bluuebunny/crossref_metadata_2025 huggingface dataset:
A Functional Metagene Incorporating TTK Protein Kinase, Aurora Kinase B and Glucosylceramide Synthase Predicts Response to Treatment in Primary Breast Cancer.
Authors: Juul N. , Eklund A. , Li Q. , Downward J. , Burrell R. , Szallasi Z. , Szallasi Z. , Swanton C. , Swanton C.
Published: December 2010

Deriving robust gene expression signatures from microarray data that predict response to a given chemotherapeutic treatment has been hindered due to over-fitting of data. To overcome this problem, we have taken the approach to combine genes known to be functionally involved in drug response into a “functional metagene” to predict pathological complete response to treatment in primary breast cancer.Using published functional genomics RNA interference data and microarray datasets we identified 46 genes that alter paclitaxel sensitivity in laboratory cell line models and are also measured by the U133A microarray platform. In order to filter genes into a functional metagene with a putative role in taxane response in breast cancer, we addressed whether the expression of these genes was predictive of pathological complete response in a primary breast cancer clinical dataset treated with taxane, 5-fluorouracil, adriamycin and cyclophosphamide (TFAC). We identified two genes, TTK protein kinase and aurora kinase B, which showed increased expression in responders, and one gene, glucosylceramide synthase, which showed decreased expression in responders (P < 0.001, AUC > 0.7, all 3 genes). We then combined these three genes into a functional metagene which we tested in a validation clinical trial cohort that had also received TFAC. We found that the functional metagene robustly predicted pCR in the validation clinical trial cohort (P < 0.001, AUC = 0.8). These data suggest a relevance of ceramide metabolism and the expression of kinases that sense tension across the sister chromatid pair in determining response to taxane combination chemotherapy schedules in vivo. We believe that this approach of using functional genomics in combination with gene expression datasets will improve the prediction of therapeutic response in cancer medicine.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2032.
Evaluation of the Predictive Value of IGF-IRa, IGF-IRb, UPA, and PAI-1 in Patients with Advanced Breast Cancer (ABC) Treated with Trastuzumab.
Authors: Kostopoulos I. , Karayannopoulou G. , Bobos M. , Skarlos D. , Briassoulis E. , Koutras A. , Pectasides D. , Linardou H. , Razis E. , Matsiakou F. , Kalogeras K. , Fountzilas G.
Published: December 2010

Background: It has been shown that the HER2 and uPA/PAI-1 pathways independently affect the aggressive behavior of breast tumors. While HER2 positive patients have been shown to respond to trastuzumab, the role of uPA and PAI-1 in patients with advanced breast cancer (ABC) treated with trastuzumab is unclear, while the IGF-IR pathway appears to mediate resistance to trastuzumab.Material and Methods: Formalin-fixed paraffin-embedded tumor tissue samples were retrospectively collected from 138 patients with ABC treated with trastuzumab in the first-line. Clinical information was retrieved from medical records. The median age of the patients was 55 years, with 31% being premenopausal. HER2, IGF-IRa, IGF-IRb, uPA, PAI-1, Ki-67, ER, and PgR were assessed centrally by immunohistochemistry (IHC), while HER2 was also assessed centrally by FISH. All stains were examined by 2 independent pathologists, using the Allred 8-unit system for IGF-IRa and IGF-IRb, a combination of a proportion score from 0 to 5 and an intensity score on a scale of 0 to 3 (none, weak, moderate, strong). uPA protein expression was considered positive if >75% of the cells showed intense staining, with PAI-1 deemed positive when >6% of the cells showed mild staining. PFS and survival from the initiation of trastuzumab were estimated by the Kaplan-Meier method and compared using the log-rank test.Results: Trastuzumab alone or in combination with chemotherapy and/or hormonal therapy was given as first-line treatment in all patients. HER2 gene amplification was confirmed in 89 cases, while in 49 patients HER2 was found to be non-amplified (HER2 negative patients). As expected, survival of HER2 positive patients was found to be significantly longer (50.7 months vs. 30.5 months, p<0.0001), with no significant differences found in PFS (14.0 months vs. 9.2 months, p=0.124). IGF-IRa, IGF-IRb, uPA, or PAI-1 positive patients were not found to have significantly different PFS or survival in either HER2 positive or negative patients.Discussion: Protein expression of IGF-IRa, IGF-IRb, uPA, or PAI-1 assessed by IHC was not found to be associated with significantly different survival in patients with advanced breast cancer treated with trastuzumab in the current analysis. Studies are ongoing to include patients receiving second-line treatment with trastuzumab and evaluation of PI3K mutations.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2036.
Comparative Analysis of Breast Cancer (BrCa) Mortality Reduction among Regions of Canada between 1950 – 2004: Impact of Systemic and Diagnostic Guidelines after 1977, with Model Definition of Number of Potentially Avoided Annual Deaths (N-PAAD).
Authors: Ragaz J. , Wong H. , Qian H.
Published: December 2010

