bluuebunny/crossref_metadata_2025 huggingface dataset:
Building prognostic and predictive models for cancer patients using expression modules and clinical variables.
Authors: Fan C , Parker J , Perou CM
Published: December 2010

Abstract #5063

Background: Prognostication for breast cancer patients is improving, in part through the use of genomic predictors. However, most predictors only utilize one data type that is gene expression data, and thus prognostication that simultaneously uses multiple data types may result in even more accurate predictors.  Methods: We recently developed a unique risk of relapse predictor based upon a Cox proportional hazards model that contained gene expression (5 intrinsic subtypes) and clinical variables (tumor size and node status)(Parker ASCO 2008 abstract #11008). This model was accurate in predicting 7 year relapse probabilities and out performed the genomic or clinical variables only models. Building upon this combined genomic plus clinical parameters approach, we reasoned that including other expression modules indicative of pathway activation and cell type signatures might further improve our models. Therefore we build a collection of >200 expression modules using 1) unsupervised hierarchical and bi-clustering analysis 600 human tumors, 2) similar cluster analyses of 250 mouse mammary tumors, 3) >50 published breast tumor genomic profiles, and 4) signaling pathway activation modules derived from our own work. Each signature, or module, was then used with LASSO variable selection to determine if prognostic Cox Proportional Hazards models could be built using a local therapy and tamoxifen only treated patient set.  Results: These analyses show that highly significant prognostic models could be built for 1) all patients, 2) ER-positive patients, and 3) Luminal patients. Less predictive, yet significant models were created Basal-like patients, and no successful models could be developed for ER-negative patients, or for the expression-defined HER2-enriched subtype. For most significant predictors, the Cox model contained human-derived modules, mouse-derived modules, and pathology variables; for example the predictor for ER-positive patients contained human modules for proliferation, hypoxia, an embryonic stem cell derived signature, three mouse modules with one containing multiple metalloproteinases, tumor size and node status. In addition, the actual modules selected for the different patient subsets varied such that the modules selected for the Basal-like patients did not overlap any module selected for all patients, or for the ER-positive patient subset.  Conclusions: These analyses further reinforce the idea that breast cancer is a heterogeneous disease and suggest that prognostic models for each important patient subset should be developed and used. Models that contain treatment variables, in addition to prognostic terms, are also being developed and will be presented. In summary, these analyses argue that the best prognostic algorithms for breast cancer patients contain biological variables coming for humans, from model systems, and from classic pathology.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5063.
Aberrant inducible nitric oxide synthase expression predicts poor survival in estrogen receptor negative breast cancer, and is associated with a gene expression signature similar to that of basal-like breast cancer.
Authors: Glynn SA , Boersma BJ , Howe TM , Ridnour L , Wink D , Yi M , Yvantis H , Ambs S
Published: December 2010

Abstract #5067

Background: Inducible nitric oxide synthase (iNOS) is a key enzyme in the inflammatory process, that catalyses the production nitric oxide (NO). NO is a free radical that affects the redox state of tumor cells and thus cell signaling. We hypothesized that iNOS expression is associated with markers of outcome and influences breast cancer survival by estrogen receptor (ER) α-independent mechanisms.  Method: 248 cases of incident breast cancer were examined by IHC for iNOS expression. Univariate and multivariate analyses were performed to assess correlations between iNOS expression and clinico-pathological features of breast cancer, and patient survival. In addition, 35 tumors were laser capture microdissected and the effect of iNOS on gene expression profiles analyzed by Affymetrix gene expression arrays.  Results: iNOS was moderately to strongly expressed in the majority of breast tumors (70%). iNOS was significantly associated markers of poor prognosis including p53 mutation accumulation, increased microvessel density, and high tumor grade. iNOS was not associated with race/ethnicity (143 African American, 105 Caucasian). In Cox regression analysis, high levels of iNOS expression was a predictor of both 5-year (Hazard Ratio - 5.41; 95% C.I. 1.25 to 23.48) and 10-year (H.R. 4.63; 95% C.I. 1.36 to 15.73) breast cancer-specific survival in women with ER-negative tumors. iNOS was not a predictor of ER positive breast cancer survival. Neither tumor p53 status nor chemotherapy modified these associations. Gene expression analysis identified changes in significant changes in gene expression with high levels of iNOS expression in ER negative breast cancer. This observation was not seen in ER positive breast cancer.  44% of the iNOS associated genes had previously been found to be associated with the ER negative breast cancer subtype, basal-like breast cancer phenotype.  Discussion: These results suggest that iNOS contributes to the pathogenicity of ER-negative breast cancers and is a predictor of patient survival. The similarity of the iNOS induced gene signature to that of basal-like breast cancer, suggests that iNOS may play a role in the aggressive nature of basal-like breast cancer and may be a potential therapeutic target for the treatment of ER negative and basal-like breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5067.
Genomic score predictive of metastatic evolution in breast cancer.
Authors: MacGrogan G , Guedj M , Primois C , Brouste V , Banneau G , Debled M , Mauriac L , Sevenet N , Petel F , Longy M , Bonnet F
Published: December 2010

