.

Conclusion: Overall women have a fair level of knowledge about the pros and cons of BCS. They are generally confident in BCS, but they underestimate its limitations and adverse effects, and have a lack of knowledge about the impact of BCS on therapeutic management. This appears to be a target for the next step in women: delivering honest and relevant information about BCS.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-04-05.
Abstract P2-06-04: p300 acts as a tumor suppressor by inhibiting pro-metastatic microRNA pathways
Authors: Birnbaum M , Yuan H , Yue K , Bishopric NH
Published: August 2014

The histone acetyltransferase p300 is an important epigenetic factor known to regulate gene silencing, DNA repair, and cell cycle. Altered p300 expression is linked to cancerous phenotypes and has potential as both a biomarker and therapeutic target. Existing anti-cancer therapies such as histone deacetylase inhibitors (vorinostat, valproic acid, trichostatin A) are known to affect p300 levels and activity. Understanding how p300 affects cancerous and metastatic development is crucial to optimizing and advancing these treatments. However, whether p300 acts as a tumor suppressor or promoter is still controversial. To address this issue, we stably knocked down p300 levels in MCF-7, BT 474 and MDA MB 231 to 30-40% endogenous levels to directly examine p300's effects on tumorigenicity. Our experiments show loss of p300 significantly increased cell motility in the scratch assay (p<0.05) and increased motility and invasion in a cell chamber migration chamber by 50% (p<0.001). Xenograft tumors formed from KD-p300 shRNA MCF-7 cells were on average about three times larger at six weeks post implantation than that of non-silencing control NS-MCF-7 tumors. KD-p300 MCF-7 xenograft tumors demonstrate a more aggressive phenotype with increased vascularity.

To identify targets of p300 that might regulate its anti-tumor effect, we observed that miR-let-7c was downregulated in KD-p300 MCF-7 by 70% (p<0.05). Consistent with this, the miR-let-7c target N-Ras was up regulated in KD-p300 MCF-7 cell lines and its xenograft tumors by three fold (p<0.05). Knockdown of p300 of MCF-7 cells also displayed downregulated miR-141 and miR-200a and upregulated their known target, ZEB1, by 40% (p<0.05). Gene expression profile assay showed that loss of p300 resulted in up regulation of ZEB1, laminin, collagen, IL-6, IFN, TGF-b, and components of the Wnt signaling pathway, which indicated a shift from epithelial to mesenchymal phenotype. Our data showed that loss of p300 was sufficient to induce a more invasive and potentially metastatic or EMT phenotype in breast cancer cells.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-06-04.
Abstract P2-06-05: Association of promoter methylation status of the FHIT gene and Fhit expression with HER2/neu status in breast cancer
Authors: Jeong YJ , Jang JI , Kim MS , Bong JG , Park SH , Oh HK
Published: August 2014

Purpose: Aberrant DNA methylation has been recognized to contribute to breast carcinogenesis, and promoter hypermethylation of many tumor suppressor genes has been correlated with decreased gene expression. The fragile histidine triad (FHIT) gene is a putative tumor suppressor gene in breast and other cancers, and loss of Fhit expression has been observed in breast cancers. The aim of this study was to evaluate the association between methylation of the FHIT gene and its expression in breast cancer, and to investigate whether methylation and expression of the FHIT gene would correlate with clinicopathological characteristics in relation to human epidermal growth factor receptor 2 (HER2) status.

Methods: Pyrosequencing of bisulfite treated DNA was performed to study the methylation status of the FHIT gene in 60 breast cancer samples from Korean women obtained at Daegu Catholic University Hospital. We examined the expression of FHIT using tissue microarrays by immunohistochemical staining. Association between the methylation status of the FHIT gene and its expression was analyzed, and the relationship between the FHIT expression and the clinicopathological characteristics of the patients was evaluated.

Results: FHIT methylation was detected in 96.7% and positive expression rate of Fhit was 87.3% of the patients. The mean methylation level of the FHIT gene was associated with intratumoral inflammation. Methylation level of the FHIT gene had no significant differences according to molecular subtypes. Loss of Fhit expression was associated with large tumor size, basal-like subtype and positive expression of EGFR. In HER2-negative breast cancers, loss of Fhit expression was significantly associated with tumor size, estrogen receptor status and Ki-67 proliferation index. There was no significant correlation between methylation of the FHIT gene and its expression in this study.

Conslusion: Our study revealed that loss of Fhit expression in breast cancer is associated with poor prognostic features, although there is no significance association between the FHIT gene methylation and Fhit expression. We found that in HER2-negatvie breast cancers, loss of Fhit expression was associated with poor prognostic features. These results support the possibility of potential complementation between HER2 and the Fhit pathway. The clinical significance of our findings needs to be further evaluated in larger cohorts with longer follow-up.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-06-05.
Abstract P2-09-12: Withaferin A-mediated inhibition of breast carcinoma involves concomitant activation of CHOP and Elk1 via ERK/ribosomal S6 kinase (RSK) signaling axis regulating death receptor 5 expression
Authors: Sharma D , Nagalingam A , Kuppusamy P , Saxena N
Published: August 2014

Introduction: Despite significant progress towards screening efforts and targeted therapies, breast cancer is still a leading cause of cancer-related mortality among women. Novel therapeutic strategies are clearly needed for effective targeting of breast cancer. Natural products continue to generate interest for identification of potential chemopreventive and therapeutic agents. Withaferin A (WFA) is a bioactive small molecule that has been proposed as a new-generation molecule capable of eliciting growth inhibitory effect on cancer cells. The molecular mechanisms by which WFA mediates inhibition of breast cancer remain elusive. The present study was designed to systematically elucidate the underlying mechanisms by which WFA inhibits growth and metastatic potential of breast cancer cells.