BACKGROUNDWe reported in the past the BrCa mortality trends in three Provinces of Canada with different Levels of Provincial Diagnostic and Therapy Guideline (ProvDgThGuide) implementation, reflecting access to optimum cancer care (LEVEL I, most uniform: British Columbia (B.C.); LEVEL II, medium: Ontario(ON); LEVEL III, least uniform (Atlantic Provinces AP), and have shown best outcomes in B.C. (Cancer Res 2009 69[S] 2:383).OBJECTIVETo estimate the number of BrCa deaths that potentially could have been avoided during the period 1978 – 2004 if the ProvDgThGuide Level I (i.e. of B.C.) had been implemented in Canada, Ontario and Atlantic Provinces, respectively.METHODSData were obtained from Statistics Canada.i. For each region, we calculated the average annual age-standardized mortality rate / 100,000 (aveASR) for the periods 1950-1977 (R1) and 1978-2004 (R2).ii. Subsequently, calculated was the Relative Change (RC, expressed in %) in mortality rate between the two time periods (RC = (R2-R1)/R1).iii. And for each region, the 1978 – 2004 expected rates (RE) based on RC from B.C. [i.e. calculated as "-13.8%" [(RE = 1- 0138) x R1].iv. These steps permitted estimates of Number of potentially avoided [annual] deaths (N-PAAD), based on the difference in observed mortality during the 1978-2004 period and the mortality that would have occurred if the regions had experienced the same relative change in mortality rate as observed in B.C. (R2-RE x # at risk).RESULTS R1(aveASR 1950-1977)R2(aveASR 1978-2004)RCREN-PAAD(N-AveAnnDeaths)BC30.025.8-13.8%----Ontario30.929.2-5.3%26.6137Atlantic27.528.8+4.7%23.760Canadaexcluding BC30.729.0-5.5%26.5315CONCLUSIONThis study confirms in most but not all regions of Canada a substantial mortality reduction after 1977, suggestive that implementation of optimum levels of Provincial Diagnostic and Therapy Guidelines (optimum access to cancer care) may affect mortality, and that their delay may prevent materialization of survival gains.Once the average annual rates of B.C. was applied to the rates of rest of Canada, the newly developed "Potentially Avoided Annual Deaths" model estimates over 8,000 avoided BrCa deaths in Canada (without B.C.) during the period 1978 – 2004 (26 [years] x 315).The model estimates over 3,500 (26 x 137) and 1500 (26 x 60) avoided deaths, respectively, for Ontario and Atlantic Provinces.These data are relevant to all world regions with differing access to optimum cancer care.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2063.
Chemotherapy Treatment and Survival in Estrogen Receptor Negative Metastatic Breast Cancer: A Population-Based Analysis.
Authors: Zuckerman I. , Schneider M. , Onukwugha E. , McNally D. , Gardner J. , Pandya N. , Seal B. , Mullins C.
Published: December 2010

Introduction: Although controlled clinical trials have demonstrated a beneficial effect of various chemotherapy regimens on survival in breast cancer (BC), little is known about treatment patterns and survival benefit in the “real world” population of elderly women with metastatic BC. Methods: We identified female Medicare beneficiaries aged ≥66 years with metastatic BC diagnosed from 1999 to 2005 in the Surveillance, Epidemiology and End Results cancer registries (SEER). Patients with a prior history of any cancer were excluded. Treatment-related data were abstracted from linked Medicare claims. Since Medicare claims have incomplete information on oral selective estrogen receptor modulators, we limited our study cohort to estrogen receptor negative (ER-) women. Chemotherapy was defined as the receipt of any chemotherapeutic regimen within 6 months after diagnosis. Initial regimens were characterized based on drugs given during the first 30 days of chemotherapy. We used a continuous-time interval-censored survival analysis to determine the effect of chemotherapy on hazard of any-cause death, controlling for sociodemographic and clinical factors, including proxy measures for performance status. Results: We identified 1518 ER(-) women diagnosed with metastatic BC in SEER. Mean age was 77.6 (SD 7.6) years, 84% were white race and 27% were married at the time of diagnosis. Of the 1518 metastatic ER(-) BC patients, 493 (32%) received chemotherapy. As compared to women who did not receive chemotherapy, women who received chemotherapy were more likely to be younger, married, have lower pre-cancer comorbidity as measured by the Charlson comorbidity index, have seen an oncology specialist and have cancer-directed surgery or radiation prior to chemotherapy. Initial regimens comprised predominantly one (31%) or two (46%) drug classes. The most common regimens were taxanes only (18%), anthracycline+alkylating agents (17%) and antimetabolite+alkylating agent (9%). Overall median followup time was 7 months; 1223 women (81%) died during followup. Median survival time was 5 months among women who did not receive chemotherapy and 15 months among women who received chemotherapy. Chemotherapy was associated with a statistically significant survival benefit (adjusted Hazard Ratio 0.61, 95% confidence interval 0.54, 0.70). Conclusion: In this population-based study of older women, there was a variety of chemotherapy regimens used for metastatic ER(-) BC. Chemotherapy received within 6 months after diagnosis was associated with a 39% reduction in hazard of death. These findings reflect chemotherapy use outside of the clinical trial setting and have important clinical and policy implications for the study of treatments among older women with advanced BC.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2064.
Comparison of Subgroup Analyses of PFS from Three Phase III Studies of Bevacizumab in Combination with Chemotherapy in Patients with HER2-Negative Metastatic Breast Cancer (MBC).
Authors: O'Shaughnessy J. , Dieras V. , Glaspy J. , Brufsky A. , Miller K. , Miles D. , Koralewski P. , Phan S. , Bhattacharya S.
Published: December 2010

