bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment-Emergent Symptoms and the Risk of Breast Cancer Recurrence in the NCIC CTG MA.27 Adjuvant Aromatase Inhibitor Trial.
Authors: Stearns V. , Chapman J. , Ma C. , Ellis M. , Ingle J. , Pritchard K. , Budd G. , Rabaglio M. , Sledge G. , Le Maitre A. , Elliott C. , Shepherd L. , Goss P.
Published: December 2010

Background: Analyses of adjuvant endocrine therapy suggest that the appearance of new vasomotor or joint symptoms within 3 months of initiating either tamoxifen or aromatase inhibitor therapy predict for lower subsequent recurrence. We hypothesized that new vasomotor or joint symptoms may predict outcomes with anastrozole or exemestane in participants in the ongoing NCIC CTG Trial MA.27. We performed a pooled analysis across treatment arms of the MA.27 trial, to examine the effects of early onset new or worsening symptoms on relapse-free survival (RFS).Methods: 7576 postmenopausal women with early breast cancer were accrued to MA.27, a randomized adjuvant trial of exemestane and anastrozole. The second interim analysis data with a 3 year median follow-up was used for this analysis. The trial's primary endpoint is event-free survival, but for this investigational analysis is RFS, which excludes non-breast cancer deaths. All 7118 participants known to be hormone receptor-positive who received trial therapy, and had no relapse in the first 3 months, were included. The association of vasomotor and joint symptoms with patient characteristics was examined with chi-square tests. Stratified log-rank and stratified univariate and multivariate Cox modeling were used to examine the association of early vasomotor and joint symptoms on disease outcomes.Results: Of 4749 women who were asymptomatic at baseline, 230 (5%) experienced vasomotor or joint symptoms at 3 months. The RFS stratified univariate Cox hazard ratio (HR) for vasomotor or joint-related symptoms was 1.184 (95% CI, 0.675-2.079). When all 7118 women were included, 361 (5%) developed new or worsening symptoms at 3 months. RFS was not statistically significant between the women with or without new symptoms (HR 1.129, 95% CI, 0.708-1.800). Higher T stage was the only factor included in the multivariate Cox RFS model that was associated with new or worsening symptoms (p<0.001).Conclusions: In contrast to prior findings, we did not observe a correlation between early emergence of symptoms and improved RFS. Longer follow-up and analysis by treatment arm and at different time points are required. Additional symptoms and time points will be added to the analysis prior to the meeting. Until further data are available, clinicians should not use treatment-emergent symptoms to counsel their patient whether to continue or change their prescribed medication.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 14.
Alcohol Consumption and Breast Cancer Recurrence and Survival among Women with Early-Stage Breast Cancer.
Authors: Kwan M. , Kushi L. , Weltzien E. , Castillo A. , Caan B.
Published: December 2010

Purpose: To describe alcohol consumption and examine its association with breast cancer recurrence and mortality in the Life After Cancer Epidemiology (LACE) study, a prospective cohort study of early-stage breast cancer survivors.Methods: Patients included 1897 participants diagnosed with early-stage breast cancer between 1997 and 2000 and recruited primarily from the Kaiser Permanente Northern California Cancer Registry. Alcohol consumption (beer, wine, and liquor) was assessed at cohort entry using a food frequency questionnaire. A total of 349 breast cancer recurrences and 332 overall deaths were ascertained after an average follow-up of 5.93 years. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals.Results: A total of 958 women (51%) were considered drinkers (>0.5 g of alcohol per day), and the majority drank wine (90%), followed by liquor (43%), and beer (36%). Drinking ≥6 g/day of alcohol compared to minimal or no drinking (≤0.5 g/day) was associated with an increased risk of breast cancer recurrence (HR = 1.34; 95% CI: 1.00, 1.82) and death (HR = 1.51; 95% CI: 1.00, 2.28). The increased risk of recurrence appeared to be greater among postmenopausal (P for trend = .03) and overweight or obese women (P for trend = .03). No associations were observed for risk of overall mortality and alcohol use.Conclusions: Consuming 3 to 4 alcoholic drinks or more per week might be related to an increased risk of breast cancer recurrence, particularly among postmenopausal and heavier women, regardless of other prognostic factors. While additional prospective studies are needed, these observations suggest that after a breast cancer diagnosis, women should consider limiting their consumption of alcohol.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 17.
A Phenotype-Based Model for Rational Selection of Novel Targeted Therapies in Treating Aggressive Breast Cancer.
Authors: Soldi R. , Gustafson A. , Zhu H. , Wilcox R. , Welm B. , Spira A. , Jeffrey S. , Bild A.
Published: December 2010

