bluuebunny/crossref_metadata_2025 huggingface dataset:
The development of a potent, multifunctional gene delivery vector driven by the cancer-selective mucin-1 promoter to detect and treat breast cancer metastasis.
Authors: Huyn ST , Burton J , Sato M , Wu L
Published: December 2010

Abstract #6022

With breast cancer, early detection and proper staging are critical, influencing both the treatment regimen and therapeutic outcome for a patient. Improvements in these areas will play a profound role in reducing mortality due to this disease. We therefore aim to develop a targeted adenoviral based gene therapy vector that can be used in the detection and staging of metastatic breast cancer. We did this through application of the two-step transcriptional amplification system (TSTA). This system was developed in our lab, and has shown the ability to greatly augment the activity of weak promoters, while still maintaining tissue specificity.  We incorporated the tumor specific promoter Mucin1 into the TSTA system to successfully target breast tumor models. Studies carried out in vitro have demonstrated that this MUC1 TSTA vector is able to achieve efficiency of up to 250 fold over basal promoter levels, without loss of specificity. Moreover, when incorporated into an adenoviral vector to express firefly luciferase (AdMUC1-TSTA-fl), it exhibits higher reporter gene expression than a AdCMV-fl virus at the same multiplicity of infection (MOI).  Biodistribution studies have shown that, depending upon the initial route of administration, this system holds great potential for use in the detection of lymph node metastais, as well as distant metastases. This vector has shown low off target expression following intravenous injection into non-tumor bearing mice. Through use of in vivo xenograft models of breast cancer, we have shown the ability to target and detect both lymph node metastais, as well as liver metastasis using our AdMUC1 TSTA-fl reporter virus in combination with in vivo optical imaging. Based on these results, we believe that this system holds strong promise for clinical application.  A critical aspect of this project will be the incorporation of cytotoxic genes for therapeutic studies. At the same time, the ability to express imaging reporter genes for bioluminescent imaging or PET (positron emission tomography) is highly desirable, allowing for efficient, non-invasive monitoring of pharmacokinetics of transgene expression in real time. To address this issue, we developed a MUC-1 driven TSTA amplification scheme able to simultaneously express two separate transgenes, the firefly luciferase and the herpes simplex virus thymidine kinase (HSV-tk sr39tk) gene. This bi-directional reporter TSTA construct has shown strong efficiency, and specificity, and is currently being evaluated for use in therapeutic application of breast tumors in vivo. This approach holds great promise for the treatment and diagnosis of metastatic breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6022.
TOP2A mRNA expression in HER2 negative breast cancer.
Authors: Gennari A , Sormani M , Pfeffer U , Morandi L , Mustacchi G , Danesi R , Mirisola V , Bruzzi P
Published: December 2010

Abstract #6036

Background Recent meta-analyses on the interaction between HER2 status and efficacy of adjuvant anthracyclines suggest that patients with HER2 negative tumors derive no added benefits from anthracycline administration. Since topoisomerase IIa is a known target of the anthracyclines, it's expression has been proposed as a more accurate and biologically related predictive factor of anthracycline responsiveness. Additional evidence suggests that TOP2A gene amplification occurs only in HER2 amplified tumors, whereas it is rare among HER2 negative patients. The aim of the present study was to address the regulation of TOP2A expression, at the level of mRNA, in HER2 negative disease. Methods We used two previously published Affymetrix gene expression datasets: GSE 1456 (159 patients) and GSE 2494 (249 patients). Microarray data preprocessing was carried out using Bioconductor software (gcrma procedure). Expression of HER2 and TOP2A were evaluated extracting the Affy probes “210930_s_at” and ”216836_s_at” (for HER2) and the Affy probe "201292_at” (for TOP2A); overexpressed samples were defined those with expression values over the 75th percentile of the whole sample of patients. The distribution of TOP2A mRNA overexpression according to molecular subtype was evaluated in the GSE 1456 dataset.  Results: Overall, 348 out of 408 patients were HER2 negative. TOP2A mRNA overexpression was detected in 65 out of 348 HER2 negative tumors (18,7%). In the GSE 1456 dataset TOP2A mRNA overexpression was detected in 48% of basal like tumors, 42% of Luminal B and 21% of Luminal A. Among HER2 positive tumors, TOP2A mRNA overexpression was detected in 40%. mRNA TOP2A overexpression was present in 27% of the ERBB2 and in 80% of the Luminal B (HER2 positive) molecular subtype.  Conclusions: TOP2A overexpression, at the level of mRNA, is present in the HER2 negative population and it is distributed in all molecular subtypes, especially among the Basal like and Luminal B subtypes. We are currently evaluating the interaction between TOP2A mRNA expression and efficacy of adjuvant anthracyclines in a retrospective analysis of data including 200 early breast cancer patients.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6036.
Hot flashes are associated with CYP2D6 genotype in breast cancer survivors taking tamoxifen.
Authors: Madlensky L , Flatt SW , Natarajan L , Lawrence H , Nikoloff D , Fontecha M , Hao S , Hillman G , Johnson A , Parker BA , Pierce JP
Published: December 2010

