bluuebunny/crossref_metadata_2025 huggingface dataset:
Multifunctional and multiplexed nanoparticles for molecular imaging and treatment of breast cancer.
Authors: Yang L , Sajja H , Cao Z , Wang AY , Smith MQ , Bender L , Mao H , Nie S , Wood WC
Published: December 2010

Abstract #6003

Multifunctional nanoparticles with the ability to target tumors, provide molecular imaging and to deliver therapeutic agents hold great promise for improving the survival of cancer patients. We have developed multifunctional nanoparticles targeted to cellular receptors that are highly expressed in breast cancer and tumor stromal cells. Fluorescent quantum dot (QD) or magnetic iron oxide (IO) nanoparticles are conjugated to either the amino-terminal fragment (ATF) of urokinase plasminogen activator (uPA) or to a single chain antibody against the epidermal growth factor receptor (ScFvEGFR), resulting in uPAR or EGFR targeted nanoparticles. Since the binding of ATF peptides or ScFvEGFR to their receptors results in blocking receptor function and internalization of the receptor-ligand complex, these targeted imaging probes can also inhibit tumor growth and deliver drugs. Using near infrared fluorescence (NIR) dye-labeled targeting peptides, we demonstrate specificity of these targeting ligands in an orthotopic human breast cancer model in nude mice. We found that tail vein injection of a mixture of Cy5.5 dye-ATF and IRDye 800-ScFvEGFR peptides leads to the selective accumulation of both probes in human breast cancer xenografts and NIR optical imaging of the tumors in the mammary fat pad of nude mice (Fig. A).    We show that uPAR- and EGFR-targeted nanoprobes display different patterns of intratumoral distribution with EGFR probes in the central area and uPAR probes in the peripheral and central regions of the tumor, which may be the results of expressing uPAR in the invasive edge of tumor cells and tumor stromal cells and EGFR only in tumor cells. In vivo optical imaging using ATF-nanoparticles is also demonstrated in human breast cancer xenograft (Fig. B) and in mouse mammary tumor lung metastatic models. Furthermore, magnetic Cy5.5-ATF IO nanoparticles are multimodality imaging probes for both optical and MR tumor imaging. Since magnetic IO nanoparticles are biodegradable and relatively safe for human use, we have developed a therapeutic imaging nanoparticle by encapsulating doxorubicin into the polymer coating of the nanoparticles and have shown selective delivery of the drug and cytotoxic effect in breast cancer cells in vitro. Results of our study show that multifunctional and multiplexed nanoparticles have great potential for the development of novel tumor imaging and therapeutic approaches.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6003.
The sensitivity of multidisciplinary triple assessment for diagnosing breast cancer in a symptomatic breast clinic.
Authors: Britton PD , Forouhi P , O'Neill A , Wallis M , Sinnatamby R , Gaskarth M , Sue B , John BR , Wishart GC
Published: December 2010

Abstract #6009

Introduction: Triple assessment by a multidisciplinary team comprising clinical and radiological examination, supplemented with tissue diagnosis is the standard of care for evaluating patients with potential breast cancer in symptomatic breast clinics in the U.K. Currently there are no guidelines for acceptable sensitivity of this process. This study reports the proportion of patients who return with breast cancer after initially having been reassured and discharged (analogues to screening “interval” cancer)  Methods: All new symptomatic episodes in the 3 year period from 01/01/2001 to 31/12/2003 were identified using a dedicated database. Patients discharged with a non-cancer diagnosis were traced through the database for a further 3 years and the clinical and imaging records of those subsequently diagnosed with cancer reviewed. Tissue diagnosis was obtained using percutaneous core biopsy in all cases.  Results: Of the 7,740 new symptomatic patients assessed 518 (6.7%) were diagnosed with breast cancer and 7222 were discharged. Of these, 32 patients were diagnosed with breast cancer over the next 3 years (5 within 12 months, 19 within 24months). This equates to a symptomatic “interval” cancer rate of 0.6 per thousand women within 12 months, 2.5 per thousand women within 24 months and 4.1 per thousand women within 36 months. This reflects an overall sensitivity for histology-based triple assessment of 99.6%. On review a definite delay in diagnosis was found in 5 (16%, 0.6/1000), a possible delay in 9 (28%, 1.1/1000) and no delay in diagnosis (no signs of disease on original radiology and no related clinical findings) in 18 (56%).  Conclusion: In this series less than 2 per thousand women discharged from a symptomatic clinic were subsequently found to have a cancer that might have been diagnosed at initial assessment, with an overall sensitivity for triple assessment of 99.6%. Modern multi-disciplinary “triple” assessment is a safe method of evaluating patients with potential breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6009.
Increase in mastectomies performed in patients in the community settings undergoing MRI.
Authors: Ayoola AG , Alagarsamy S , Jaboin J , Rao S
Published: December 2010