BackgroundGlobal transcriptional profiling has facilitated breast cancer research, and has led to analyses of breast cancer phenotypes and clinical outcomes. While gene expression signatures can identify patients with aggressive tumors who require chemotherapy, data that guide drug selection are relatively sparse, generally obtained in clinical trials that treat patients with standard therapies and often limited by small study size. We propose a method that incorporates genomic and in vitro and in vivo preclinical testing of patient tumors to identify optimal and novel therapeutic regimens for individual breast tumors.Methods and FindingsNine independent microarray datasets comprised of 1,723 breast cancer cases were used in a meta-analysis to examine patterns of drug sensitivity predictions. Drug sensitivity signatures were developed based on the Broad Institute Connectivity Map, and applied using binary regression to individual tumor gene expression data. These analyses provide probabilities for each individual tumor's sensitivity to specific drugs, and allows us to identify patterns of drug sensitivity for unique breast cancer phenotypes. We found consistent patterns of drug sensitivity that were specific to individual tumor subtypes. Notably, we discovered that over 80% of basal-like breast cancers were predicted to respond to inhibitors of the phosphatidylinositol 3-kinase pathway and that normal-like tumors were most likely to respond to a heat shock protein 90 inhibitor. Among the more aggressive breast cancer phenotypes, there was a high predicted response to valproic acid (VPA), a histone deacetylase inhibitor. Using a subset of targeted therapeutics that are currently in clinical trials with solid tumors and for which we have drug response signatures, we performed in vitro drug testing on a panel of 18 breast cancer cell lines and found significant correlation between predicted and actual drug sensitivity. Additionally, predicted sensitivity to VPA for specific patient breast tumors was confirmed in vitro and in vivo, using 3-D primary cell culture and orthotopic xenografts generated from the same human tumors for which the predictions were made. These studies highlight VPA as an effective therapy for aggressive breast cancer tumors, and underscore the suitability of our genomic approach to identify optimal targeted therapeutic strategies for women with breast cancer.ConclusionsWe provide a drug sensitivity prediction model using primary tumor gene expression profiles and offer preclinical examples of drug response based on this model. This approach can be used to personalize drug therapy for patients with breast cancer. This will hopefully improve clinical responses for patients while sparing them toxicity from agents that will have no effect on their tumors.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2007.
Estrogen Receptor α Phosphorylation on Serine 305, p21-Activated Kinase 1 and Tamoxifen Response in Postmenopausal Breast Cancer.
Authors: Bostner J. , Fornander T. , Skoog L. , Nordenskjöld B. , Stål O.
Published: December 2010

Background: Tamoxifen is an adjuvant treatment for estrogen receptor (ER) positive breast cancer. Despite high response rates, resistance is a widespread problem. p21-activated kinase 1 (Pak1) is suggested to phosphorylate the serine 305 residue of the ERα and influence the response to tamoxifen. We aimed to investigate the combination of Pak1 and pERαser305 in relation to treatment prediction and prognosis.Material and Methods: We examined Pak1 and pERαser305 protein by immunohistochemistry in a series of 912 tumors from node negative postmenopausal breast cancer patients randomized to tamoxifen or no adjuvant endocrine treatment.Results: Cytoplasmic Pak1 correlated to large tumors and ER negativity while nuclear Pak1 and pERαser305 correlated to small tumors and ER positivity. Nuclear expression of Pak1 and pERαser305 predicted reduced response to tamoxifen in patients with ERα-positive tumors (tamoxifen versus no tamoxifen, HR=1.33; 95% CI, 0.42-4.2, p=0.63), whereas patients lacking this combination of protein expression in the tumor benefitted significantly from tamoxifen (HR=0.42; 95% CI, 0.29-0.61; p<0.0001). Similar non-significant trends were detected in analyses of the two proteins separately. Pak1 in the cytoplasm was an independent prognostic marker, indicating increased recurrence rate (HR=1.80; 95% CI, 1.18-2.76, p=0.006) and breast cancer mortality (HR=2.02; 95% CI, 1.16-3.52, p=0.014) for patients randomized to no adjuvant treatment.Discussion: Our results suggest that patients with tumors expressing nuclear Pak1 and nuclear pERαser305 in combination represent a subgroup in which tamoxifen treatment is insufficient. Our findings support previous studies showing that Pak1 has differential roles in the cytoplasm and the nucleus. In addition, the Pak1-ER pathway may be of interest as drug target in breast cancer.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2013.
An Exploratory Study of the Biological Activity of Sunitinib as a Component of Neoadjuvant Therapy for Breast Cancer.
Authors: Miller K. , Estes M. , Perkins S. , Schneider B. , Matei D. , Storniolo A. , Ingram D. , Yoder M. , Kern K. , Sledge G.
Published: December 2010

Background: The neoadjuvant setting provides an ideal opportunity to explore the impact of sunitinib alone and in combination with paclitaxel on the functional status of tumor vasculature as indicated by changes in tumor interstitial pressure (IFP) and circulating progenitor cell (CPC) subsets.Methods: Patients(pts.) with newly diagnosed stage Ic-IIIc breast cancer were treated with sunitinib monotherapy (100 mg Day 1; 37.5 mg D2-14) prior to the initiation of paclitaxel (80 mg/M2 D1,8,15 every 28 days x 4 cycles) with sunitinib (25 mg/d). IFP and CPC subsets were assessed at baseline and after sunitinib monotherapy. IFP was measured in three separate areas of the tumor using a micropressure transducer catheter; mean and highest IFP recorded were analyzed. Improvements in poly-chromatic flow cytometry allowed distinction of pro-angiogenic (pCPC = Live/AC133+CD34bright/CD31+CD45dim\), from non-angiogenic (nCPC = Live/AC133-CD34bright/CD31+/CD45dim\), CPCs that cannot be quantified separately using previously reported protocols1. Baseline CPC subsets were also compared to age and gender matched healthy controls.Results: From July 2008 to May 2009, 14 pts were enrolled; baseline and post-sunitinib IFP and CPC data are available for 12 and 11 pts respectively. The median age was 48 (range 32-69). Mean pretreatment tumor diameter was 3.2 cm. Sunitinib monotherapy was generally well tolerated; two patients developed grade III toxicities including hypertension (n=1) and hand-foot syndrome (n=1). Sunitinib significantly decreased mean IFP (18.87 mmHg vs. 6.38 mmHg; p=0.002); similar results were obtained when only the maximum IFP was considered (22.32 mmHg vs. 8.36 mmHg; p=0.003). pCPC frequency was not different between pts and healthy controls (0.099% vs. 0.076%, p=0.24) but the p:nCPC ratio was significantly higher in pts compared to healthy controls (3.26 vs. 1.46; p=0.001) suggesting a shift toward vascular damage and/or active angiogenesis. Both pCPC frequency (0.099 vs. 0.022; p=0.001) and p:nCPC ratio (3.26 vs. 0.78; p=0.001) significantly decreased after sunitinib monotherapy. Analysis of paclitaxel + sunitinib is too early (n=4).Conclusion: Sunitinib, through its effects on VEGF-mediated vascular permeability, markedly reduces tumor IFP. In addition sunitinib profoundly reduces pCPCs that are thought to be important for angiogenesis in human cancers. Accrual is ongoing (planned N=40). Analysis of IFP and CPC subsets after paclitaxel + sunitinib as well as additional correlates will be presented.1 Duda et al. (2007). Nat. Protocol 2, 805-810.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 202.
TIMP-1 Status Measured by Immunohistochemistry in 268 ER Positive Postmenopausal High-Risk Breast Cancer Patients Treated with Adjuvant Tamoxifen: Association to Recurrence Free Survival.
Authors: Bjerre C. , Knoop A. , Lyng M. , Ditzel H. , Brünner N. , Bartels A. , Laenkholm A.
Published: December 2010

