bluuebunny/crossref_metadata_2025 huggingface dataset:
A Retrospective Analysis of Risk Factors of Central Nervous System Metastases in Operable Breast Cancer: Different Survival by Biological Subtype and Ki67 Overexpression.
Authors: Ishihara M. , Mukai H. , Onozawa M. , Nihei K. , Shimada T. , Wada N. , Nagai S.
Published: December 2010

Background: New agents have improved systemic disease control, but the control of central nervous system (CNS) metastases is still insufficient. The identification of factors that may predispose to CNS metastases may help lead to earlier detection possibly to improvement in disease management.Methods: Patients (pts) with metastatic who were diagnosed with clinical stage I-III primary breast cancer at National Cancer Center Hospital East from January 2003 to December 2005 were screened. All pts with CNS metastases were identified by CT or MRI. Cox proportional hazards models were fitted to find risk factors of CNS metastases. Factors included age, menopausal status, clinical stage, T stage, histological grade, lymphovascular invasion, hormone and HER2 status, and Ki67 (at least 30% tumor cells positive). Survival was calculated by the Kaplan-Meier method.Results: Median follow-up from operation was 53.5 months. Of 591 breast cancer pts, 76 pts (12.9%) relapsed. Seventeen pts (2.9%) developed CNS metastases; 5 pts developed as the first recurrence site. Multivariable analysis indicated the higher risk for developing CNS metastases were triple negative (TN) tumors (HR 5.532, 95% CI 1.445-21.180, p=0.013) and Ki67 overexpression (HR 3.906, 95% CI 1.179-12.939, p=0.026). There were no statistically significant differences in other factors. CNS metastasesCumulative incidence of CNS metastases (4 yrs)Median duration to CNS metastases (Months)Overall survival (4 yrs)Disease free survival (4 yrs)TN9.7% (9/93 pts)9.4%11.378.5%73.3%HER2 positive3.7% (4/107 pts)4.4%20.391.0%84.9%Others1.0% (4/391 pts)0.8% (p<0.0001)24.197.5% (p<0.0001)92.4% (p<0.0001)      Ki67 ≥30%8.6% (12/140 pts)9.4%12.382.4%75.0%Ki67 <30%1.1% (5/446 pts)0.7% (p<0.0001)23.996.7% (p<0.0001)92.0% (p<0.0001) Discussion: In our analysis, TN or Ki67 overexpression breast cancer showed earlier CNS metastases and shorter overall survival. In case of these tumors, there is higher probability for early detection of limited CNS metastatic involvement.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6053.
Prognostic Value of mib-1 in Patients with Early Invasive Breast Cancer and Its Correlation with Other Biologic Parameters in a Monoinstitutional Series.
Authors: Ferro A. , Barbareschi M. , Eccher C. , Caldara A. , Frisinghelli M. , Triolo R. , Aldovini D. , Pellegrini M. , Bernardi D. , Galligioni E.
Published: December 2010

INTRODUCTION: Mib-1 is a proliferation biomarker and a prognostic factor for breast cancer as reported in several studies.PURPOSE: The aim of the present study was to examine interactions between mib-1 and other clinical-pathological markers and their impact on outcomes in early invasive breast cancer.PATIENTS AND METHODS: Mib-1 was identified by immunohistochemical staining in 2660 EIBC patients treated in our institution from 2000 to 2008. Mib-1 was dichotomized at the value of 20%. Correlation between mib-1 (> or ≤10620%) and age, tumour size (T), nodal status (N), ER, PR, HER-2, grading (G) was performed by χ2 test. Log-rank test and Cox regression model were performed to test mib-1 as prognostic factor for overall survival (OS) and Disease Free Survival (DFS) and evaluate its correlation with other known prognostic factors.RESULTS: Mib-1 was > 20% in 1276 and ≤106 20% in 1384. Mib-1> 20% was significantly (p=.000) associated with younger age, greater size, positive lymph nodes, poor grading, absent or low ER and/or PR expression level, HER-2 over-expression or amplification with or without co-expression of ER and/or PR, triple negative subtypes. Mib-1 was a significant predictor of worse DFS and OS (p=.000). At a median follow up of 32 months the DFS and OS were 97.4 and 99.2% respectively in Mib-1 ≤20% group and 92.4 and 97.2% respectively in Mib-1 > 20%. There were 195 relapses (7,3%): 139 (5.2%) in Mib-1 > 20% and 56 (2.1%) in Mib-1 ≤ 20%. Breast cancer related deaths were 74 (2.8%) with 58 (2.2%) in mib-1 > 20% group and 16 (0.6%) in mib-1 ≤ 20%.Mib1 >20% was predictive of poorer prognosis in > 40 years patients, small tumors (T1), lower grading (G1 and G2), positive ER and/or PR group with high or intermediate expression, negative HER-2 tumors. However, in Cox multivariate analysis mib-1 didn't maintain independent prognostic value.CONCLUSIONS: In our experience, Mib-1 confirms to be a significant prognostic biomarker for DFS and OS in early breast cancer. It could provide additional information beside other clinico-pathological parameters to perform the risk stratification of early breast cancer patients.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6054.
The Early Prediction of Response to Neoadjuvant Chemotherapy Using MRI.
Authors: Kim H. , Ko E. , Kim E. , Jo E. , Kim M. , Noh W.
Published: December 2010