Abstract #5069

Background: Despite of the existence of clinical and pathological prognostic factors, the metastatic evolution in breast cancer remains uncertain in a substantial proportion of cases. Previous studies have suggested that genome profiling could address this question. In this context we developed a genomic score to evaluate the total level of copy number aberrations in a given tumor, based on data from array-CGH analysis.  Material and Methods:We performed array-CGH analysis in a series of 135 sporadic, operable breast cancers treated at our institution between 1989 and 1992 (more than 10 years follow-up). These cases included 45 invasive ductal carcinomas with metastatic evolution (M+) and 90 cases that did not relapse at 11 years (M- ). Cases were paired on patients age and initial axillary lymph node status (pN +/pN0), and were equally distributed between the two groups of evolution: 25 pN0/M+, 20 pN+/M+, 50 pN0/M- and 40 pN+/M-. Tumoral DNA was co-hybridized with pooled normal germline DNA from 20 individuals on a 4407 BAC-array (CIT-V6) provided by the CIT program and manufactured by Integragen. Gain, normal and loss status (GNL) were generated from the CapWeb pipeline developped by the bioinformatics plateforme from Institut Curie (Paris). Clinical, pathological and genomic data were retrieved through Annotator, the CIT cancer database and the analysis has been driven by using the R statistical software along with the CIT R packages.  Results:The proposed score of genomic instability is based on two items: (i) the proportion of alteration and (ii) the number of altered genomic regions. By applying a set of appropriate thresholds on these two items we were able to define three highly different prognostic subgroups, 95 % (18/19), 74 % (65/88) and 25 % (7/28) 11 years metastatic-free survival respectively (p-value = 4.04e−10) while univariate analysis of histological parameters such as tumor size and SBR grade showed weaker associations (p-values of 0.006 and 0.065 respectively). The predictive properties of the genomic score have been assessed by cross-validation but also on other independent large data sets. A signature of genome instability inferred from genomic and gene expression profiles will also be proposed.  Conclusion: Genomic profiling in breast carcinoma is a strong tool for prognostication in breast cancer. We developed a computational method to characterize genome instability of that predict clinical outcome in breast cancer and could be useful for more accurate therapeutic choice but also for identifying new therapeutical targets.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5069.
Prognostic impact of tumor-specific HMG-CoA reductase expression in primary breast cancer.
Authors: Borgquist S , Jögi A , Pontén F , Ryden L , Brennan D , Jirström K
Published: December 2010

Abstract #5071

Background  We have previously reported that tumour-specific expression of the rate-limiting enzyme in the mevalonate pathway, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) is associated with more favourable tumour parameters in breast cancer. In the present study, we examined the prognostic value of HMG-CoAR expression in a large cohort of primary breast cancer patients with long-term follow up.  Methods   The expression of HMG-CoAR was assessed by immunohistochemistry (IHC) on tissue microarrays with tumour specimens from 498 consecutive breast cancer cases with a median follow-up of 128 months. Kaplan Meier analysis and Cox proportional hazards modelling were used to estimate the risk of recurrence free and breast cancer specific survival.  Results   In line with our previous findings, tumour-specific HMG-CoAR expression was associated with, low grade (p <0.001), small (p = 0.007), ERα positive (p =0.01), Ki-67 negative (p =0.02) tumors. Patients with tumours expressing HMG-CoAR, had a significantly prolonged disease-free-survival, also when adjusted for established prognostic factors; RR= 0.60, 95% CI (0.40-0.92); p=0.02. In estrogen receptor negative tumours, however, there was a trend, however non-significant, towards a shorter DFS in HMG-CoAR expressing tumours.  Conclusion  HMG-CoAR expression is an independent predictor of a prolonged disease-free-survival in primary breast cancer. This may, however, not be true for ERα negative tumours. Further studies are needed to shed light on the value of HMG-CoAR expression as a surrogate marker of response to statin treatment, especially with respect to hormone receptor status.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5071.
JNK, essential for anticancer therapy-induced apoptosis, promotes breast cancer progression.
Authors: Wang J , Kuiatse I , Casa AJ , Lee AV , Cui X
Published: December 2010

Abstract #5075

The c-Jun N-terminal kinase (JNK) is a critical mediator of stress-induced apoptosis and is required for the cytotoxic effect of anticancer therapies. Interestingly, recent clinical studies showed that high JNK activity is associated with poor prognosis in human breast cancer. The molecular basis of this potential dual function of JNK in breast cancer is poorly understood. Here we report that overexpression of a constitutively active JNK in breast cancer cells increased cell migration and invasion. In agreement with this, fibroblast-specific markers like the intermediate filament vimentin and the extracellular matrix protein fibronectin were up-regulated. AP-1 transcription factor, which induces expression of these two proteins, was markedly increased by JNK overexpression. In addition, hyperactive JNK reduced Akt1 activation but enhanced Erk activation in breast cancer cells. In relevance, we also found that JNK levels are significantly higher in invasive breast cancers including those with distant metastases (n = 235, p < 0.0001, Wilcoxon rank sum test) than in normal breast tissues (n = 69). Most surprisingly, an increase of JNK attenuated the apoptosis of breast cancer cells treated with chemotherapy drugs doxorubicin and taxol. This suggests that the role of JNK changes when its activity/expression increases above the basal levels associated with apoptosis. Our data, together with a recent finding that cells undergoing cytotoxic agent-induced apoptosis can induce compensatory hyper-proliferation of proximal cancer cells, suggest a novel mechanism of breast cancer therapeutic resistance. Therapy-elicited apoptosis of tumor cells with basal JNK activity may release mitogens that induce hyperactive JNK in neighboring cells to promote growth and invasion. Thus JNK activation may serve as a marker of breast cancer progression.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5075.
Levels of 25-hydroxy-vitamin D in pre-menopausal women at high risk for development of breast cancer.
Authors: Fabian CJ , Kimler BF , Phillips T , Zalles CM
Published: December 2010