Background: A proportion of ER positive breast cancer patients do not benefit from adjuvant tamoxifen treatment. Tamoxifen has been shown to induce apoptosis in human breast cancer cells in vitro and Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) protects cancer cells against apoptosis. We therefore raised the hypothesis that ER positive breast cancer cells with high TIMP-1 immunoreactivity would show reduced benefit to tamoxifen treatment.Material and methods: Tumor tissue from 268 high-risk postmenopausal ER positive breast cancer patients was used for this study. All patients underwent surgery for primary invasive breast cancer. The majority of the patients were lymph node positive: 92% (246/268). Patients were allocated to 1, 2 or 5 years of adjuvant tamoxifen as mono-therapy. Recurrent disease was diagnosed in 33% (89/268) of the patients. Median time to recurrence was 3.1 years and the median time of follow-up was 12.4 years. Archival formalin-fixed and paraffin-embedded primary tumor tissue was used to generate tissue microarrays comprising two, 2 mm cores from each tumor. TIMP-1 immunoreactivity was evaluated using the mouse monoclonal antibody (clone VT7) raised against recombinant human TIMP-1. This antibody exclusively reacts with TIMP-1. A central assessment of TIMP-1 status was performed. Tumors were analysed by bright field microscopy and scored semi-quantitatively as 0 - 3 with regard to the number of stained tumour cells and intensity of the staining. An index combining the number of positive tumor cells and staining intensity was created: low (0-2), median (3-4) and high expression (5-6).Results: IHC was successfully performed in 266 cases. TIMP-1 IHC negative cases were observed in 39% (105/266) of the tumors and 61% (161/266) were TIMP-1 IHC positive. The index combining the number of positive tumor cells and staining intensity showed low expression in 59% (157/266), median expression in 24% (65/266) and high expression in 17% (44/266) of the tumors. TIMP-1 negativity and low TIMP-1 index showed no significant association with tumor grade, tumor size or lymph node status. When performing Kaplan-Meier plots, TIMP-1 expression was not significantly associated with recurrence free survival in univariate analyses (p = 0.1).Conclusion: This study did not confirm our hypothesis that TIMP-1 immunoreactivity in ER positive breast cancer cells are associated with reduced benefit from adjuvant tamoxifen treatment. This is partly in contrast with prior studies on endocrine therapy of metastatic breast cancer (Lipton et al 2008) where high serum TIMP-1 was associated with reduced response to endocrine therapy.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2025.
Evaluation of Changes in Plasma Protein Profiles during Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer Using MALDI-TOF/MS Procedure.
Authors: Mazouni C. , Baggerly K. , Hawke D. , Tsavachidis S. , André F. , Buzdar A. , Martin P. , Kobayashi R. , Pusztai L.
Published: December 2010

Background: Comparison of protein profiles of the plasma before chemotherapy and after completion of neoadjuvant chemotherapy may reveal tumor markers that could be used to monitor tumor response.Patients and Methods: We examined matching pre- and post-treatment serum samples 39 HER2-postive breast cancer patients (n=78 samples) who all received 6 months of preoperative chemotherapy with or without trastuzumab in the context of a randomized clinical trial. Serum was analyzed with an Applied Biosystems 4700 Proteomics Analyzer matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometer. Samples were grouped and pooled into those who achieved pathological complete response (pCR, n=20) and those who had residual disease (RD, n=19). We compared matching baseline and post-chemotherapy/pre-surgery samples separately in both response groups and also compared baseline samples between the two response groups.Results: MALDI-TOF analysis revealed a total of 2329 and 3152 peaks in pooled samples of cases with pCR and RD, respectively. A total of 32 peaks were differentially expressed between base line and post-chemotherapy pCR samples and 643 peaks in cases with RD (false discovery rate ≤ 20%). A total of 8 differentially expressed proteins were identified in the before- and after-chemotherapy samples from their peptides after digestion and LC-MALDI-TOF/TOF. These included 4 AFM, C3, hemopexin, SAP in pCR samples and AP1, hemopexin, Complement B, amyloid P component in the RD group.Conclusion: Our study suggests that MALDI mass spectrometry may be used to detect differences in baseline serum profiles of patients who are highly sensitive to chemotherapy and those who are less sensitive. Also, changes occur in the serum during chemotherapy and this may offer the possibility of monitoring response to treatment in the future.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2037.
Predictors of Response to Exemestane as Primary Endocrine Therapy in Estrogen Receptor-Positive Breast Cancer.
Authors: Yoshimoto N. , Takahashi S. , Ito Y. , Yamashita T. , Ando Y. , Toyama T. , Sugiura H. , Kobayashi S. , Fujii Y. , Iwase H. , Yamashita H.
Published: December 2010