Abstract #6045

Background: We have previously shown that participants in the Women's Healthy Eating and Living (WHEL) study comparison group who reported hot flashes after breast cancer treatment had more favorable disease-free survival than women who did not report hot flashes. However, this was not the case in the intervention group. The polymorphic CYP450 enzyme CYP2D6 catalyzes the conversion of tamoxifen (TAM) to one of its key active metabolites, endoxifen. Some studies have suggested that certain genetic variants of CYP2D6 are associated with a decreased likelihood of hot flashes, reduced endoxifen levels and an increased risk of disease recurrence in women receiving adjuvant TAM therapy. This analysis was performed to estimate the association between CYP2D6 genotype and hot flashes in early stage breast cancer survivors who took adjuvant TAM in the WHEL study.  Methods: The WHEL study was a randomized trial of a dietary intervention in breast cancer survivors, who enrolled in the study within 4 years of diagnosis from 1995-2000. Participants self-reported TAM use, hot flash severity and menopausal status at study entry. Clinical characteristics (tumor stage, estrogen receptor status, chemotherapy) were extracted from medical records. Blood samples were obtained by venipuncture, separated and stored at -80 deg. DNA was extracted from stored buffy coat and analyzed using the Roche AmpliChip CYP450 Test. Women were classified according to their predicted CYP2D6 phenotype as Extensive (EM), Heterozygous Extensive (Het EM), Intermediate (IM), Poor (PM), or Ultrarapid (UM) Metabolizers.  Results: Overall, 1434 WHEL participants had verified estrogen receptor-positive stage I or II breast cancers and reported taking TAM at baseline for at least 4 months. A total of 1411 women were successfully genotyped and their CYP2D6 phenotypes were classified as follows: 468 EM (33.2%); 665 Het EM(47.1%), 164 IM (11.6%), 86 PM (6.1%) and 28 UM (2.0%). In univariate analyses, there was a significant difference among CYP2D6 genotype in relation to hot flashes reported at baseline: 79.8% of EMs, 76.3% of Het EMs, 80.1% of IMs, 63.9% of PMs, and 75% of UMs reported hot flashes (χ2= 11.3, p=0.02). After controlling for age, menopausal status, and time since diagnosis, the PM group was half as likely to report hot flashes as the referent EM group (OR= 0.46; 95% CI= 0.28-0.78; p=0.003). Additional analyses of serum endoxifen levels and associations with disease outcome are underway.  Conclusion: In the WHEL study, women who were classified as Poor Metabolizers of TAM, based on their CYP2D6 genotype, were half as likely as Extensive Metabolizers to report experiencing hot flashes while receiving adjuvant TAM treatment for early stage breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6045.
Assays of circulating tumor cells and outcome in the triple-negative breast cancer trial TBCRC001.
Authors: Rugo HS , Carey LA , Mayer E , Marcom PK , Liu M , Ma C , Storniolo AM , Forero A , Esteva FJ , Wolff AC , Hobday T , Ferraro M , Davidson NE , Winer EP , Moore D , Scott J , Park JW
Published: December 2010

Abstract #6048

Introduction. Basal-like breast cancer (BBC) has low expression of ER, PR, and HER2, and is often called triple negative (TN) BrCa. TBCRC 001 is a multicenter randomized phase II study of cetuximab (C) alone or combined with carboplatin (P) in TN BrCa. Pts randomized to Arm 1 received C alone (400 mg/m2, then 250 mg/m2 weekly) with P (AUC 2, 3 of 4 weeks) added upon progression (PD). Pts on Arm 2 received C+P throughout. The primary endpoint was objective response. To explore markers of activity and response, we measured circulating tumor cells (CTCs) in pts on study and directly compared two methods of CTC enumeration; CellSearch (Veridex) and immunomagnetic enrichment followed by flow cytometry (IE/FC). A subset of samples were isolated for molecular profiling.  Methods. Blood was obtained from consenting pts at baseline, 7 to 14 days after the first infusion, then monthly until the end of the study. CellSearch assay was performed as previously described using 7.5 cc blood in a CellSave tube and the CellSpotter analyzer, and the percent of CTCs staining for EGFR was also measured. For IE/FC, 20 ml of blood was subjected to IE using anti-EpCAM MAb-conjugated iron particles, followed by multiparameter FC for EpCAM, CD45, and nucleic acid content. CTC results were correlated by method, and to time on study treatment. In this preliminary analysis, the endpoint is time on study treatment (to progression/toxicity, TST).  Results: Safety and efficacy data from arms 1 and 2 have been presented (Carey et al; SABCS 2007, ASCO 2008). Of 102 TN pts enrolled in this study, 65 had CTC measurements by both methods on at least one time point. CTC levels by the two assays were highly correlated at all time points. At baseline, Spearman's rank correlation coefficient was 0.67 (p<0.0001). Using the cutoffs shown below, CTC by IE/FC or CellSearch at baseline and first follow-up correlated with TST. This relationship was observed in both arm 1 and 2.    Conclusion: In this phase II trial of C or C+P in pts with TN metastatic BrCa, CTCs measured by two different techniques were highly correlated. CTC levels at baseline and 7-14 days predicted longer vs. shorter TST, suggesting that CTCs may be an early marker of response to targeted therapy. Additional molecular data on CTCs will be presented.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6048.
Circulating tumor cells and FDG-PET/CT: biological and functional methods for therapeutic monitoring in metastatic breast cancer.
Authors: Cristofanilli M , De Giorgi U , Rohren E , Ueno NT , Miller C , Doyle GV , Jackson S , Andreopoulou E , Handy BC , Reuben JM , Hortobagyi GN , Macapinlac HA , Fritsche HA , Valero V
Published: December 2010

