bluuebunny/crossref_metadata_2025 huggingface dataset:
Preventing the Development of Breast Cancer by Immunizing with Multi-Antigen Vaccines Targeting Proteins Associated with Oncogenesis.
Authors: Disis M. , Cecil D. , Gad E. , Park K. , Lai V. , Lubet R. , Lu H.
Published: December 2010

Vaccines have been extremely successful in the prevention of infectious diseases. Although cancer vaccines have long been studied for the treatment of cancer, they have not been exploited as chemoprevention agents except in virally mediated malignancies. Human breast cancer is immunogenic and a variety of proteins involved in the malignant transformation or maintenance of the malignant phenotype have been identified as tumor antigens. Transgenic animal models are uniquely suited for evaluating the potential efficacy of preventative cancer vaccines. TgMMTV-neu mice, for example, develop neu-mediated breast cancer at about 150-200 days of life. Tumors are histologically similar to human breast cancer and have a molecular profile consistent with the luminal subtype. We have developed two multi-antigen vaccines targeting immunogenic proteins associated with oncogenesis and evaluated whether we could prevent the development of breast cancer in TgMMTV-neu mice. Each vaccine was composed of 3 different antigens. Class II epitopes derived from antigenic proteins involved in growth factor pathways comprised one vaccine and the other vaccine was plasmid DNA based and encoded immunogenic proteins involved in cell proliferation. The ability of active immunization to prevent breast cancer was evaluated in both older (18 week) and younger (5 week) mice. Vaccines were administered intradermally every two weeks for 3 immunizations and then monthly until the development of disease or 1 year had passed. Both vaccines prevented breast cancer development in older animals. 40% of peptide immunized older mice were cancer free at 1 year compared to 5% of controls (p=0.02). The DNA vaccine appeared to be even more effective in older animals with 60% of vaccinated mice tumor free as compared to 20% of controls (p=0.01). Protection from the development of cancer was mediated by T cells as evidenced by adoptive transfer of CD3+ cells purified from vaccinated and protected mice, sham immunized mice, and naïve mice. T cells from protected mice resulted in significant inhibition of tumor growth after a syngeneic tumor challenge (p=0.01 protected vs. sham vaccine). The cancer protective effect of immunization was more pronounced when vaccines were administered to the younger mice. The Class II epitope vaccine prevented cancer development in 65% of mice as compared to 5% of controls. The plasmid based vaccine protected 70% of mice from breast cancer. Active immunization was associated with a survival benefit in all groups. These data suggest breast cancer vaccines targeting biologically relevant proteins may be an effective approach to the prevention of breast cancer.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1045.
Effect of Body Mass Index on Recurrence in Hormone Receptor Positive Early Breast Cancer – A Retrospective Exploratory Analysis from the ATAC Trial.
Authors: Sestak I. , Distler W. , Forbes J. , Howell A. , Cuzick J.
Published: December 2010

Background: Third generation aromatase inhibitors have been widely used in postmenopausal women for the adjuvant treatment of hormone receptor positive breast cancer. As aromatase inhibitors work by inhibiting the conversion of androgens to oestrogens in adipose tissue the effectiveness of aromatase inhibitors might be dependent on body mass index (BMI).Methods: The ATAC study was a double-blind randomised clinical trial in which postmenopausal women with early breast cancer were randomly assigned to receive oral daily anastrozole (1mg) alone, tamoxifen (20mg) alone, or the combination in a double blind fashion. In this retrospective investigation, analyses were based on those women with hormone receptor positive breast cancers (oestrogen (ER) and/or progesterone (PgR) positive) for whom a baseline BMI measurement was available (anastrozole=2469; tamoxifen=2470). Here, we investigate the influence of BMI on time to recurrence (TTR) and time to distant recurrence (TTDR), and also the relative benefit of anastrozole versus tamoxifen according to baseline BMI, using a proportional hazard model.Results: After 100 months of median follow-up, obese women (BMI>30 kg/m2) at baseline had a significantly higher breast cancer recurrence rate than lean women (BMI<23 kg/m2) (adjusted HR=1.27 (1.02-1.57), Ptrend= 0.003) (Table 1). Obese women also had 38% more distant recurrences compared to lean women (adjusted HR=1.38 (1.08-1.76), Ptrend < 0.0001). The relative benefit of anastrozole versus tamoxifen was slightly greater in women with a low BMI but this was not significant for recurrence or distant recurrence (data not shown).Conclusions: These results confirm the poor prognosis of obese women with early breast cancer. Recurrence rates were lower in anastrozole than tamoxifen for all BMI quintiles and these results do not support an increased efficacy for anastrozole in obese women.Table 1: Number of breast cancer recurrences (% of group) and hazard ratios according to approximate BMI quintile for all recurrences and distant breast cancer recurrences. All breast cancer recurrences Distant recurrences Approx. BMI quintileNumber of events (%)HR* (95% CI) for TTRNumber of events (%)HR (95% CI)* for TTDR<23 (N=966)134 (13.9)Reference97 (10.0)Reference23-25 (N=810)137 (16.9)1.14 (0.89-1.45)97 (12.0)1.11 (0.83-1.47)25-28 (N=1171)204 (17.4)1.22 (0.98-1.52)149 (12.7)1.21 (0.94-1.57)28-30 (N=643)117 (18.2)1.26 (0.98-1.62)86 (13.4)1.26 (1.08-1.69)>30 (N=1582)253 (18.8)1.27 (1.02-1.57)203 (15.1)1.38 (1.08-1.76)P-trend 0.003 <0.0001*HR adjusted for age, region, chemotherapy, radiotherapy, mastectomy, tumour size, tumour grade, nodal status