Endocrine therapy is the most important treatment of choice for estrogen receptor-positive breast cancer. Potential mechanisms for resistance to endocrine therapy involve estrogen receptor (ER)-coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. However, the factors and pathways responsible for endocrine therapy resistance, particularly resistance to aromatase inhibitors, have not been clearly established. Sixteen postmenopausal patients with ERΑ-positive primary breast cancer were treated daily with 25 mg of exemestane (an aromatase inhibitor) for 6 months. Expressions of ERΑ, ERΒ, progesterone receptor (PgR), androgen receptor (AR), AIB1, aromatase, EGFR, HER2, Ki67, cyclin D1, p53, Bcl2, Stat5 and IGFBP5, and phosphorylations of ERΑ serine (Ser) 118, ERΑ Ser167, Akt Ser473 and p44/42 MAPK threonine (Thr) 202/ tyrosine (Tyr) 204 were examined by immunohistochemistry on pretreatment tumor biopsies and posttreatment surgical specimens. Analyses were made to test for correlations with response to exemestane. Of the 16 patients, 7 responded and 9 retained stable disease. High-level expression of AIB1 and phosphorylation of Akt Ser473 were significantly associated with a better response to exemestane, suggesting that these factors could be considered as predictors of exemestane response. Expressions of ERΑ, ERΒ, PgR, aromatase, Ki67, cyclin D1 and p53, and phosphorylations of ERΑ Ser118, ERΑ Ser167 and p44/42 MAPK Thr202/Tyr204 were decreased, whereas expressions of Stat5 and IGFBP5 were increased in posttreatment specimens compared to the values in pretreatment biopsies. Thus, the analysis of factors involved in the estrogen-dependent growth-signaling pathways may be useful in identifying patients responsive to exemestane.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2041.
Changing Patterns and Present Status of Female Breast Cancer in China over 30 Years.
Authors: Fan L. , Zheng Y. , Yu K. , Liu G. , Shen Z. , Shao Z.
Published: December 2010

Introduction: As a metropolis with rapid social and economic development over the past three decades, Shanghai has a breast cancer incidence that surpasses all other cancer registries in China.Methods: In order to estimate the regular changing patterns of female breast cancer in urban Shanghai, population-based incidence data from 1975 to 2004 were studied. In addition, a one-hospital-based in-patient database of 9709 female breast cancer patients treated surgically between Jan-1990 and Dec-2008 were reviewed, retrospectively.Results: We observed that breast cancer incidence increased dramatically over the past 30 years and documented a peak incidence represented by the middle-age group (45-59 yrs), which emerged in the last 20 years. The incidence peak moved from the 40-44 year group in the previous two decades to the 50-54 year group in the most recent decade. Median age at diagnosis was earlier in Shanghai than in the western countries, although it increased from 47.5-yr in 1990 to 51-yr in 2008. Considerably higher exposure to reproductive risk factors and relatively fewer hormone-dependent cases were observed- only 49.2% of breast cancers were estrogen receptor(ER) positive, 46.1% were progesterone receptor positive. The proportion of asymptomatic cases detected by screening gradually increased, as well as that of early-stage cases (from 78.6% in 1990 to 87.9% in 2008 and carcinoma in situ (14.9% in 2008). Analysis of surgical treatment patterns suggested a trend of less-invasive options.Conclusions: Rapid socioeconomic growth and birth-control policies have revealed some unique risk factors, which pushed the pattern of breast cancer in Shanghai towards that of the western countries. Age of peak incidence as well as median age at diagnosis increase with time, which suggests that increased incidence trending along with increasing age will be observed in the future. The middle-age group born after 1950s would be involved in current birth-control policies and they are also the cohorts related to the incidence boom. Thus specific screening protocols should be refined for the Chinese population, considering not only increasing age but also birth cohorts. Improvements in breast cancer detection provide patients with more opportunities for less invasive treatment options.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2058.
East of England Breast Cancer Survival Close to Best in Europe.
Authors: Wishart G.
Published: December 2010