Abstract #6052

Introduction: The combination of Computed Tomography (CT) and [18F] Fluorodeoxyglucose - Positron Emission Tomography (FDG-PET) scanning technologies provides a more complete picture of disease activity than CT alone. Circulating tumor cell (CTC) levels were shown to be more predictive than standard imaging (CT) when used to monitor disease progression in women with metastatic breast cancer (MBC). We performed a retrospective study to compare the ability of combined FDG-PET/CT to CTC to predict clinical outcomes in patients treated for MBC.  Methods: One hundred and two MBC patients with either measurable or evaluable disease starting a new line of therapy had CTC counts and FDG-PET/CT scans done at baseline (BL) and at mid-therapy. CTC: 7.5mL of blood collected in CellSave tubes at both time points was assayed for CTC using the FDA approved CellSearch® System. Patients were categorized as having a favorable (<5CTC) or unfavorable (≥5CTC) outcome. Imaging: non-contrast-enhanced CT images were acquired first, then FDG-PET/CT scans were performed after administering a mean dose of 555 MBq FDG (range 444-740 MBq) to fasting patients. CT, PET, and co-registered CT-PET images were reviewed independently by 2 radiologists. The highest recorded FDG uptake was semi-quantitatively analyzed and maximum standardized uptake value (SUV) calculated with response = SUV of <50% in target lesions and no response = SUV of >50%. Changes in CTC and SUV at mid-therapy were compared to progression free survival (PFS) and overall survival (OS).  Results: CTC: 50% (51/102) patients had ≥5 CTC at baseline (BL). At mid-therapy (median 2.5 months from BL), 21/102 progressed (≥5CTC) with a median PFS of 2.8 months vs. 7.8 months for those with no progression (<5CTC) (p<0.0001). OS was 10.0 months for patients with ≥5CTC at mid-therapy vs. 29.6 months for those with <5CTC (p<0.0001). PET/CT: 48% (49/102) patients showed no response at mid-therapy with median OS = 17.4 months vs. 29.6 months for those responding (p=0.0020). Overall, there was approximately 75% concordance in predicting outcomes between imaging and CTC assay changes [Table 1]. The majority of patients with discordant results had more advanced aggressive disease, i.e., >2nd line chemotherapy and triple-negative disease.    Conclusion: ≥5 CTC and/or no response at FDG-PET/CT at mid-therapy accurately predicted significantly shorter OS.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6052.
HER2 amplification does not alter outcome in small (≤1 cm) tumors.
Authors: Ananthakrishnan P , Patrick RJ , Rybicki LA , Tubbs RR , Crowe JP , Budd GT
Published: December 2010

Abstract #6058

INTRODUCTION: Amplification of human epidermal growth factor receptor-2 (HER2) has been associated with an aggressive clinical phenotype, however the management of patients with small tumors (<1 cm) that amplify HER2 is controversial. The goals of this study were: 1) to describe characteristics of HER2 amplified tumors based on tumor size, and 2) compare outcomes among 4 groups based on tumor size (small tumors <1 cm or large tumors >1 cm) and HER2 amplification (+ or -.)  METHODS: Data were collected prospectively in our institutional review board approved breast center patient registry for patients with infiltrating ductal or infiltrating ductal-lobular mixed breast cancer. There were 770 patients with N0 tumors who were diagnosed between January 2001 and April 2005 (prior to treatment of HER2 amplified tumors with Trastuzumab). Categorical variables were compared using the Chi-squared test; outcomes were estimated using the Kaplan-Meier method and the log-rank test.  RESULTS: At 4 years, estimated disease free interval was 97% in small HER2- tumors, 92% in large HER2- tumors, 91% in small HER2+ tumors, and 86% in large HER2+ tumors.    At 4 years, breast cancer specific survival was 97% in small HER2- tumors, 92% in large HER2- tumors, 91% in small HER2+ tumors, and 86% in large HER2+ tumors.  CONCLUSIONS: In our series, larger as opposed to smaller HER2+ tumors tended to be of higher histologic grade (SBR), and showed a trend toward more frequent lymphovascular invasion (LVI) and negative hormone receptor status. In small tumors, HER2 amplification did not predict recurrence-free survival or breast cancer disease specific survival at 4 years. The survival curves do show trends towards worsening outcomes for small tumors with HER2 amplification; these trends may show significance with additional follow-up.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6058.
A functional SNP in the leader sequence of the manganese superoxide dimutase gene is a predictor of breast cancer patient survival and response to chemotherapy.
Authors: Glynn SA , Boersma BJ , Howe TM , Ridnour L , Wink D , Edvardsen H , Børresen-Dale A , Ambs S
Published: December 2010