Methods: Efficacy of WFA treatment on cell growth was evaluated by using clonogenicity, and anchorage–independent growth. Western blot and immunofluorescence analysis were used to examine activation of ERK/RSK (extracellular signal-regulated kinase/ ribosomal S6 kinase) and downstream signaling axes. Functional importance of ERK/RSK and CHOP (C/EBP homologous protein) in the biologic effects of WFA was examined by using overexpression, phospho-deficient constructs and specific inhibitors. Finally, mouse xenografts, immunohistochemical, RT-PCR and western blot analysis of tumors were used.

Results: Analysis of the underlying molecular mechanisms revealed that WFA treatment induced phosphorylation of RSK2 in an ERK-dependent manner. Further, WFA-induced ERK/RSK signaling resulted in concomitant upregulation of CHOP and Elk-1(ETS-like transcription factor 1). By using ERK1/2 siRNA and FMK-MEA inhibitor, we found that ERK/RSK signaling axis is required for WFA-mediated modulation of CHOP and Elk-1. Intriguingly, we discovered that WFA triggers the nuclear translocation of CHOP and Elk1 resulting in transcriptional upregulation of Death Receptor protein (DR5). CHOP and Elk1 overexpression potentiated while phospho-deficient Elk-1 inhibited WFA-induced DR5 expression exhibiting that CHOP/Elk-1 cooperatively regulate DR5 expression. Furthermore, using nontoxic doses of WFA, we showed that WFA treatment effectively inhibited breast tumorigenesis in vivo. Analysis of WFA-treated breast tumors showed increased activation of ERK/RSK axis and DR5 along with higher nuclear accumulation of CHOP and Elk-1.

Conclusion: These data provided first in vitro and in vivo evidence of the integral role of a previously unrecognized crosstalk between WFA and ERK/RSK and CHOP/Elk-1 axes in breast tumor growth inhibition. WFA treatment could potentially be a rational therapeutic strategy for breast carcinoma.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-12.
Abstract P2-09-18: Identification of synergistic drug combination for HER2 positive breast cancer
Authors: Chalugun P , Shim JS , Liu JO
Published: August 2014

Breast cancer is one of the leading causes of death worldwide. 25-30% of breast cancer has HER2 gene amplification, which tend to give rise to poorly-differentiated and high grade tumor with a higher likelihood of spreading. Currently, trastuzumab and lapatinib are the only two FDA-approved treatments that target HER2 positive breast cancer. However, resistance to both drugs is already reported. Since breast cancer is considered to be one of genetic diseases caused by multiple gene aberrations, we used synergistic drug combination as a strategy to overcome these growth signaling pathway abnormalities. To identify new drug combination with lapatinib, we performed a cell-based screen against a library of clinical drugs of 3,200 compounds. Triptolide, a traditional Chinese medicine emerged from the screen with strong synergistic effect with lapatinib in HER2 positive breast cancer cells. This effect was specific to HER2 positive breast cancer. The whole HER2 signaling pathway was inhibited and more cells underwent apoptosis. Besides, both HER2 protein and mRNA levels were decreased in cells treated with the combination. This drug combination was also effective in breast cancer xenograft models of mice. Together, these findings suggest that both triptolide and lapatinib can be used as a promising drug combination for HER2 positive breast cancer.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-18.
Abstract P2-10-02: PD-L1 protein expression is a prognostic biomarker in breast cancer
Authors: Wimberly H , Schalper K , Chen L , Velcheti V , Pusztai L , Rimm D
Published: August 2014

BACKGROUND: Programmed death ligand 1 (PD-L1) and its receptor, PD1, are involved in limiting immune response. In the context of cancer, tumor cells expressing PD-L1 can suppress the immune response of PD1-expressing tumor infiltrating lymphocytes (TILs). Disruption of this pathway with antibodies to either the ligand or the receptor has shown promise in the treatment of non small cell lung cancer, melanoma and renal cell cancer. Here we investigate the pathway in breast cancer.

METHODS: PD-L1 protein expression was assessed on two Yale TMA breast cancer cohorts with two-fold redundancy by quantitative immunofluorescence (QIF) using AQUA technology. Cohort 1 (YTMA201) consists of 400 patients with has extensive follow-up and adjuvant treatment information. Cohort 2 (YTMA128) consists of 245 patients with limited follow-up and no treatment information. The PD-L1 antibody (Lieping Chen, clone 5H1) has been previously validated for specificity and reproducibility using transfected cell models. TILs were assessed by a pathologist for each cohort using a score from 0-3 based on the amount of TILs within the spot. AQUA scores for PD-L1 were used as a continuous variable and also cut at the median for outcome analysis.