BackgroundThree multicenter, randomized, placebo-controlled Phase III trials of taxane (T), or capecitabine (Cape), or anthracycline (Anth) chemotherapy plus or minus bevacizumab (B) established that the addition of B improves progression-free survival (PFS). Outcomes in clinically important subsets are important to demonstrate the consistency of treatment effect and may guide physicians when considering treatment options for patients. Here we compare various clinically relevant subgroups across three studies to assess the activity of B in patients for these subgroups.MethodsResults for PFS based upon investigator assessments were used from all trials. Kaplan-Meier methodology was used to estimate median PFS for chemo+placebo and chemo+B for patient subgroups from the E2100, AVADO, and RIBBON-1 studies. For the overall study results, stratified hazard ratios (HRs) are presented with the same stratification factors as the variables that were used for the randomization, while unstratified HRs are presented here for the subgroups.ResultsIn all 3 studies we observed an improvement in PFS upon addition of B to chemotherapy. For patients with triple-negative (ER-, PR-, HER2-) tumors, the addition of B led to an increase in median PFS (mPFS) from 4.7 mo to 10.2 mo (HR=0.45; 95% confidence interval [CI], 0.33-0.61) in E2100, from 6.0 to 8.1 mo in the AVADO 15 mg/kg B arm (HR=0.60, 95% CI, 0.39-0.92); from 4.2 to 6.1 mo in the RIBBON-1 Cape cohort (HR=0.72, 95% CI, 0.49-1.06); and from 8.2 to 14.5 mo in the RIBBON-1 T/Anth cohort (HR=0.78, 95% CI, 0.53-1.15).For patients ≥65 yr, the addition of B led to an increase in mPFS from 7.4 to 10.4 mo (HR=0.69, 95% CI, 0.46-1.03) in E2100, from 7.6 to 8.4 mo in the AVADO 15 mg/kg B arm (HR=0.62, 95% CI, 0.36-1.08); from 6.2 to 9.1 mo in the RIBBON-1 Cape cohort (HR=0.69, 95% CI, 0.47-1.02); and from 8.5 to 10.1 mo in the RIBBON-1 T/Anth cohort (HR=0.83, 95% CI, 0.52-1.34).For patients who had received prior adjuvant T, the addition of B led to an increase in mPFS from 4.4 to 13.3. mo in E2100 (HR=0.29; 95% CI, 0.19-0.46), 6.6 to 8.5 mo in the AVADO 15 mg/kg B arm (HR=0.42; 95% CI, 0.23-0.77), 4.2 to 8.7 mo in the RIBBON-1 Cape cohort (HR=0.62; 95% CI, 0.45-0.84); and from 6.7 to 9.1 mo in the RIBBON-1 T/Anth cohort (HR=0.65; 95% CI, 0.39-1.09).ConclusionsAlthough the addition of bevacizumab consistently improved mPFS across a number of clinically relevant subsets, regardless of the chemotherapy backbone used, absolute improvements in HRs and median PFS varied within subsets and across the three trials.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 207.
Relationship of Age at First Live Birth, Parity and Duration of Breast Feeding with Non Familial Breast Cancer in Pakistani Women. A Study of the Cancer Research Group Pakistan.
Authors: Ahmad S. , Mahmood H. , Kanwal S. , Mahmood A. , Ahmad K. , Masood M. , Faheem M. , Akbar N. , Hafeez M.
Published: December 2010

Background and objectives; This multicenter case control study is being conducted at seven different centers in Pakistan in order to find out the association and relationship of different hormonal and reproductive factors with breast cancer. These factors have been identified either as risk factors or protective factors for breast cancer in other communities but not in Pakistani women. Preliminary results from four centers are being reported here.Method; Patients attending these cancer treatment centers were interviewed by the trained medical personals and the findings were recorded in a proforma. Age and area matched unrelated controls were randomly selected and interviewed with same questions and findings were recorded in a corresponding proforma. SPSS version 11.5 was used for statistical analysis.Results; From June, 2008 to May, 2009 six hundred eighty eight cases were compared with an equal number of controls. Median age of cases was 47 years (26-70 years) and controls 47.5 years (25-71 years). One hundred ninety eight of cases (28.78%) and 208 of controls (30.23 %) gave first full term live birth before the age of 20. Sixty two cases (09.01%) and 38 controls (5.52%) gave first full term live birth after the age of 30. Seventy one cases and 65 controls were nulliparous.Fifty cases (07.27%) and 51 controls (07.41%) had only one child whereas 104 (15.12%) cases and 118 controls (17.15%) had more then 7 children.Breast feeding duration was more then 24 months in 410 (72.31%) of all women who had more then 1 child. Duration of breast feeding in cases Vs. control in women with 2-4 children, 5-7 children and more then 7 children was similar. Statistical analysis reveals that first live birth below the age of 20 and duration of breast feeding of greater then 24 months duration are not associated as protective factors in this patient population. Odds ratio of 1.35, 95% CI; 1.01-1.70 and 1.014, 95% CI; 0.80-1.22 respectively. Age at first live birth after 30 years of age seems to be positively associated with breast cancer. Odds ratio of 1.75, 95% CI; 1.15-2.65. These results do not support the young age at first full term pregnancy and prolonged duration of breast feeding as protective factors against the breast cancer.Key Words: Breast Cancer, Breast feeding, Parity, Risk Factor

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2071.
Features of Recurrence of Triple Negative (TN) Non-Metastatic Breast Cancer (NMBC) Patients: A Single Institution Study.
Authors: Alarcon-Rozas A. , Cueva M. , Galarreta J. , Ramirez J. , Torres J. , Gonzales E. , Gamarra L.
Published: December 2010

Background.- TN breast cancer (BC) are the most agressive type of BC, and we do not have a target therapy against this type. Our goal is to determine the rate of recurrence, the affected organs and the DFS in these patients.Materials and Methods.-We reviewed 1042 charts of all diagnosed BC patients from January/2000 to December/2005 and choose 215 who were TN-NMBC. The data was analized by analitic and descriptive statistics in SPSS v. 17.0Results.- The rate of TN-NMBC were 20.6%(215) of them 18.6%(40) patients had recurrences with an average age of 52.5(31-93) years. The median DFS were 27 months with a median follow-up of 64 months. The Stage I, II and III were 7.5%(3); 32.5%(13) and 60%(24) respectevely for patients with recurrence. The most frequent involved organs with recurrence were visceral (lung and liver) 37.5%(15), bone 25%(10), skin 20%(8), CNS 12.5%(5) and contralateral breast 5%(2). Additionally we found five patients with history of familiar BC, and four of them were stage II with negative lymph node at diagnoses.Conclusion.- TN-NMBC are 20.6% of all BC, the majority of them were stage III (60%), the median DFS for patients with recurrence were 27 months, and the most frequent sites involved were visceral (37.5%) and bone (25%). It is very interesting pay attention even in early stages to patients with history of familiar BC for risk of recurrence, BRCA positive?