Abstract #6010

Background: It is estimated that about 182,460 new cases of breast cancer will be diagnosed in 2008 with an estimated 40,500 deaths. Contrast-enhanced MRI has been shown to have a high sensitivity for the detection of breast cancer in high-risk women with variable specificity. MRI offers an advantage that it is less operator dependent and can demonstrate small cancers, ductal carcinoma in-situ (DCIS), and multifocal disease effectively. The role of MRI in average-risk women however is not well elucidated. In these patients, MRI detects more lesions than mammography but it is uncertain if these lesions have significant pathologic potential or if the use MRI alters the ultimate surgical intervention in these patients.  Material and Methods:This is a retrospective study of 178 female patients over the age of 18 with breast carcinoma who underwent mammogram and MRI between January 2000 and December 2005. The patients' records were obtained from physician offices affiliated with three community hospitals in Baltimore, Maryland. The radiological and pathological reports of these patients were also examined.Of the 178 charts screened, 18 patients were excluded in the analysis because of missing data.  Results: MRI detected more lesions than mammogram; however, these lesions were not cancerous. The lesions detected by mammogram correlated more with pathological lesions. MRI detected more lesions as compared to the pathological specimens.    More patients who had both imaging modalities underwent mastectomies compared to those who had mammogram alone.    Discussion: The ability of MRI to detect an increased number of truly pathologic lesions has been a matter of controversy. In our patient pool, we demonstrated that MRI lesions did not correlate significantly with the number of pathological lesions found in subsequent surgical specimens. These findings suggest that MRI has a high sensitivity and low specificity in the detection of pathologic lesions in our study population. Based on this data, we can hypothesize that the use of MR imaging resulted in a higher number of lesions necessitating conversion to a mastectomy over treatment with lumpectomy alone.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6010.
Prevalence of BRCA1 and BRCA2 genes mutations in a sample of families with high risk of breast and ovarian cancer in Brazil.
Authors: Esteves VF , Thuler LS , Amendola L , Frankel PP , Vieira RJ , Koifman RJ , Koifman S
Published: December 2010

Abstract #6020

Introduction: Of all malignant neoplasia among women, breast cancer has the highest incidence rate in Brazil. The objective of the present study was to ascertain the frequency of genetic modifications in a high risk population for breast and ovarian cancer from different regions of Brazil. Methods: An exploratory, descriptive study was carried out on the prevalence of the BRCA1 and BRCA2 mutations in case series of high risk families to breast and/or ovarian cancer. Following the respective heredogram construction, a sample of blood was taken and DNA extraction was performed to all index cases. The protein truncation test (PTT) was used to screen for truncated mutations in exon 11 of the BRCA1 gene and in exons 10 and 11 of the BRCA2 gene. Results: Of the 612 individuals submitted to genetic testing, 21 (3.4%), 19 women and 2 men, had mutations in the BRCA1 or BRCA2 genes. BRCA1 mutations consisted of ins6kb, 5382insC, 2156delGinsCC, 185delAG, C1201G, C3522T and 3450del4 mutations, while BRCA2 mutations were 5878del10, 5036delA and 4232insA. Conclusion: The prevalence of germline mutations in the BRCA1 and BRCA2 genes found in the present study was lower than reported by other studies in Brazil. The inclusion of individuals with medium risk may have contributed towards the lower observed prevalence. Nevertheless, individuals with a high probability of carrying mutations should be advised with respect to the possibility of undergoing genetic testing, and of the risks, benefits and limitations of these tests.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6020.
Obesity, insulin resistance and oxidative stress: implication for breast carcinogenesis.
Authors: Lewis CM , Bu D , Euhus DM
Published: December 2010

Abstract #6025

Background: Obesity is associated with a modest increase in the risk of postmenopausal breast cancer (RR = 1.5 – 2.0); but, because nearly a third of the U.S. population is obese, the population attributable risk is estimated at 15%. Obesity can cause insulin resistance culminating in Type II diabetes. Notably, breast cancer incidence is significantly increased in the years preceding a diagnosis of type II diabetes. Because IGFBP-1 expression is tightly regulated by insulin, it is an excellent marker of insulin resistance in healthy individuals.  Methods: These data are based on well-annotated prospectively acquired baseline blood and breast tissue samples from 72 high risk women between the ages of 37 and 86 years who participated in a chemoprevention trial. None of the women had been diagnosed with Type II diabetes. Women with plasma IGFBP1 levels in the lowest tertile (mean 2.1 ng/ml) were classified as insulin-resistant.  Results: Plasma IGFBP1 was strongly inversely correlated with BMI (R2 = 0.247, P < 0.0001). Insulin-resistant women had marginally higher mean plasma free estradiol levels than women not classified as insulin-resistant (2.13 x 10-12M versus 1.53 x 10-12M, P = 0.072). There was no difference in plasma IGF1, IGF2, or IGFBP3 levels. Illumina whole genome expression microarray data was available for breast tissue from 55 women. Women classified as insulin-resistant showed evidence of an adaptive response to oxidative stress based on significant upregulation of NQO1, GSTK1, CYP4ZP2, and SRXN1 (P < 0.001).  Conclusions: Marginally increased circulating estradiol may contribute to the increased breast cancer risk observed in insulin-resistant women. However, insulin resistance increases oxidative stress in breast tissue and may promote carcinogenesis through induction of oxidative DNA damage.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6025.
Relationships between estrogen receptor co-regulators and intrinsic subtypes in breast cancer.
Authors: McCafferty MP , McNeill RE , Miller N , Kerin MJ
Published: December 2010