Abstract #5079

Background: There is biologic and epidemiologic evidence to suggest an inverse relationship between vitamin D intake and the risk of developing breast cancer, particularly for adolescent and premenopausal women. A recent meta-analysis of nested case control studies in an average risk cohort has suggested that those with >50 ng/ml of the pro-hormone 25-hydroxy-vitamin D, 25(OH)D, a good measure of recent vitamin D intake from all sources, have 50% fewer breast cancers than women with 25(OH)D levels regarded as severely deficient (<12 ng/ml) and 20% fewer breast cancers than those with levels regarded as deficient (12-20 ng/ml) or insufficient (20-30 ng/ml) [Garland et al. J Steroid Biochem Mol Biol 2007;103:708].  Materials and Methods: To determine if vitamin D supplementation should be explored as a prevention strategy in young women, we assessed the distribution of 25(OH)D levels in 100 high risk pre-menopausal women being screened for possible participation in Phase II prevention trials of a COX-2 inhibitor. These women were between the ages of 20 and 52, had undergone a random periareolar fine needle aspiration (RPFNA) and had serum frozen at -80°C within 2 months of the RPFNA. Serum was batch assayed for 25(OH)D, using the Liaison kit by DiaSorin (chemiluminescent assay) in a CLIA approved lab.  Results: Of 100 high risk women, 15% exhibited 25(OH)D levels considered severely deficient, 34% deficient, and 27% insufficient, Only 24% women exhibited 25(OH)D levels above 30 ng/ml, considered to be sufficient for bone health while only 4% had levels suggested as optimal for breast health. We have previously reported that high risk women with cytologic evidence of atypia had a 5 fold increase in their 4 year risk of developing DCIS or invasive cancer compared to those who do not [Fabian et al. J Natl Cancer Inst 2000; 92:1217]. Ninety-nine percent of women in our cohort were considered to have cytologic evidence of hyperplasia without (70%) or with (29%) atypia and median 25(OH)D levels were not different between samples regarded as hyperplastic and those assessed as atypical.  Discussion: These results indicate that 75% of high risk pre-menopausal women likely to participate in tissue biomarker-based chemoprevention trials will exhibit 25(OH)D levels that are insufficient for bone health and only 4% will have levels suggested from case control studies as being optimal for breast health. In this retrospective study, no association was observed between serum 25(OH)D levels (a marker of recent vitamin D intake) and a cytologic marker of increased breast cancer risk. A prospective trial is in progress to confirm the high prevalence of vitamin D insufficiency in young high risk women and to correlate 25(OH)D levels with a variety of tissue, imaging and serum-based risk biomarkers.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5079.
Comparison of weight loss with a National Cancer Institute diet and a plant-based olive oil diet in overweight women with invasive breast cancer.
Authors: Flynn MM , Fenton M
Published: December 2010

Abstract #5080

Background: Breast cancer risk increases with increasing body weight, higher blood levels of fasting insulin and triglycerides, and lower HDL-c. Weight loss and diet can affect these variables. Lower fat diets are routinely recommended for weight loss and cancer prevention, yet no firm evidence indicates an advantage compared to moderate fat diets. Further, lower fat diets can adversely affect fasting blood levels of insulin, triglycerides and HDL-c.  Methods: Overweight women diagnosed with invasive breast cancer after the age of 50 consumed a National Cancer Institute diet (NCI; total fat: >15% to <30%) and a plant- based, olive oil diet (PBOO; total fat: >35%, primarily from extra virgin olive oil) for 8 weeks each in a crossover trial with random assignment to order. Fasting blood samples at the end of each diet were analyzed for insulin, triglycerides and HDL-c.  Results: Results for 20 subjects. Percent weight loss (NCI: 4.2+1.9; PBOO: 5.6+2.2) in this preliminary group exhibited a significant diet-order effect.    Conclusion: These initial results suggest that weight loss can be achieved with a plant- based, higher- fat diet emphasizing extra virgin olive oil, and such a diet may have a metabolic advantage compared to the standard, lower-fat diet. This study was funded by Susan G. Komen for the Cure Grants Program.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5080.
Postmenopausal hormone therapy in a prospective randomized trial of termination versus long-term continuation results in greater regional brain metabolism.
Authors: Silverman DH , Geist CL , Kenna HA , Rasgon NL
Published: December 2010