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2072.
Breast Cancer Survivors Often Meet Multiple Criteria for Lymphedema.
Authors: Armer J. , Stewart B. , Shook R.
Published: December 2010

Introduction:Assessment and diagnosis of lymphedema (LE) has been problematic, in part due to the fact that various measurement approaches and criteria have been applied. This analysis examines four different criteria for diagnosing lymphedema among breast cancer survivors. Recent scientific literature reports that anywhere from 6 to 30 percent (Petrek and Heelan, 1998) or 6 to 62.5 percent (Passik, 1998) of the breast cancer population has LE. The discrepancies among the reported percentages stem from difficulties in measurement, diagnosis, and follow-up (Petrek and Heelan, 1998, Passik, 1998, Rockson, 1998, Meek, 1998, Armer and Stewart, 2005, Hayes et al., 2008). Traditionally, finding >2cm difference in limb girth between the affected and non-affected limbs warranted clinical diagnosis of LE (Callaway, 1988, Armer and Stewart, 2005). Measuring a 200 ml limb volume difference or a 10 percent limb volume change (LVC) from baseline and/or between limbs as well as self-reported signs and symptoms are also documented methods of LE diagnosis (Petlund, 1991, Armer and Stewart, 2005).Methods:Participants were enrolled post-breast cancer diagnosis but pre-surgery, and followed every 3 months for 12 months, then every 6 months until 2.5 years post-surgery. Limb volume changes (LVC) were measured using: (a) circumferences via tape measure at 4 cm intervals, (b) infra-red laser perometry, and (c) symptom experience (SS) via interview. Four diagnostic criteria for LE were used: (i) 2cm circumferential change; (ii) 200 mL perometry LVC; (iii) 10% perometry LVC; and (iv) self-report of limb heaviness/swelling.Results:In this cohort, 84% met at least one criterion to identify lymphedema by 2.5 years post-treatment (Figure 1). The most common single criterion met was 2-cm circumferential change (25%). When examining meeting multiple criteria, 13% of participants met the combination of 200mL LVC, 10% LVC, and 2cm change. In addition, 11% of participants met all four lymphedema criteria by 2.5 years post treatment.Conclusions:This analysis demonstrates breast cancer survivors who develop lymphedema often meet multiple criteria for the condition. We found 62% of those with lymphedema met two or more criteria used in this analysis, and 31% met three or more criteria. The most common criterion to identify lymphedema, either alone or associated with one or more criteria, was 2 cm circumference change (77%), while 10% LVC was least likely to be met (26%).

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2074.
Analysis of Bevacizumab (Bev) Therapy, Bisphosphonate Use and Osteonecrosis of the Jaw (ONJ) in >1900 Patients Treated in Two Randomized, Controlled Trials.
Authors: Guarneri V. , Miles D. , Robert N. , Dieras V. , Glaspy J. , Smith I. , Thomssen C. , Biganzoli L. , Taran T. , Conte P.
Published: December 2010

Background: Long-term bisphosphonate therapy is known to increase the risk of ONJ. A 16% incidence of ONJ was reported in a retrospective analysis of 116 patients receiving bisphosphonates with anti-angiogenic therapy (Bev or sunitinib) for bone metastases from breast, colon, or renal cell cancers.Methods: To assess the incidence of ONJ with Bev, we analyzed data from >3500 patients with locally recurrent or metastatic breast cancer (LR/MBC) treated in three large trials of Bev-containing therapy: AVADO (Bev in combination with docetaxel); RIBBON-1 (Bev in combination with taxane, anthracycline-based combination therapy, or capecitabine); and MO19391 (single-arm safety study of >2000 patients receiving Bev-containing therapy in the general oncology practice context). The incidence of ONJ was compared in patients treated with Bev versus placebo and in patients with or without bisphosphonate exposure.Results: Data from the blinded phase of two randomized, placebo-controlled trials demonstrated an ONJ incidence of 0.3%. ONJ was more common in patients who also received bisphosphonate therapy than in those who received no bisphosphonates (Table). This observation is supported by data from 2216 patients treated in the single-arm MO19391 study (2.4% with bisphosphonate versus 0% without). AVADO*RIBBON-1**TotalIncidence of ONJ, no. of pts (%)Bev (n=492)Pla (n=238)Bev (n=817)Pla (n=412)Bev (n=1309)Pla (n=650)Overall population receiving Bev (n=1309)3 (0.6%)O1 (0.1%)O4 (0.3%)OBisphosphonate (n=233)1 (1.2%)O1 (0.6%)O2 (0.9%)ONo bisphosphonate (n=1076)2 (0.5%)OOO2 (0.2%)O *Bev 15 and 7.5 mg/kg arms pooled**Taxane/anthracycline and capecitabine cohorts pooledConclusions: This is the largest analysis of ONJ in patients receiving Bev for LR/MBC. The 0.3% incidence of ONJ with Bev is considerably lower than previously reported by Christodoulou et al. with anti-angiogenic therapy. As in the general population, the risk of ONJ is increased in patients exposed to bisphosphonates. The 0.9–2.4% incidence seen here in a large population of patients receiving Bev and bisphosphonate therapy is substantially lower than the 16% observed in a small cohort of patients from a retrospective analysis and within the range reported in the literature for bisphosphonates alone (1–4%). Good oral hygiene, dental examination and avoidance of invasive dental procedures remain important in patients receiving bisphosphonates, irrespective of Bev treatment.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 208.
Post-Operative 5FU-Docetaxel after High-Dose of Pre-Operative Epirubicin-Cyclophosphamide for Treatment of Inflammatory Breast Cancer: Results of the FNCLCC-Pegase 07 Trial.
Authors: Viens P. , Palangié T. , Ferrero J. , Chollet P. , Bachelot T. , Delva R. , Fabbro M. , Janvier M. , Lotz J. , Linassier C. , Dohollou N. , Eymard J. , Leduc B. , Genève J. , Martin A. , Boher J. , Roché H.
Published: December 2010