RESULTS: PD-L1 protein is positively correlated with TILs (p<0.0001 on cohort 1 and p = 0.0072 on cohort 2) and inversely correlated with estrogen receptor status (p<0.0001 on cohort 1 and p = 0.0188 on cohort 2) on both breast cancer cohorts examined (total n = 594). On cohort 1, PD-L1 protein expression is a marker of good prognosis as a continuous variable (p = 0.0271) as well as when cut at the median (p = 0.0151), particularly in the estrogen receptor positive subset of patients.

CONCLUSIONS: PD-L1 expression in breast cancer is positively associated with TILs and inversely associated with estrogen receptor status on two independent breast cancer cohorts. PD-L1 protein expression shows prognostic value in breast cancer patients, particularly the ER positive subset of patients. Further assessment of PD-1 axis marker expression may be valuable as the associated therapeutics are being tested in breast cancer patients.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-10-02.
Abstract P2-10-05: Lymphatic and pro-inflammatory candidate gene variations and breast-cancer related lymphedema
Authors: Fu MR , Axelrod D , Guth AA , Goldberg J , Li X , Cartwright F , Haber J , Conley Y
Published: August 2014

Background

Traditionally, breast cancer-related lymphedema is considered to be mainly due to the mechanical injury from cancer surgery. Recent research identified that inflammation-infection may be one of the important predictors for breast cancer-related lymphedema. This pilot study aimed to explore the associations between lymphatic and pro-inflammatory candidate gene variations and lymphedema following breast cancer treatment.

Methods

A prospective, longitudinal, repeated-measure, and comparative design was used to recruit a sample of 178 breast cancer survivors. To ensure the accuracy of lymphedema phenotype, lymphedema was classified into two phenotypes: lymphedema of arm and breast. Arm lymphedema refers to swelling in the affected arm that must have been validated by infra-red perometer-S350 and a bioimpedance device. Breast lymphedema refers to swelling in the affected breast validated by self-report and an observational scale since no objective measure is available.

Saliva samples were collected for DNA extraction from all the 178 participants. Candidate Gene Association Research Method was used to examine the eight genes known for inflammation and lymphatic specific growth factors, including candidate genes for inflammation, cytokines (IL1A, IL6, IL8, IL10, IL13) and PTGS2 (COX2), and lymphatic specific growth factors [VEGF-C & D]. Descriptive statistics, Chi-Squared tests for contingency tables and one-way analysis of variance for continuous variables were used to compare the genotypes for each of these genes in patients with and without lymphedema. Odds ratios of developing lymphedema are estimated.

Results

Among 178 survivors, 39 women were confirmed to have arm lymphedema by infra-red perometer-S350 and a bioimpedance device and 43 women had breast lymphedema. Five genes were significantly associated with breast cancer-related lymphedema. Specific single nucleic polymorphisms (SNPs) for lymphatic specific growth factors VEGF-C (rs4604006) and cytokine IL13 (rs1800925) were related to arm lymphedema. Specific SNPs of cytokine IL1A (rs1800587) and PTGS2 (COX2) (rs20417) were associated with breast lymphedema.

Conclusion

Our findings provided preliminary data on genetic susceptibility as a risk factor for breast cancer-related lymphedema. Findings of our study may serve as a preliminary foundation for a priori recognition of genetic risk that may facilitate lymphedema risk prediction prior to surgery and raises the potential for early intervention for a high-risk group.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-10-05.
Abstract P2-11-15: Immunohistochemical assessment of Ki67 with the antibodies SP6 and MIB1 - A comparison of prognostic information and reproducibility
Authors: Ekholm M , Beglerbegovic S , Grabau D , Lövgren K , Malmström P , Werner-Hartman L , Fernö M
Published: August 2014

Background

Proliferation is a key feature in breast cancer and also a clinical important factor for prognosis and treatment prediction. In the St Gallen Consensus of 2011, immunohistochemically analysed Ki67 was adopted as a surrogate marker to distinguish the “luminal A” from the “luminal B” subtype, in order to select patients with estrogen receptor positive disease expected to benefit from adjuvant chemotherapy. The mouse monoclonal antibody MIB1 is the generally accepted antibody for assessment of Ki67. However, other antibodies have been developed, e.g. the rabbit monoclonal antibody SP6. The assessment of Ki67 with MIB1 is unfortunately associated with a considerable lack of reproducibility. Rabbit monoclonal antibodies generally tend to have higher specificity without loss of sensitivity, compared to corresponding mouse monoclonal antibodies. SP6 has also been found to have reduced background staining compared to MIB1. According to these advantages, SP6 may be an alternative to MIB1 for routine staining of Ki67. Any methodological modification should, according to international recommendations, be compared against a clinically validated assay and demonstrate acceptable concordance before being introduced in clinical routine. The analysis of Ki67 with SP6 therefore needs to be evaluated and compared to MIB1 in a cohort of breast cancer patients with clinical follow-up.

Aims

To compare the antibodies SP6 and MIB1 for immunohistochemical assessment of Ki67 in primary breast cancer regarding prognostic strength and reproducibility of the evaluation.