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1047.
Breast Cancer Prevention by Letrozole in Post Menopausal BRCA1/2 Mutations Carriers: The Onco-03/LIBER Trial.
Authors: Pujol P. , Mijonnet S. , Karen S. , Martin A. ,   on Behalf the French Genetic and Cancer Group
Published: December 2010

Women carrying germline BRCA1/2 deleterious mutations are an extreme risk population for developing breast cancer, with a cumulative life-time risk of 56-80%. Prophylactic bilateral mastectomy provides a valid option for reducing the risk of breast cancer by nearly 90 %. Although it greatly affects the quality of life, breast prophylactic surgery in BRCA1/2 mutation carriers have increased in Europe and in US over the last decade.The major breast cancer prevention trials using tamoxifen and raloxifen showed an approximately 50% risk reduction in high risk women. The contralateral risk reduction in current adjuvant trials comparing aromatase inhibitors (AI) to tamoxifen therapies reveals a higher preventive efficacy of AI after menopause. Two ongoing randomized studies using exemestane (MAP3) or anastrozole (IBIS2) are assessing the risk reduction of breast cancer in menopausal women but none are designed for BRCA1/2 carriers.The French federation of cancer centres, "FNCLCC" (Federation Nationale des Centres de Lutte Contre le Cancer) has developed a randomized phase III study to determine the efficacy of the aromatase inhibitor letrozole to reduce the incidence of invasive breast cancer in post menopausal BRCA1/2 carriers. The ONCO-03 (LIBER) study is a double-blind, letrozole versus placebo, controlled study involving 28 centres in France. The study opened for recruitment in march 2008. The study design, procedures and first analysis of patients enrolment are presented.Based on the known preclinical and clinical profile of AI, a greater reduction in breast cancer incidence with fewer side effects is hypothesized with this class of agents than with tamoxifen or raloxifen. For postmenopausal women bearing a BRCA1/2 genetic predisposition, prevention of breast cancer risk by letrozole could provide a precious alternative to bilateral mastectomy.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1048.
Return to Work after Treatment for Breast Cancer: Single Center Experience in a Cohort of 273 Patients.
Authors: Peugniez C. , Peugniez C. , Fantoni S. , Leroyer A. , Leroyer A. , Skrypczak J. , Duprey M. , Bonneterre J. , Bonneterre J.
Published: December 2010

Background: An increasing number of patients (pts) are treated for breast cancer during professional life. The aim of this study was to assess medical as well as socio-professional factors impacting on the likelihood of patients to return to work after treatment.Patients and methods: 1067 pts who were less than 60 years of age, and surgically treated in our institution between January 1, 2004 and December 31, 2005 received a questionnaire with medical, sociodemographic and professional items. An answer was obtained in 586 cases. After excluding in situ carcinoma, local relapses, bilateral tumors and pts without professional activity before treatment, 273 were evaluable. All the clinical files of these patients were reviewed. We studied return to work qualitatively (by univariate, then multivariate logistic regression) and quantitatively, by measuring time until return to work (by log-rank and then multivariate Cox model).Results: Overall, 79.8% of the patients returned to work after a median delay of 11.5 months. In the multivariate analysis, the factors affecting the return to work were: age (p<.0001), particularly pts >55 years returning to work in 58% of cases vs more than 80% in younger ones, education level (p<.001), colleagues support (p<.001), chemotherapy (p<.05), lymphedema (p<.01), and the physical (p=.01) and psychological constraints of the job (p<.01). Surprisingly, local pain with ankylosis of the shoulder was significant only in the univariate analysis (p<.0001). In the multivariate analysis, the factors affecting the delay between treatment and return to work were very similar: age (p<.01), education level (p<.0001), colleagues support (p<.0001), chemotherapy (p<0001), lymphedema (p<.01), and the professional constraints of the job (p<.0001). No significant difference was observed according to type of surgery, tumorectomy vs mastectomy, sentinel lymph node vs axillary clearance, radiation therapy or not, hormonotherapy or not.Conclusion: in our study, 80% of the pts with a professional activity before treatment returned to work; the factors affecting the return to work as well as its delay were: medical (chemotherapy and lymphedema), demographic (age) and socioprofessional (education level, which induces differences in the socio-professional groups, constraints of the job, colleagues support). We could not find any influence of the other treatments such as radiotherapy or hormonotherapy.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1060.
Prevalence and Risk Factors for Insomnia in Breast Cancer Survivors Receiving Aromatase Inhibitors.
Authors: Mao J. , Gehrman P. , Su I. , Bruner D. , Xie S. , El Sehamy A. , DeMichele A.
Published: December 2010