Purpose: Neoadjuvant chemotherapy is an effective method for down-staging the primary tumor before surgery. However, some of patients do not respond. In these patients, neoadjuvant chemotherapy is just an ineffective, toxic and expensive procedure. Therefore, it is very important to find the reliable method to differentiate the responder from non-responder as early as possible. In order to evaluate the role of magnetic resonance imaging (MRI) for the assessment of tumor response, we examined the correlation between the early MRI changes after the 1st cycle of neoadjuvant chemotherapy and later pathologic response after the 3rd cycle of neoadjuvant chemotherapy.Patients and method: 31 breast cancer patients who underwent neoadjuvant chemotherapy prior to surgery were analyzed. The baseline MRI was taken before neoadjuvant chemotherapy. Anthracycline plus taxane were administered to all patients. Post-chemotherapy MRI assessment was done just before the 2nd cycle of neoadjuvant chemotherapy. If the primary tumor was reduced more than 20% in the product of the longest and perpendicular diameter, those cases were classified as responders. Surgery was performed after the 3rd cycle of neoadjuvant chemotherapy. The pathologic response was assessed by measuring pathologic tumor size of viable tumor cells. Sensitivity, specificity, positive predictive value, and negative predictive value of MRI findings were calculated on the basis of histopathological examination.Results: Total 31 patients were examined. Of these patients, 2 patients had bilateral breast cancer. Therefore, a total of 33 lesions were evaluated. The median tumor size on baseline MRI was 4.5cm (range:2.1-10.0cm). 27 cases were classified as responders on early MRI findings. Of these cases, pathologic response was confirmed in 26 cases after surgery. Six cases were classified as non-responder on MRI. In this group, 3 cases showed pathologic response and 3 cases did not. Sensitivity, specificity, positive predictive value and negative predictive value of early MRI findings for the prediction of pathologic response were 89.7%, 75.0%, 96.3% and 50.0%, respectively.Conclusion: Post-chemotherapy MRI after the 1st cycle of neoadjuvant chemotherapy could differentiate responders from non-responders with high accuracy. It would be helpful to determine whether the chemotherapy regimen should be continued or not in the early phase of neoadjuvant therapy.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6057.
Interaction between Family History of Breast Cancer and the Remaining Gail Risk Factors.
Authors: Ni X. , Muram D.
Published: December 2010

Background: The Gail breast cancer risk assessment model takes into account the relative contribution of various breast cancer risk factors (RF) and provides 5-year and lifetime breast cancer risk estimates. The purpose of this analysis was to determine the relative contribution of the Gail model RF in patients with and without family history of breast cancer (FHBC).Materials and Methods: Patients from the RUTH trial, consisting of postmenopausal women with or at high risk for coronary artery disease (CAD), were included in this analysis, with the exception of women ≥86 years of age or with medical history of any breast cancer, ductal carcinoma in situ, or lobular carcinoma in situ. Patients with missing values for RF were also excluded. For the resulting study population (N=10015), the risk score was calculated using the breast cancer risk assessment (BCRA) tool from the National Cancer Institute. A descriptive analysis of the BCRA risk scores for each RF stratified based on the presence or absence of a FHBC was performed. Risk factors were categorized as follows: advancing age (<65 or ≥65; 65 was the mean age); age at menarche (>12 or ≤12), number of biopsies (None or ≥1), age at first live child birth (<30 or ≥30; nulliparty included in <30 group per model). Interaction plots based on the two-way analysis of variance (ANOVA) model were generated for each category of the RF.Results: Of the 10015 women, 9123 (91.1%) did not have FHBC, while 892 (8.9%) did. Among women without FHBC, the mean BCRA score (%) was 1.54±0.40; 62.2% were 65 years or older, 28.8% had early menarche, 8.4% had first child at ≥30 years of age, and 8.1% had a previous breast biopsy. Among women with FHBC, mean BCRA score was 3.46±1.24; 70.3% were 65 years or older, 30.4% had early menarche, 9.3% had first child at ≥30 years of age, and 15.4 % had a previous breast biopsy. A statistically significant (p<0.001) amplification in the risk conferred by advancing age, previous biopsy, and early menarche was observed in patients with FHBC compared with patients with no family history for the disease (Figure 1). In contrast, the relative contribution to risk by late childbearing is more pronounced (p<0.001) in patients without FHBC.Discussion: Family history is an independent and important determinant of breast cancer risk in postmenopausal women. Other RF have a different influence on the overall risk estimate in women with FHBC when compared to women without FHBC. Increased risk was observed for advancing age, early menarche, and previous breast biopsy. A different pattern was seen for late childbearing. While the data were obtained from a large cohort of women, further analysis may be required to determine if these results are generalizable for all women regardless of menopausal status or CAD.Figure 1. Mean BCRA risk within each risk factor group, stratified by FHBC.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6062.
Evaluation of the Tyrer-Cuzick Model in Women with Atypical Hyperplasia.
Authors: Boughey J. , Hartmann L. , Anderson S. , Degnim A. , Vierkant R. , Frost M. , Reynolds C. , Pankratz V.
Published: December 2010