Abstract #6067

Background: A functional single nucleotide polymorphism (SNP) in the Manganese Superoxide Dismutase (SOD2) gene, characterized by a T-C transition located at codon 16, leads to a Val to Ala (Val16Ala) switch. The Val (T) allele disrupts the alpha-helix structure of SOD2 and causes the protein to be retained at the level of the mitochondrial inner membrane, with 30 to 40% lower activity and increased susceptibility to oxidative stress. We investigated whether the Val16Ala SOD2 polymorphism was associated with breast cancer survival.  Methods: Two independent populations, one from the United States (n=244) and from Norway (n=329) were genotyped for the Val16Ala SOD2 polymorphism. Kaplan-Meier survival and multivariate Cox proportional hazards regression analyses were used to examine the relationship between the polymorphism and disease-specific survival, and response to chemotherapy.  Results: We observed an association between Ala (C) allele and an increased risk of disease specific mortality. Carriers of the Ala/Ala genotype had an increased risk of poor survival in the combined analysis (Greater Baltimore and Norwegian datasets combined) when compared to carriers of Val/Val genotype using multivariate Cox regression analysis [Hazard ratio (HR) = 1.89; 95% confidence interval (CI), 1.16–3.07; p=0.011]. In the stratification analysis, the association was significant in those who underwent chemotherapy (HR = 2.54; 95% CI, 1.44–4.47; p=0.001), compared to those who did not (HR = 0.55; 95% CI, 0.16–1.94; p=0.353). Analysis by type chemotherapy received, showed that the Ala/Ala genotype had the strongest effect in patients receiving cyclophosphamide containing chemotherapy (HR = 18.88; 95% CI, 4.17–85.37; p<0.001). Other drugs with an effect included 5-fluorouracil and doxorubicin. These results suggest that the Val16Ala SOD2 polymorphism may be a predictor of response to chemotherapy.  Conclusion: We found that the Val16Ala SOD2 polymorphism, was associated with breast cancer survival, and is a potential predictor of response to chemotherapy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6067.
Reductions in tumor RNA integrity associated with clinical response to epirubicin/docetaxel chemotherapy in breast cancer patients.
Authors: Parissenti AM , Chapman JW , Kahn HJ , Guo B , Han L , O'Brien P , Clemons MP , Jong R , Dent R , Fitzgerald B , Pritchard KI , Shepherd LE , Trudeau ME
Published: December 2010

Abstract #6068

Background: Optimal doses and dosing intervals for neoadjuvant anthracycline/taxane chemotherapy are poorly studied. Moreover, biomarkers for measuring response to such combination regimens are unknown. This study investigated these issues in sequential phase I/II cohorts of women with locally advanced or inflammatory breast cancer treated with epirubicin and docetaxel with pegfilgrastim support at 3- or 2-weekly intervals in association with the NCIC-CTG MA.22 clinical trial.  Methods: Accrual has been completed for the 3-weekly regimen (maximum tolerated dose: epirubicin 105 mg/m2, taxotere 75 mg/m2), and continues for the phase II portion of the 2-weekly regimen. Six core biopsies were obtained from 50 patients pre-, mid-, and post-treatment. Immunohistochemical staining was performed to determine baseline levels of ER, PR, HER2 and Topo II expressed as % positive stain. Tumour RNA integrity (RIN) and tumor extent were measured pre-, mid- and post-treatment by capillary electrophoresis and light microscopy after haematoxylin/eosin staining, respectively. Associations between maximum and average RIN at the three time points and tumour extent, clinical response, pathologic complete response, or baseline levels of ER, PR, HER2 and Topo II were assessed using Spearman correlation coefficients after data transformation to improve symmetry and stabilize variances. The association between both RIN and tumour extent, and baseline drug dose was assessed using a 1-way ANOVA.  Results: Low mid-treatment maximum RIN was associated with high drug dose level (p=0.05) and eventual pathologic complete response (p=0.01). Post-treatment, low maximum and average RIN were found to be associated with low tumor extent (p=0.004 and p=0.01, respectively). As well, low average RIN was significantly associated with clinical complete response post-treatment (p=0.01). As expected, post-treatment low tumor extent was significantly associated with pathologic complete response (p=0.01). High pre-treatment Topo II levels were also significantly associated with high RIN (p = 0.03). No association was observed between RIN and HER2, ER or PR.  Discussion: The association of RIN with tumour extent, pathologic complete response, clinical response, a known risk factor (Topo II), and drug dose suggests that the RIN may represent an important new biomarker for measuring response to anthracycline/taxane combinations (and possible other chemotherapy regimens) in breast cancer patients.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6068.
HER2 amplification predicts breast cancer recurrence but not overall survival.
Authors: Ananthakrishnan P , Patrick RJ , Rybicki LA , Tubbs RR , Budd GT , Crowe JP
Published: December 2010

Abstract #6070

INTRODUCTION: Human epidermal growth factor receptor-2 (HER2) amplification has been associated with an aggressive breast cancer phenotype. The aims of this study were: 1) to determine if a relationship between HER2 amplification and local recurrence or overall survival (OS) existed; and 2) to compare prognostic effects of HER2 amplification with race, age, TNM stage, Scarff-Bloom-Richardson (SBR) grade, and hormone receptor status.  METHODS: Data were collected prospectively in our institutional review board approved breast center patient registry for patients with infiltrating ductal or infiltrating ductal-lobular mixed breast cancer; all other histologic types, including pure infiltrating lobular, were excluded from this analysis. Variables analyzed included race, age at diagnosis, tumor size, overall TNM stage, SBR grade, HER2 status, and hormone receptor status. Outcomes were defined as disease-free survival (local and distant) and OS. The prognostic effect of HER2 amplification on disease-free survival (DFS) and OS was assessed after adjusting for race, age, TNM stage, SBR grade, and hormone receptor status; Cox proportional hazards analysis was used in the multivariable analysis. A stepwise selection procedure was used in the multivariable analysis with p<0.10 required to allow a variable into the model and p<0.05 required to retain it in the final model.   RESULTS: Data were available for 1750 patients (mean age at diagnosis 60 years) diagnosed between January 2001 and July 2007; mean tumor size 1.8 cm, of which 384 (22%) were hormone receptor negative and 296 (17%) were HER2 amplified. Risk factors for DFS included HER2 amplification (Table 1), black race, increasing TNM stage, and negative hormone receptors. Risk factors for OS included black race, increasing TNM stage, and negative hormone receptors. HER2 amplification was associated with decreased disease-free survival (Fig 1a) but not OS (Fig 1b).        CONCLUSIONS: Although HER2 amplification predicted disease-free survival, it did not predict OS in the multivariable analysis. A possible explanation for this finding is the increasing use of Trastuzumab for HER2 amplified tumors after relapse.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6070.
Immunoglobulin G fragment C gamma receptor (FcGR) polymorphisms and efficacy of single-agent trastuzumab in patients treated with metastatic breast cancer.
Authors: Shimizu C , Tamura K , Koizumi F , Aogi K , Kinoshita T , Fujiwara Y
Published: December 2010