Abstract #5088

Objective: Beyond the potential effects of sex steroids on the risk of developing breast and other cancers, the effect of postmenopausal hormone therapy on human brain aging and cognition is also currently highly controversial. In a prospective study of women at increased risk for developing Alzheimer disease (AD), we examined the influence of exogenous and endogenous estrogen exposure on regional cerebral metabolism. Methods: Women on postmenopausal hormone therapy (HT) and at increased risk for AD were randomized to immediately terminate or continue HT. Of 81 total subjects studied to date, data from the first 25 consecutive subjects to complete the 2-yr protocol are presented. Subjects in each randomized arm were similar in average yrs of education (16.5 vs. 16.6), age at menarche (13.1 vs. 12.6), age at menopause (47.3 vs. 47.9), and age at recruitment (58.4 vs. 58.9). All subjects underwent FDG-PET imaging at baseline as well as 2 yrs after randomization, and scans were assessed for interactions of time-, exogenous therapy arm-, and endogenous hormonal covariate-based effects, with statistical parametric mapping. Results: Across all subjects, yrs of endogenous estrogen exposure (age at menopause minus age at menarche) positively correlated most significantly (t=4.23,p<0.0005) with metabolism of the precuneus area of the posterior medial cortex (area where perfusion is most significantly diminished in early stages of AD), which is consistent with experimental animal and human epidemiologic data supporting a neuroprotective role for estrogen. Two years after termination of HT, subjects demonstrated a highly significant negative correlation (t=-9.27,p<0.0005) of yrs of endogenous exposure with metabolism of anterior medial frontal cortex (area of the brain undergoing the most significant decline of perfusion and metabolism with normal aging), suggesting that the levels of frontal metabolism reached during the years of greater endogenous exposure were more rapidly lost during 2 yrs of estrogen deprivation. Moreover, those women who continued HT during the 2 yr interval of randomization, actually demonstrated a significant increase in the most anterior portion of their medial prefrontal cortex during that period (t=5.06,p<0.0005), while those women who discontinued HT did not, and this part of the brain was the location of the largest increase over 2 yrs (4083 contiguous voxels having signigicance of p<0.01) throughout the brain. Conclusion: Both exogenous and endogenous hormone exposure were associated with changes in medial cortical metabolism consistent with neuroprotective roles relevant to metabolic changes occurring in brain aging and dementia.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5088.
Day surgery for breast cancer: a pilot randomised controlled trial.
Authors: Marla S , Proctor M , Romics L , Ogston K , Cooke T , Stallard S
Published: December 2010

Abstract #5090

Background: Over the past 10 years, surgical management of Breast Cancer has undergone a huge change. More patients are now treated by breast conserving surgery (BCS) and lesser axillary surgery. Therefore, great potential exists to carry out Breast Cancer surgery in day surgery (DS) setting. However, at present few centres in the United Kingdom are practicing this.  The objectives of the present study were: (i) to review the evidence in literature, (ii) analyse current practice and (iii) conduct a pilot randomised controlled trial (RCT) comparing DS and inpatient surgery (IS) for patients undergoing BCS for Breast Cancer.  Methods:  (i) A systematic review of literature searching DS for breast cancer was performed using standard search tools.  (ii) Age, treatment and length of stay information about all breast patients admitted at a tertiary centre from March, 07 to Jan, 08 was prospectively collected.  (iii) Newly diagnosed breast cancer patients undergoing BCS with axillary sampling who had passed the DS preassessment were randomised to DS or IS. Physical and psychosocial outcomes were assessed using a Surgical Site Infection Form (Day 7 and Day30), FACT-B questionnaire (Baseline, Day7 and Day30) and a Patient Diary for the first post-operative week.  Results:  (i) No RCTs were found in the literature. Ten observational studies describing DS for breast cancer were included. Seven of these found DS to be safe with equivalent complications to IS and 3 highlighted its economic benefits. Only 1 study used a validated psychological distress scoring system and found results in favour of DS.  (ii) Over the 10-month period there were 288 breast cancer operations. Of these, only 112 (38.9%) stayed in the hospital for > 23 hours. Hence, it would be ideal to consider breast cancer for DS.  ((iii) There were 18 patients in the pilot RCT; 11 in the DS arm and 7 in the IS arm.  Physical outcomes: There were no significant differences in pain, nausea or vomiting scores and infection rates. Patients in the DS group mobilised and stepped out of their house earlier (Day2 vs. Day4) after surgery and also more frequently (4 days vs. 3 days) in the first week than the IS group.  FACT-B: Longitudinal differences in overall FACT B scores obtained on Day 7 and Day 30 compared to Baseline scores are detailed in Table1. A difference of > 5% was considered significant.    Conclusions: Systematic review of literature showed DS to be safe for the patient but there is lack of evidence in the form of RCTs.  This pilot RCT shows that DS patients mobilise earlier and have equivalent results for the other physical outcomes. FACT-B scores suggest better quality of life a week after surgery in the DS group.Larger RCTs are needed to support these results.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5090.
Choosing chemotherapy: who says “yes please”?.
Authors: Price RK , Morgan CZ , Roe T , Massey E , Chaudry A , Jenkins* P , Bristol JB , Chan CH
Published: December 2010