Background: Risk prediction models are important clinical tools for counseling and decision making for women with an elevated risk of breast cancer, such as women with atypical lobular or ductal hyperplasia (atypia). The Gail model has been shown to underestimate the risk of breast cancer in women with atypia. We sought to evaluate the performance of the Tyrer-Cuzick model in a well-defined cohort of women with atypia.Methods: The Mayo Benign Breast Disease (BBD) Cohort includes 9,376 women aged 18 to 85 who had an open breast biopsy with benign pathological findings between 1967 and 1991. The subset of women with atypia was identified by our study pathologists. Risk factor data required by the Tyrer-Cuzick model were collated for each woman, and the model was used to predict each woman's risk of developing invasive breast cancer within ten years. The predicted numbers of breast cancers were compared to the observed numbers to assess overall model calibration, and the concordance between breast cancer outcomes and predicted probabilities was used to measure the accuracy of the model on the individual level. Subset analysis of women with strong family history was performed. Strong family history was defined as: at least one first-degree relative with breast cancer before the age of 50 years or two or more relatives with breast cancer, at least one being a first degree relative.Results: Three hundred and thirty one women with atypia were identified. Over a mean follow up of 13.7 years, 62 (19%) women have developed invasive breast cancer. Thirty one women developed invasive cancer in the first ten years after biopsy. The Tyrer-Cuzick model predicted that 64.6 invasive breast cancers would occur in the first ten years after biopsy. Thus, the predicted to observed ratio was 2.08 [95% CI: 1.47 – 2.96], p < 0.001).The concordance statistic was 0.51, revealing that the Tyrer-Cuzick model did not accurately distinguish, on an individual level, between women who were diagnosed with invasive breast cancer within ten years of biopsy and those who were not.Performance was somewhat better in the subset of 68 women with a strong family history of breast cancer. The model predicted 12.3 invasive breast cancers, and 7 were observed, for a predicted to observed ratio of 1.76 [95% CI: 0.84 – 3.70]. The concordance statistic was 0.57.Conclusion: The Tyrer-Cuzick model significantly overestimated the risk of breast cancer in the first ten years after biopsy for this group of women with atypia. Individual risk estimates showed poor concordance. Performance was slightly improved in women with a strong family history of breast cancer. Physicians should be cautious when using the Tyrer-Cuzick model to predict ten-year risk in patients with atypia.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6063.
Microtubule Associated Protein Tau Expression as a Predictive and Prognostic Marker in a Trial Assessing Sequential Docetaxel as Adjuvant Chemotherapy for Early Breast Cancer (TACT).
Authors: Tutt A. , Gillett C. , Pinder S. , A'Hern R. , Dowsett M. , Ellis I. , Bartlett J. , Bliss J. , Johnston S. , Ellis P. , TACT Trial Trialists .
Published: December 2010

Objective: TACT, which compared sequential anthracycline-taxane (FEC-D) adjuvant chemotherapy with an anthracycline regimen of similar duration (Lancet 2009:373, 1681-1692) provides an opportunity to correlate tau expression levels with disease-free survival (DFS) and to explore the interaction between tau expression and docetaxel benefit. Patients and Methods: 4162 patients were randomized to FE60C (fluorouracil, epirubicin and cyclophosphamide,- 4 cycles) followed by docetaxel (4 cycles) or control. Control, determined by local centres, was FE60C (8 cycles) or epirubicin (4 cycles) followed by classical CMF (cyclophosphamide, methotrexate and fluorouracil - 4 cycles). Patients with hormone receptor positive tumours also received adjuvant endocrine treatment. Tissue blocks were obtained for 3610 TACT patients (87 % of total) to create tissue microarrays (TMA). Tau protein expression was assessed by immunohistochemistry (IHC). Tau was successfully scored by 2 observers (blinded to treatment allocation and clinical outcome), scoring 2 cores from separate TMAs for each of 2977 patients. Intensity (negative, weak, moderate or strong) and the proportion of tumour cells stained (in 5% increments) were recorded. Results: A very strong association was observed between level of intensity and proportion of staining (p<0.001), subsequent analysis used tau intensity only. Fifty one percent of tumors were tau-positive defined as demonstrating weak or greater intensity of staining. Tau expression was positively correlated with ER status (p<0.001), negatively correlated with grade (p<0.001) and negatively correlated with HER2 status (p<0.001). In absence of overall treatment benefit for docetaxel, significant factors predicting DFS on univariate analysis were tau, ER and HER-2 expression in addition to nodal status, grade, tumour size and age. With the exception of age these variables were also significant on multivariate analysis. No significant interaction between tau expression and efficacy of docetaxel was observed in all patients or in patients within the ER+HER2-ve, HER2 +ve and ER -ve HER2 –ve subsets. Exploratory analyses to assess interactions using tau intensity and proportion IHC staining as continuous variables are underway and will be reported. Conclusion: Tau expression was associated with improved DFS but there was no evidence of an interaction between tau and docetaxel benefit. These results are similar to NSABP-B28, which evaluated addition of paclitaxel to doxorubicin/cyclophosphamide.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 607.
Increased Radiation Resistance of Breast Cancer Cells by Endocrine Disrupting Chemical Bisphenol A.
Authors: Kil W. , Camphausen K.
Published: December 2010