Purpose: Insomnia is increasingly recognized as a major symptom outcome in oncology; however, its prevalence and risk factors have not been previously defined in women receiving aromatase inhibitors (AI) for breast cancer.Patients and Methods: We performed a cross-sectional analysis of a cohort of postmenopausal women with stage 0-III breast cancer receiving adjuvant AI therapy at an outpatient breast oncology clinic at a large university hospital. The validated Insomnia Severity Index (ISI) was the primary outcome (Cronbach's alpha of 0.91 in this population). According to ISI, Insomnia was categorized as: no clinically significant insomnia, 0-7; sub-threshold insomnia 8-14; clinical insomnia (moderate severity), 15-12; clinical insomnia (severe), 22-28. We defined anyone who had clinical insomnia with a score of 15 or above. Multivariate logistic regression analyses were performed to assess risk factor(s).Results: 367 patients have been analyzed, with a mean age of 61.6 +/- 10 years. 83.6% were White and 12.9% Black. While 124 (34.1%) had sub-threshold insomnia, 67 (18.4%) met criteria for clinical insomnia based on ISI: 58 (15.9%) for clinically moderate insomnia and 9 (2.5%) clinically severe insomnia. Of the entire sample, 31% considered seeking treatment for insomnia over the previous month. In a multivariate logistic regression model, clinical insomnia was independently associated with current joint pain (odds ratio [OR], 4.41, 95% confidence interval [CI], 2.17-8.96, p<0.001) and hot flashes (OR, 3.00, 95% CI, 1.58-5.71, p=0.001). While education level (college only vs. graduate or professional degree) was also associated with increased risk for clinical insomnia (OR, 2.46, 95% CI, 1.18-5.14, p=0.016), no other demographic, clinical or treatment variable was related to clinical insomnia.Conclusions: Insomnia is a substantial problem among breast cancer survivors receiving aromatase inhibitors and is highly associated with joint pain and hot flashes. Thus, effective treatment of joint pain and hot flashes may help improve insomnia in this population.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1062.
Psychosocial Interaction from the Patients Point of View – Patient Satisfaction by CPQ-BC (Cologne Patient Questionnaire – Breast Cancer) in 51 German Breast Centers.
Authors: Wuerstlein R. , Steffen P. , Kowalski C. , Alich M. , Warm M. , Pfaff H. , Harbeck N.
Published: December 2010

Background: The implementation of breast centers aims at improving the quality of care for breast cancer patients. Hereby the quality of psychosocial interaction from doctors and nursing staff is an essential aspect for patient satisfaction. This presentation based on empirical data shows the quality of psychosocial interaction from the point of view of patients in 51 german breast centers and if it has changed in annual comparison. Moreover, it analyses how the individual breast centers differ from each other and gives benchmarking data as well as data concerning the increasing significance attributed by patients to the assessment of quality of care and patient satisfaction.Material and Methods: Basis for the data is a retrospective survey of 10837 newly diagnosed breast cancer patients after primary surgery between 2006 and 2008 in 51 breast centers in Germany. After being inpatients, they were sent the specially developed Cologne Patient Questionnaire for Breast Cancer (CPQ-BC) which comprises key data to relevant aspects of psychosocial interaction such as support from physicians or nursing staff, doctor facilitation scale, patient information scale, patient participation in decision making, empathic provision of information, provision of information by physicians (basic and additional information), physical functioning, psychological well-being and tendency to excuse.Results: 88% of the contacted patients returned a completed questionnaire. The results of the descriptive analyses show that the quality of psychosocial interaction in the breast centers was overall evaluated very positively and that it is relatively stable in three years time. However, there are clear differences between the individual centers.Discussion: We noted that the quality of psychosocial interaction in the german breast centers already has a high standard from the patients point of view. This standard needs to be maintained and developed further. Moreover, the declared aim should be to dismantle the existing differences in quality between the centers. A specific evaluation of various structure and process features can give information on the reasons for these differences. Benchmarking data and specially developed benchmarking workshops help breast centers and their teams to improve quality of care and provide a good psychosocially supportive provider-patient interaction.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1071.
Medical Oncology Breast Cancer Quality Indicators: Adherence by the Florida Initiative for Quality Cancer Care (FIQCC) Consortium.
Authors: Gray J. , Laronga C. , Siegel E. , Lee J. , Fulp W. , Jacobson P.
Published: December 2010

Background: The Florida Initiative for Quality Cancer Care (FIQCC) is comprised of 11 practice sites across the state that participate in a comprehensive review of quality of care specific to cancer patients across many disease sites. Quality indicators were scripted based on accepted QOPI, NCCN, ACOS, and site-specific PI panel consensus indicators for breast cancer (BRCA) patients. An evaluation was performed to assess adherence to the performance indicators across sites within the FIQCC.Methods: Comprehensive chart reviews were conducted for all patients with BRCA first seen in 2006 by a medical oncologist at one of the 11 FIQCC sites (3 academic/8 community). Quality measures included: 1) documentation of menopausal status; 2) documentation of receptor status in the chart and evidence that it guided treatment recommendations accordingly; 3) documentation that consent for chemotherapy was obtained; 4) documentation of the planned chemotherapy regimen; and 5) documentation that chemotherapy started within 8 weeks of surgery. A pilot measure included: 6) documentation of fertility preservation being addressed in pre-menopausal women. Pearson's Chi-square test was used to test variability on the quality measurements across practice sites.Results: Charts of 622 patients (99% female), median age of 60 years (range 22-95) were reviewed. Menopausal status was documented in 49% (307/622). Documentation of the receptor status (ER/PR/ Her2Neu) was excellent, 99% (532/537). For those with ER/PR positive, non-metastatic disease measuring at least 1cm, 98% (432/441) were considered for an aromatase inhibitor or tamoxifen within one year of diagnosis. For patients with Stage II-III BRCA with over-expression of Her2Neu (H2N), consideration or administration of trastuzumab was documented in 82% (95/116). With respect to chemotherapy, there was documentation of consent in 75% (247/330), planned chemotherapy regimen in 75% (226/302), and initiation of chemotherapy with 8 weeks of surgery in 84% (233/279). Fertility preservation was only addressed in 11% (10/88) of patients who were documented as pre-menopausal. A statistically significant difference (p< 0.05) across the sites was found for all quality indicators above, except two: documentation of consideration or administration of trastuzumab and discussions of fertility preservation.Discussion: The FIQCC allows for the identification of the need for quality improvements in multiple aspects of breast cancer care. Findings based on 2006 cases identified need for improvements in documentation and consenting for chemotherapy, reporting of menopausal status, consideration and administration of trastuzumab, and consideration of fertility counseling. These findings are now being used at the participating institutions to guide quality improvement efforts.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1078.
Breast Cancer Stem Cells Identified by ALDH1 Expression Were Associated with Resistance to Sequential Paclitaxel and Epirubicin-Based Chemotherapy for Human Breast Cancers.
Authors: Tanei T.
Published: December 2010