Abstract #603

Background: Gene expression profiling has characterised breast cancers into distinct subtypes largely based on the ER, PR and HER2/neu receptor status (i.e., luminal A, luminal B, HER2/neu over-expressing and basal-like groups). This study aims to investigate relationships between expression levels of genes representing these receptors i.e., ESR1, ESR2, PGR and ERBB2, and selected estrogen receptor co-activator genes (NCOA3, CREBBP) and co-repressor genes (NCOR1 and NCOR2). We also sought to identify whether these co-regulator genes were differentially expressed across subtype, related to patient outcome or known prognostic factors.  Materials and Methods: Using quantitative real-time PCR, we measured mRNA expression in sixty primary breast tumors and ten normal mammary glands. Relationships between gene expression levels and clinicopathological parameters, intrinsic subtype and clinical outcomes were analysed using Pearson's correlation coefficient, student t-test, ANOVA, Kaplan-Meier survival curves and Cox's proportional hazards model. P<0.05 was considered significant.  Results: Statistically significant correlations were observed between CREBBP expression and ESR1 (r =0.324); ESR2 (r=0.387); PGR (r=0.397); and ERBB2 (r=0.306). CREBBP also correlated with NCOA3 (r=0.447), a steroid receptor co-activator previously shown to be over-expressed in breast cancers; and was differentially expressed in the luminal B subtype compared to the others (P<0.001). An increase in tumour stage and NCOA3 expression was associated with shorter overall survival (Log Rank; P=0.009 and P=0.043). Prognostic significance of these parameters remained after multivariate analysis. We found no correlation between co-regulator expression and age at diagnosis, macroscopic tumour size and lymph node status.  Discussion: These findings demonstrate a relationship between CREBBP, breast cancer subtype, and the expression of genes known to be prognostic indicators or indicators of treatment response in breast cancer. Further investigations are required to establish how co-regulator expression influences these intrinsic groups.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 603.
mTOR modulates cellular fat metabolism by regulating stearoyl-CoA desaturase 1 transcription.
Authors: Luyimbazi D , Akcakanat A , Zhang L , Zheng Y , Meric-Bernstam F
Published: December 2010

Abstract #6030

mTOR (mammalian target of rapamycin) signaling is a central regulator of cell growth and proliferation. Rapamycin and its analogues have been shown to inhibit breast cancer cell growth in preclinical models, and are actively being pursued in clinical trials. We performed a high-throughput microarray polysome analysis to identify novel genes whose expression was regulated by rapamycin at the level of transcription or translation. In three breast cancer cell lines representing different breast cancer subtypes, we found a significant decline in polysome-associated mRNA for stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme in monounsaturated fatty acid synthesis. Insulin and insulin-like growth factor, both activators of mTOR, increase SCD1 expression. Rapamycin and PI3K inhibitors decrease SCD1 protein, as does mTOR siRNA. Quantitative RT-PCR of total, polysomal and monosomal RNA, northern analysis and stability studies demonstrate that rapamycin regulates SCD1 at the level of transcription. Furthermore, rapamycin inhibits the SCD1 promoter activation by mevinolin, an inhibitor of cholesterol biosynthesis. We demonstrate that mTOR regulates SCD1 expression. This establishes a novel link between cell signaling and cancer cell fat metabolism. In doing so, we also present SCD1 as a potential marker of response to treatment by mTOR inhibitors.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6030.
Lack of TIMP-1 tumor cell immunoreactivity predicts effect of adjuvant anthracycline based chemotherapy in patients (n=647) with primary breast cancer.
Authors: Willemoe GL , Hertel PB , Bartels A , Jensen M , Balslev E , Mouridsen H , Ejlertsen B , Brünner N
Published: December 2010

Abstract #6042

Background: Randomized trials have in general demonstrated that anthracycline-based chemotherapy prolongs disease-free and overall survival as compared to CMF-based regimens. In the Danish Breast Cancer Cooperative Group (DBCG) 89D randomised trial a 21% improvement in overall survival was observed from substitution of methotrexate in the CMF combination with epirubicin. This suggests that the additional effect of anthracyclines is confined to a subset of the patients. We have previously shown that in vitro grown cancer cells devoid of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) are more sensitive towards chemotherapy than cells expressing TIMP-1 (Davidsen et al., Br J Cancer, 2005). In addition, we have recently published (Schrohl et al., Clin Cancer Res., 2006), that patients with metastatic breast cancer and high levels of TIMP-1 in their primary tumor tissues, have a significantly reduced likelihood of obtaining an objective response to chemotherapy.  Purpose: The aim of the present study was to evaluate if Tissue Inhibitor of Metalloproteinses-1 (TIMP-1) tumor cell immunoreactivity could be used to identify a subset of patients who benefits from adjuvant chemotherapy.  Patients and Methods: Formalin fixed paraffin embedded tissue micro arrays from 647 patients who were enrolled in the Danish Breast Cancer Cooperative Group randomized trial 89D comparing adjuvant CMF versus adjuvant CEF were analysed for tumor cell TIMP-1 immunoreactivity. The primary end-point was invasive disease free survival (IDFS). Immunohistochemistry was performed using the anti-TIMP-1 monoclonal antibody VT7 as described previously (Sørensen et al., J. Hist. Cytochem., 2006) and the slides were scored as + or – for positive immunoreactivity.  Results: Tumor cell TIMP-1 immunoreactivity was found in 75% of the tumor samples. In the CEF treated patients, individuals with TIMP-1 negative tumors had a significant longer IDFS than patients with TIMP-1 positive tumors (p=0.047). The multivariate Cox regression analysis of IDFS showed that CEF was superior to CMF among patients with TIMP-1 negative tumors (HR: 0.51; 95%CI: 0.31 to 0.84, p=0.008), while no significant difference could be demonstrated among patients with TIMP-1 positive tumors (HR: 0.86; 95%CI: 0.66 to 1.11, p=0.24). However, only a non-significanct trend could be demonstrated between TIMP-1 status and CEF versus CMF (p=0.07 for interaction).  Conclusion: Lack of TIMP-1 tumor cell immunoreactivity seems to predict a favourable effect of epirubicin containing adjuvant therapy in primary breast cancer. However, an independent study is awaited to validate the potential predictive value of TIMP-1 immunoreactivity.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6042.
Diffuse optical spectroscopic imaging measures tumor functional response to bevacizumab: initial studies.
Authors: Tanamai W , Cerussi AE , Mehta R , Hsiang D , Tromberg BJ
Published: December 2010