Background: The Eurocare-4 (2000-2002) period analysis documents a mean European age-adjusted 5-year relative breast cancer survival of 79% with higher individual figures for Finland (85.7%), Norway (84.1% and Sweden (86.3%) (Lancet Oncol 2007; 8: 784-96). The corresponding figure for England was 77.8%. We now compare these predicted survival estimates with actual age-adjusted relative 5-year breast cancer overall survival (Corazziari et al, European Journal of Cancer 2004; 40:15: 2307-2316) for women diagnosed with invasive breast cancer in the East of England from 2000-2002Method: The East of England covers a population of 5.5 million people. 5-year age-adjusted relative breast cancer survival was calculated overall, and in specific age groups, for all women with invasive breast cancer diagnosed from 2000-2002 in the East of England for comparison with the results from the Eurocare-4 study.Results:Age-adjusted 5-year relative breast cancer survival in East of England for period 2000-2002.AGE GROUPRELATIVE SURVIVAL95% CI45-5487.5%86.1-88.9%55-6489.5%88.1-90.9%65-7483.9%81.1-86.1%75+73.3%70.1-76.4%ALL WOMEN82.5%81.4-83.6% Conclusion: These data confirm breast cancer survival rates for East of England that are close to European best figures for women aged 45-64. The age-adjusted survival of 82.5% for all women however is being reduced by worse survival in women aged 65+ and a strategy that ensures optimal breast cancer treatment for women in this age group should allow overall survival to improve even further.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2069.
Evaluation of Cardiac Comorbidities in Patients with Metastatic Breast Cancer Receiving Doxorubicin-Based and Non-Doxorubicin-Based Chemotherapy.
Authors: Lafeuille M. , McKenzie R. , Yameogo N. , Senbetta M. , Vekeman F. , Piech C. , Lefebvre P.
Published: December 2010

Background: Some metastatic breast cancer (MBC) treatments are associated with cardiac toxicity. Real-world data regarding baseline cardiac comorbidities in patients with MBC prior to chemotherapy initiation are scarce. Such information would be useful in guiding treatment decisions. This study aims to describe the cardiac comorbidity profile of patients with MBC initiating doxorubicin-based (DOX) versus non-doxorubicin-based (Non-DOX) chemotherapy regimens from a managed-care perspective.Methods: Medical claims from the Ingenix Impact National Managed Care Database between 07/2002 and 06/2008 were analyzed. Patients included were aged ≥ 18 years, and had ≥ 2 diagnoses for breast cancer as well as ≥ 1 diagnosis for metastatic site within 12 months of chemotherapy initiation. Cardiac comorbidities [hypertension (HTN), cardiac arrhythmia (CAr), coronary artery disease (CAD), congestive heart failure (CHF), and myocardial infarction (MI)] were evaluated within 6 months prior to chemotherapy initiation. Patients were categorized based on receipt of DOX vs. Non-DOX-based chemotherapy.Results: A total of 12,345 patients (Non-DOX: 7,023, DOX: 5,322) formed the study population. Compared with the DOX group, the Non-DOX group was slightly older. Both groups reported a significant proportion of patients with cardiac comorbidities prior to chemotherapy, with significantly greater proportions reported in the Non-DOX group. Mean age (SD)HTNCArCADCHFMINon-DOX (n=7,023)56.9 (10.6)35.7%11.8%5.5%3.5%1.3%DOX (n=5,322)52.1 (9.1)30.8%8.1%3.3%2.0%0.5%P-value<.001<.001<.001<.001<.001<.001 Conclusions: Cardiac comorbidities were commonly reported in women with MBC prior to chemotherapy, with significantly greater proportions reported in the Non-DOX group. Such information is useful to healthcare professionals when considering potential interventions for patients with MBC.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2078.
Myelodysplastic Syndrome and Acute Myeloid Leukemia Incidence Following Primary Breast Cancer Treatment.
Authors: Kaplan H. , Malmgren J. , Atwood M.
Published: December 2010

Background: Breast cancer (BC) patients receiving surgery plus radiation and/or adjuvant chemotherapy treatment are routinely monitored for incidence of myelodysplasia (MDS) and leukemia.Methods: A cohort of all breast cancer patients TNM stage 0-III treated with surgery and/or radiation or chemotherapy from 1989 to 2005 at our institution were followed for incidence of blood disorders of any type by our registry system and by linkage to the Surveillance, Epidemiology and End Results registry (SEER) for our area. Cases without surgery (n=111), with stem cell transplantation (n=98), unknown or non-standard chemotherapy regimens (n=23 + 71= 94), lost to follow up (n=66) or cancer status unknown at follow up (n=67) were excluded. The remaining 5790 cases were reviewed for incidence of leukemia including MDS and acute myelogenous leukemia (AML) post breast cancer treatment by chart review including pathology reports, SEER coding for MDS/AML, and death certificates if appropriate. Mean length of follow up was 7.17 years, range 2-18 years.Results: The mean age of MDS/AML patients was 57 years, range 33-76 years. The crude rate of MDS/AML occurrence was .29% (17/5790). 17 cases of MDS/AML (10 MDS/7 AML) occurred during the follow up period as compared with 6.22 (4.03 MDS/2.19 AML) expected on the basis of rates in the general population by age <65, ≥ 65 years calculated from SEER registry data (risk ratio (observed/expected)). The risk of MDS in women <65 was 11.68 times that expected and the risk of AML in women <65 was 9.2 times the expected rate. Risk among women over 65 was not as large (1.38 MDS, ≥ 65, 1.21 AML, ≥ 65). Average time from treatment with radiation or chemotherapy to MDS diagnosis was 5.50 years (range 1.03-12.95) and 3.42 years (range .41-6.84) for AML. The majority of MDS/AML cases occurred in the first five years post treatment (n=10) with 7 more cases observed from 5 to 12.95 years (see figure). Initial treatment of MDS/AML patients was surgery only (n=2), surgery/chemotherapy (n=1), surgery/ radiation (n=7), and surgery/chemotherapy/radiation (n=7). The two MDS patients who had initial treatment of surgery only were subsequently treated with chemotherapy and radiation for recurrence. Fifty percent of MDS patients (5/10) received surgery and radiation treatment without adjuvant chemotherapy treatment.Discussion: The incidence of MDS/AML is very small in this cohort but significantly greater than that expected in the population at large especially among women less than 65 years of age. A significant number of women who received radiation treatment without chemotherapy developed MDS post breast cancer treatment. Average time from treatment to MDS diagnosis exceeded the 2-5 year time period previously reported as an expected interval.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2082.
Brain Metastases in Women with Inflammatory Breast Cancer (IBC): Incidence, Treatment and Outcome.
Authors: Dawood S. , Ueno N. , Valero V. , Andreopoulou E. , Hsu L. , Lara J. , Woodward W. , Buchholz T. , Hortobagyi G. , Cristofanilli M.
Published: December 2010