Purpose: to evaluate the benefit of a post-operative Fluorouracil-Docetaxel (D-5FU) regimen after pre-operative Epirubicin-Cyclophosphamide (EC) and loco-regional treatment for women with inflammatory breast cancer (IBC).Patients and Methods: Women with non-metastatic IBC, age <60 years, life expetancy >3 months, and normal hematological, hepatic and cardiac function were randomized to receive either 4 cycles of EC (epirubicin 150 mg/m² and cyclophosphamide 4000 mg/m² every 3 weeks) then mastectomy with axillary lymph node dissection and radiotherapy (ArmA) or the same treatment followed by 4 cycles of DCT-5FU (docetaxel 75 mg/m², day 1 and 5FU 2500 mg/m²/day continuous infusion, days 1-5 every 3 weeks) (ArmB). Patients (pts) with hormone receptor positive (HR+) tumors received hormonotherapy. Pts were to be followed for five years, disease-free survival (DFS) being the primary study endpoint.Results: From January 2001 to May 2005, 174 pts (87 in each arm) were enrolled. All pts received at least one cycle of intensive chemotherapy and 160 pts (92%) completed the whole intensive regimen. Pts characteristics were well balanced. Main Grade 3-4 toxicities during EC regimen were neutropenia (98%), and trombopenia (94%). Other Grade 3-4 toxicities were vomiting (53%), infection (13%), fever (9.2%) and nausea (8.6%). One patient progressed before surgery (Arm B). Among 71 pts treated with D-5FU, Gr 3-4 neutropenia occurred in 61%.As of April 2009, the median follow-up was 59.8 months. Overall 78 pts experienced at least one event: 12 (6.9%) loco-regional relapses, 58 (33.3%) metastasis, 5 (2.9%) contra-lateral breast cancers and 3 (2.9%) deaths. The estimated 3-year and 5-year disease-free survival (DFS) rates were similar in both arms, 63.0% (95%CI: 51.9-72.2) and 55.5% (95%CI: 44.3-65.3) in arm B compared to 59.8% (95%CI: 48.7-69.2) and 55.0% (95%CI: 43.9-64.7) in arm A. Despite a trend to non proportional hazards between arms (p=0.07), no significant differences were observed on 3-year (p=0.55) and 5-year DFS (p=0.81). No differences were observed on survival rates (p=0.94) with a total of 27 pts (both arms) who died during their follow up period and an estimated 5-year survival rate equal to 70% (95%CI: 59-79) in both arms.In a preliminary multivariate analysis, only HR+ and pathologic complete response in breast and nodes were predictive for 5-year DFS (p<0.0001 and p<0.01) and 5-year OS (p<0.001 and p<0.05).Conclusion: 4 cycles of post-operative D-5FU did not improve DFS or OS of IBC after pre-operative high dose EC and standard therapy. However, at 70% the 5-year survival for the whole population is of great interest.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2081.
Chemotherapy Induced Febrile Neutropenia of Docetaxel with Cyclophosphamide (TC) for Adjuvant Therapy of Breast Cancer in the Community – Reality Check.
Authors: Myers R. , Higgins B. , Myers J. , Leung M. , Rajagopal S. , Jones G. , Stakiw J.
Published: December 2010

Following the publication of the paper utilising docetaxel and cyclophosphamide as adjuvant therapy for breast cancer Jones et al JCO 24:5381-5387/2006, we elected to use this program for low to intermediate risk breast cancer patients at the Carlo Fidani Cancer Centre in Mississauga Ontario. From January 2008 until June 2009 we have treated 86 patients. After treating our first 16 patients 6 had developed febrile neutropenia requiring admission to hospital. These patients were subsequently treated with either dose reduction or filgastrim/pegfilgastrim was added. For all 70 subsequently treated patients with this program, either dose reduction or primary prophylaxis with filgatrim or pegfilgastrim was used,prophylactic antibiotics were not used. In this cohort 2 patients required admission to hospital with infection and only 1 was neutropenic (2/70=3%). Details of all patients will be presented. The likelihood of this difference occurring from chance was small p< .0005. (Fischer exact test) Within the paper the quoted febrile neutropenia rate was 5% for the TC group. In the first publication JCO 24:5381-5387, 2006 it is stated that neither prophylactic antibiotics nor growth factors were routinely used whereas in the second paper JCO 27:1177-1183,2009 it is stated that prophylactic quinoline antibiotics were recommended but not required. It is important in a landmark study like this one that details regarding anciliary treatments be detailed so that it may be used safely in the community. Our rate of febrile neutropenia without filgastrim/pegfilgastrim was 6/16=37.5%. The causes of the differences between our rate of fne and that seen in the paper will be discusseed. In addition the differences we saw in the fne rate when either filgastrim/pegfilgatrim were added were markedly improved. In conclusion the TC program given a fne rate > 30 % would mandate the usage of filgastrim or pegfilgastrim for primary prophylaxis. The addition of figastrim/pegfilgastrim markedly reduced our fne rate.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2092.
Superiority of Docetaxel + Capecitabine Compared to Docetaxel + Epirubicin as First-Line Therapy for Metastatic Breast Cancer – Final Results of the ERASME-4 Study.
Authors: Bachelot T. , Bajard A. , Ray-Coquard I. , Provencal J. , Coeffic D. , Dramais D. , Ferri-Dessens R. , Guastalla J. , Perol D.
Published: December 2010