Abstract #6056

Background: Diffuse Optical Spectroscopic Imaging (DOSI) is a non-invasive, bedside functional imaging technique that quantifies the concentrations and molecular states of tissue hemoglobin, water, and lipids. Pilot studies have shown that DOSI may be a useful tool for quantifying neoadjuvant chemotherapy response, typically by comparing the degree of change in tumor water and deoxy-hemoglobin concentrations before and after therapy. DOSI may offer a point-of-care measurement of tumor responses to therapeutic intervention. The majority of these DOSI studies have measured responses to Anthracyclines. However, the optical response to Bevacizumab has not been demonstrated in vivo in human subjects.  Materials and Methods: Twenty-one patients diagnosed with stage II/III cancers were followed with DOSI prior to and during their two-stage neoadjuvant chemotherapy regimen that featured (a) Anthracyclines (2-4 cycles) and (b) Trastuzumab/Bevacizumab (for HER2+/HER2- status, respectively). Changes between pre-treatment and pre-surgical DOSI-measured parameters were compared against final surgical pathology (complete, partial, or non-responder). A functional tissue optical index (TOI) was calculated that has been shown to discriminate between normal and malignant tissues.  Results: Both short-term and long-term changes in tumor physiology were observed. For both therapy strategies (N=21), statistically significant changes were measured in TOI from baseline to pre-surgery between complete (95+/-15%), partial (79+/-11%) and non-responders (38+/-42%). TOI changes after the initial therapy stage were strongest in patients with more favorable pathological responses (78%, 56%, and 12% for complete, partial, and non-responders respectively). For patients receiving Bevacizumab (N=9), more detailed serial image analysis of tumor deoxy-hemoglobin revealed short-term changes (7-14 days) where initial decreases in hemoglobin were soon followed by slow increases back to pre-treatment levels. Two of the patients who received Bevacizumab demonstrated detectible residual disease by DOSI after completion of all neoadjuvant therapy, despite that contrast-enhanced MRI signals had disappeared.  Discussion: We have provided evidence that DOSI may be well-suited to monitor the response of different cancer drugs, including anti-angiogenic compounds such as Bevacizumab, in breast cancer patients. While the usage of Bevacizumab in human subjects is still under investigation in breast cancer, we foresee that DOSI may be a useful tool in general for the development of drugs and dosing strategies.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6056.
Validation of the predictive value of tissue inhibitor of metalloproteinases-1 for the response to first-line chemotherapy in metastatic breast cancer.
Authors: Würtz S[ , Klintman M , Christensen IJ , Hertel PB , Fernø M , Malmberg M , Mouridsen H , Cold F , Schrohl A , Foekens JA , Malmström P , Brünner N
Published: December 2010

Abstract #6057

*Würtz SØ and Klintman M contributed equally, Malström P and Brünner N shares the senior authorship.  Background. Predictive markers are scarcely represented in breast cancer. TIMP-1 has in a previous study (n = 173) performed in our laboratory been shown to carry predictive information for the response to chemotherapy in metastatic breast cancer as high tumor tissue levels of TIMP-1 were significantly associated with a low objective response rate to treatment with the most frequently used chemotherapeutic drugs (CMF or anthracyclines). The purpose of the present study was to validate these previous results with a new independent patient population.  Methods. The TIMP-1 level was measured using a validated ELISA in 168 primary tumor extracts from patients with metastatic breast cancer and levels were associated with the objective response to CMF and anthracyclines. Patients were included in the study provided that they had received chemotherapy for their metastatic disease and that frozen tumor tissue as well as data on their objective response to chemotherapy was available.  Results. The median TIMP-1 level in responders was 17.3 (2.9 – 75.8) ng TIMP-1/mg protein and in non-responders it was 19.6 (0-190.3) ng TIMP-1/mg protein. When analysed as a continuous log-transformed variable, increasing tumor levels of TIMP-1 were associated with a decreasing probability of objective response to CMF or anthracyclines (OR = 1.59, 95% CI: 0.97 – 2.62, p = 0.07). This is very similar to the original study and thus supporting previous data. Next, we used a more clinically relevant approach for analysing the data from the validation study. For this analysis, objective response was scored as complete or partial response versus stable disease lasting at least six months (clinical benefit) versus progressive disease (non-response). This analysis showed that increasing levels of TIMP-1 were associated with a poor clinical benefit rate from chemotherapy (OR = 1.56, 95% CI: 0.98 - 2.51, p=0.06). The original study has not previously been analysed using this endpoint. When performing this analysis, similar results were found (OR = 1.62, 95% CI: 1.06 - 2.48, p = 0.02). Combining the new population and the original population in a pooled analysis (n = 341) using a random effects model showed that high levels of TIMP-1 were highly significantly associated with a poor clinical benefit rate from chemotherapy compared with patients with low levels (OR = 1.59, 95% CI: 1.16 - 2.18, p=0.003).  Conclusion. The present validation study supports previous findings that primary tumor tissue levels of TIMP-1 carries predictive information in metastatic breast cancer treated with chemotherapy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6057.
Phosphatidyl-inositol-3-kinase Alpha catalytic subunit kinase domain mutations impart a favorable prognosis on estrogen receptor positive breast cancer through a mechanism that is independent of responsiveness to endocrine treatment.
Authors: Ellis MJ , Lin L , Crowder R , Tao Y , Evans DB , Steinseifer J , Bandaru R , Liu W , Gardner H , Semiglazov V , Baselga J
Published: December 2010