Purpose: Bisphenol A (BPA) is used in the manufacture of plastics and belongs to a family of compounds called endocrine disrupting chemicals (EDCs). Because of extensive use of BPA in the manufacture of consumer goods and products, humans are exposed to levels of BPA which may cause adverse effects on endocrine-sensitive organs. Here, we evaluated the effects of BPA on the proliferation of breast cancer cells and the effect of BPA on tumor cell radioresponse.Materials/Methods: Proliferation was evaluated in estrogen-sensitive (MCF-7) and estrogen-insensitive (MDA-MB-231) human breast cancer lines that were treated for 72 hour with BPA (0.1µM; environmentally relevant concentration). The effect on radiation sensitivity was evaluated using clonogenic survival assays after exposure to various dose of BPA (0.1, 1, and 10 µM-) followed by irradiation (IR). DNA damage was evaluated using phosphorylated histone H2AX (γH2AX) and the neutral comet assay. BPA induced cell cycle changes were evaluated by staining of phosphor-H3 and flow cytomety. To investigate the mechanism of BPA±IR induced cell growth, we explored the activation of Akt and mitogen-activated protein kinase (MAPK) after treatments.Results: Exposure of BPA at low-dose (0.1µM) for 72 hour resulted in an increase survival rate in MCF-7 cancer cell (150 ± 19% of control) with more limited effects on MDA-MB-231 cancer cell (123 ± 17% of control). Exposure of MCF-7 to BPA for 72 hour before radiation resulted in an increase in radioresistance with dose-reduction factors at a surviving fraction of 0.1 of 1.23 and 1.31 with BPA 0.1µM, 10µM, respectively. BPA had no effect on the number of cells in each phase of the cell cycle nor on the activation of the G2 cell cycle checkpoint after IR. As a measure of DNA double strand breaks, γH2AX were determined as a function of time after the BPA±IR treatments. BPA also significantly decreased γH2AX expression at 24 hours after IR. Expression of phosphorylated Akt and phosphorylated mitogen-activated protein kinase (MAPK) increased with BPA± IR but decreased with IR alone at 24 hr.Conclusions: These results suggest that BPA can enhance phosphorylation of Akt and MAPK possibly leading to a resistance to radiation-induced cell death after IR. Further studies are needed to determine the clinical relevance of these findings.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6073.
The Impact of National Press Coverage on Early Phase Clinical Trial Recruitment and Enrollment.
Authors: Bates N. , Higgins D. , Childs J. , Boettcher M. , Salazar L. , Disis M.
Published: December 2010

The American Society of Clinical Oncologists reports that only 5% of cancer patients ultimately enroll in a clinical trial. According to the National Cancer Institute, one key barrier to participation is a lack of knowledge about clinical trials, both on behalf of oncologists and the patients themselves. Unfortunately, many investigator-initiated and academic clinical trials simply do not have budgets that permit implementation of large-scale recruitment efforts. Recent experience by our group demonstrates that press coverage by national media is a particularly effective tool for generating public interest in clinical research, as well as increasing trial enrollment.In the third quarter of 2008, our academic translational research group was featured on a national news program. In the week following the broadcast, our group's website, which had been listed in the broadcast and accompanying web story, received an unprecedented number of hits. Not only did the broadcast generate interest in our group's research; more specifically, it translated to substantial increases in potential clinical trial candidates, and subsequently, increased trial enrollment. In the month following the broadcast, our group received 125 new clinical trial inquiries as a result of the feature. That number represented a seven-fold increase in new inquiries during the same period in 2007. Of those 125 contacts, more than half of patients were potentially eligible for one of our clinical trials based on an initial screening. From November 2008 to the present, nearly one-third of all clinical trial enrollments can be attributed to the news story. Enrollment to the vaccine trial specifically described in the news feature increased four fold in comparison to the same 6-month period in 2008-2009, with half of all new enrollments attributable to the news feature.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6078.
Sucess of Brochure/One Page Universal Consent for Biospecimen Donation.
Authors: Singh B. , Singh B. , Roses D. , Roses D. , Guth A. , Guth A. , Schnabel F. , Schnabel F. , Shapiro R. , Shapiro R. , Axelrod D. , Axelrod D. , Ginsberg A. , Ziguridis N.
Published: December 2010

Background: Accrual of biospecimens to biorepositories is a challenge and has been recognized as a critical barrier for translational research. HIPAA mandates that patients sign a separate Informed ConsentForm (ICF) for donating biospecimens for research. This poses a significant challenge to the medical staff and may negatively impact accrual to biorepositoriesMaterials and Methods: At NYU Cancer Institute, the ten page ICF was reformatted as a tri-fold brochure and one page ICF in 2005. The brochure is given to patients during the office visit or at time of registration and the triplicate one-page ICF on the day of surgery. The brochure contains information regarding biospecimen banking.The triplicate, one page consent is signed by the patient on the day of surgery.Results: In a 3-year period (2003-2005), the 10-page ICF was used to consent 433 patients from Breast, Gynecologic Oncology and GI Oncology, with an average of 2.77 patients per week. After the implementation of the novel brochure and single page ICF format, 1,426 patients were consented in the next 3- year period (2006-2008), with an average of 9.14 patients per week (10)Patients in the Breast Surgical Oncology Clinic at NYUCI were initially targeted. This was done in close cooperation with the breast surgical oncologists, nurses and operating room staff. The brochure/1-page ICF method doubled the accrual of patients from 141 to 304 patients in the first year (2005-6). However, the number of patients who consented did not increase in the next two years in spite of a significant increase in the total number of patients in the breast surgical oncology service.A root cause analysis was performed and it was determined that either the patients were not approached in the physician's office or the consenting process was not followed. It was concluded that a dedicated consenting professional was required to overcome these hurdles, who will primarily works in the operating room, where patients with diagnosis of cancer are targeted. This has yielded a significant increase in number of patients consenting for biospecimen donation. shows a significant increase in accrual since her recruitment in February 2009.Conclusions: A novel consenting mechanism with a brochure and one page consent has been successfully implemented at NYU Cancer Institute and has resulted in a significant increase in patients consenting for biospecimen donation. The process is being replicated institute wide for accrual to all biorepositories at NYULMC. This novel method can be widely employed to accrue specimens for clinical trials.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6081.
Phase II Trial with Gemcitabine, Paclitaxel and Bevacizumab for the First Line Treatment of Metastatic Breast Cancer.
Authors: Guardino A. , Chen M. , Levy M. , Chen C.
Published: December 2010