Abstract #5091

Introduction:  Increasing numbers of patients are being offered adjuvant chemotherapy for early breast cancer. In the United Kingdom, the National Health Service provides cancer treatment free at the point of delivery. So what makes people decide whether to have chemotherapy?  Methods:  We examined the decision made by patients treated in our centre in 2007. Data were obtained from our prospectively collected database about age, prognosis (Nottingham Prognosis Index/Score - NPI), ER, HER2 status, and residential ZIP code. The UK Government Index of Multiple Deprivation (ID2000, Office for National Statistics) is based on the 2000 national census and provides two measures, the ID 2000 score and the ID2000 Rank (1 to 8414 in England and Wales). We matched ID2000 scores and ranks to ZIP codes. Low ID2000 scores and ranks are seen in affluent areas. Chemotherapy uptake was examined by age, NPI, ER, HER2 status and ID2000 using Stat View 5.0® software (SAS Institute).  Results:  282 patients (279 women and 3 men) with invasive breast carcinoma were treated in 2007 at our centre. 135 (47.9%) were offered chemotherapy. 103/135 (76.3%) decided to have chemotherapy and 32/135 (23.7%) declined.  Chemotherapy was more commonly accepted by patients of young age (Mann Whitney U, p=0.0003), high NPI (Mann Whitney U, p=0.0012) and with HER2 positive tumours (Chi2 test, p=0.05). ER status (Chi2 test, p=0.27) and deprivation (Mann Whitney U, ID2000 score p=0.46, ID2000 rank p=0.46) had no effect on whether patients chose to have chemotherapy.  Conclusion:  Significant numbers of patients are now being offered adjuvant chemotherapy. Most patients accept chemotherapy when this is offered, although a significant minority (23.7%) decline the offer. Younger patients and those with poorer prognosis are more likely to accept this. Social deprivation, however, is not an influence in patient choice, when the patient has care 'free at the point of delivery'.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5091.
Influence of private practice setting on adjuvant chemotherapy use for elderly women with early-stage breast cancer.
Authors: Hershman DL , Buono D , McBride RB , Tsai W , Neugut AI
Published: December 2010

Abstract #5096

Background:  For elderly women with breast cancer (BC), the decision to undergo treatment with adjuvant chemotherapy may be associated with non-medical factors, such as physician and practice characteristics. Since physicians influence medical decision-making, we evaluated the association between oncologist characteristics and receipt of adjuvant chemotherapy in elderly women at both high and low-risk for breast cancer recurrence.  Methods:  We used the SEER-Medicare database to identify women >65 years, diagnosed with stages I-III BC, between 1992-2002, and used the Physician Unique Identification Number linked to the American Medical Association Masterfile to obtain information on oncologists. We investigated the association of patient demographic, tumor, and oncologist-related factors with receipt of chemotherapy for both women with high and low risk of recurrence, using Generalized Estimating Equations to control for clustering. We defined patients as low-risk who had hormone sensitive, stage I/II cancer, and high-risk if they were hormone receptor negative and stage II/III.  Results:  Of 42,544 women with stage I-III BC, 8,714 (20%) were treated with adjuvant chemotherapy. The proportion of women with high-risk tumors treated was 61% while the proportion with low risk cancers was 15%. Patients who received chemotherapy were younger, of higher SES, and had less favorable tumor characteristics. They were also more likely to be married, diagnosed more recently and have fewer comorbid conditions. In a multivariable analysis, women who underwent chemotherapy were more likely be treated by an oncologists who was primarily employed in a private practice (OR=1.40; 95%CI 1.23-1.59), and completed training after 1975 (OR=1.12; 95%CI 1.01-1.26), and were less likely to have an oncologist who trained in the United States (OR=0.83; 95%CI 0.74-0.93), than oncologists of patients who did not receive chemotherapy. The association between oncologists in private practice and receipt of chemotherapy was slightly stronger for patients who were at high-risk (OR=1.55) than those for low-risk (OR=1.35) for cancer recurrence.  Conclusions:  After controlling for confounding variables, elderly women with both high risk and low risk BC treated by oncologists who were primarily employed in a private practice were more likely to receive adjuvant chemotherapy. Other oncologists characteristics, such as gender, patient volume and type of degree were not independent predictors of receipt of chemotherapy. Efforts to differentiate whether these associations reflect experience, practice setting, insurance type, or other economic incentives are warranted.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5096.
Preliminary findings from a patient navigator program with Hispanic women from community clinics in South Texas.
Authors: Ramirez AG , Gallion KJ , Miller AR , Velez LF , San Miguel de Majors SL , Falkenberg M , Covarrubias SV , Munoz E
Published: December 2010

Abstract #5097

A patient navigator program that uses a trained community health worker to assist Hispanic women in utilizing cancer care services has been successfully implemented in South Texas for the past two years. The objectives of this program are to 1) reduce the rate of noncompliance after reception of abnormal breast and cervical cancer screening results, which will in turn reduce the time between screening and the commencement of treatment, and 2) improve patient satisfaction with the health care system experience. Participants include low-income Hispanic women who receive abnormal breast and/or cervical cancer screening results from two community clinics, a Treatment and a Comparison clinic. Participants from both clinics are administered a pre-(baseline) and a post-survey. The pre-survey is administered upon recruitment into the study, and the post-survey is administered six months after the baseline survey. Clinical data about participants' abnormal screening results are also extracted from their medical records. In addition, a patient navigator facilitates scheduling clinic visits, resolving medical problems and avoiding non-medical delays in evaluation for patients participating in the Treatment Arm. This session will present preliminary results, lessons learned, common patient barriers and strategies to address the barriers.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5097.
Biomarkers associated with pathologic complete response to neoadjuvant chemotherapy in women with locally advanced breast cancer: results from the I-SPY TRIAL (CALGB 150007/150012 & ACRIN 6657).
Authors: Livasy C , Carey L , DiMichelle A , Cowan D , Little D , Markey J , Moore D , Investigators I-SPY Clinical , Dressler L
Published: December 2010