Abstract #6060

Background. Mutations in the alpha catalytic subunit of phosphoinositol-3-kinase (PIK3CA) occur in approximately 30% of ER positive breast cancers but the impact of PIK3CA mutation status on the response to endocrine therapy has not been adequately studied.  Methods. cDNA and genomic DNA derived from baseline formalin-fixed core biopsy specimens from two neoadjuvant endocrine therapy trials (P024 and the letrozole alone arm of the RAD 2222 trial) were sequenced to detect exon 9 (helical domain - HC) and exon 20 (kinase domain - KD) mutations in PIK3CA. Interactions between mutation status and clinical, pathological and biomarker response to neoadjuvant letrozole and tamoxifen were determined.  Results. No impact of PIK3CA KD mutation on the efficacy of letrozole or tamoxifen on either clinical, pathological or Ki67 biomarker response to neoadjuvant endocrine therapy was detected in either study. In the 2222 trial, PI3KCA mutation status (KD and HD) was associated with higher levels of pAKT (P=0.01) confirming these mutations activate the PI3 kinase pathway. Despite the lack of an interaction with short term endocrine therapy efficacy endpoints, PIK3CA KD mutation, but not HD mutation, was a favorable prognostic factor for relapse free survival in the P024 trial (RFS log rank P=0.02) and the protective effect was maintained in a Cox proportional hazards model for relapse that included post treatment (surgical), Ki67 and ER and pathological node status and tumor size (HR for no KD mutation, 14, CI:1.9-105 P=0.01). The KD mutation-associated protective effect was particularly dramatic in a tumor subset that exhibited a biomarker profile indicative of endocrine therapy resistance and poor outcome (RFS Log Rank P=0.007 within worst outcome group).  Conclusion: In agreement with other studies, PIK3CA KD mutations but not HD mutations are associated with a favorable outcome in ER+ breast cancer but the protective effect of KD mutation is apparently independent of the degree of sensitivity to endocrine treatment. An alternative explanation for the protective effect of the presence of a KD domain mutation is that this mutation class reduces the metastatic potential of breast cancer. Pharmacological strategies that plan to specifically target tumors with PIK3CA KD mutations should take this possibility into account.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6060.
Predictive value of p27 for the benefit of adjuvant anthracycline-based chemotherapy in early breast cancer.
Authors: Conforti R , Moeder CB , Tomasic G , Boulet T , Nahta R , Yuan LX , Spielmann M , Delaloge S , Michiels S , Rimm DL , Esteva FJ , Andre F
Published: December 2010

Abstract #6063

Background: p27 is a cyclin-dependent kinase (cdk) inhibitor that plays a role in cell cycle regulation. The expression of this protein, assessed by immunohistochemistry (IHC), has prognostic value for overall survival in breast cancer patients (Porter P.L., J Natl Cancer Inst., 2007). Based on this, we hypothesized that p27 could be a predictive factor for the efficacy of adjuvant anthracycline (A)-based chemotherapy in early breast cancer.  Methods: Tumor samples from 823 patients, included at Institut Gustave Roussy (IGR) in two randomized trials comparing an A-based chemotherapy with no adjuvant treatment, were used to construct a tissue microarray. We previously reported predictive values of ER, Her2 expression and molecular subclassification using the same tissue array (Conforti R., Ann Oncol., 2007). Nuclear and cytoplasmic expression of p27 was assessed by the AQUA system. A p27 ratio of nuclear and cytoplasmic expression (p27 N/C ratio) was calculated for each tumor sample. The prognostic and predictive value of the continuous value of p27 N/C ratio was assessed by a Cox regression model adjusted for treatment, age, tumor grade, stage and ER expression (IHC) and stratified by trial.  Results: p27 was assessable in 715 primary tumors. The p27 N/C ratio was significantly different according to the molecular subclasses (p=0.001) and was higher in Her2- versus Her2+ and in EGFR+ versus EGFR- tumors (p=0.0075 and p<0.0001 respectively). There was an almost significant interaction between p27 N/C ratio and disease-free survival in the adjusted Cox model (p=0.052). The adjusted hazard ratios (HR) of relapse or death of a unit increase in p27 N/C ratio was HR = 1.27 (95% CI = [0.58-2.81], p = 0.55) in the control arm and HR = 0.30 (95% CI = [0.12-0.77], p= 0.01) in the A-arm. For overall survival, the adjusted interaction p-value was equal to 0.08. The adjusted HR of death of a unit increase in p27 N/C ratio was HR=1.67 (95% CI = [0.61-1.73], p=0.32) in the control arm and HR=0.32 (95% CI = [0.10-0.99], p=0.05) in the A-arm.  Conclusion: p27 N/C ratio, determined by the AQUA system, was borderline predictive for the efficacy of adjuvant A-based chemotherapy. However, this study is hampered by a relatively low number of events, a low dose of anthracycline, and multi-hypotheses testing (overall 20 biomarkers tested in different studies).