Abstract #6073

Background: Antibody-dependent cell-mediated cytotoxicity (ADCC) may be involved in antitumor effect of therapeutic monoclonal antibodies and their effector functions are induced following the interactions of IgG with FcGR. Studies have shown that FcGRIIIa-V158F and FcGRIIa-H131R polymorphisms may predict response to retuximab, cetuximab in patients with follicular lymphoma, colorectal cancer, and recently, trastuzumab-combined chemotherapy in breast cancer patients (J Clin Oncol 25; 1789, 2008). We tested the hypothesis of whether these two polymorphisms are associated with clinical outcome in metastatic breast cancer patients treated with single-agent trastuzumab treatment.  Patients and Methods: Patients with HER2-positive (HercepTest (3+) or (2+) with gene amplification either in primary or metastatic site) metastatic breast cancer were enrolled onto this prospective study. Eligible patients were hormone receptor negative or endocrine therapy resistant, and had received no prior chemotherapy for metastatic disease. Study patients received single agent trastuzumab at a loading dose of 4 mg/kg followed by 2 mg/kg per week until disease progression. The first clinical response was assessed at 8 week. FcGRIIIA-V158F and FcGRIIA-H131R genotypes were assessed from genomic DNA extracted from peripheral blood samples. The present study has been approved by the institutional review boards of National Cancer Center and Shikoku Cancer Center Hospital and all registered patients have given written consent to participate in this study.  Results: To date, 33 patients have been enrolled. The frequency of FcGRIIIa-V158F genotypes were V/V 48%, V/F45%, F/F 6%, and that of FcGRIIA-H131R genotypes were H/H 59%, H/R38%, R/R 3% , respectively. 8-wk response could be evaluated in 29 patients (CR 1, PR 4, SD 13, PD 11). Clinical benefit was observed in 13 patients (CR 1, PR 6, SD>6months 6). FcGRIIIa-158V/V genotype was significantly correlated with 8-wk response (p=.017) and clinical benefit (p=0.02) of single-agent trastuzumab, while there was no significant difference in clinical response to trastuzumab by FcGRIIA-H131R polymorphism.  Conclusion: Although still preliminary, these data support the previous finding that FcGRIIIa-V158F polymorphisms play an important role in the clinical activity of trastuzumab. Updated results will be presented at the 31st annual San Antonio Breast Cancer Symposium.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6073.
Breast cancer in the United States: the burden on an aging, changing nation.
Authors: Smith BD , Smith GL , Hurria A , Buchholz TA
Published: December 2010

Abstract #6076

Background: Over the next 20 years, important demographic changes in the US will emerge, with the number of older and non-white Americans increasing dramatically. Though breast cancer incidence is known to vary by both age and race, the projected impact of impending population changes on breast cancer incidence has never been quantified. To delineate the future burden of breast cancer, we calculated population-based projections of breast cancer incidence through 2030.  Material and Methods: SEER data provided current age- and race-specific incidence rates for invasive or in situ female breast cancer. Age- and race-specific projections for the US population through 2030 were derived from Census Bureau data. Assuming stable race- and age-adjusted incidence, the total number of breast cancer cases by race and age through 2030 was estimated.  Results: From 2008 to 2030, the total number of breast cancer cases is expected to increase from 264,000 to 357,000. Of cases diagnosed in 2030, 60% will occur in women ages 65 and older. This represents a 67% increase in the number of breast cancer cases in women age 65 and over (from 127,000 to 212,000), compared to a 6% increase in women under age 65 (from 137,000 to 145,000). In 2030, 19% of all cases will occur in non-whites, representing a 70% increase in non-whites (from 40,000 to 68,000), compared to a 29% increase in whites (from 224,000 to 289,000). While cases in older non-white women currently represent only 13% of older patients, they will comprise 17% by 2030.  Discussion: With major demographic shifts on the horizon, an imminent wave of older breast cancer patients will impose a substantial burden on the US healthcare system. Efforts to expand capacity, contain cost, and define optimal treatment for older patients are urgently needed. Moreover, the projected increase in the percentage of breast cancer in non-whites heightens the importance of efforts to identify and minimize health care disparities.   