Background: Brain metastases are an uncommon metastatic recurrence site in breast cancer with a median incidence of approximately 6% in unselected populations. Inflammatory breast cancer (IBC) is an aggressive disease associated with dismal outcome. The purpose of this study was to determine the incidence of and survival following brain metastases among women with IBC.Material and Methods: Two hundred and six women with newly diagnosed stage III or IV IBC diagnosed between the period of between 2003 and 2008 were identified in a prospectively maintained IBC database at the MD Anderson Cancer Center. Cumulative incidence of brain metastases was computed. Cox proportional hazards models were fitted to explore factors that predict for the development of brain metastases. Survival was computed using the Kaplan-Meier product limit method.Results: Median follow-up was 20 months. Eighty three (40.3%) women had de-novo stage IV disease and 123 (59.7%) had stage III disease at diagnosis. Thirty-three (16%) patients developed brain metastases with a cumulative incidence at 1 and 3 years of 2.7% and 22% respectively. Eleven (5.3%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 1 and 3 years of 1.6% and 6.7% respectively. In the multivariable model, no specific factor was observed to be significantly associated with time to brain metastases, including HER-2 status. Median overall survival for the whole cohort was not reached. 3-year overall survival for the whole cohort was 78% (95% CI 69%-86%). Median survival following a diagnosis of brain metastases for all women who developed brain metastases or those who developed brain metastases as the first site of recurrence was 6 months.Conclusion: In this single-institutional study, women with IBC demonstrated a high early incidence of brain metastases associated with poor survival. As such IBC may be an ideal cohort to target screening procedures for brain metastases and/or enrollment of these women in clinical trials evaluating additional adjuvant preventive strategies.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2102.
HOXB13 May Predict Response to Neoadjuvant Letrozole in Patients with Estrogen Receptor-Positive Breast Cancer.
Authors: Ma X. , Bandaru R. , Letzkus M. , Philips P. , Barrett J. , Erlander M. , Goetz M. , Sgroi D. , Gardner H. , Baselga J.
Published: December 2010

Background. Third generation aromatase inhibitors (AIs) have been shown to be superior to tamoxifen in multiple randomized clinical trials and become the new standard of treatment for postmenopausal women with early or advanced endocrine-sensitive breast cancer. It is thus important to identify biomarkers predicting resistance to AIs so that alternative therapeutic options can be employed. A two gene expression index, HOXB13:IL17BR, and HOXB13 in particular, has been shown to be a negative predictor of clinical benefit from tamoxifen. It is unclear whether HOXB13:IL17BR or HOXB13 is also predictive of AI therapy.Methods. We performed a retrospective analysis of a phase II randomized neoadjuvant study of everolimus+letrozole vs. placebo+letrozole in patients with estrogen receptor-positive breast cancer. Total RNA was extracted from frozen tissue biopsies taken either prior to treatment or after 15 days of treatment. HOXB13:IL13BR and a molecular grade index (MGI) were measured in 107 pre-treatment samples and 111 samples after 15 days of treatment. Antiproliferative response as defined by a ln[Ki767] <1 at day 15 in the samples analyzed was correlated with these gene expression indices.Results. In the placebo+letrozole treatment arm, the antiproliferative response rate was 30% (14/47). Using a pre-specified cutpoint of 0.06, the response rate was 40% for low HOXB13:IL17BR patients, compared to 12% for high HOXB13:IL17BR patients (p=0.05). In the everolimus+letrozole arm, the antiproliferative response rate in the samples analyzed was 55% (33/60), and the response rates for low and high HOXB13:Il17BR patients were 70% and 37% (p=0.02), respectively. When examined separately, high HOXB13 expression was significantly associated with nonresponse to therapy (everolimus+letrozole arm, p=0.02; placebo+letrozle arm, p=0.03), but IL17BR was not (everolimus+letrozole arm, p=0.6; placebo+letrozle arm, p=0.88). As expected, we observed a significant correlation between MGI and Ki67 staining (Spearman r=0.67, p<0.0001).Conclusions. High HOXB13:IL17BR index and high HOXB13 expression may identify a possible subset of patients with estrogen receptor-positive tumor that could be less responsive to aromatase inhibitors such as letrozole. Furthermore, use of MGI may enable rapid assessment of antiproliferative response by fine needle aspiration.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2120.
Resequencing of the Vascular Endothelial Growth Factor Promoter Reveals Haplotype Structure and Functional Diversity.
Authors: Hancock B. , Radovich M. , Kassem N. , Mi D. , Skaar T. , Schneider B.
Published: December 2010