Abstract #5102

Background: The I-SPY trial is a multi-institutional study of locally advanced breast cancers in which serial biopsies of breast tumors are performed at multiple timepoints, allowing comparison of tumor biomarker status pretreatment, during treatment, and after treatment. The primary objective is to identify markers of response to neoadjuvant chemotherapy. The aim of this study was to identify immunohistochemical biomarkers associated with pathologic complete response (pCR).  Methods: Eligible patients had biopsy-confirmed primary breast cancer measuring at least 3 cm. Required initial treatment was an anthracycline based neoadjuvant chemotherapy regimen: AC followed by T (91%), AC without T (6%), and chemotherapy beyond AC +/- T 2%. Immunohistochemistry (IHC) for HER2, EGFR, p53, Bcl2 and Ki-67 was performed centrally on core samples at baseline. Estrogen receptor and progesterone receptor results were obtained from each institution. Proxy IHC tumor subtypes were defined as follows: luminal A (ER or PR+/HER2-), luminal B (ER or PR+/HER2+), basal-like (ER-/PR-/HER2-), and HER2 (ER-/PR-/HER2+). Following completion of chemotherapy, post-surgical excision/mastectomy cases were reviewed centrally to determine residual cancer burden including pCR rate.  Results: 221 patients were enrolled and completed therapy. The median age was 49 years, with a range of 27-69. Median tumor size was 6 cm; 58% had clinically positive nodes. The positive rate for each biomarker was as follows: ER+ (57%), PR+ (47%), HER2+ (23%), EGFR+ (14%), p53+ (44%), Bcl2+ (49%), Ki-67 index ≥25% (38%), Ki-67 index ≥10% but <25% (34%), and Ki-67 index <10% (27%). The pCR rates based on biomarkers results are shown in the table below.    Conclusion:  For patients with locally advanced breast cancer, pCR to neoadjuvant chemotherapy was associated with tumor HER2 overexpression, hormone receptor-negative status, high Ki-67 index, EGFR expression, and absence of Bcl2 expression. Luminal A tumors, defined by IHC proxy, showed a very low pCR rate following neoadjuvant chemotherapy.  Support: CALGB CA31964 and CA33601, ACRIN U01 CA079778 and CA080098, NCI SPORE CA58207.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5102.
Weekly paclitaxel improved pathological response of primary chemotherapy compared with standard 3 weeks schedule.
Authors: Ouyang T , Li J , Xie Y , Lu A , Li B
Published: December 2010

Abstract #5109

Background: Weekly paclitaxel is superior to every-3-wk schedule in the management of MBC. This single institute, prospective randomized trial was designed to compare the efficacy of the weekly paclitaxel to every-3-wk schedule in terms of pathological response.  Material and methods: Histologically confirmed T1-3 N0-1M0 invasive breast cancer pts planed to receive adjuvant chemotherapy were eligible. After the completion of 2 cycles of CTFci ( CTX 500mg/m2 d1/d8, pirarubicin 35 mg/m2 d1/d8, 5-Fu 200 mg/m2.day.ci d1-28, every 4 weeks) primary chemotherapy, pts were randomized to received 4 cycles of PTq3w (arm A: carboplatin AUC 6mg/ml.min day1, paclitaxel 175mg/m2 day1, every 3 weeks) or PTq1w (arm B: carboplatin AUC 6mg/ml.min day1, paclitaxel 60mg/m2 day1/8/15, every 3 weeks) before surgery, stratified by clinical response to 2 cycles of CTFci. Status of axillary node were determined by sentinel node biopsy or ultrasound guided FNA (if abnormal ultrasonographically) before primary chemotherapy. Pathological response of the primary tumor was evaluated by using Miller and Payne system, clinical response was determined by ultrasonography.  Results: From 05/2005 to 10/2007, 220 pts ( 196 were planed) under 65yr entered in this trial. 201 pts completed planed treatment and 12 pts(arm A 4 pts, arm B 8 pts)choice to have surgery after 2 cycles of paclitaxel treatment, other 7 pts (5 protocol violation, 1 without surgery, 1 treated in other hospital) were excluded for analysis. Clinical tumor status, node status, estrogen receptor expression, Her-2 expression and clinical response to CTFci were no different between two arms.    Arm A resulted more G1/G2(loss of tumor cells less than 30%) and less G5/G4 ( loss of tumor cells more than 90%) than arm B (28.70% vs. 14.28% p=0.011, 44.44% vs. 58.10% p= 0.047 ). The pCR rate of positive node were 39.29%(11/28) in arm A and 54.17%(13/24) in arm B ( p=0.283).    There were 17(15.74%) pts in arm A and 67(61.81%)pts in arm B experienced treatment delay caused by neutropenia(G3), thrombocytopenia(G2), anemia(G2) or hepatotoxicity(G2). There was no treatment related death.  Conclusion: Weekly paclitaxel was well tolerant and more effective than 3 week schedule.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5109.
Changes in ER beta versus ER alpha in short-term studies of antiestrogen therapies.
Authors: Dzagnidze G , Robertson JF , Ellis I , Green A , Zhang H , Speirs V , Shaaban A , Garnett S , Lindemann J
Published: December 2010