Methods

Tissue microarray from a cohort of 237 premenopausal women with node-negative breast cancer was used for assessment of Ki67, with both SP6 and MIB1, by three different investigators. The 7th decile was applied for defining cut-off. Distant disease-free survival (DDFS) was used as endpoint and the follow-up was restricted to 5 years.

Results

Ninety per cent of the samples were classified into the same group, either high or low Ki67, irrespective of antibody used. Ki67 (high vs. low), analysed with both antibodies was associated to DDFS (34 events) in the univariable analyses (SP6: HR 2.6, 95% CI 1.3-5.2, p = 0.01 and MIB1: HR 2.8, 95% CI 1.4-5.7 p = 0.004) and showed borderline significance for DDFS in the multivariable analyses, also including HER2, age, and tumour size (SP6: HR 2.0, 95% CI 0.93-4.5, p = 0.074 and MIB1: HR 2.2, 95% CI 0.97-4.8, p = 0.058). The agreement between different assessors was somewhat higher for MIB1 than for SP6 (kappa-values 0.83-0.88 vs. 0.72-0.77).

Conclusions

SP6 was not superior to MIB1 and the two antibodies were comparable in the assessment of Ki67 for prognostic considerations in primary breast cancer.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-15.
Abstract P2-12-08: Genetic testing for breast cancer risk estimation: A cost-effectiveness analysis
Authors: Folse HJ , Dinh TA , Allman R
Published: August 2014

Genetic testing based on seven single-nucleotide polymorphisms (7SNP) can improve individualized estimates of lifetime risk of breast cancer relative to the Gail risk test alone, for the purpose of recommending MRI screening for women at high risk.

An individual-based, continuous-time simulation model of breast cancer and health care processes was used to simulate women in a virtual trial comparing the use of the 7SNP test to the Gail risk test alone to categorize patients as either low risk or high risk. Low risk patients received annual mammogram, while high risk patients received annual MRI.

Cancer incidence was based on Surveillance, Epidemiology, and End Results (SEER) data and validated to the Cancer Prevention Study II (CPS-II) Nutrition Cohort data set. Risk factors are drawn from the National Health and Nutrition Examination Survey (NHANES-4) and Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) data sets. Mammogram characteristics were derived from the Breast Cancer Surveillance Consortium (BCSC) dataset. Other parameters were derived from published literature.

The 7SNP test (vs Gail alone) saved 0.00734 quality-adjusted life-years (QALYs) per person at a cost of $1,971 per person ($268,386 per QALY). Limiting the 7SNP test to only those patients with a lifetime Gail risk of 16 - 28% resulted in a cost of $163,264 per QALY. These results were sensitive to the age at which the test is given, the discount rate, and the costs of the genetic test and MRI.

The cost-effectiveness of using the 7SNP test for patients with intermediate Gail risk is similar to that of other recommended strategies, including annual MRI for patients with a lifetime risk greater than 20% or BRCA1/2 mutations.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-12-08.
Abstract P2-12-09: Developing clinical sequencing assays at Einstein-Montefiore
Authors: Delio M , Patel K , Maslov A , Golden A , Greally J , Morrow B , Vijg J , Montagna C
Published: August 2014

The Department of Genetics in collaboration with a group of Montefiore's clinicians initiated the development of clinical sequencing tests with the final goal to incrementally build clinical sequencing assays to improve clinical care in the Bronx. The use of next generation sequencing is particularly relevant for cancer biology since the heterogeneity of cancer requires deep sequencing and high read depth, which prior to recent advances in technology was expensive and labor intensive.

We designed a custom gene panel for target sequencing using the Illumina HiSeq 2500 consisting of 650 genes for multiple disorders and diseases, including various cancers, in addition to rare and complex mendelian disorders. We sequenced 17 samples, including a tumor-normal breast cancer pair, where we identified a novel, pathogenic stop variant in the highly mutated TP53 tumor suppressor gene. In addition to our custom target panel, we sequenced this sample pair on two additional cancer panels (AmpliSeq Cancer Hotspot and the Comprehensive Cancer Panel using the Ion Torrent Technology) and performed Whole Exome Sequencing (WES) to ensure the sensitivity and specificity of our custom panel. This variant was detected on all platforms.

We found targeted capture high-throughput sequencing to be a cost effective, time sensitive and efficient approach in detecting pathogenic variants to aid diagnosis of individuals affected by cancer or mendelian disorders. We are currently receiving samples to sequence and plan to expand our program to various groups within the Einstein-Montefiore community. Using a personalized medicine approach we expect to detect biomarkers and prospective targets to develop an accurate and effective treatment plan for these individuals.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-12-09.
Abstract P2-16-17: Characterization of response to everolimus (EVE) in BOLERO-2: A phase 3 trial of EVE plus exemestane (EXE) in postmenopausal women with HR+, HER2- advanced breast cancer
Authors: Burris H , Gnant M , Hortobagyi G , Hart L , Yardley DA , Eakle J , Provencher L , Brechenmacher T , Saletan S , Taran T , Rugo H
Published: August 2014

Introduction: The BOLERO-2 trial demonstrated that combining the oral mammalian target of rapamycin (mTOR) inhibitor, EVE, with the steroidal aromatase inhibitor, EXE, more than doubled median progression-free survival (PFS) compared with placebo (PBO) plus EXE in postmenopausal women with hormone-receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) breast cancer (BC) who relapsed or progressed following a nonsteroidal aromatase inhibitor (NSAI). Patients also achieved responses per Response Evaluation Criteria in Solid Tumors (RECIST) during treatment with EVE+EXE.