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6076.
Breast cancer in the elderly: histoclinial features and phenotypical characterization on tissue microarrays (TMA).
Authors: Jauffret EA , Boher J , Esterni B , Rousseau F , Jacquemier J , Viens P
Published: December 2010

Abstract #6079

Most breast cancer patients are diagnosed over the age of 65 years, and older cancer patients represent an increasing major public health problem. Research efforts are mainly focused on younger patients and the elderlies are initially excluded from most clinical trials. Improving kwnoledge related to elderly breast caner is urgently needed.734 patients over the age of 70 years out of the 4503 treated in our institution for primary breast cancer from 1975 to 2006 were studied. Pathological data revealed 716 (97.5%) invasive breast cancers, and 633 (88.5%) of ductal type including only 31 (8%) with predominant ductal in situ component. Lobular and mucinous carcinomas were present in11.5 and 3.5%.The tumors were mostly medium size (pT2); displayed no differences in lymph node involvement compared to younger patients and were treated by surgery (680, 93%) with 338 (50%)mastectomy, and with chemotherapy in only 22% (vs 48% in younger). Compared to youngers, tumors were mostly grade II (47%) and displayed less grade III ,estrogen receptors were expressed in 73% and tumors were less proliferative as assed on KI67/Mib1 expression (28 vs 38% positive <70 years) . Phenotypic characterization was done on Tissue-microarrays containing 305 spotted breast samples from patients over the age of 70 for 28 differents markers corresponding to different pathways : adhesion molecules (E-cadherin, p-cadherin, b-catenin), cell cyle and mitosis (fox a1, Ki67, p53, p27 ), differentiation markers (luminal CK8/18, basal/mesenchymal CAV1 &2, CK5/6, CK14, moesin, S100A9, SMA, vimentin, and stem cell markers ALDH1 and CD44), hormonal (hormonal and androgen receptors, bcl2, gata3), tyrosine kinases (ERBB2, EGFR), angiogenesis (angiogenin, CD146,VEGF) pathways. Compared to younger, no marker was significantly different in patients older than 70, except for hormonal pathway (a tendancy to be more positive). Nevertheless, specific survival and metastasis free survival (considering chemotherapy) revealed a worst outcome for older patients. Cox 's univariate model revealed claasical prognostic factors (hormonal pathway,ERBB2, EGFR, Mib1/Ki67) but did not highlight specific pathways. In conclusion, breast cancer in the Elderly is an heterogenic group that display less aggressive histo clincal features, a little more ER-phenotype with less proliferation but an adverse outcome. Specific factors remains to be discover to better treat these patients.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6079.
Breast cancer mortality trends in the WEST compared to the EAST: lives gained, lives lost.
Authors: Ragaz J , Bao P , Pisani P , Zheng Y
Published: December 2010

Abstract #6082

INTRODUCTION: Breast Cancer (BrCa) Mortality trends between 1950 – 2005 were reviewed between the Western (WEST) and Eastern Asian (EAST) countries, with the objective to gain understanding between therapeutic and diagnostic interventions and underlying epidemiology factors determining BrCa outcomes.  METHODOLOGY: We compared BrCa mortality trends in the WEST (Canada, UK, USA) and in the EAST (Japan and China-Shanghai). Data were obtained from WHO - IARC, Lyon (Canada, USA, UK, Japan); and from the Shanghai Cancer Registry (China-Shanghai). We analyzed age-standardized annual mortality rates per 100,000 / population (as per 1960 world standard population). Mortality trends were expressed relative to the baseline (year 1950 for all, year 1973 for China-Sha).  RESULTS: The baseline mortality rates were: 22.5 for Canada; 23.5 for UK; 21.6 for USA, 4.1 for Japan; and 7.3 for China-Shanghai.    CONCLUSION. These data confirm a substantial mortality reduction in the WEST evident after the 1980's - 1990's, likely reflecting the interaction of diagnostic and therapeutic interventions (mammography, education, systemic / locoregional therapies, etc). The different timing and extent of mortality reduction in the WEST probably reflect different degree of implementation of the interactive factors.  On the other hand, mortality is increasing in the EAST, in parallel with the “westernization” of those regions (industrialization, diet, etc, Ref. [NEJM; 2008:358;3)]. For the EAST, our data also support a correlation between the timing / extent of the “westernization” and mortality trend dynamics (i.e. mortality increase in Japan 20 years earlier than China).

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6082.
Low penetrance breast cancer predisposition SNPs are site specific.
Authors: Mc Inerney NM , Colleran G , Walther A , Rowan A , Spain S , Jones AM , Tuohy S , Barclay E , Curran C , Miller N , Kerin MJ , Tomlinson I , Eli S
Published: December 2010