Background: Breast cancer stem cells have been demonstrated to be associated with resistance to chemotherapy in vitro, but their clinical significance has yet to be examined in human breast cancers. The aim of this study was to investigate whether breast cancer stem cells were clinically associated with chemo-resistance or not.Material and Methods: The subjects recruited for this study comprised 108 primary invasive breast cancer patients treated with neoadjuvant chemotherapy (NAC) consisting of sequential paclitaxel and epirubicin-based chemotherapy. Cancer stem cells were identified by immunohistochemical staining of CD44/CD24 or ALDH1 in tumor tissues obtained before and after NAC.Results: The pathological complete response (pCR) was achieved in 30 patients (27.8%) of the 108 patients treated with NAC. ALDH1 positive tumors were significantly associated with a low pCR rate (9.5% vs. 32.2%; P = 0.037), but there was no significant association between CD44+/CD24- tumor cell proportions and pCR rates. Changes in the proportion of CD44+/CD24- tumor cells or ALDH1 positive tumor cells before and after NAC were examined in 78 patients who did not achieve pCR. The proportion of ALDH1 positive tumor cells significantly increased (p<0.001) after NAC, but no significant change was observed in the proportion of CD44+/CD24- tumor cells before and after NAC. In addition, we were able to show, by multivariate analysis, that tumors with negative ER, high Ki67, and negative ALDH1 were significantly more likely to achieve pCR.Discussion: Our findings suggest that breast cancer stem cells identified as ALDH1 positive, but not CD44+/CD24-, play a significant role in resistance to chemotherapy. ALDH1 positive tumor cells are likely to serve as a better marker for breast cancer stem cells than CD44+/CD24- tumor cells for the prediction of resistance to chemotherapy.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1084.
Effectiveness of Neoadjuvant Letrozole of Invasive Lobular Cancers.
Authors: Dixon J. , Renshaw L. , Evans D. , Thomas J.
Published: December 2010

Background:Invasive lobular cancers are poorly responsive to neoadjuvant chemotherapy. They are commonly hormone sensitive. This study set out to investigate the efficacy of neoadjuvant letrozole in post-menopausal women with large operable or locally advanced breast cancers.Patients and Methods:48 consecutive patients with large operable or locally advanced invasive lobular ER positive (Allred score 8 = 38, 7 =8, 6=1, 5=1) were treated in a single Breast Unit by neoadjuvant letrozole for 3 months or longer. The mean age was 76.7 years with a range of 55 to 91 years. 6 tumours measured >2-4 cm (T2), 26 tumours measured >4 cm (T2, T3) and 16 were locally advanced (T4). Response was assessed by a single observer at 3 months.Results:Response to TreatmentThe mean reduction in clinical volume at 3 months was 60% (95% CI 50-79%) with a median of 67% (95% CI 60-79%). Responses were classified as 1 Complete Response (CR), 25 Partial Response (PR), 16 Minimal Response (MR), 4 Stable Disease (SD) and 2 Progression.The mean USS in volume was 69% (60-78%), with a median of median 80% (66-84%). Response was classified as CR= 12, PR = 25, MR = 7, SD = 3 and Progression = 1.Surgery and Outcome32 have come to surgery and 16 have continued on letrozole.24 patients were considered suitable for breast conserving surgery (WLE) of whom 16 successful had WLE (67% with Clear Margins), 4 had a WLE and then a successful re- excision of margins and 4 had a WLE followed by mastectomy. The final rate of successful breast conservation was thus 20/24 (83%).8 patients with locally advanced breast cancer became operable and were treated by mastectomy.SummaryThis is the largest series of invasive lobular carcinomas treated by neoadjuvant letrozole ever reported.Invasive lobular carcinomas are often large at diagnosis.They are mainly ER rich.In post-menopausal women they respond well to endocrine therapy with letrozole.Neoadjuvant therapy with letrozole allows many women with large invasive lobular carcinomas to be treated successfully with breast conservation.This contrasts with the poor results obtained with neoadjuvant chemotherapy.ConclusionNeoadjuvant letrozole therapy is an effective treatment for shrinking invasive lobular ER positive breast cancers in post-menopausal women.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1085.
Comparison of Methods for Detection of Fulvestrant-Induced Changes in Breast Tumor Estrogen and Progesterone Receptor Expression in a Neoadjuvant Trial (NEWEST).
Authors: Kuter I. , Anderson E. , Emeribe U. , Finlay P. , Nicholson R. , Gee J.
Published: December 2010