Methods: The phase 3, double-blind, BOLERO-2 trial randomized postmenopausal women with HR+ BC progressing or recurring after NSAIs in a 2:1 manner to EVE 10 mg once daily plus EXE 25 mg once daily (EVE+EXE; n = 485) or placebo (PBO) plus EXE (PBO+EXE; n = 239). The primary endpoint was PFS by local assessment. Overall response rate (ORR; complete + partial response per investigator assessment based on RECIST 1.0) and duration of overall response were secondary endpoints. In addition, best percentage change from baseline in sum of longest diameters of target lesions was assessed.

Results: At the time of final PFS analyses at 18 months’ median follow-up, ORR was significantly higher in the EVE+EXE arm compared with the PBO+EXE arm (12.6% vs 1.7%, respectively, by local assessment; P<.0001). Among patients with measurable disease at baseline, 71% in the EVE+EXE arm had a decrease in the sum of longest diameters of target lesions compared with baseline vs 30% in the PBO+EXE arm. Median duration of overall response was 10.5 months (95% confidence interval [CI]: 8.2, 21.9 months) for EVE+EXE and 6.9 months (95% CI: 4.2, 6.9 months) for PBO+EXE. Of note, only 4 patients in the PBO+EXE arm had an objective response to treatment.

Conclusions: In addition to PFS, the combination of EVE plus EXE significantly improved ORR vs PBO+EXE in patients with HR+, HER2− advanced BC progressing during or after NSAI therapy. Furthermore, greater than two-thirds of patients treated with EVE+EXE experienced tumor shrinkage during treatment. These results further support the rationale for combining EVE with EXE to improve clinical outcomes in HR+, HER2− advanced BC progressing after NSAI therapy.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-17.
Abstract P3-01-03: Vitamin D levels at breast cancer diagnosis: Association with patient and tumor characteristics
Authors: Cate SP , Berger N , Boolbol SK , Klein P , Gillego A , Estabrook A , Malamud S , Chadha M , Lucido D , Shao T
Published: August 2014

Background: Despite many preclinical studies showing the anti-neoplastic effects of vitamin D on breast cancer, findings from epidemiologic studies and randomized trials remain inconclusive. It is possible that tumor heterogeneity in breast cancer may mask these associations. Variations in vitamin D metabolism may explain some racial disparities in breast cancer. We aimed to examine the association of serum vitamin D levels with individual patient and tumor characteristics.

Methods: We conducted an IRB approved retrospective chart review, identifying all breast cancer patients with documented pretreatment serum levels of 25-hydroxyvitamin D (25(OH)D) between February 2011-May 2013. The following clinical data were collected for each patient: age at diagnosis, ethnicity, menopausal status, tumor size (mm), lymph node status, estrogen receptor (ER), progesterone receptor (PR), and HER2 status. Based on ER, PR, and HER2, patients were categorized into three molecular subtypes: 1) Hormone receptor (HR)+ (ER or PR positive, HER2 negative), 2) HER2+, and 3) triple negative (TN; ER, PR, and HER2 negative). Descriptive variables were analyzed using a one-way Anova test.

Results: Among the 200 breast cancer patients identified, the mean age was 55.9 years (range 29-90). Ethnicities of the patients were as follows: 104 (52%) Caucasian, 43 (22%) African American, 29 (15%) Hispanic, and 16 (8%) Asian. Seventy six patients (38%) were premenopausal, and 124 (62%) were postmenopausal. African Americans were found to have higher rates of triple negative tumors compared to all other ethnicities (24.4% vs. 11.6%, p = 0.029). Younger women had lower mean serum 25(OH)D levels compared to older women (p = 0.033). Lower mean 25(OH)D levels were seen in ER negative tumors compared to ER positive tumors (p = 0.0102). Mean 25(OH)D levels were lower in African American, Hispanic, and Asian breast cancer patients when compared to Caucasians (p = 0.0004). When stratifying by menopausal status, serum 25(OH)D levels differed more by tumor characteristics among premenopausal women than postmenopausal women. In premenopausal women, lower vitamin D levels were seen in patients who were African Americans (p = 0.0185), and with tumors that were ER negative (p = 0.0083). There was also a trend toward lower mean vitamin D levels in those with TN breast cancer compared to other molecular subtypes.