Background: Both gemcitabine and paclitaxel in combination, and paclitaxel and bevacizumab in combination, have shown higher response rates and improved time to progression (TTP) over single agent paclitaxel for the first line treatment of metastatic breast cancer. This phase II study was initiated to evaluate the efficacy and tolerability of combination gemcitabine, paclitaxel and bevacizumab as first line treatment for HER2 negative metastatic breast cancer.Methods: Women with HER2 negative metastatic breast cancer who have not received prior chemotherapy for metastatic disease are eligible for the study. The primary end point is time to progression (TTP). Secondary endpoints include duration of response, objective response rate and toxicities. Patients receive gemcitabine 1000 mg/m2 IV on days 1, 8, & 15, paclitaxel 80 mg/m2 IV on days 1, 8, & 15, and bevacizumab 10 mg/kg on days 1 & 15, on an every four week cycle. Patients are evaluated with imaging studies including CT and bone scan at baseline and every 3 months. Response to treatment is evaluated using RECIST methods. Treatment continues until disease progression or unacceptable toxicities and at which point the drug thought to cause the toxicity will be discontinued.Results: As of January 2009, 21 patients with a median age of 54 years (range: 30-76) have been enrolled. Estrogen and progesterone receptor was positive in 16 and 10 patients, respectively and 4 patients were negative for both. Among 17 evaluable patients, the clinical benefit rate (CR+PR+SD ≥ 24 weeks) is 88%. 10 patients have reached the study endpoint with a median TTP of 12 months (mean TTP of 13.3 months). In addition, the combination treatment with bevacizumab has been well tolerated without clinically significant bleeding and with less than 10% of patients experiencing grade 3 peripheral neuropathy, grade 3 hypertension and less than 5% experiencing grade 3 proteinuria. 4 patients experienced a thrombotic event, of which 2 were catheter-related. The primary toxicities were hematological which were expected. 16 patients experienced grade 3/4 hematological toxicities and responded to dose reductions. 9 patients remain on treatment.Discussion: The addition of bevacizumab to combination chemotherapy with gemcitabine and paclitaxel is well tolerated for first line therapy of HER2 negative metastatic breast cancer. Clinical activity has been observed and phase II enrollment is ongoing.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6089.
Phase II Study of the Novel Epothilone Sagopilone (ZK-EPO) in Patients with Progressive Metastatic Breast Cancer.
Authors: Campone M. , Dittrich C. , Cufer T. , Dudov A. , Dao Phan P. , Schmelter T. , Giurescu M. , Martin M.
Published: December 2010

Background: Sagopilone, a microtubule-stabilizing agent, is a novel, fully synthetic epothilone undergoing clinical development in a variety of tumor types. Proof-of-concept has been demonstrated in Phase II trials of platinum-resistant and -sensitive ovarian cancer, prostate cancer, and melanoma. Sagopilone has shown significant preclinical activity in taxane-resistant breast cancer cell lines, and preliminary clinical activity in patients (pts) with taxane-sensitive and -resistant disease in Phase I. This Phase II study assessed the efficacy, safety, and tolerability of sagopilone in metastatic breast cancer (MBC).Methods: Pts with progressive MBC who received a maximum of 2 previous chemotherapies not containing taxanes or vinca alkaloids were randomized to either i.v. sagopilone 12, 16, or 22 mg/m2 over 3 h or 22 mg/m2 over 0.5 h, every 21 days, for up to 6 cycles. The primary endpoint was the proportion of pts with a complete response (CR) or partial response (PR) as best overall response. A Simon's 2-stage design was used: 15 pts were to be initially accrued per arm; a further 12 pts were recruited per arm if ≥5/15 pts showed a response. The study was to be considered successful if an objective response (CR or PR) was observed in ≥10/27 pts.Results: Eighty-two female pts (median age 59 years) were randomized to treatment. The median number of treatment cycles was 3 (range 1-9). Of 77 pts evaluable for best response (per protocol set), 11 (14%) had PR, 32 (42%) stable disease (SD), 30 (39%) progressive disease (PD), and 4 (5%) unknown (Table 1).Table 1. Number of pts (%) with best overall responseSagopilone12 mg/m² 3 h16 mg/m² 3 h22 mg/m² 3 h22 mg/m² 0.5 hTotalNo. of pts14 (100.0)26 (100.0)16 (100.0)21 (100.0)77 (100.0)PR0 (0.0)3 (11.5)3 (18.8)5 (23.8)11 (14.3)SD5 (35.7)10 (38.5)8 (50.0)9 (42.9)32 (41.6)PD9 (64.3)11 (42.3)4 (25.0)6 (28.6)30 (39.0)Unknown0 (0.0)2 (7.7)1 (6.3)1 (4.8)4 (5.2) The study outcome was not considered successful for any of the 4 regimens tested. All 82 pts were evaluable for safety. Thirty-six pts discontinued the study prior to cycle 6: 35 due to adverse events (AEs) and 1 due to consent withdrawal. Treatment-related AEs documented in ≥20% pts were: sensory neuropathy 60% (18% grade 3, 1% grade 4); asthenia 26% (6% grade 3); alopecia 23%, myalgia 20% (2% grade 3); fatigue 20%; and nausea 20% (1% grade 3).Conclusions: Sagopilone did not meet the primary endpoint in this pt population with progressive MBC. Treatment-related AEs appeared to be considerable but manageable at all dose levels.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6107.
Preliminary Phase II Data Suggest That Entinostat (SNDX275), a Class 1 Selective Histone Deacetylase Inhibitor (HDACi), May Resensitize Breast Cancer Patients Progressing on Aromataste Inhibitor (AI) Therapy to Their AI Therapy.
Authors: Wardley A. , McCaffrey J. , Crown J. , Stein R. , Malik Z. , Rea D. , Barrett-Lee P. , Lee G.
Published: December 2010