Abstract #5113

Background: Fulvestrant (Faslodex™) is a novel estrogen receptor (ER) antagonist with no agonist effects used in the treatment of postmenopausal women with advanced breast cancer. Compared with other antiestrogen therapies, fulvestrant has a distinct and different mode of action; on binding to the ER it induces a rapid and dose-dependent degradation of ER alpha and concomitant decreases in progesterone receptor (PgR) levels and Ki67 labeling index (LI). The action of fulvestrant on ER beta is unknown and has been investigated in relation to other biomarkers in this study.  Methods: This randomized, multicenter study included postmenopausal patients with previously untreated breast tumors (stage T1-T3) that were either ER+ or ER unknown. Patients were randomized to receive a single intramuscular dose of fulvestrant (50 mg [n=39], 125 mg [n=38], or 250 mg [n=44]), continuous daily tamoxifen (Nolvadex™) (20 mg/day [n=36]), or matching tamoxifen placebo (n=33) for 14–21 days prior to surgery. The effects of antiestrogen therapy on ER beta 1 and ER beta 2 levels and the relationship between these effects and changes in ER alpha, PgR and Ki67 LI were investigated. Effects on ER (alpha and beta) and PgR were determined by immunohistochemistry and expressed as mean percentage change from baseline H-score. Ki67 LI was determined as described previously1 and was expressed as median percentage change from baseline.  Results: There was no overall treatment effect following placebo or antiestrogen therapy on ER beta 1 H-score (p=0.8537) or ER beta 2 H-score (p=0.5494). There were no significant differences between the individual fulvestrant dose groups, tamoxifen and placebo for mean changes in either ER beta 1 (50 mg: +34.8%, 125 mg: +42.8%, 250 mg: +15.5%; tamoxifen: +29.8%; placebo: +29.7%) or ER beta 2 (50 mg: +87.9%, 125 mg: +82.9%, 250 mg: +97.4%; tamoxifen: +98.1%; placebo: +64.2%). No correlations were observed between changes in ER beta 1 and changes in ER beta 2, nor between either ER beta 1 or 2 and ER alpha, PgR or Ki67 LI.  Conclusion: Changes in ER beta did not correlate with fulvestrant dose (50 mg, 125 mg, or 250 mg) or other variables that have previously been shown to be related to fulvestrant activity. This study does not support the investigation of ER beta 1 or 2 as markers of the biological activity of fulvestrant high dose (500 mg/month) in ongoing trials such as FIRST and CONFIRM.  1Robertson et al. Cancer Res 2001; 61: 6739-6746.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5113.
Is the sentinel lymph node biopsy accurate for patients with initially clinically axilla-positive locally advanced breast cancer after neoadjuvant chemotherapy?.
Authors: Ozmen V , Muslumanoglu ME , Igci A , Canbay E , Ozcinar B , Mudun A , Eralp Y , Saip P , Tuzlali S , Dincer M , Dagoglu T , Kecer M , Parlak M
Published: December 2010

Abstract #5123

Background: Approximately one third of patients with locally advanced breast cancer (LABC) have no axillary metastatic lymph node(s) after neoadjuvant chemotherapy (NAC). Axillary dissection could be omitted in these patients if SLNB is negative. The aim of this study is to evaluate the accuracy of sentinel lymph node biopsy (SLNB) after NAC for LABC.  Materials and Methods: Between January 1992 to May 2008, a total of 69 patients with clinical or radiological positive axilla (N1 or N2) in LABC were enrolled in this study. After NAC, all patients underwent SLNB followed by complete axillary lymph node dissection. SLNB was performed with either a combined detection using blue dye and radiocolloid or blue dye alone. All the sentinel lymph nodes were examined by multisection hematoxylin eosin staining and cytokeratin- immunohistochemistry, whereas the non-sentinel nodes were examined by routine histology.  Results: Sentinel lymph nodes were successfully identified in 58 patients among 69 patients (85%). The median age was 46 (range 25 to 76). The clinical stages before chemotherapy were as follows: IIB:46%, IIIA: 22%, and IIIB: 32%, respectively. All of 58 patients had either clinically or radiologically suspicious node-positive disease based on ultrasound findings before neoadjuvant chemotherapy. Pathologic complete response were obtained in 5 patients (9%). The false negative rate was found to be 17.4 % (8/46), whereas the accuracy rate was 86.2% (50/58) among patients with succesful lymphatic mapping.  Conclusion: The accuracy of the SLNB procedure seems to be not reliable in patients with locally advanced disease with a positive axilla before NAC therapy due to its high false negative rates. Therefore, complete axillary dissection is still required in patients with a positive-axilla before chemotherapy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5123.
A randomised controlled trial to evaluate both the role and optimal fractionation of radiotherapy in the conservative management of early breast cancer.
Authors: Spooner D , Stocken DD , Jordan S , Bathers S , Dunn JA , Jevons C , Morrison M , Oates G , Grieve R
Published: December 2010

Abstract #5125

Background: Postoperative radiotherapy is routinely used in early breast cancer using 50Gy in 25 daily fractions (Long). Both the role of radiotherapy and shorter regimens require validation.  Methods: Patients with clinical stage 1 and 2 disease were randomised to receive immediate postoperative (RT) or delayed salvage treatment (No RT). Patients receiving RT were further randomised to Long or Short (40Gy in 15 daily fractions) regimens. The primary outcome measure was time to first relapse. Reported results are at median follow up of 16.9 years (IQR 15.4 - 18.8).  Results: 707 women were recruited between 1985 and 1992: median age 59 years (range 28-80), 72% post menopausal, median tumour size 2.0cms (range 0.12-8.0). 271 patients have relapsed: 110 RT, 161 No RT. Site of first relapse was reported as 158 (64%) locoregional and 87 (36%) distant. Immediate RT significantly reduced the risk of relapse by 42% (HR=0.58 (95%CI: 0.45, 0.73), chi2LR=20.40, p<0.001) consistent across all prognostic subgroups. Immediate RT reduced the risk of locoregional relapse by 65% (HR=0.35 (95%CI: 0.25, 0.47), (chi2LR=40.47, p<0.001). No difference in relapse site, or frequency was seen between the 2 fractions. No differences were seen in overall or breast cancer specific survival.  Discussion: With a median follow-up of 17 years, this study confirms the benefit for patients with early breast cancer receiving radiotherapy. We conclude that a radiotherapy schedule of 40 Gy in 15 daily fractions is a safe, efficient and effective regime at least as good as the international conventional regime of 50 Gy in 25 daily fractions.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5125.
No positive effect of postmastectomy radiotherapy on mortality at 20 years in pre menopausal women with stage II breast cancer also treated with adjuvant oral cyclophopsphamide. South Sweden Breast Cancer Group, trial SBII:I.
Authors: Killander F , Anderson H , Möller T , Rydén S , Malmström P
Published: December 2010