Our group has previously reported that SNPs in the VEGF promoter are strongly associated with efficacy and toxicity to the anti-VEGF antibody bevacizumab in metastatic breast cancer. In order to better understand the biologic mechanism for our previously reported biomarkers, we embarked on a comprehensive evaluation of the genetic variation in the VEGF promoter coupled with a study of its intrinsic function. By resequencing 96 DNA samples (48 Caucasians, 48 African-Americans) for the VEGF promoter, we elucidated its complete haplotype structure and identified SNPs that were not previously reported in prior resequencing efforts. SNPs that were identified included twenty previously reported SNPs/insertions/deletions, one novel SNP, and one novel deletion. Among these variants, we identified five SNPs (VEGF-3818G/T, -2305G/T, -1210C/A, -1154G/A, & -7C/T) that tag six haplotypes capturing 74% of the genetic variation of the VEGF promoter. Subsequently, we cloned the six major haplotypes into reporter constructs in order to determine the effect of genetic variation on function. The reporter assays were performed in 5 breast cancer cell lines representing all ER and HER-2 statuses along with an inflammatory breast cancer cell line. We demonstrate that there is significant variation in promoter-induced expression among the haplotypes. More importantly, we show that the haplotypes containing the SNPs previously reported to be associated with increased survival with the use of bevacizumab are high-expressing haplotypes, thus lending putative functional evidence to the prior clinical finding. Further, we also report the presence of a low-expressing haplotype predominantly in African-Americans. Altogether, these results set the foundation for future studies elucidating the role of VEGF genetic variation with response to anti-angiogenic therapy and associations with angiogenesis-related diseases.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2122.
PI3K Pathway Activation in Breast Cancer Is Associated with the Basal-Like Phenotype and Cancer-Specific Mortality.
Authors: Lopez-Knowles E. , O'Toole S. , O'Toole S. , McNeil C. , McNeil C. , Millar E. , Millar E. , Millar E. , Qiu M. , Qiu M. , Crea P. , Daly R. , Daly R. , Musgrove E. , Musgrove E. , Sutherland R. , Sutherland R.
Published: December 2010

Background: Current biological therapies for breast cancer are tailored to steroid hormone (ER, PR) and HER2 receptor status. Understanding the biological basis of resistance to current targeted therapies and the identification of new potential therapeutic targets is an ongoing challenge. The PI3K pathway is altered in a high proportion of breast cancers and may be associated with specific phenotypes and therapeutic resistance. We undertook an integrative study of mutational, copy number and expression analysis of key regulators of the PI3K pathway in a cohort of 292 invasive breast cancer patients with known treatment outcomes.Material and Methods: Mutations in 3 "hotspots" in exons 9 and 20 of the PIK3CA gene were determined by sequencing and PIK3CA gene copy number by qPCR. PTEN loss and Akt activation i.e. pAkt (Ser473) were assessed by immunohistochemistry using tissue microarrays. Cores were scored by 2 independent observers blinded to clinicopathological data and patient outcome and a histoscore calculated by multiplying the percent positive cells and staining intensity in a range 0-3. Standard statistical tests were applied to assess relationship between the measured parameters and patient outcome.Results: Alterations identified included PIK3CA mutations (12/168 i.e. 7%), PIK3CA copy number gain (28/209 i.e. 14%), PTEN loss (73/258 i.e. 28%) and AKT activation (62/258 i.e. 24%). Overall at least one parameter was altered in 72% i.e. 139 of 193 assessable primary breast cancers. PI3K pathway activation was significantly associated with ER negative (P=0.0008) and PR negative (P=0.006) status, high tumor grade (P=0.032) and a "basal-like" phenotype (P=0.01), where 92% (25/27) of tumors had an altered pathway. In univariate analysis PI3K pathway aberrations were associated with death from breast cancer however this relationship was not maintained in multivariate analysis. No association was identified between an activated pathway and outcome in tamoxifen- or chemotherapy-treated patients.Discussion: We conclude that >70% of breast cancers have an alteration in at least one component of the PI3K pathway and this might be exploited to therapeutic advantage especially in "basal-like" cancers.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2123.
Expression Levels of Co-Regulators in Early Breast Cancer.
Authors: Spears M. , Pedraza J. , Thomas J. , Kerr G. , Kerr W. , Campbell F. , McKay L. , Kunkler I. , Cameron D. , Chetty U. , Bartlett J.
Published: December 2010

Introduction: The p160 (SRC) family of estrogen receptor (ER) co-activators have important implications in tamoxifen resistance. The SRC family play a central role in ER mediated transcription. There are three family members; SRC-1, SRC-2 and AIB1. AIB1 is amplified in 5-10% of human breast cancers. SRC-1 expression is associated with HER2 expression, increased risk of recurrence and insensitivity to endocrine treatment. Co-factors interact with the ER and basal transcriptional machine to activate or repress ER-mediated transcription. To investigate the role of ER and its co-factors in breast cancer we have carried out quantitative RT-PCR (qRT-PCR) to measure the relative expression of ERa and its co-factors.Methods: In this study we examined patients which were untreated or treated with chemotherapy or hormonal therapy following breast conservation surgery. RNA was extracted from 340 early breast cancer specimens from the Edinburgh Breast Conserving Surgery cohort (BCS). The BCS is a fully documented consectutive cohort of breast cancers treated by conservation surgery, axillary node sampling or clearance, and whole breast radiotherapy between 1981-1998. Clinico-pathological features and complete follow up (duration >10 years) is available for this cohort. qRT-PCR was carried out using primers for ER, SRC-1, SRC-2, AIB1, NCoR1 and SMRT.Results: This study demonstrated SRC-1 expression to be negatively correlated with both SRC-2 and AIB1 expression. SRC-1 expression was also negatively correlated with the co-repressors NCoR1 and SMRT expression. There was a strong correlation between the co-repressors, NCoR1 and SMRT and the co-activators SRC-2 and AIB1. Relapse-free survival (RFS) was estimated using Kaplan-Meier curves. Patients who had high expression of all three co-activators had reduced relapse-free survival (HR: 2.15 95%C.I. 1.175-3.921, p=0.01). No significant association was noted with overall survival. Exploratory subgroup analysis was under powered and showed no significant association with outcome.Conclusion: In conclusion, our study of expression levels of ER and its cofactors by quantitative RT-PCR in breast cancer samples revealed a correlation between the co-factors and co-repressors. These findings would suggest that ER and cofactors may play a synergistic role in the development and progression of breast cancer.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2127.
Fra-1 Expression in In Situ and Invasive Ductal Breast Carcinomas: Association with Worse Prognosis in Invasive Basaloid Tumors.
Authors: Logullo A. , Stiepcich M. , Toledo Osório C. , Pasini F. , Soares F. , Nonogaki S. , Brentani M.
Published: December 2010