Abstract #6085

Introduction  A locus on chromosome 8q24.21 has been shown to harbours variants that predispose to breast cancer, colorectal cancer and prostate cancer. The finding of risk variants clustering at 8q24 suggests that there may be common molecular mechanisms that predispose to the common epithelial cancers. The aim of this study was to determine whether the colorectal and prostate susceptibility alleles on 8q24 and other recently identified colorectal and prostate susceptibility alleles elsewhere in the genome are also associated with breast cancer risk.  Methods  In this study, we have studied three SNPs on 8q24.21: the breast cancer susceptibility SNP, rs13281615; the colorectal/prostate cancer susceptibility SNP, rs6983267; and the prostate susceptibility SNP, rs16901979; and eleven other SNPs outside of this region that have recently been shown to predispose to either prostate or colorectal cancer. Each SNP was genotyped in 988 sporadic breast cancer cases and 1016 controls from the West of Ireland using KASPar genotyping technology. We combined our data with publicly available datasets (breast: CGEMS, Fletcher et al.; prostate: CGEMS, Eeles et al.; CRC: Tomlinson et al.) by allelic, genotypic, dominant and recessive models using standard techniques of meta-analysis for SNPs previously identified to confer an increased cancer risk in specific tissue types. All analyses were done in Stata 9.2 (Stata Corp, TX).  Results  rs13281615 was associated with breast cancer (Pallelic test= 1.8 -2) with an odds ratio of 1.17. However there was no association between any of the prostate or colorectal susceptibility SNPs at 8q24 or elsewhere with breast cancer risk in our cohort. The data support the existence of a low-penetrance susceptibility locus for breast cancer near rs13281615; this locus seems to be distinct from the prostate and colorectal cancer loci in that region, even if the functional effects of the predisposition loci affect the same target gene or protein. Meta-analysis did not show an association between reported cancer SNPs and cancers in other tissue types.  Conclusions  This study suggests that low penetrance susceptibility SNPs for breast, colorectal and prostate cancer are distinct and argues against the presence of ''general' cancer predisposition SNPs. Although 8q24 harbours variants that predispose to all three cancers the susceptibility loci within the region appear to be specific for the different cancer types.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6085.
Breast cancer and renal insufficiency.
Authors: Wildiers H , Janus N , Byloos E , Machiels J , Duck L , Kerger J , Wynendaele W , Canon J , Lybaert W , Nortier J , Deray G , Launay-Vacher V
Published: December 2010

Abstract #6086

Background:  The Belgian IRMA study (Renal Insufficiency and Anticancer Medications) reported the high prevalence of renal insufficiency (RI) in 1208 cancer patients, with a glomerular filtration rate (GFR) <90 ml/min for 64%. Furthermore, 78.1% were receiving potentially nephrotoxic drugs and 78.8% drugs necessitating dosage adjustment in case of renal dysfunction. We present here the results for the 510 BIRMA patients with breast cancer.  Methods:  Data were collected for patients presenting at one of the 7 BIRMA centers in March 2006: tumor, sex, age, weight, height, serum creatinine (SCR), bone metastasis (BM) and anticancer drugs (including dose modification). Glomerular Filtration Rate (GFR) was estimated by the aMDRD formula.  Results:  510 breast cancer patients were included: mean age 58.7 years, weight 68.1 kg, height 161.6 cm, 4 men, 46.9% of patients had BM. The prevalence of elevated SCR (>=1.2 mg/dL) was 7.3%, of GFR<90 ml/min/1.73m² 67.8%, and of GFR<60 (threshold for many anticancer drugs to consider dose modification) 15.9% (Table). 86.6% of treated patients (n=486) were receiving at least one drug needing dosage adjustment in case of renal dysfunction and 73.4% received at least one potentially nephrotoxic drug. Furthermore, the prevalence of GFR<90/60 was 74.9/24.3% for breast cancer patients with BM (Table). When comparing the prevalence of GFR<90 between patients with or without BM (for patients with available GFR), the frequency of RI was significantly higher for BM patients (78.9 vs 69.9%, p=0.03).  Conclusions:  The results of the BIRMA study showed that RI is highly frequent in breast cancer patients in Belgium and that nearly 94% of the patients receive potentially nephrotoxic drugs and/or drugs for which dosage must be adjusted in RI. Furthermore, patients with BM had a higher rate of RI than patients without. These frequencies are higher compared to data from the NHANES study in the US general population, especially for breast cancer patients with a stage 3 RI for whom SCR was normal in 55.7% of the cases. This underlines that estimating renal function with formulae such as aMDRD is mandatory in every breast cancer patient, even when SCR is within the normal range.   

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6086.
Obesity and postmenopausal breast cancer: impact on risk, tumour stage and survival in an Irish population.
Authors: Healy LA , Ryan AM , Rowley S , Connolly EM , Kennedy MJ , Boyle T , Reynolds JV
Published: December 2010

Abstract #6089

Background   The evidence that obesity adversely affects women's health is overwhelming and indisputable. The risk of postmenopausal breast cancer increases with obesity. Furthermore it is reported that obesity is associated with poorer prognosis of breast cancer.  Objective  To assess the relationship between obesity and postmenopausal breast cancer by examining the incidence, tumour size, pathological stage, axillary nodal involvement and survival in an Irish population.  Design & Setting  A retrospective case control study was undertaken in 200 patients presenting to a tertiary centre between 1998-2006. Data were compared to 519 healthy female controls. Multivariate logistic regression models were used to calculate the odds ratio (OR) of developing postmenopausal cancer according to body mass index (BMI), as well as the impact BMI has on tumour size, nodal involvement, pathological stage and survival. Actuarial survival was calculated from date of diagnosis by the Kaplein-Meier method and comparisons between the groups were made by the log rank test.  Results  Postmenopausal breast cancer patients were significantly heavier than age matched controls with 65% being overweight or obese versus 54% of controls (p=0.030). A dose dependent relationship existed between BMI and postmenopausal breast cancer incidence. The adjusted odds ratio was 2.2 (95%CI 1.3-3.7) for individuals in the highest BMI quartile compared to the lowest BMI quartile (P=0.002). Using common cut-offs for BMI, obese patients had double the risk of postmenopausal breast cancer compared to normal weight patients OR 2.04 (95%CI 1.3-3.3; p=0.004). There was no difference in symptomatic detection, assessment or treatment of breast cancer, however operative times were significantly longer for obese patients (P=0.05). Obesity was associated with larger tumours (P= 0.002) and a later stage of disease at presentation (P=0.026) but not with axillary nodal involvement (P=0.332). Median and overall survivals were equivalent (P=0.172) when comparing obese to non obese.  Conclusion  Obese women are twice as likely to get postmenopausal breast cancer compared to normal weight women. Understanding why obese women have a higher breast cancer incidence may lead to more effective breast cancer prevention and treatment interventions. Obesity is a preventable risk factor for breast cancer and given the high and increasing prevalence of obesity in Ireland, obesity needs to be addressed on a national level with targeted lifestyle treatment programs.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6089.
Ethnic and geographical variability of breast cancer at the Osh region in Kyrgyzstan.
Authors: Makimbetov EK , Samieva N , Karabaeva J , Dgumabaev AR , Rzaev R
Published: December 2010