Conclusion: In premenopausal women, lower vitamin D levels were associated with African American race, younger age, and ER negative tumors. This may suggest that African Americans have defective vitamin D metabolism that may contribute to a more aggressive breast cancer phenotype. Further studies are warranted.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-01-03.
Abstract P3-01-04: Obesity induces functional transcriptomic changes enhancing the cancer hallmarks of estrogen receptor-positive breast cancer
Authors: Fuentes-Mattei E , Phan L , Velazquez-Torres G , Zhang F , Chou P-C , Shin J-H , Choi H-H , Chen J-S , Chen J , Gully C , Carlock C , Zhao R , Qi Y , Zhang Y , Wu Y , Esteva FJ , Lou Y , McKeehan WL , Ensor JE , Hortobagyi GN , Pusztai L , Symmans WF , Lee M-H , Yeung S-CJ
Published: August 2014

Obesity increases the risk of cancer death among postmenopausal women with estrogen receptor-positive (ER+) breast cancer, but the direct evidence for the mechanisms is lacking. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating this epidemiologic phenomenon. Transcriptomic profiles of pretreatment biopsies from a prospective cohort of 137 ER+ breast cancer patients were analyzed. A transgenic and an orthotopic/syngeneic obese mouse models were created to phenocopy obese patients and evaluate the effect of obesity on breast carcinogenesis and tumor progression, and to explore further direct mechanisms. Functional transcriptomic analysis of untreated human ER+ breast cancer revealed that obesity was associated with increased insulin signaling among others. Many of the functional changes in obese patients were linked to cancer hallmarks. Obese mouse models recapitulated the functional transcriptomic landscape of obesity-associated changes seen in human ER+ breast cancer and demonstrated the role of the Akt/mTOR pathway in obesity-induced breast carcinogenesis and tumor progression. Functional transcriptomic analysis identified 85 biological functions common to humans and mice. An in vitro co-culture model revealed that adipocyte-secreted adipokines (e.g., TIMP-1) regulate adipocyte-induced breast cancer cell proliferation and invasion. The human transcriptomic data provided direct evidence for the roles of hyperinsulinemia, estrogen signaling, adipokine secretion, and inflammation in the link between obesity and ER+ breast cancer. Our animal experiments provide strong evidence for the causal relationship between obesity and accelerated carcinogenesis and cancer progression and for potential therapeutic interventions by blocking these signaling pathways.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-01-04.
Abstract P3-06-01: Association between metformin use and improved survival in breast cancer patients: A population-based study
Authors: Li YR , Tchou J
Published: August 2014

Background: Long-term use of AMP-kinase agonist Metformin, the first-line oral hypoglycemic agent, has recently been shown to be associated with both a decreased incidence of and improved survival following diagnosis of breast and other solid tumors. However, the sample size of most reported studies has been limited and has not been able to clearly delineate if there are molecular subtype-dependent effects.

Method: We implemented a population-based, retrospective case-control analysis of the effect of metformin on breast cancer outcomes. We comprehensively searched the electronic medical records of all female patients who were cared for within the University of Pennsylvania Health System between the years 1997 and 2013. To ensure the accuracy of patient selection, we focused our preliminary analysis on only patients (n = 20,684) who received an ICD9 code for breast cancer (BC) on at least 2 separate in-person visits. We assessed the use of metformin by identifying those patients who have at least a record of a metformin prescription both before the first breast cancer diagnosis ICD9 code and after the first breast cancer diagnosis visit. Overall survival was determined by assessing a combination of electronic medical record of patient expiration and the SSN Death Certificate Index. Statistical tests, including chi-sq and cox-hazard modeling were implemented in R, Graphpad Prism or EXCEL.

Results: In the preliminary analysis, we identified a total of 29,251 female patients either diagnosed or reported a history of BC within the UPHS EMRs. Stratifying by per patient visits, we limited the subsequent analysis to the 20,684 BC patients with at least 2 in-person visits where BC was recorded as a diagnosis code. Of these, there were 534 patients who had a record of metformin prescription prior to and after the first BC diagnosis code and 20,150 BC patients who did not. We found that with a mean follow up of (6.40 years), there were a total of 8 deaths (1.28%) in metformin users and 526 deaths (2.62%) among the no metformin users. Using a two-tailed chi-sq test, we found that metformin use was significantly associated with improved overall survival rates (98.50 vs 96.94%, p<0.05). We are currently assessing the role of age, ethnicity, the presence of diabetes, health metrics related to insulin resistance, and the use of other metabolic regulators (insulin, sulfonylurea) using a cox-hazard proportional risk model.

Conclusion: Our preliminary analyses suggest that metformin use before and following diagnosis may be protective against overall mortality among women diagnosed with breast cancer. A more refined Cox proportional hazard modelling is ongoing, which will shed light on how factors such as the use of other metabolic agents, age, and breast cancer subtype may interact with metformin's effect on overall and disease-free BC survival.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-06-01.
Abstract P3-06-04: Differences in survival among women with primary and secondary metastatic breast cancer
Authors: Barinoff J , Schmidt M , Schneeweiss A , Hinke A , Schoenegg W , Henken S , Kutscheidt A , Pintoffl J , Jackisch C
Published: August 2014

Background

Retrospective analyses have shown survival differences in patients with primary metastatic breast cancer (PMBC) in comparison to patients with secondary metastatic breast cancer (SMBC). A subgroup analysis of 2,708 patients with metastatic breast cancer from two prospective non-interventional studies (NIS) allows exploring this hypothesis. The Her2-positive-NIS investigated trastuzumab therapy for Her2 positive metastatic disease additional to predominantly first line chemotherapy. The second NIS observed bevacizumab therapy for predominantly Her2 negative disease additional to chemotherapy as first- line option.