Abstract #5128

Purpose: To study long term loco-regional recurrence rate and survival after postmastectomy radiotherapy in combination with oral cyclophosphamide in premenopausal women with stage II breast cancer.  Study design: A three-armed randomised, multicenter, phase III trial comparing 1) Radiotherapy (RT) 2) RT+ oral cyclophosphamide for one year (RT+C) and 3) cyclophosphamide only (C).  Radiotherapy was administered with 48 Gy in 20 fractions to chest wall and locoregional lymph nodes (Arwidi Å, Acta Oncol Scand 18:273-281, 1979). Cyclophosphamide was prescribed as 12 courses of 130 mg/m2 od for14 days every 4 weeks.  Patients and methods: 367 patients from 15 departments in Southern Sweden, representing 80% of all eligible patients, were included in the trial between 1978-1983; n=124 (RT), n=118 (RT+C), n=125 (C). Median age was 47 years, median tumour size was 25 mm, and 33 % of the patients were lymph node negative. Median follow up for survival was 24 years and 21 years for other events.  Results: RT reduced the risk at twenty years for locoregional recurrence in C treated patients with 75 %, 13.9 vs 3.5 %. The risk reduction was highly significant in both N0 and N+ patients. RT did not decrease systemic disease or mortality, see table 1. Chemotherapy did not decrease mortality when added to radiotherapy, though difficult to evaluate because of lack of information on delivered doses in many cases.    Conclusion: Postmastectomy radiotherapy reduces loco regional recurrences in this premenopausal population, but no effect was seen on mortality at 20 years. Possible explanations are 1) low number of loco regional recurrences and superior survival in comparison to other trials investigating postmastectomy radiotherapy, which might have modified the effect of RT on survival, 2) too low intensity of adjuvant, single agent chemotherapy, and 3) chance, since relatively small study with little power.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5128.
Radiation induced molecular modulations in human breast adenocarcinoma cells after single (10Gy) and fractionated (2Gy x 5) dose irradiation.
Authors: Madhusoodhanan R , Terence HS , Aravindan N
Published: December 2010

Abstract #5133

Background: Radiotherapy a recognized treatment modality for breast cancer patients is now considered mandatory for most patients undergoing conservative surgery and is considered appropriate for women at high risk of recurrence after mastectomy. However, relapse due to radio-resistance of cancer cells significantly affects the success of radiotherapy and cancer patient survival. Ascertaining the fractionated irradiation (FIR) modulated molecular targets is important to make tumors more susceptible to molecular targeted therapy. Accordingly, we investigated the (i) expression of 84 genes representing 6 functional pathways including Cell cycle and DNA damage repair, Apoptosis and cell senescence, Signal transduction and transcription, Adhesion, Invasion and metastasis and Angiogenesis; (ii) nuclear translocation and DNA-binding activity of NFκB and; (iii) expression of radio-responsive TNFα, IL-1α, pAKT, cIAP1, cIAP2 and survivin molecules after single dose (SDR) radiation and FIR protocols in human breast adenocarcinoma cells.  Methods: MCF-7 cells exposed to either SDR (10Gy) or FIR (2Gy x 5 days) and harvested after 24h were analyzed for alterations in gene expression using real-time Q-PCR-profiling. NFκB-DNA binding activity was analyzed using electrophoretic mobility shift assay and pIκB levels was measured using immunoblotting. Relative changes in the expression patterns of TNFα, IL-1α, pAKT, cIAP1, cIAP2 and survivin were determined using Q-PCR analysis and immunoblotting.  Results: Compared to the SDR, FIR treated cells showed an induced expression 61 (Cell cycle & DNA damage repair - 12, Apoptosis & cell senescence - 10, Signal transduction & transcription - 7, Adhesion - 8, Invasion & metastasis – 11 and Angiogenesis – 13) genes. Furthermore, we observed a relatively induced DNA binding activity of NFκB and phosphorylation of IκBα after FIR. Like-wise, we observed an induced expression of TNFα, IL-1α, pAKT, cIAP1, cIAP2 and survivin mRNA in cells exposed to FIR. The changes in these genes were confirmed at the protein level.  Discussion: These results along with the differential gene expression pattern support our hypothesis that FIR can induce molecular targets. In this initial analysis, NFκB and known NFκB regulated radio-responsive genes were found to be modulated. Currently, we are in the process of identifying similar FIR-induced targets and evaluate their potential for selective drug-targeted manipulation.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5133.