Background: Fulvestrant downregulates breast tumor estrogen and progesterone receptor (ER and PgR) levels in a dose-dependent manner. Using an Automated Cellular Imaging System (ACIS), NEWEST (NCT00093002) reported that 4-wks' treatment with fulvestrant high-dose (HD, 500mg/month+500mg on Day 14 of Month 1) significantly reduced ER levels in primary breast tumors v approved-dose (AD, 250mg/month). However, no significant difference was detected between the two doses on PgR levels. To allow comparison with previous studies, a non-automated H-score assessment was performed and compared with ACIS.Methods: ER and PgR H-scores were derived by manual assessment of % tumor cells in each of 5 staining categories (negative, very weak, weak, moderate, strong) in the same sections scored by ACIS. This microscopic assessment was performed by 2 experienced observers blind to ACIS and clinical data. Mean % changes in H-scores were then calculated (table).Results: Both scoring methods showed a greater effect for fulvestrant HD v AD on ER expression at Wk 4, but H-score provided better dose discrimination. ACIS showed no difference between fulvestrant HD v AD on PgR expression at Wk 4, however, a significantly greater reduction in PgR expression was detected with fulvestrant HD using H-score.Wk 4Mean % change from baseline ACISH-score HDADHDADER-25.0%-13.5%-50.3%-13.7% n=60(n=63)(n=58)(n=60) p=0.0002 p<0.0001 PgR-22.7%-17.6%-80.5%-46.3% (n=43)(n=45)(n=31)(n=34) NS p=0.0018 Baseline mean H-score for HD and AD: 151.6 and 157.7 for ER; 103.8 and 122.9 for PgR.Conclusion: The choice of scoring method for determining ER and PgR expression in pharmacodynamic studies such as NEWEST is critical. Compared with H-scores, ACIS has a narrower dynamic range and reduced ability to discriminate fulvestrant HD v AD, particularly on PgR expression.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1087.
A Pilot Trial of Pre-Operative (Neoadjuvant) Letrozole in Combination with Bevacizumab in Post-Menopausal Women with Newly Diagnosed Estrogen and/or Progesterone Receptor Positive Breast Cancer.
Authors: Forero A. , Saleh M. , Galleshaw J. , Jones C. , Shah J. , Percent I. , Nabell L. , Carpenter J. , Falkson C. , Krontiras H. , Urist M. , Bland K. , De Los Santos J. , Meredith R. , Caterinicchia V. , Bernreuter W. , O'Malley J. , Li Y. , LoBuglio A.
Published: December 2010

Purpose Tumor content or expression of vascular endothelial growth factor (VEGF) is associated with impaired efficacy of anti-estrogen adjuvant therapy. We designed a pilot study of neoadjuvant letrozole and bevacizumab (anti-VEGF) to assess feasibility and short term efficacy in post-menopausal women with stage II/III, ER/PR positive breast cancer. Patients and Methods Patients were treated with a neo-adjuvant regimen of letrozole, 2.5mg/day (P.O.) and bevacizumab 15mg/kg Q3 weeks (I.V.) for a total of 24 weeks prior to surgical treatment of their breast cancer. Patients were followed for toxicity at 3 week intervals and tumor assessment (physical exam and tumor ultrasound) at 6 week intervals. PET scans were carried out prior to therapy and 6 weeks after initiation of therapy. Surgery was done 4 weeks after the last dose of bevacizumab. Results Twenty five evaluable patients were treated. The regimen was well tolerated except for 2 patients who were taken off-study for difficult to control hypertension. Objective clinical response occurred in 17/25 patients (68%) including 16% CR and 52% PR. The 4 patients with clinical CR had pathologic CR in their breasts (16%) although one had residual tumor cells in axillary nodes. 8/25 patients (32%) attained stage 0 or 1 status. PET scan response at 6 weeks correlated with clinical CR and breast pathologic CR at 24 weeks (p < 0.0036). Conclusion Combination neo-adjuvant therapy with letrozole and bevacizumab was well tolerated and resulted in impressive clinical and pathologic responses. The Breast Cancer Translational Research Consortium has an ongoing randomized phase II trial of this regimen in this patient population.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1088.
Pilot Neoadjuvant Trial with Combination of Lapatinib and Nab-Paclitaxel in HER2+ Breast Cancer.
Authors: Kaklamani V. , Uthe R. , Khan S. , Hansen N. , Bethke K. , Jeruss J. , Cianfrocca M. , Von Roenn J. , Rosen S. , Gradishar W.
Published: December 2010

Background: Lapatinib, a dual kinase inhibitor against EGFR and HER2, has activity in metastatic HER2+ breast cancer. Nab-paclitaxel has been found to be one of the most active agents in metastatic breast cancer. Its combination has not been studied in the neoadjuvant setting. We have conducted a pilot neoadjuvant trial in HER2+ patients (pts) combining lapatinib with nab-paclitaxel.Methods: Females with newly diagnosed breast cancer (stage I-III) received four cycles of lapatinib 1000 mg po/day and nab-paclitaxel 260mg /m2 IV every three weeks. Postoperative therapy was at the discretion of the investigator. The accrual goal of 30 pts has been met. The primary endpoint was clinical response rate (CRR) with secondary endpoints including pathologic complete response (pCR), toxicity, and proliferation, apoptosis and angiogenesis markers.Results: A total of 28 pts have completed all therapy to date. The most common toxicities were rash, neuropathy, fatigue and myalgias. Most toxicities were grade 1/2 although one pt developed grade 3 rash and five pts grade 3 diarrhea. Nab-paclitaxel was dose reduced in 8 and lapatinib in 10 of 104 cycles. No cardiac toxicity was observed. Response data is available on 25 pts. CRR was 88% with four complete clinical responses and 18 patients with partial clinical response. Three patients had stable disease. Four patients achieved pCR.Summary of efficacy and toxicityResponse Non-hematologic ToxicityGrade 1/2Grade 3/4Hematologic toxicity Overall response22 (88%)Nausea7 (25%)1 (3.6%)Anemia9 (32.1%)Complete response4 (16%)Rash19 (67.8%)1 (3.6%)  Partial response18 (72%)Fatigue17 (60.7%)2 (7.2%)  Stable disease3 (12%)Neuropathy14 (50%)0  pCR4 (19.0%)Arthralgias/17 (60.7%)1 (3.6%)    Diarrhea15 (53.6%)5 (17.9%)   Conclusions: The combination of lapatinib and nab-paclitaxel is very active as first-line treatment in HER2+ breast cancer. Toxicities, including rash and diarrhea were observed and medically managed. Patients did not receive prophylactic medications for rash or diarrhea Updated clinical data on all 30 patients as well as correlative markers will be presented.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1091.
Five Years of Exemestane as Initial Therapy Compared to 5 Years of Tamoxifen Followed by Exemestane: The TEAM Trial, a Prospective, Randomized, Phase III Trial in Postmenopausal Women with Hormone-Sensitive Early Breast Cancer.
Authors: Rea D. , Hasenburg A. , Seynaeve C. , Jones S. , Vannetzel J. , Paridaens R. , Markopoulos C. , Hozumi Y. , Putter H. , Hille E. , Asmar L. , Urbanski R. , van de Velde C. , Bartlett J. , Smeets J. , Kieback D.
Published: December 2010