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6063.
Socio-economic deprivation independently predicts early recurrence in estrogen receptor positive breast cancer.
Authors: Mansell J , Monypenny IJ , Skene AI , Abram P , Carpenter R , Gattuso JM , Wilson CR , Angerson WJ , Doughty JC
Published: December 2010

Abstract #6081

Introduction: Socio-economic deprivation is associated with reduced survival in breast cancer, but little is known about how it affects the pattern of disease recurrence. We investigated the relationships between deprivation, other risk factors and recurrence in post-menopausal women with operable ER+ breast cancer.  Methods: Patients who underwent potentially curative surgery for ER+ breast cancer between 1995 and 2005 at four UK centres were studied. Those patients whose area of residence was ranked in the highest quintile group according to the appropriate national Index of Multiple Deprivation were classed as deprived. The cumulative risk of recurrence was calculated using the Kaplan-Meier method, and hazard ratios were calculated using conventional and time-dependent Cox regression analysis stratified by centre.  Results: 4110 patients were available for analysis, of whom 821 (20.0%) were classed as deprived. The median age at diagnosis was 62 years in both deprived and non-deprived groups. Tumour size and grade did not vary with deprivation status, but nodal involvement (38.0% vs 34.3%, p=0.05, Fisher's exact test) and lymphovascular invasion (28.1% vs 23.6%, p=0.01) were more prevalent in deprived patients. The latter were also more likely to undergo mastectomy (53.3% vs 47.2%, p=0.002) and less likely to receive adjuvant radiotherapy (50.4% vs 58.5%, P<0.001) or chemotherapy (19.1% vs 22.8%, p=0.03).  Median follow up was 5 years from diagnosis. Raw cumulative recurrence at 2.5 years was 8.4% (95% confidence interval 6.4-10.4) in deprived and 6.1% (5.3-6.9) in non-deprived patients. At 5 years the corresponding rates were 15.8% (13.1-18.5) and 13.3% (11.9-14.7). Only distant recurrence contributed to this difference, the local and contralateral recurrence rates being almost identical in deprived and non-deprived groups. Time-dependent Cox regression analysis showed that deprivation was a significantly stronger predictor of recurrence within 2.5 years of diagnosis than at later intervals, with or without adjustment for other prognostic variables (p<0.05). For recurrence within 2.5 years, the unadjusted hazard ratio for deprivation was 1.64 (95% CI 1.22-2.22, p=0.001). After adjustment for age, mode of presentation, pathological variables and treatment, the hazard ratio was 1.51 (1.07-2.14, p=0.02).  Conclusions: Post-menopausal women with ER+ breast cancer who are resident in areas of high deprivation are at increased risk of early recurrence, independently of known differences in tumour pathology and treatment.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6081.
Breast cancer mortality reduction in the western world: therapeutic versus diagnostic interventions. Implications for cancer care organization processes.
Authors: Ragaz J , Spinelli JJ , Semeniciw R , Hryniuk W , Budlovsky J , Franco E
Published: December 2010

Abstract #6083

INTRODUCTION. Recent epidemiology data show a substantial Breast Cancer (BrCa) mortality reduction in the western countries over the last decade. The literature indicates that both Adjuvant systemic treatments (Adj. SystTh) and Screening mammography (ScrM) contribute, but their interaction is not clear.  Our study examines if contribution of Adj. SystTh separate from ScrM could be more clearly identified; and also, - as a second objective, - if organization of cancer care could be correlated with BrCa mortality outcomes.  METHODOLOGY:  The mortality trends were compared among three Provinces of Canada with different Levels of Provincial Diagnostic and Therapy Guidelines (PDTG):  LEVEL I: most uniform coordination of PDTG: British Columbia (Brit.Col.), with a single Provincial budget; earliest implementation of Provincial Community Oncology Program (since the mid-1970's); and a uniform start of Adj. SystTh (late 1970's); and of ScrM (late -1980's).  LEVEL II: medium (Ontario).  LEVEL III: least uniform (Atlantic Provinces)*.  BrCa annual age-standardized mortality rates per 100,000/population were obtained from Statistics Canada for the years 1950-2004, and expressed relative to the year 1950 (the baseline).  RESUTLS: The 1950 BrCa mortality rates were: 30.9 for Canada; 31.4 for BC; 30.7 Ontario; 26.1 for Atlantic Provinces*.    CONCLUSIONS:  While both Adj. SystTh and ScrM contribute towards recent BrCa mortality reduction, the British Columbia data indicate that the impact of Adj. SystTh antedates that of ScrM, at least by a decade.  Our data support a correlation of BrCa mortality trends with the organization of cancer care: Effective implementation of PDTG (- i.e. incorporating early curative interventions into guidelines), will have a strong impact on mortality trends, particularly if executed  a. ongoingly,  b. uniformly, and  c. across the whole population.  Our data therefore indicate that early implementation of curative systemic therapy - or of any curative intervention - is essential, as their delay may prevent materialization of survival gains.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6083.
Survival analisis in breast cancer's women in Santa Catarina, Brazil.
Authors: Schneider IJ , Orsi ED
Published: December 2010