Background: Fos-related antigen 1 (Fra-1) is an immediate early gene encoding a member of AP-1 family of transcription factors involved in cell proliferation, differentiation, apoptosis, and other biological processes. A high level of Fra-1 expression is found in various tumors and tumorigenic cell lines, suggesting that Fra-1 may be involved in malignant progression. Objective: Evaluate the significance of Fra-1 expression in breast carcinogenesis and its possible help in sub typing and prognosis of breast carcinomas. Methods: Fra-1 expression was investigated by immunohistochemistry in a Tissue Microarray composed by neoplastic breast tissue from 85 in situ breast carcinomas lesions and 769 invasive ductal carcinomas NOS (IDC), ranging from early stage T1 N0M0 to very aggressive metastatic disease (TxN1-3M1). Positive and negative controls were present in each reaction. Nuclear staining were considered positive. Correlations of Fra-1 expression with other indicators of breast carcinoma prognosis (ER, PR TNM, survival) were analyzed. Results: IDC showed 22.8 % of positivity while in situ lesions maintained a 42.2% of reactive cases. In IDC samples, Fra-1 expression correlated with markers of invasiveness, as Node status, histological grade (P= 0.005 and 0.001, chi-square test) and marginally with presence of metastasis (P= 0.07). Fra-1 was also associated to Cytokeratin (CK) 14 (P= 0.043) and marginally to CK18 and her-2 status (P=0.063 and 0.05), and indirectly to estrogen receptor (P= 0.01). When we select basaloid (CK6 positive, ER negative) cases Fra-1 was associated to worse prognosis (P= 0. 013 - Log Rank test). Conclusions: The data shown here suggest that Fra-1 expression is progressively lost during cancer progression from DCIS to IDC. Fra-1 expression in IDC basaloid tumors confers a worse prognosis. Supported by FAPESP nº 04/04607-8.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2129.
Validation of FOXA1 as a Prognostic Marker in Breast Cancer in a Large Population-Based Tissue Microarray.
Authors: Badve S. , Mehta R. , Jain R. , Nielsen T. , Leung S. , Huntsman D. , Nakshatri H.
Published: December 2010

FOXA (Forkhead box protein A) proteins play major roles in development and differentiation. However, recently, FOXA1 has been identified to play a role in controlling nearly 50% of estrogen receptor target genes and has been deemed as a 'pioneer factor'. It is believed to have a dual role in breast cancer: (1) growth promotion by coactivating ERα and (2) growth inhibition by regulating factors like p27Kip1 and E-cadherin. We studied the expression of FOXA1 in a population based tissue microarray of 4,046 invasive breast cancer cases with a median follow- up of 12.4 years using immunohistochemistry and studied its correlation with estrogen receptor and other clinicopathological variables. The percent positivity (P) and intensity (I) of nuclear FOXA1 expression were multiplied to generate a numerical score (S = P × I) that ranged from 0 to 30. Scores between 0 and 3 were defined as low FOXA1 expression and 4 to 30 were defined as high FOXA1 expression. Variable FOXA1 expression was noted in the 3581 interpretable tumors: none (10.6%), weak (3.5%), moderate (19.3%) and strong (55.1%). High level of FOXA1 expression (FOXA1 score greater than 3) was seen in nearly 86% of the tumors. FOXA1 expression correlated positively with ER (p< 0.0001), PR (p< 0.0001), E-cadherin (p<0.0001), age (p< 0.0001) and negatively with basal subtype (p< 0.0001), Ki67 (p<0.0001), tumor size (p< 0.0001) and tumor grade (p<0.0001). Univariate analyses showed small tumor size (T1 tumors), low grade (Grade I), node negative disease, absence of lymphovascular invasion, ER, PR, Her2, cyclin D1 and Ki67 as independent predictors of better overall survival. Patients with Luminal A subtype breast cancers had better overall survival than those with non-Luminal A subtype breast cancers. FOXA1 is found to be a significant predictor of breast cancer specific survival (p=0.012) and locoregional relapse free survival (p=0.0001). However, FOXA1 did not reach statistical significance for disease free survival (p=0.110) and distant relapse free survival (p=0.147). When stratified by molecular subtypes using IHC, FOXA1 did not show any trend for overall survival. In those treated with tamoxifen, low FOXA1 expression was associated with poor overall survival (p<0.0001). In a subset of ERα-positive breast cancer cases, FOXA1 was a significant predictor of breast cancer specific survival (p=0.012). To summarize, FOXA1 expression in ERα-positive breast cancer is of prognostic significance.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2130.