Methods

Information on PMBC or SMBC was available in 2,401 patients diagnosed with metastatic breast cancer and treated with targeted therapy between 2000 and 2011. Previously endocrine therapy in palliative status was allowed. Progression free survival (PFS) was defined as the time from the start of antibody therapy to disease progression or death; overall survival (OS) was defined as the time from the start of targeted therapy with antibody to death of any cause; PFS and OS were estimated by Kaplan-Meier product limit method.

Results

570 (24%) women had PMBC and 1831 (76%) had SMBC. Median follow-up was 23 months (range: 0.2 - 137). Median PFS in patients with PMBC and SMBC was 13.0 and 10.4 months, respectively (p = 0.0043); median OS for women with PMBC and SMBC was 33.5 and 28.5 months, respectively (p = 0.0023). 5 years after start of the study treatment 28% patients with primary and 23% with secondary metastatic disease were alive.

Conclusion

In a population of breast cancer patients treated with modern antibody therapies, woman with PMBC live significantly longer than those with SMBC. A possible explanation for this observation might be a negative selection process of patients suffering from secondary disease in spite of adequate primary treatment. Every fourth patients with metastatic breast cancer is a long survivor. The clinical-pathological characteristics and risk factors for this group are unclear. Prospective trials including translational investigations for these patient populations are needed.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-06-04.
Abstract P3-06-13: Transient increase in breast cancer risk after a full term pregnancy among African women
Authors: Sighoko D , Hou N , Ogundiran T , Adebamowo C , Ademola A , Ojengbede O , Anetor I , Akinleye S , Ndom P , Gakwaya A , Huo D , Olopade OI
Published: August 2014

Background

African women affected by breast cancer (BC) have high parity with five children or more, are relatively young at first full term pregnancy (FFTP), are diagnosed at a young age and are often premenopausal at diagnosis. While several studies have assessed the role of reproductive factors for BC risk among African women, none of them have assessed whether there is dual effect of age at full term pregnancy (FTP). In this communications, using a large dataset from an on-going hospital-based case-control study, we examine the role of age at full term pregnancy on breast cancer risk among African women.

Methods

The study includes sites in Nigeria (University College Hospital, Ibadan), Cameroon (Yaoundé General Hospital) and Uganda (Breast Clinic of Mulago Hospital of Kampala). It was initiated in 1998 in Nigeria and extended to Cameroon and Uganda in 2011. Cases were consecutive females diagnosed with invasive BC. Controls were recruited from the community or within the hospital and have never being diagnosed with any cancer. Cases and controls were aged 18 years or more and gave informed consent. Full term pregnancy was defined as a pregnancy that lasted at least 7 months and included both live birth and stillbirth. Logistic regression models were used to assess the effects of age at first and second FTP, and their interaction with current age on BC risk. Age at menarche, parity, body mass index and hormone contraception use were included in the models.

Results

The study includes 1668 cases and 2399 controls recruited between 1998 and May 2013. Mean duration of live birth was 9 months (SD±0.52) and 8.8 months (SD±0.66) for a stillbirth. Overall, the mean age at FFTP was 23 years (SD±4.91) for both cases and controls. Compared to nulliparous women, parous women who had FFTP at 20 years have increased risk (OR = 1.59, CI 95%, 1.16-2.21) to develop BC in the year following the pregnancy. Up to 5 years following the FFTP, this OR is 1.38 (CI 95%, 1.06-1.80) while it is 0.77 (CI 95%, 0.62-0.95) 25 years later. This observation was also true for parous women who have had their FFTP at 25, 30, or 35 years. Moreover, a similar pattern was observed when comparing uniparous women to women with 2 or more children.

Conclusion

Our results show a transient increase in risk of BC after a full term pregnancy which declined and became protective over time. This observation is consistent with the effect of pregnancy on BC that has been described in other populations and may partially explain the current profile of breast cancer among African women.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-06-13.
Abstract P3-06-18: The health of women study: A novel approach to the cohort study
Authors: Love SM , Sykes N , Fischetti CA , Sullivan-Halley J , Clague J , Bernstein L
Published: August 2014

PURPOSE: The purpose of the Health of Women (HOW) Study is to examine risk factors for breast cancer and factors that may contribute to long-term survivorship through an innovative online system that allows for participant engagement and data sharing with the research community.

METHODS: The HOW Study is conducted through online and mobile phone platforms. Questionnaires are developed in our custom built survey tool and are available for completion on the study's website. The system allows for automated skip patterns within questionnaires and collection of data directly into a SQL database. The cohort is open to anyone 18 years or older; recruitment sources include the Love/Avon Army of Women and the general public. Participants will be given the opportunity to pose questions they would like to see answered. The HOW Study is also a novel resource allowing outside researchers to submit questions to be incorporated into HOW questionnaires and creating a data sharing platform that facilitates researcher access to HOW data after an application process.

RESULTS: The HOW Study launched October 2012 and currently has 41,800 participants from across the nation and the globe. We have released 1 baseline questionnaire and breast cancer-specific questionnaires to capture diagnosis and treatment with greater than 90% completion rate for each.