Abstract #6093

BACKGROUND: Overall survival after breast cancer diagnosis is influenced by the characteristics study's group, the study's place and biological factors.  OBJECTIVES: Define overall survival in five-years and the associated factors with the prognosis of breast cancer's women in Santa Catarina, Brazil.  MATERIALS AND METHODS: this is a historic cohort study, with data from diagnoses from January 2000 to December 2002 from Registro Hospitalar de Cancer of the Centro de Pesquisas Oncológicas,SC and the Hospital de Caridade, both in south Brazil, and complemented with data from the Mortality Information System until December 2007. The time of survival was calculated as the range of the date of diagnosis (biopsy or surgery) until the date of death or end of monitoring (5 years). The survival curves were estimated by the Kaplan-Meier method, using the log-rank test for comparison of the curves stratified. The effect of co-variable model was estimated by the semi-parametric risk proportionate, Model Cox, with the Schoenfelder analysis of residuals to assess whether the co-variables of the final model respect the principle of proportionality over time. The analysis was made using R 2.5.0.  RESULTS: 1002 women were included, and 262 deaths occurred, this 235 by breast cancer. The overall survival after 5 years was 76.2% (CI 95% 73,6-78,9%). Variables were associated with survival by the Kaplan-Meier curves: age, race/color, education, clinical stage, treatments received. This includes these variables in the model of Cox, remaining in the final model, as independent factors: age until 30 years (HR: 3,09, CI 95% 1,25-7,67); illiterate (HR 3,70, CI 95% 1,44-9,55); staging III (HR 5,27, CI 95% 2,56-10,82) and staging IV (HR 14,07, CI 95% 6,81-29,06); treatment with chemotherapy alone (HR 1,95, CI 95% 1,12-2,40), surgery, chemotherapy and radiotherapy (HR 2,38, CI 95% 1,36-4,16), compared to surgery and hormontherapy (HR 1.00). The Cox model variables respect the principle of proportionality over time (p=0,25).  CONCLUSIONS: The overall survival in breast cancer, proved to be better than in other Brazilian states. The instruction presents itself as a strong influence on survival, where illiterate women have worse prognosis. The combinations of treatment are also factors independent and influenced by biological factors. The diagnosis in advanced stages is one of the most important factors for worse survival, and modifiable through campaigns of early detection and mammography screening.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6093.
Modifications in breast cancer presentation patern in Goiânia, Brazil: descriptive analyzes of a population based of 15 years in a developing country.
Authors: Freitas-Júnior R , Martins E , Freitas NM , Curado M , Oliveira J , Silva CB
Published: December 2010

Abstract #6095

Objective: To epidemiologically describe breast cancer among women living in Goiania, Brazil. Patients and Methods: cases were identified from the Population-Based Cancer Registry of Goiania for the period from 1989 to 2003. The variables studied were age, diagnostic method, topographic sublocation, morphology and breast cancer extent. Frequency analyses were carried out on the variables and means and medians for the age were determined. The SPSS® 15.0 software was used for statistical analyses. Results: 3,204 breast cancer cases were collected. The mean age was 56 years and the median was 53 years. Histological confirmation increased from 86.8% to 96.9%. Over the first five-year period, 91.3% of the cases did not present any specific location for the tumor, while 84.7% did not in the second and 59.1% in the third. Infiltrating ductal carcinoma (IDC) was the most frequent type, with 2,627 cases (82%). Regarding extent, 45.6% of the cases were found to be localized and 10.2% presented distant metastases. The in-situ case rate was 0.2% in 1989-1993 and increased to 6.2% in 1999-2003. On the other hand, the advanced case rate was seen to decrease from 24.1% to 6.3%. Discussion: The diagnostic profile of breast cancer in the city of Goiania is changing. Substantial increases in the numbers of early breast cancer are occurring, to the detriment of the numbers of advanced cases. This therefore suggests that the sporadic screening programs used up to the present time have in some way changed the face of breast cancer in our region.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6095.
Racial discripancies in breast cancer in urban hospital retrospective analysis.
Authors: Rana FN , Jasani N
Published: December 2010