Abstract #6096

Background. To study age, regional and ethnic breast cancer incidence at the Osh region of the Kyrgyz republic.  Material and methods. Calculated the incidence of breast cancer between 1995 and 2005. There were registered 386 females with a new diagnoses of breast cancer. Collected dates from histological or cytological findings, and deaths certificates.  Estimated population relative risk (RR) for breast cancer in the urban and rural areas. The population figures and cancer incidence rates for this report were provided in for age groups (0-4, 5-9, 75 >) and ethnic groups. Counted crude, age-standardized rates (ASR) per 100 000. The classification scheme used by ICD-10.  Results. Only one patient (0.3%) has T1N0M0 stage of disease. Stage distribution: II – 107 (28%), III – 233 (60.9%), IV – 41 (10.8%).  ASR annual incidence in breast cancer was 6.51 (1995), 8.54 (2000), and 12.53 in 2005. Cancer incidence was significantly higher at the Osh city (17.87). Average rate was registered at the Karasu (8.06), Uzgen (7.09), Aravan (6.09), Naukat (6.4), and Karakuldga (6.14) regions. Low incidence was registered at the Alay (2.12), and Chonalay (4.55) areas.  High incidence of breast cancer was registered in the urban (ASR-16.6) compared with rural regions with ASR 5.16 (RR=3.21, CI 95%- 2.7; 3.8)  Relative risk for breast cancer was significantly higher in the Slavic ethnic groups (Ukraines and Russians with ASR of 66.4 cases per 100 000) compared with 3.75 for Kyrgyzs (RR=17.7), or 7.16 for Uzbek females (RR=9.27).  High incidence rate of breast cancer was registered in female with the richest socioeconomic status (more than 80% cases), compared with poorest status. Also high incidence was demonstrated in female in reproductive time of live (53.1%), dysmenorrheal status (78.8%), and aborts in anamnesis (65.4%).  Discussion. Breast cancer incidence at the Osh region of Kyrgyzstan is very low and similar to those reported from some developing countries. These analyses suggest that relative high risk in Russians compared with native ethnic groups may be related to some reproductive characteristics, number of child, socioeconomic status, and other.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6096.
Ixabepilone plus capecitabine vs capecitabine in patients with metastatic breast cancer receiving ixabepilone in the first line setting: a pooled analysis from two phase III studies.
Authors: Vahdat L , Fein LE , Karwal MW , Campone M , Peck R , Mukhopadhyay P , Jassem J
Published: December 2010

Abstract #6117

Background: Patients (pts) with breast cancer who progress within 1 year of adjuvant anthracycline (A) / taxane (T) therapy have limited options for first line treatment. Ixabepilone (ixa), the first in a new class of antineoplastic agents, showed clinical benefit in combination with capecitabine (C) in 2 large clinical trials in metastatic breast cancer (MBC) pts whose tumors were resistant to (study 046; JCO, 2007) or pretreated with A and T (study 048). In 048, ixa plus C, compared to C alone, demonstrated significant increases in PFS (HR 0.79 [0.69-0.90]) and ORR (43 vs. 29%). A trend towards increased OS was seen in both 048 (HR 0.90 [0.78-1.03] and 046 (HR 0.90 [0.77-1.05]) which did not reach statistical significance. Here we present a pooled analysis of efficacy outcomes (ORR, PFS and OS) from the 2 studies of pts who recurred within 1 year of adjuvant A/T therapy and received no prior metastatic treatment.  Methods: 1973 pts with MBC previously treated with A and T were randomized in open-label, multinational trials (046 and 048) to receive either ixa (40 mg/m2 IV over 3h Q3w) + C (1000 mg/m2 PO BID x 14d Q3w) or C alone (1250 mg/m2 PO BID x 14d Q3w). Due to the similarity of the study populations, individual patient data from both studies was pooled to better evaluate treatment effect within pre-planned patient subgroups. 293 pts were randomized to ixa + C or C alone in the first line setting.  Results: ORR and PFS favored ixa + C in this pt population, and there was a trend towards increased OS, which did not reach statistical significance (see table).    Conclusions: Pooled analysis of individual studies confirmed significant ORR and PFS benefit of ixa + C compared to C in pts whose disease relapsed within 12 months of adjuvant A/T.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6117.