Background: Exemestane (E) is a steroidal aromatase inhibitor (AI) with an established role in early breast cancer after 2–3 years of tamoxifen (T). Additionally, AIs have shown superiority to T as initial adjuvant therapy. The Tamoxifen Exemestane Adjuvant Multinational (TEAM) study has been prospectively designed to compare the role of E as initial adjuvant therapy with a sequential approach of T followed by E (T→E).Methods: Postmenopausal patients with hormone receptor–positive early breast cancer were randomized to open-label E 25 mg/d or T 20 mg/d. All patients completed surgery and chemotherapy, if indicated. Data were collected and analyzed by the Central Data Center in Leiden, The Netherlands. The trial was initiated in 2001 with the primary objective being a comparison of disease-free survival (DFS) with T vs E. In 2004, TEAM was modified in response to new data; all those initially receiving T were switched to E after 2.5–3 years. An additional 2500 patients were recruited and randomized at diagnosis to E or T→E for 5 years. The modified study design includes 2 coprimary endpoints: (1) DFS of T vs E that was previously reported at 2.75 years median follow-up (Jones S et al, abstract #15 presented at SABCS 2008); and (2) DFS at 5 years of E vs T→E that will be the focus of results presented here.Results: Between 2001 and January 2006, 9775 women were randomized to TEAM. In total, 99% of patients were ER+ and/or PgR+, 50% were node-negative, 44% underwent mastectomy, 68% received radiotherapy, and 36% received chemotherapy. In September 2009, median follow-up will be 5.5 years and the protocol-specified 1285 overall DFS events (locoregional or distant recurrence, second breast cancers, or death without recurrence) will have occurred, allowing for analysis of the second coprimary endpoint. We will present a detailed analysis of the 5-year results from theTEAM trial, the only prospectively powered randomized trial to compare 5 years of an initial AI vs T→AI, 2 commonly received adjuvant therapies for women with hormone receptor–positive early breast cancer.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 11.
A Phase II Trial of Capecitabine and Docetaxel Followed by 5-FU/Epirubicin/Cyclophosphamide (FEC) as Preoperative Treatment in Women with Stage II/III Breast Cancer.
Authors: Jinno H. , Takahashi M. , Hayashida T. , Sakata M. , Mukai M. , Kitagawa Y.
Published: December 2010

Backgound: capecitabine (X) and docetaxel (T) have demonstrated synergistic effect in preclinical models and survival benefit in metastatic breast cancer. The sequential combination of anthracycline and taxane is a standard of care as preoperative setting, as well as adjuvant setting. This study's purpose was to determine the efficacy of X and T followed by 5-FU/epirubicin/cyclophosphamide (FEC) in the preoperative setting.Patients and Methods: Patients with stage II/III breast cancer received 4 cycles of XT (capecitabine 1650 mg/m2 on days 1-14 and docetaxel 60 mg/m2 on day 8 every 3 weeks), followed by 4 cycles of FEC (fluorouracil 500 mg/m2, epirubicin 90 mg/m2, cyclophosphamide 500 mg/m2 on day 1 every 3 weeks). Primary endpoints were the pathological complete response (pCR) rate and adverse drug reactions. pCR was defined as no microscopic evidence of residual viable tumor cells, invasive or noninvasive, in all resected specimens of the breast. Secondary endpoints were the clinical response rate, the breast conservation rate, and predictors for pCR.Results: From February 2005 to October 2008, 72 patients were enrolled and 71 patients were assessable for clinical and pathologic responses. The median age was 51 years (range, 27-69 years). The median tumor size was 3.5 cm (range, 2-8.3 cm). Forty-six (64.8%) patients were clinically node-positive. Overall, 50 (50.1%) patients had hormonal receptor (HR)-positive tumors, and 21 (29.6%) had HR-negative tumors. The overall response rate was 91.5%, including a complete response in 29 patients and a partial response in 36 patients. No patients showed clinical progression of disease. The pCR rate was 14.1% (10/71). Fifty-six patients (78.9%) underwent breast-conserving surgery. The breast-conserving rate in patients whose tumor size was 3 cm or smaller was 92.6%, and 69.0% of patients whose tumor size was larger than 3 cm underwent breast-conserving surgery. Grade 3/4 neutropenia was observed in 32.4% of patients, and febrile neutropenia was observed in 5.6% of patients. The most common grade 3/4 non-hematologic adverse event was hand-foot syndrome, observed in 11.3% of patients. The median relative dose intensities of FEC, T, and X were 0.982, 0.968, and 0.933, respectively. HR status and Ki67 expression were significantly correlated with pCR.Conclusions: These data indicate that the sequential combination of XT followed by FEC is a well-tolerated, effective preoperative treatment for stage II/III breast cancer.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1101.
Circulating Tumor Cells and FDG-PET/CT for the Therapeutic Monitoring of Bone Metastases from Breast Cancer.
Authors: De Giorgi U. , De Giorgi U. , Mego M. , Rohren E. , Valero V. , Handy B. , Jackson S. , Reuben J. , Macapinlac H. , Cristofanilli M. , Ueno N.
Published: December 2010