Abstract #6098

Background: Certain races, specifically African-Americans, have less overall lifetime risk of developing breast cancer, but have higher mortality rates for the disease. Race has been found as an independent risk factor and may be associated with variables such as treatment differences, socio-economic factors and differences in biological behavior of tumor . The search for explanations for persistent disparity in outcomes of breast cancer between races particularly between African-American and Caucasian women stills seems to be elusive.The objective of this study was to help us better define if differences in outcomes for African-American women are due to specific tumor biology and/or socioeconomic issues. This will allow us to create programs with regards to screening, education and prevention directed toward high risk populations at our institution.  Methods and Participants: Subjects included 446 women ( 189 blacks and 257 non blacks) aged 27 to 91 residing in metropolitan Jacksonville, Fl who were diagnosed with invasive or noninvasive breast cancer. Information on stage, insurance status, tumor profile/subtype, demographics and menopausal status was obtained from analysis of tumor registry at University of Florida/Shands Hospital between 2000 and 2005. Aggressive subtype was defined as triple negative (ER-, PR-, Her2 -) or HER2 + only. Indigent insurance was defined as Medicaid or no insurance. Advanced stage disease was defined as Stage IIb or greater. Menopausal status was defined as age greater than 50 as post menopausal and equal to or less than 50 as pre-menopausal. Comparisons were made by race with breast cancer subtype, insurance status, menopausal status and advanced stage presentation with differences analyzed by Chi-Square test.  Results: There was a statistically significant difference in advanced stage disease between black and non-black patients (p= .0007). Advanced stage disease was present in 42% (95% confidence intervals [CI] 35% to 49%) of black females and in 28% (95% CI 22% to 33%) of non-blacks. There was a statistically significant difference in aggressive subtype between black and non-black females (p= .0012). Aggressive subtypes were present in 30% (95% CI 24% to 37%) of black females and 17% ( 95% CI 13% to 22%) in non-black females. Based on Cochrane Mantel-Haenszel analysis the odds of having an aggressive subtype are 1.81 (95% CI 1.13 to 2.89) times greater in pre-menopausal than post-menopausal females. An aggressive subtype was seen in 39% of black pre-menopausal females and in 27% of black post-menopausal females. There was no statistically significant difference in insurance status between black and non-black females.  Conclusion: Black females tend to have more advanced breast cancer at initial presentation and aggressive tumor subtypes than non-black females. Aggressive tumor subtypes occurred at a higher prevalance in pre-menopausal black females compared.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6098.
Bevacizumab in combination with paclitaxel for HER-2 negative metastatic breast cancer: an economic evaluation.
Authors: Dedes KJ , Matter-Walstra K , Schwenkglenks M , Pestalozzi BC , Fink D , Szucs TT
Published: December 2010

Abstract #6104

Background: The addition of bevacizumab to weekly paclitaxel as primary chemotherapy for HER-2 negative metastatic breast cancer (MBC) prolongs progression-free survival without relevant increase of toxicity. However, the health economic implications of this costly treatment option have not yet been assessed.  Material and Methods: We constructed a Markov model comprising three health-states: stable or responsive disease, disease progression and death. Markov cohort simulation was used to follow the clinical course of typical patients with MBC. Cycle length was one month. Information on response rates, major adverse effects was derived, and transition probabilities were estimated, based on the results of the E2100 clinical trial. Direct costs of treatment, major adverse events, laboratory tests, and disease progression were assessed from the perspective of a Swiss statutory health insurance perspective. Utilities for health states were obtained from the literature. Costs are reported in 2008 Euros (EUR).  Results: Over the patients' lifetime, the addition of bevacizumab to weekly paclitaxel until disease progression is estimated to cost an additional 35'564 EUR and to yield a gain of 0.22 quality-adjusted life years (QALYs), resulting in an incremental cost-utility ratio of 164'921 EUR/QALY. In univariate and probabilistic sensitivity analyses, results showed a 95% CI from 117'998 to 484'251 EUR/QALY and were most sensitive to the cost of bevacizumab. Subgroup analysis indicated a more favourable cost-utility ratio (136'177 EUR/QALY, 95 % CI 97'999-435'823) in the age group < 50 years.  Discussion: Compared with commonly accepted willingness to pay thresholds in oncology, the addition 10 mg of bevacizumab per kilogram [body weight] to paclitaxel in MBC patients is expensive given the clinical benefit in terms of QALYs gained. Further research should consider patient age and alternative dosages for a more cost-effective utilisation of bevacizumab.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6104.
Adjuvant chemotherapy in breast cancer: is TC a cost-effective regimen compared to AC?.
Authors: Younis T , Rayson D , Skedgel C
Published: December 2010

Abstract #6110

Background: Adjuvant TC (taxotere 75 mg/m2 and cyclophosphamide 600 mg/m2 q 21 days X 4 cycles) has recently been shown to improve disease-free and overall survival compared to AC (adriamycin 60 mg/m2 and C 600 mg/m2 q 21 days X 4 cycles) for women with breast cancer. Given the possible differences in cost between the two regimens, an economic evaluation was undertaken to examine the cost-utility (CU) of TC relative to AC in terms of cost per quality-adjusted life year (QALY) gained. Methods: A Markov model was developed to calculate the cumulative costs and QALYs gained over a 10-year horizon for hypothetical cohorts of women with breast cancer treated with AC or TC. Event rates, costs, and utilities were derived from the literature. Costs expected with the delivery of standard courses of TC and AC at the Queen Elizabeth II Health Sciences Centre in Halifax, Canada were estimated. Costs included chemotherapy drug acquisition, supportive medications, laboratory investigations, health resource utilization, and significant adverse events associated with chemotherapy. Efficacy outcomes were based on the updated results of the clinical study of TC vs AC (Jones et al, SABCS 2007). The model took a third-party direct payer perspective and reports results in 2008 Canadian dollars ($). Both costs and benefits were discounted at 3%. Sensitivity analysis for key parameters in the model was conducted. Results: TC is associated with $4,080 incremental cost and 0.25 QALY gain compared to AC at 10-year horizon, with a favorable CU of $16,611/QALY gained. Results were robust to model assumptions and input parameters. Conclusions: TC is cost-effective compared to AC with a cost-effectiveness ratio well below commonly employed thresholds.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6110.