Background: Docetaxel plus capecitabine (DC) combination therapy improves both time to disease progression and overall survival over docetaxel alone in metastatic breast cancer (MBC). The aim of the ERASME-4 trials was to assess the efficacy of DC vs. docetaxel plus epirubicin (DE) combination regimens as first-line therapy for MBC.Material and Methods: Patients with MBC, previously untreated with chemotherapy were randomly assigned to receive either DC (docetaxel 75 mg/m² on day 1 and oral capecitabine 1,000 mg/m² twice daily on days 1 to 14 every 3 weeks) or DE (docetaxel 75 mg/m² and epirubicin 75 mg/m² on day 1 every 3 weeks). The primary endpoint was progression-free rate 6 months after randomization. The planned sample sizes were 106 patients (pts), based on a randomized phase II selection design. The main secondary endpoints were progression-free survival (PFS) and overall survival (OS).Results: Between June 2004 and April 2006, 68 pts were randomized. Slow accrual led to premature termination the study. Final analysis included 33 pts randomized to DC and 35 pts to DE. This sample size allowed to effectively selecting the best arm for non-progression rate with a power of 82%. Patient characteristics were well balanced between the two treatment arms, except for pleural metastasis, alkaline phosphatase and SBR III more present in DE arm or adjuvant hormonotherapy given in more DC patients. Toxicity has been mild or moderate; 62% of patients reported at least one grade 3-4 episode. Hand-foot syndrome grade 3-4 was reported for 18% of DC arm patients, vs. none in the DE arm (p=0.008).Complete/partial response rates were 20/44% in DC and 7/41% in DE (p=0.3). Six months after randomization, 75.8% (95%CI: 57.7-88.9) of pts in the DC arm vs. 65.7% (95%CI: 47.8-80.9) in the DE arm were progression-free (p=0.36). After a median follow-up of 42 months, (95%CI: 32.5-21.1), median PFS was 12 months and 7 months in the DC and DE groups, respectively (p=.004). Median OS was 27 and 37 months for DE and DC respectively (p=0.49).Conclusion: Despite our low accrual, these results show that DC combination therapy is associated with a superior progression-free rate at 6 months and a longer PFS than DE.DC provides a highly active, non-anthracycline-containing, first-line treatment option for MBC patients previously exposed to anthracycline in the adjuvant setting.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2099.
Zoledronic Acid for Treatment of Osteopenia and Osteoporosis in Women with Primary Breast Cancer (BC) Undergoing Adjuvant Aromatase Inhibitor (AI) Therapy.
Authors: Hines S. , Sloan J. , Atherton P. , Perez E. , Dakhil S. , Johnson D. , Reddy P. , Dalton R. , Mattar B. , Loprinzi C.
Published: December 2010

Background: Postmenopausal women with significant osteopenia/osteoporosis are at increased risk of fracture, a risk that is exacerbated by the use of Aromatase Inhibitors (AIs). Bisphosphonates may be used for these patients because there is no known interaction with estrogen and/or progesterone receptors (ER, PR). This study evaluated the concurrent use of zoledronic acid in patients with significant osteopenia or osteoporosis who received initial adjuvant letrozole therapy for primary BC, to determine if further bone mineral density (BMD) loss could be prevented.Methods: Postmenopausal women with Stage I-IIIa, ER and/or PR + BC, no evidence of metastatic disease, and a BMD T-score < -2.0 were treated with daily letrozole 2.5 mg/d, vitamin D 400 international units/d, calcium 500 mg twice daily, and 4 mg I.V. zoledronic acid every 6 months (for 5 years). The BMD was measured at baseline and at one year. Kruskall-Wallis p-value methodology was used as the method of statistical analysis. Since this was a single-arm study, the analysis plan was primarily descriptive. The primary endpoint was the mean change in lumbar spine (LS) BMD at 1 year.Results: 60 patients were enrolled; 46 completed 1 year of treatment. Mean patient age was 67 years, with 44% having taken prior tamoxifen. At 1 year (see figure 1), LS BMD increased 2.66% (p=0.01), femoral neck (FN) BMD increased 4.81% (p=0.01), and any measured endpoint (within the LS or FN) increased 4.55% (p=0.0052). 7% of patients experienced a fracture vs.13% with a pre-existing history of fracture before enrollment. No patients had disease recurrence during year 1. Toxicity was minimal with arthralgia as the most common complaint. There were no reports of osteonecrosis of the jaw.Conclusion: Zoledronic acid prevents additional bone loss in postmenopausal women with significant osteopenia or osteoporosis initiating letrozole. Treatment with zoledronic acid was associated with an improvement in BMD.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2103.
Comparative Biomarker Analysis in 523 Matched Male and Female Breast Cancers.
Authors: Speirs V. , Verghese E. , Brannan R. , Reall G. , Hanby A. , Pollock S. , Honarpisheh H. , Kanthan R. , Kanthan S. , Litwiniuk M. , Mottolese M. , Shousa S. , Stephens M. , Dent J. , Shaaban A.
Published: December 2010