Background: Circulating tumor cells (CTCs) and [18F]fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) are two promising new tools for monitoring therapy in patients with metastatic breast cancer. The two modalities showed high sensitivity in detection of bone relapse/progression from breast cancer (De Giorgi U et al. Ann Oncol 2009). In this study, we sought to evaluate the prognostic significance of two different modalities represented by the detection of CTC and FDG-PET/CT in patients with bone metastases from breast cancer treated with standard therapies. Our objective was to compare the two modalities to identify which technology could be more sensitive in prospectively monitoring such patients.Patients and Methods: This is a retrospective study of 54 patients with bone metastases from breast cancer without visceral metastases treated at The University of Texas M. D. Anderson Cancer Center from September 2004 to May 2008. CTC were detected and enumerated using the CellSearch system (Veridex LLC, Rariten NJ, USA). Patients were categorized according to first follow-up CTC counts as having a favorable (< 5 CTC/7.5 mL of blood) or unfavorable (≥ 5 CTC) outcome. Reassessment of disease status by CTC count and FDG-PET/CT was performed approximately 2-3 months after initiation of the new treatment, depending on treatment type and schedule. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier product limit method, and compared between groups with the log-rank test.Results: In 54 evaluable patients, the median overall survival time was 17 months (range, 3 to >36). Follow-up CTC levels and FDG-PET/CT response predicted both PFS (p = 0.02 and p = 0.0001, respectively) and OS (p = 0.01 and p = 0.02, respectively), while baseline CTC predicted neither PFS (p = 0.8) nor OS (p = 0.76). In patients with either CTC or FDG-PET/CT response PFS has been 13 months, while in patients with discordant CTC and FDG-PET/CT response PFS has been 6 months and in patients with neither CTC nor FDG-PET/CT response PFS has been 5 months (p = <0.00002). In patients with either CTC or FDG-PET/CT response, OS has not been reached (>31 months); in patients with discordant CTC and FDG-PET/CT response, OS has been 24 months; and in patients with neither CTC nor FDG-PET/CT response, OS has been 18 months (p = 0.02).Conclusions: CTC and FDG-PET/CT are useful tools for therapeutic monitoring of bone metastases from breast cancer. Prospective studies in this specific clinical context are needed to assess the critical roles that CTC and FDG-PET/CT individually as well as collectively play in the prognostic and therapeutic monitoring of bone metastases from breast cancer.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1109.
A Genomic-Profile Derived Summary Measure of Chromosomal Breakpoints Predicts Response to Treatment with the DNA-Damaging Agent Cisplatin.
Authors: Juul N. , Wang Y. , Kim J. , Eklund A. , Li Q. , Carlton V. , Gerlinger M. , Swanton C. , Garber J. , Silver D. , Faham M. , Richardson A. , Szallasi Z. , Szallasi Z. , Wang Z.
Published: December 2010

Cisplatin-based chemotherapy promotes DNA inter- and intra-strand cross-links and is effective treatment in multiple cancer types, yet it is rarely used for first-line therapy of breast cancer. Cisplatin is an effective cytotoxic in BRCA1 mutant cancer cell lines and in breast and ovarian cancers with BRCA1 mutations, prompting speculation that defective DNA double-strand break repair is associated with cisplatin sensitivity. Furthermore, tumors with BRCA1 mutation are presumed to be defective in various aspects of DNA repair and also display increased levels of chromosomal instability. Thus, we hypothesized that the total number of chromosomal breakpoints in a specific tumor may reflect defective DNA repair and/or chromosomal instability, and may therefore be used as a predictor of cisplatin sensitivity. Supporting this relationship, we identified a correlation (r = 0.8, P = 0.08) between the total number of chromosomal breakpoints, estimated by the number of genomic regions showing allelic imbalance, and cisplatin sensitivity in five triple negative breast cancer cell lines. To validate this relationship in a clinical setting we compared the total number of chromosomal breakpoints to therapy response in a cisplatin treated breast cancer cohort. A total of 28 women with stage II or III ER-/PR-/HER2- breast cancer were treated with cisplatin in the neo-adjuvant setting followed by surgery and standard adjuvant chemotherapy. A core biopsy was obtained before treatment commenced, tumor cells were enriched by needle microdissection, and DNA was extracted for genotyping. As only limited amounts of DNA were available, we used a Molecular Inversion Probe assay (in collaboration with Affymetrix), which allowed us to genotype 42,000 SNPs with only 40 ng of starting DNA. We then estimated the total number of putative genomic breakpoints in 21 samples containing at least 75% tumor cells. We compared this summary genomic measure to the response rate as quantitated by the Miller-Payne score determined on the pathological specimen obtained at surgery. This genomic measure showed a remarkably accurate separation of patients by degree of response, correctly classifying 20 out of 21 patients (P < 0.001).These results suggest that the total number of DNA breakpoints may be an accurate biomarker of breast cancers which may be sensitive to cisplatin treatment. The molecular explanations for these findings await further work.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 111.
Inhibition of Calcitonin Gene-Related Peptide and Insulin-Like Growth Factor: A Potential New Therapeutic Strategy To Reduce Bone Pain in Bone Metastases of Breast Cancer.
Authors: Sakurai T. , Sakurai T. , Sakurai T. , Umemura T. , Jinta E. , Suzuma T. , Williams P. , Yoshimura G. , Wakabayashi H. , Sakurai T. , Yoneda T. , Yoneda T.
Published: December 2010