Background: Aromatase inhibitors (AI), reduce peripheral conversion of androgen to estrogen, and are standard treatment for ER+ breast cancer (BCA); however, despite initial benefit, the disease eventually progresses. Once patients become resistant to AI, cytotoxic chemotherapy is often used for palliation. Histone deacetylase inhibitors (HDACi) have been shown preclinically to reverse AI resistance and sensitize tumor to AI. Entinostat, an oral selective HDACi, reverses both de novo and acquired hormone resistance in BCA in cell lines and xenograph models and has been well-tolerated, in humans, as a single agent and in combination with other agents tested to date.Methods: Postmenopausal women with ER+ BCA progressing while receiving AI for > 3 months were enrolled. Eligibility criteria included: measurable disease by RECIST criteria, PS 0 or 1, and ≤ 1 chemotherapy for metastatic disease. Exclusion criteria included: rapidly-progressing BCA, life-threatening metastases, chemotherapy within 3 months, and previous exposure to epigenetic modulating agents. Patients continued the AI therapy on which the cancer was progressing, with the addition of entinostat 5 mg weekly in 28-day cycles. Primary objective was to determine clinical benefit rate during the first 6 cycles, defined as the proportion of patients achieving CR, PR or SD lasting > 6 months. Secondary objectives included ORR and PFS. Exploratory biomarkers for anti-tumor activities and entinostat pharmacology were also measured.Results: To date, 24 patients have been enrolled from October 2008 – May 2009. Interim results from 20 patients are described here. The median age is 69 yrs. Eight (40%) and 12 (60%) patients had ECOG scores of 0 and 1, respectively. Fifteen patients (80%) had received tamoxifen; 12 (60%) had prior chemotherapy or immunotherapy. Nine patients (45%) had visceral involvement (lung, pleura, and liver), and 10 had metastases to bone, 3 to breast, and 1 to skin. Among the 10 patients who have completed ≥ 2 cycles, preliminary analysis indicates that the longest durations of SD thus far are > 6 months in 1 and > 5 months in 2 patients. Preliminary analysis of biomarkers in paired samples from 6 patients indicates that HDAC inhibition correlates with changes in cellular molecular targets. Entinostat has been well-tolerated. The majority of AEs were mild to moderate in severity, and the character of AEs was generally consistent with that seen with AI therapy.Conclusion: Entinostat in combination with AI was well-tolerated in patients with progressive BCA. Disease stabilization in several patients was observed. At dose administered, expected pharmacological effects were achieved.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6111.
Synergistic Growth Inhibition with a PI3 Kinase/mTOR Inhibitor Plus Lapatinib.
Authors: Speicher T. , Hackl W. , Lipton A.
Published: December 2010

The mammalian target of rapamycin, mTOR, is a member of the phosphatidylinositol 3-kinase (PI3-K) /Akt family and plays a key role in cell growth and survival. The PI3-K/mTOR pathway is activated by many growth factor receptors in human tumor cells. In addition, the PI3-K pathway is constitutively activated by mutation in one-third of breast cancers. Therefore, blockade of the PI3-K/mTOR pathway may sensitize breast cancers to HER-2/neu inhibition. BEZ235 (Novartis Pharma AG) is a potent, oral, dual PI3-K/mTOR inhibitor currently in Phase I clinical trials. The purpose of this study was to assess the in vitro effects of combining a dual PI3-K/mTOR inhibitor (BEZ235, Novartis Pharma AG) and a lapatinib-like dual inhibitor of EGFR and HER-2/neu (GW2974) on the growth of HER-2/neu-transfected MCF-7 human breast cancer cells. Cells were exposed to the lapatinib-like compound [GW2974 (0.05-5.0µM)] or the dual PI3-K/mTOR inhibitor [BEZ235 (0.5-3nM)] alone or in combination for 3 days (12 different dose combinations were tested). Cell growth was determined using the colorimetric MTT tetrazolium dye assay. The Chou-Talalay method of isobologram analysis was performed to determine the inhibitory effect. Dose-dependent growth inhibition was observed in HER-2/neu-transfected MCF-7 cells after 3 days exposure to GW2974 (IC50: 5.0 mM) or BEZ235 (IC50: 2.2 nM). Exposure to the combination of GW2974 (0.05-0.50 mM) and BEZ235 (0.50-1.0 nM) resulted in synergistic growth inhibition in HER-2/neu-transfected MCF-7 human breast cancer cells. In summary, the combination of lapatinib plus PI3-K/mTOR warrants further investigation as a therapeutic strategy for breast cancer.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6114.
Antitumoral Activity of 3rd Generation Derivative Lobaplatin in In Vitro Models of Triple-Negative Breast Cancers.
Authors: Honig A. , Martens T. , Häusler S. , Buchholz S. , Rack B. , Wishhusen J. , Dietl J. , Engel J.
Published: December 2010