Incidence rates of male breast cancer (MBC) are rising. MBC etiology is poorly understood with most of our current knowledge regarding its biology, natural history and treatment extrapolated from our knowledge of female breast cancer (FBC). Retrospective studies on MBC have suffered from small numbers of cases available from any one centre thus a significant problem in studying this disease is accruing sufficiently large numbers to allow comparative analysis of possible prognostic markers. Using a co-ordinated multi-centre approach, the aim of this study was to conduct the first large scale study to address the relevance of the expression of recognised biomarkers in FBC in the same disease in males. Five hundred and twenty three cases were obtained retrospectively and assimilated into TMAs, including 260 MBCs and 263 cases of stage-matched FBCs. MBC comprised 21 grade 1, 121 grade 2, 68 grade 3, 50 unknown, mean age 67 (range 39-90) with 167 ductal, 4 lobular, 10 papillary, 10, mucinous, 4 DCIS, 1 mixed and 64 unknown. FBC comprised 29 grade 1, 140 grade 2, 94 grade, mean age 58 (range 27-92) with 220 ductal, 23 lobular, 14 mixed and 6 unknown. Four µm TMA sections were analysed using the following biomarkers: hormone receptors (ERα, ERβ1, ERβ2, ERβ5, total PR, PRA, PRB, AR), apoptosis markers (p53, bcl2), basal (CK5/6, CK14) and luminal epithelial markers (CK18, CK19), E-cadherin and HER2. Biomarkers were scored according to published criteria; for ERβ isoforms both nuclear and cytoplasmic immunoreactivity was determined Statistical analysis was conducted using SPSS. Luminal A (ERα+, and/or PR+, HER2-) was seen in 93% of MBC vs. 84% of FBC, Luminal B (ERα+, and/or PR+, HER2+) or HER2 subgroup (ERα-, PR-, HER2+) was not seen in MBC but found in 6% and 2% of FBC, respectively. Basal-like tumours (ERα-, PR-, HER2-, CK5/6+) were infrequent (MBC 2%, FBC 1%) and in MBC these tumours also expressed ERβ isoforms. No differences were observed in grade, stage or LN status between genders. Univariate analysis showed ERα, ERβ1, ERβ5, PRA, AR, p53 were significantly associated with FBC while cytoplasmic ERβ2, bcl2 and e-cadherin were associated with MBC (all P<0.001). Although membranous HER2 was not seen in MBC, many cases displayed nuclear staining. Biomarker profile with respect to clinical outcome is on-going. This work has shown the luminal A phenotype is common in MBC and that gender-specific biomarkers are expressed. As MBC is becoming more common, this information may be useful in identifying biomarkers which might affect outcome.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2109.
Stage at Diagnosis and Management of Breast Cancer in Men and Women – A Population-Based Study (Sweden).
Authors: Nilsson C. , Nilsson C. , Holmqvist M. , Blomqvist C. , Blomqvist C. , Bergkvist L. , Lambe M. , Lambe M. , Fjällskog M.
Published: December 2010

Background: Male breast cancer is an uncommon disease, representing less than 1% of all breast cancer. Due to the rareness of the disease there is a lack of prospective randomized studies to guide treatment decisions. While current guidelines recommend that male breast cancer should be treated in the same way as female breast cancer, concerns have been raised regarding the quality of management in men. Results from earlier studies indicate that men with breast cancer are not as aggressively treated as women and that outcomes are worse. The aim of this population based study was to assess and compare stage at presentation and management of breast cancer in men and women in Sweden.Material and methods: In a case-control approach, we identified male and female patients with a record of a breast cancer diagnosis in the Breast Cancer Register of Central Sweden between 1993 and 2007. 99 men (cases) with breast cancer were matched on age at and time of diagnosis to four women with breast cancer (controls). Data on tumor characteristics and treatment were retrieved from the Breast Cancer Register.Results: There was no difference in the distribution of stage at diagnosis between men and women; stage I (33% and 36%, respectively), stage II (42% and 41%), stage III (6% and 4%) and stage IV (3% and 4%,). At the time of diagnosis 31% of male patients and 32% of female patients were node positive. Men underwent mastectomy more often than women (95% versus 45%). The proportion of men receiving loco-regional radiotherapy postoperatively was lower compared to women (44% vs. 58%). There were no proportional differences regarding adjuvant chemotherapy (16% vs. 18%) and adjuvant hormonal therapy (60% vs. 55%).Conclusion: At the time of diagnosis, men and women presented with a similar distribution of stage of disease. Our concerns regarding less extensive treatment in male breast cancer patients were not supported by our findings. Additional data including survival analyses will be added and presented at SABCS.Clinical VariablesMale breast cancer patients (cases) N=99Female breast cancer patients (controls) N=396Stage  I33%36%II42%41%III6%4%IV3%4%Missing16%15%N+31%32%M13%4%Mastectomy95%45%Partial mastectomy5%54%No surgery2%4%No axillary surgery11%12%Preoperative radiotherapy1%1%Preoperative chemotherapy5%2%Preoperative hormonal treatment2%3%Chemotherapy16%18%Radiotherapy44%58%Tamoxifen58%45%Aromatase inhibitor2%10%No treatment21%14%    

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2111.
Decreased CD10 Expression Is Associated with a Higher Risk of Relapse in Ductal Carcinoma In Situ (DCIS).
Authors: Toussaint J. , Durbecq V. , Haibe-Kains B. , Altintas S. , Rouas G. , Tjalma W. , Larsimont D. , Piccart M. , Sotiriou C.
Published: December 2010