Bone pain caused by bone metastases is one of the most common complications in patients with breast cancer. However, the precise molecular mechanism of bone pain is unknown. We have shown that the acid released upon bone resorption by osteoclasts and the transient receptor potential vanilloid receptor (TRPV1), an acid-sensing receptor on the algetic nerves terminating at the bone, are involved in the mechanism underlying this bone pain. In this study, we investigated the relationships among TRPV1, bone-derived insulin-like growth factor-1 (IGF-1) which is released from bone due to increased bone resorption during the progression of bone metastases, and neuropeptide calcitonin gene-related peptide (CGRP) and examined whether cancer-induced bone pain can be decreased by the inhibition of IGF-1 and CGRP. To study this in vitro, we established organ cultures of mouse dorsal root ganglions (DRGs), which are the primary sensory neurons innervating bone. Culture supernatants harvested from the mouse neonatal calvariae, which had abundant growth factor in bone, showed elevated TRPV1 and CGRP mRNA expressions in mouse DRGs. These up-regulated mRNA expressions were inhibited by the administration of a TRPV1 inhibitor (I-RTX); AG1024, a specific inhibitor of IGF receptor tyrosine kinase; or zoledronate. Taken together, these results suggest that CGRP and bone-derived IGF-1 may play a role in the induction of bone pain. To approach the role of CGRP and bone-derived IGF-1 in vivo, we established a mouse model of cancer-induced bone pain by inoculating the 4T1 mouse breast cancer cells into the marrow cavity of tibiae. Tumor-inoculated tibiae showed significantly increased pain behaviors compared with the non-tumor-bearing tibiae, indicating 4T1 cells induced bone pain. RT-PCR showed elevated mRNA expression of TRPV1 and CGRP in the ipsi-lateral tumor-bearing DRGs. The administration of a CGRP inhibitor (CGRP 8-37) in a continuous manner using an ALZET osmotic pump implanted under the mouse skin; the intraperitoneal administration of AG1024; and the administration of alendronate significantly reduced pain behaviors in tumor-bearing tibiae. In addition, mRNA expression of CGRP was decreased by CGRP 8-37, and mRNA expression of TRVP1 and CGRP was also decreased by AG1024 in the ipsi-lateral DRGs. Neither of these drugs showed a direct effect on the growth of the tumor in this study. In conclusion, our results suggest that TRPV1, CGRP, and the bone-derived IGF-1 are strongly related and might play a role in breast cancer-induced bone pain. The inhibition of the CGRP and bone-derived IGF-1 could be a potential therapeutic strategy to reduce bone pain; although further investigations are required in this direction.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1110.
Economic Evaluation of Zoledronic Acid for the Prevention of Osteoporotic Fractures in Post-Menopausal Women with Early Breast Cancer Receiving Aromatase Inhibitors in the United Kingdom.
Authors: Logman F. , Heeg B. , Botteman M. , Kaura S. , van Hout B.
Published: December 2010

Background: Aromatase inhibitors (AIs) are increasingly used as adjuvant therapy in early-stage breast cancer (EBC) and are associated with accelerated bone-loss. Adjuvant therapy with zoledronic acid (ZOL) has been shown to prevent aromatase inhibitor-associated bone loss (AIBL) in postmenopausal women (PMW) with EBC. This analysis assessed, via a model projecting lifetime incidence of osteoporotic fractures as a function of BMD, the cost-effectiveness of adjuvant ZOL for the prevention of fractures in PMW with hormone receptor positive breast cancer (stage I-IIIa) who receive adjuvant letrozole 2.5 mg daily for 5 years and who had a baseline bone mineral density (BMD) T score of ≥-2. Methods: A Markov model was developed to project the lifetime incidence of osteoporotic fractures, quality-adjusted life years (QALY), and healthcare costs as a function of BMD for women with EBC (aged 60 years) receiving adjuvant AIs (for up to 5 years) alone or with ZOL upfront or delayed. Two strategies of adjuvant ZOL therapy compared to no treatment were modelled: starting ZOL treatment only when BMD levels decreased (“delayed ZOL”) and starting ZOL 4mg i.v. q 6mo simultaneously with AI therapy (“upfront ZOL”). ZOL efficacy was derived from the ZO-FAST study (N=1,060) which reported a 5.41% (p<0.0001) difference in percentage BMD change between both strategies after 3 years. Data for the no-treatment arm came from a separate trial of AI in which patients did not receive ZOL. The model runs in annual cycles, over a lifetime horizon. Future costs and effects were discounted at 3.5% annually. Results: Compared to no treatment, delayed ZOL therapy was associated with an estimated QALY gain of 0.026 (CI95%:0.007 – 0.045) and an additional cost of £ 419 (CI95%: £ 367 – £ 473). Delayed ZOL therapy vs. no treatment was estimated to cost £ 16,069 per QALY. Compared to no treatment, upfront ZOL was associated with a gain of 0.079 QALY (CI95%: 0.059 – 0.100), at an additional cost of £ 1,742 (CI95%: £ 1,676 – £ 1,810). The corresponding cost per QALY gained was therefore estimated at £ 21,973. Compared to delayed ZOL therapy, upfront ZOL resulted in a gain of 0.053 QALY (CI95%: 0.039 – 0.062) and additional costs of £ 1,323 (CI95%: £ 1,280 – £ 1,366). The cost-effectiveness ratio for upfront vs. delayed therapy was therefore £ 24,868 per QALY gained. Conclusions: Based on this analysis, upfront ZOL is shown to result in better health outcomes (QALYs) than either delayed ZOL or no therapy. Both ZOL therapy strategies were shown to result in highly acceptable cost-effectiveness ratios compared to no treatment.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1111.