CONCLUSION: We have shown that we can recruit and engage participants in an online cohort study. We believe that this study has the potential to transform epidemiologic research by engaging both participants and the research community. Our second baseline questionnaire will launch in the summer of 2013, which will give us the opportunity to increase enrollment and assess retention.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-06-18.
Abstract P3-07-11: Nipple aspiration fluid yielders and non-yielders: Genetic characteristics
Authors: Shidfar A , Wang J , Allu S , Scholtens D , Chatterton R , Khan S
Published: August 2014

Background: Nipple aspiration fluid (NAF) is a noninvasively acquired biosample that can provide a window of observation into the breast environment, but NAF yield is variable across studies, and is related to a variety of demographic and reproductive factors. We have recently observed a positive correlation between serum prolactin level and NAF yield status. The genetic traits determining NAF yield are unknown, but data from the 1970s linked wet type ear wax to NAF yield, and recent studies point to single nucleotide polymorphisms (SNPs) in the ABCC11 gene as a determinant of earwax type. Further, prolactin and prolactin receptor SNPs are related to serum prolactin level. We have investigated associations between NAF yield and SNPs in prolactin, prolactin receptor and ABCC11 genes in a recently completed case-control study.

Method: NAF and/or blood were collected from 916 women. Subjects were defined as yielder if NAF volume was equal or more than 2μL and non-yielder if it was less than 2μL. According to this definition, our subjects categorized as 557 yielders and 359 non-yielders. DNA was extracted from blood using Qiagen kit and 20 ng of DNA was used to amplify and genotype for ABCC11 (rs17822931), PRLR (rs37364), PRL (rs2244502), PRL (rs849872) SNPs using Taqman genotyping assay on an Applied Biosystems 7900HT machine.

Results: The median age of Yielders and Non-yielders was 51 and 54, respectively, with the same range of 31-70 for both groups (P<0.0001). There were 209(38%) premenopausal, 257(46%) postmenopausal and 81(15%) perimenopausal of yielders vs. 99(28%) premenopausal, 229(64%) postmenopausal and 26(7%) perimenopausal of non-yielders (P<0.0001). ABCC11 genotype distribution was significantly different between yielders and non-yielders (P = 0.00163). However, genotype distribution was not significantly different for PRLR (rs37364), PRL (rs2244502) and PRL (rs849872).

 YNYTotalP (N vs. NY)ABCC11 (rs17822931)5413578980.00163CC437 (81%)269 (75%)706 TT5 (1%)16 (4%)21 CT99 (18%)72 (20%)171 PRLR (rs37364)5483599070.176GG89 (16%)43 (12%)132 TT272 (50%)181 (50%)453 GT187 (34%)135 (38%)322 PRL (rs2244502)5393588970.087AA73 (14%)32 (9%)105 TT233 (43%)155 (43%)388 AT233 (43%)171 (48%)404 PRL (rs849872)5433599020.102CC17 (3%)11 (3%)28 TT332 (61%)244 (68%)576 CT194 (36%)104 (29%)298 

Conclusion: Our analysis demonstrates a correlation between ABCC11 (rs17822931) SNP and NAF yield status, with the major homozygous CC allele associated with NAF yielder and minor homozygous TT allele associated with non-yielder status. If NAF-based risk biomarkers are to be developed, a better understanding of the genetics of NAF yield is required.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-07-11.
Abstract P3-08-06: ROK study: Breast cancer survivorship cohort in Japan - Characteristics of 2,600 study participants
Authors: Mizota Y , Yamamoto S
Published: August 2014

[Background] Although there is growing epidemiologic studies to investigate the etiological role of lifestyle factors and psychosocial factors on female breast cancer, few studies have examined the effect of these factors on breast cancer prognosis. To investigate the influence of lifestyle factors and psychosocial factors on prognosis including the quality of life, recurrence and survival of patients with breast cancer, we designed a large-scale cohort study of breast cancer patients in Japan. In our study, lifestyle factors include diet, physical activity, and use of complementary/alternative medicine, psychosocial factors include hope, perceived positive changes such as growth from breast cancer, depression, support and so on.

[Methods] Our goal is recruiting 6,000 breast cancer patients. Main part of this study is being conducted as a collaborative study with three randomized clinical trials and one cancer registration. Participant's information on clinical factors, treatment, and follow-up will be obtained from the clinical trials and cancer registration. In addition, we started recruitment at National Cancer Hospital. A self-administered questionnaire will be delivered to participants before and every year (1 to 5 years) after surgery, and their responses will be employed as baseline data. At National Cancer Center Hospital blood samples and tissues are also to be collected. The primary endpoint is disease-free survival. The secondary endpoints are overall survival and the health-related quality of life. The follow-up period will be 5 years after the last participant enrollment. We will examine the association of lifestyle factors, psychosocial factors, biomarkers and genetic polymorphisms with the prognosis based on follow-up data.

[Results] Recruitment began in November, 2007, and as of March, 2013, 2,655 women have been enrolled along with 2,591 questionnaire data, 236 blood samples and tissues.

As it is now, approximately 50 women a month newly enrolled. Recruitment will be continued at least into 2018, the Rainbow of KIBOU Study will become one of the largest breast cancer cohorts in the world. In this presentation, we describe the study design and report baseline demographic among the study participants.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-08-06.