Background: The Van Nuys Prognostic Index (VNPI) is the most widely used tool to predict local recurrence and guide therapy for DCIS. Nevertheless, many patients are still over-treated. Pre-clinical evidence indicates myo-epithelial cell (MEC) death in DCIS is a pre-requisite to tumor invasion. In this study we hypothesized that loss of CD10, (a marker of MECs), would be a surrogate for basement membrane disruption and tumor invasion. The aim of the present study was to retrospectively evaluate the prognostic value of CD10 in pure DCIS.Methods: CD10 expression was evaluated by qRT-PCR and immuno-histochemistry (IHC) using FFPE tissues on normal samples (N=11) and two independent pure DCIS populations: a training set (N=66) and a validation set (N=88).Results: MECs were the only cells that showed CD10 staining using IHC in normal and DCIS samples. All normal breast tissue samples demonstrated high expression levels of CD10 using both IHC and RT-PCR. In contrast, DCIS samples showed a wide range of CD10 expression levels: 1/3 of DCIS expressed high CD10 levels similar to those observed in normal breast tissue (high expression), whereas 2/3 expressed CD10 at a level below normal breast tissue (low expression). DCIS tumors with low CD10 mRNA levels were significantly associated with a higher risk of local relapse (HR= 2.49; [95%CI: 1.13-5.49], p=0.02). These results were validated in an independent dataset (HR= 1.805 [95%CI: 1.11-2.92], p=0.016). Of interest, no local relapses were observed in the high CD10 expression DCIS group. In multivariate analysis, CD10 expression by qRT-PCR was significantly associated with relapse (HR= 2.25, [95%CI: 1.24-4.09], p=0.008) in addition to VNPI score (HR: 2.03; [95%CI: 1.23-3.35], p=0.006).Conclusion: Decreased expression of CD10 in DCIS is associated with a higher risk of local relapse. These promising results are currently being validated in a larger patient series. Assessment of CD10 in addition to VPNI may lead to improved treatment tailoring for women with DCIS.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2112.
Low-Dose Tamoxifen for the Treatment of Breast Ductal Intraepithelial Neoplasia: Results of a Large Observational Study.
Authors: Guerrieri-Gonzaga A. , Botteri E. , Lazzeroni M. , Lazzeroni M. , Bonanni B. , Rotmensz N. , Goldhirsch A. , Varricchio C. , Serrano D. , Cazzaniga M. , Luini A. , Viale G. , Viale G. , Mora S. , Bollani G. , Albertazzi E. , Decensi A. , Decensi A.
Published: December 2010

Background: The cost-benefit ratio of tamoxifen for breast ductal intraepithelial neoplasia (DIN) is unclear. Since low-dose tamoxifen showed a favorable safety profile and modulation of breast cancer biomarkers in phase II trials, we analyzed a large mono-institutional cohort of women with DIN treated with low-dose tamoxifen or no systemic treatment.Material and Methods: A total of 309 patients with ER positive DIN received either tamoxifen 5 mg/day or 20 mg/week, as part of clinical trials or institutional guidelines and were compared with 371 patients who received no systemic treatment after surgery with or without radiotherapy due to personal preference, allocation to placebo or contraindication to tamoxifen.Results: The 5-year cumulative incidence of recurrence was 14.5% (95% CI, 11.9-17.5), with a negative trend according to age. Women with ER/PgR >50% DIN who were untreated had a higher incidence of breast events than women on tamoxifen (HR 1.76; 95% CI, 1.00-3.12) or women with ER/PgR<50% DIN (HR 1.72; 95% CI, 1.14-2.58). Among untreated patients with ER>50% DIN, recurrence was higher in PgR ≥50% DIN than in PgR <50% DIN, whereas it was similar among low PgR (<50%) DIN against which tamoxifen had no effect. No difference in endometrial cancer incidence was noted.Discussion: High ER and especially high PgR expression is a significant adverse prognostic indicator of DIN against which low-dose tamoxifen appears to be a safe and active treatment. Conversely, women with low expression ER or PgR DIN do not seem to benefit from tamoxifen. A definitive clinical trial is warranted.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2113.
Long-Term Survival of Breast Ductal Carcinoma In Situ in Women with Different Gene-Expression Types.
Authors: Zhou W. , Johansson C. , Jirström K. , Olorunsola A. , Garmo H. , Wärnberg F.
Published: December 2010

Background: Basal-like invasive breast cancer has been shown to be associated with a worse prognosis. However, we do not know if basal-like ductal carcinoma in situ (DCIS) relates to a worse prognosis. The purpose of this study was to relate the DCIS basal-like subgroup, evaluated by immunohistochemistry (IHC), with prognosis.Material and Methods: Women diagnosed with a primary DCIS 1986-2004 in Uppsala and Västerås, Sweden were recruited (n=458). TMA blocks were constructed and IHC for Estrogen receptor (ER), Her2, epidermal growth factor receptor (EGFR/Her1) and cytokeratin 5/6 (CK 5/6) was employed to evaluate the gene-expression subgroups. Subtype definitions were as follows: luminal A (ER+ and HER2–), luminal B (ER+ and HER2+), basal-like (ER–, HER2–, CK 5/6+ and/or EGFR+), HER2+ (ER– and HER2+), and others (negative for all markers or data missing).Results: We followed 458 patients for local recurrence, general disease and all-causes mortality. Median follow-up was 122 months. Of the 458 primary DCIS breast cancers, 224 (48.9%) were luminal A subtype, 63 (13.8%) were luminal B, 80 (17.5%) were Her2+, 29 (6.3%) basal-like and 62 (13.5%) unclassified. Local recurrence and general disease rates were similar when comparing basal-like group with each of the other four groups. Compared with the most common luminal A tumors, basal-like tumors were related with poorer survival (hazard ratio 2.56, 95% confidence interval 1.05 – 6.22). When compared with luminal B, Her2+ and unclassified group, basal-like tumors were related with non-significant poorer survival, with a HR (95% CI) of 1.37 (0.52 – 3.64), 1.80 (0.69 – 4.72) and 2.61 (0.61 – 11.2), respectively. We also compared basal-like group with the rest combined as one non-basal-like group. Local recurrence and general disease rates were similar in these two groups. Women with basal-like DCIS had higher mortality than women in the non-basal-like group (HR 2.26, 95% CI 1.00 - 5.10).Conclusion: Basal-like DCIS women may have poorer overall survival, particularly in comparison with luminal A DCIS.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2114.