Introduction:Triple-negative breast cancers are characterized by aggressive growth and early metastasic spread. Some preliminary clinical data have demonstrated good anti-tumor activity of platinum derivatives. 3rd generation compound Lobaplatin* has shown a favorable toxicity profile as compared to Cisplatin. We therefore evaluated this compound in in vitro models of triple negative breast cancers.Study design:Triple-negative humane breast cancer cell lines HCC 1937 and HCC 1806 were treated with increasing concentrations of Lobaplatin and Cisplatin (0,16-10 μm). Cells were incubated for 24, 48 and 72 h with both substances in serum-free and serum-containing medium, in order to evaluate cytotoxic effects in proliferating as well as in metabolically inactive cells. Induction of apoptosis was tested by cleavage of PARP and Caspase 3 as demonstrated by western blot analysis. Subsequently cells were coincubated with Lobaplatin and multi-caspase inhibitor ZVAD-fmk, in order to check if cell death induced by Lobaplatin can be abrogated by inhibition of classical apoptosis. Cytotoxic effects were evaluated by crystal-violet assay. To investigate in which phase of the cell cycle cytotoxicity is most pronounced, cell cycle FACS analysis was performed after treatment with various concentrations of Lobaplatin.Results:Lobaplatin showed a somewhat better anti-tumor activity in both cell lines than Cisplatin. Lobaplatin Induced cleavage of PARP and procaspase 3 indicative for induction of classical apoptosis. However, cytotoxic effects of Lobaplatin were not decreased by multi-caspase inhibitor ZVAD-fmk. Cell-cycle FACS analysis showed, that sub-G0/1 fraction (indicactive for apoptotic/necrotic cells) was increased and G2 fraction was decreased dose-dependently by treatment with Lobaplatin.Conclusion:Lobaplatin showed a good anti-tumor activity in in vitro models of triple negative breast cancers which was at least equal to Cisplatin. Main mechanism of ytotoxicity was programmed cell death, which could not be abrogated by multi-caspase inhibition. Due to the good anti-tumor activity and the favorable toxicity profile, Lobaplatin should be considered for clinical studies in triple negative breast cancers.*Aeterna/Zentaris GmbH, Frankfurt/M

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6115.
MicroRNA Expression Profiling of Inflammatory Breast Cancer.
Authors: Lerebours F. , Clairac G. , Tozlu-Kara S. , Vacher S. , Lidereau R. , Bieche I.
Published: December 2010

Background: IBC (Inflammatory Breast Cancer) is a rare but very aggressive form of breast cancer with a particular phenotype. The molecular mechanisms responsible for IBC remain largely unknown. In particular, gene alterations specific to IBC remain to be identified. Emerging data suggest that microRNAs, a small class of non-coding RNAs able to regulate gene expression, are dysregulated in certain types of cancer and may therefore serve as tool for diagnosis and prediction. We aimed to determine a miRNA expression profiling (microRNAome) in IBC.Methods: We measured the miRNA expression levels of 936 miRNAs by using real-time quantitative RT-PCR in a well-defined series of 12 IBCs (stage T4d according to UICC classification), by comparison with 31 non stage-matched non inflammatory breast cancers (stage I to non inflammatory IIIB) and 8 normal breast tissues.Results: 573 microRNAs were retained for analysis (Ct < 32). Among these 573 miRNAs, 31 were significantly up-regulated (p<0,05 and fold-change > 2,5) in IBC compared with both non IBC and normal breast tissues. Five of the 31 up-regulated miRNAs were also significantly up-regulated in non IBC versus normal tissues. Eleven of the 31 up-regulated miRNAs showed fold-changes greater than 4 times between IBC and non IBC: miR-1308, miR-503, miR-1234, miR-1247, miR-612, miR-671, miR-1825, miR-1306, miR-99, miR-7-1, and miR-937.The expression levels of the 31 up-regulated candidate miRNAs are currently being measured using real time QRT-PCR in a new larger independent prospective series of 66 IBC collected in our institution between jul-03 and dec-08. Sixty-six non stage-matched non inflammatory breast tumor tissues are used as controls.Conclusions: This study represents the first analysis of miRNA expression in IBC. It may serve as a basis for functional studies of the role of miRNAs in the etiology of IBC.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6118.
Transcriptional Profile Changes Induced by Rapamycin in Breast Cancer Maintained in Organ Culture.
Authors: Grosso S. , Katayama M. , Roela R. , Nonogaki S. , Soares F. , Brentani M. , Goes J.
Published: December 2010

Background: mTOR (mammalian target of rapamycin) is a serine threonine kinase, member of the AKT/PI3K pathway, which is involved in multiple biologic functions such as transcription, translation, protein degradation and ribosome biogenesis. The activation of this protein results in phosphorilation and activation of S6K1 and 4EBP1. Rapamycin is a potent fungicide, immunossupressive and anti-cancer agent that inhibits the mTOR pathway and is an emerging cancer therapeutic. Objective: The aim of this study was to determine genes regulated by rapamycin in samples of ductal invasive breast cancer to identify novel markers of rapamycin response. Material and Methods: Inhibition of some elements of AKT pathway was assessed by immunohistochemistry in samples of breast carcinoma maintained in organ culture of fresh cut slices that preserves the interaction between epithelium and stroma before and after treatment with rapamycin. Additionally changes of the gene expression profile was analyzed by microarray in these samples subdivided in positive and negative Erb-B2. Results: Immunohistochemistry analysis indicated a significant decrease of 4EBP1 in the samples of tumor treated with rapamycin compared with the control cases. Microarray analysis revealed that few common genes were regulated in both tumor types but rapamycin affected the expression of genes mainly involved in cellular transcription and translation in both groups. To confirm the results obtained through microarray technique, RT-PCR analysis was performed in independent samples and we validated the genes WWOX, EXT1 and GTF2E2 in 60% of our cases. Over expression of the autophagy related beclin 1 indicated a contribution of autophagy to cytotoxicity of rapamycin. Conclusion: The organ culture represents a simple method to determine the effects of rapamycin and using gene profile analysis, novel genes that possible could be used as markers of mTOR inhibition were identified. Supported by FAPESP nº 04/04607-8

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6129.
Molecular Subtype Profile Reveals Therapy Predictive Power.
Authors: de Snoo F. , Krijgsman O. , Roepman P. , Bender R. , Glas A.
Published: December 2010

BackgroundClassification of breast cancers into molecular subtypes may be important for accurate selection of therapy for patients. Here we report the respective chemotherapy responsiveness of the molecular subtypes profile defined Luminal, ERBB2 and Basal type.MethodsAn 80-gene subtype profile was developed based on a series of 200 samples with concordant ER, PR and Her2 receptor IHC and single gene readout status. Previously we reported the excellent validation of the profile classification using 784 samples. Here we report a second in silico validation consisting of 133 samples (Hess et al, JCO, 2006) which tested the profile as a predictor of pathological Complete Response (pCR) in these patients treated with T/FAC neoadjuvant chemotherapy.ResultsIn the 133 publicly available samples the profile classified 62% (82) as Luminal-type, 18% (24) as ERBB2-type and 20% (27) as Basal-type. These results were consistent with percentages found in the training and validation cohorts (n=1079; 295 training and 784 validation samples); 66% (712) Luminal-type, 18% (194) as ERBB2-type and 16% (173) Basal-type. Chemotherapy response was measured by pathological Complete Response (pCR) at the time of surgery In the Luminal-type subgroup 9% (7) of patients showed pCR, in the ERBB2-type subgroup 50% (12) of patients had a pCR and in the Basal-type subgroup 56% (15) of patients had a pCR.ConclusionsThe developed multi-gene profile can classify breast cancer tumors into Luminal-, ERBB2- and Basal-type subgroups. Within the subgroups, a significant difference in chemotherapy response, as measured by pCR, is observed. Implementation of this knowledge may improve the clinical management of breast cancer patients, by enabling the physician to decide who is most likely to benefit from chemotherapy or endocrine therapy prior to surgery.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6131.
Determination of Molecular Profiles of BRCA1 and BRCA2 Breast Cancers.
Authors: Banneau G. , Guedj M. , Schiappa R. , Petel F. , Sevenet N. , De Mascarel I. , Mac Grogan G. , Longy M. , Bonnet F.
Published: December 2010

BackgroundBRCA1 and BRCA2 genes are known to be the target of germline mutations in familial breast cancers, which represent 5% of the total breast cancer population. Mutation screening of these genes is performed in suspected familial breast cancer cases but a causative mutation is found in only 30% of patients. Therefore the development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1 - or BRCA2 - mutated breast cancers.Material and MethodsArray-CGH and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the bases of at least 3 affected first degree relatives or at least 2 affected first degree relatives with breast cancer at an average age of 45 years. Tumoral DNA was co-hybridized with pooled normal blooded DNA from 21 individuals on a 4407 BAC-array (CIT-V8) provided by the CIT program and manufactured by Integragen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Clinical, pathological and genomic data were retrieved through Annotator, the CIT cancer database and the analysis was performed by using the R statistical software along with the CIT R packages.ResultsUsing supervised clustering analyses we identified 2 transcriptomic signatures, one for BRCA1-mutated breast cancers consisting of 600 probes sets and another for BRCA2-mutated breast cancers also consisting of 600 probes sets. We also defined CGH-array signatures, based on a presence of specific genomic rearrangements, one for BRCA1-mutated breast cancers and one for BRCA2-mutated breast cancers.ConclusionThis study has identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. Moreover, we identified specific genomic rearrangements in these breast cancers which could be screened for in a diagnostic setting using FISH thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6132.
Stage 2 Genome-Wide Association Study of Candidate Low Penetrance Genes Implicated in Breast Cancer Risk.
Authors: Ross G. , Johnson N. , Fletcher O. , Orr N. , Hosking F. , Ashworth A. , dos Silva Santos I. , Lathrop M. , Houlston R. , Peto J.
Published: December 2010

The risk of breast cancer in the first-degree female relatives of breast cancer cases is approximately double the risk in the general population. BRCA1 and BRCA2 account for less than 20% of this excess risk; the majority is probably due to the multiplicative effects of large numbers of low penetrance risk alleles. Genome-wide association studies (GWAS) have successfully identified 13 low-penetrance breast cancer risk alleles (Easton et al 2007, Hunter et al 2007, Stacey et al 2007, Zheng et al 2009, Ahmed et al 2009, Thomas et al 2009) but power calculations suggest that many more are still to be discovered.We have recently conducted a genome wide association study of 1,500 bilateral breast cancer cases, 200 cases with at least two affected first degree relatives and 1,450 controls from the 1958 birth cohort (WTCCC, 2007) using the Illumina HumanHap 370 chip. Based on these data and publicly available data from the Cancer Genetic Markers of Susceptibility (CGEMS) study we have selected 1,200 of the most significant SNPs to genotype in a stage 2 study comprising 5,500 breast cancer cases and 4,500 controls. All 13 of the known loci were replicated in this 2-stage analysis.Additional candidates at novel genomic loci are being genotyped in a replication study of 6,000 cases and 6,000 controls.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6136.