bluuebunny/crossref_metadata_2025 huggingface dataset:
Male Breast Cancer: A Population-Based Comparison with Female Breast Cancer.
Authors: Anderson W. , Jatoi I. , Rosenberg P.
Published: December 2010

Purpose: Because of its rarity, male breast cancer is often compared to female breast cancer.Materials and Methods: To compare and contrast male and female breast cancers, we obtained case and population data from the NCI's Surveillance, Epidemiology, and End Results program for breast cancers diagnosed from 1973 through 2005. Standard descriptive epidemiology was supplemented with age-period-cohort models and breast cancer survival analyses.Results: Men with breast cancer comprised less than 1% of all breast cancers. Male compared to female breast cancers occurred later in life with higher stage, lower grade, and more estrogen receptor positive tumors. Recent breast cancer incidence and mortality rates declined over time for men and women, both overall and within each age group, but these trends were greater for women than men. Comparing cases diagnosed in 1996 through 2005 versus 1976 through 1985, and adjusting for age, stage, and grade, cause-specific hazard rates for breast cancer death declined by 28% among men (p = 0.03) and by 42% among women (p ∼ 0).Conclusion: There were three intriguing results. Age-specific incidence patterns showed that the biology of male breast cancer resembled the late-onset and hormone sensitive type of female breast cancer. Similar breast cancer incidence trends among men and women suggested that there are common breast cancer risk factors that affect both sexes, especially hormone positive breast cancer. Finally, breast cancer mortality and survival rates have improved significantly over time for male breast cancer, but progress has lagged behind for men compared to women.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2075.
Sensitivity to Taxane Chemotherapy for Metastatic Breast Cancer in BRCA1 and BRCA2 Mutation Carriers Compared to Sporadic Breast Cancer Patients.
Authors: Seynaeve C. , Jager A. , Hooning M. , den Bakker M. , Bontenbal M. , Blom J. , Collee M. , van den Ouweland A. , Kriege M.
Published: December 2010

Purpose: Data of in vitro and small retrospective studies suggest that breast cancer (BC) (cells) without functional BRCA1 or BRCA2 protein have an increased sensitivity to chemotherapeutic agents causing double strand DNA breaks, while sensitivity to spindle poisons, such as paclitaxel and docetaxel, has been found to be decreased. Clinical data on the latter, however, are very scarce. In this study, we assessed the sensitivity to taxane chemotherapy for metastatic BRCA1/2-associated compared with sporadic breast cancer.Methods: From the family cancer clinic database, we retrieved 36 BRCA1 and 13 BRCA2-associated BC patients treated with taxane chemotherapy for metastatic disease before October 1, 2008, and with available data on follow-up and response assessment. Objective response (OR), and progression-free survival (PFS) after start of taxane chemotherapy were compared with those of 62 sporadic patients with comparable age at diagnosis and year of detection of metastatic BC. A t-test or chi-square test was used to test for differences in characteristics and response types, and Kaplan-Meier survival analysis to calculate PFS.Results: Taxane chemotherapy consisted of docetaxel (n= 76) or paclitaxel (n=21), while 10 (9%) patients received a taxane/trastuzumab regimen. It was given as first-line palliative therapy in 9 BRCA1, 1 BRCA2 and 22 sporadic patients; but mainly as second/third line treatment (BRCA1 n=27, BRCA2 n=12, sporadic patients n=40, respectively). As compared to sporadic patients, BRCA1-associated patients had a significantly lower OR rate (ORR) overall (22% vs 46%, p<0.001) and to 2nd/3rd line taxane treatment (19% vs 46%, p<0.001). Median PFS was shorter in BRCA1 patients (2.0 vs 4.1 mo, p=0.08), with a trend for significance for 2nd/3rd line therapy (1.6 vs 3.9 mo, p=0.05). Also, compared to BRCA2 patients, the ORR in BRCA1 patients was significantly lower, overall as well as to 2nd/3d line therapy (both p=0.003). In BRCA2 mutation carriers compared to sporadic patients, the ORR was higher (75% vs 48%, p=0.28) and PFS longer (6.4 vs 4.1 mo, p=0.33). After exclusion of the patients receiving a taxane/trastuzumab schedule, similar data were observed.Conclusion: Objective response rate to taxane chemotherapy for metastatic disease is lower in BRCA1-associated BC in comparison with sporadic as well as BRCA2-associated BC, resulting in a shorter PFS. If confirmed, these data may have substantial clinical relevance.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2098.
Zoledronic Acid Prevents Bone Loss in Premenopausal Women with Early Breast Cancer Undergoing Adjuvant Chemotherapy: A Phase III Study of Korean Cancer Study Group (KCSG-BR06-01).
Authors: Ahn J. , Jung K. , Kim S. , Lee K. , Ro J. , Park Y. , Ahn J. , Im Y. , Im S. , Lee M. , Kim S.
Published: December 2010

Background: Adjuvant chemotherapy results in early menopause in the majority of premenopausal patients due to premature ovarian failure and consequent skeletal morbidity. Zoledronic acid (ZA) is known to prevent bone loss in postmenopausal women. The purpose of this study was to determine whether ZA can prevent bone loss in premenopausal women undergoing adjuvant chemotherapy for breast cancer.Methods: This study is a randomized, open-label, phase III multicenter trial. Premenopausal women older than age 40 were randomly assigned to ZA group (two infusions of 4 mg IV, every 6 months) or observation group after surgery. All patients were treated with the same adjuvant chemotherapy regimen (AC-->T; 4 cycles of AC followed by 4 cycles of paclitaxel or docetaxel). The first infusion of ZA was given on day 1 of the first chemotherapy. All patients received supplementations with oral calcium 600 mg/d and vitamin D 400 IU/d. The bone mineral density (BMD) was measured at the baseline, 6th and 12th months. Bone turnover markers were measured before chemotherapy and in 3, 6, 12 months.Results: Between March 2007 and May 2008, a total of 110 premenopausal women were enrolled in this study and the majority of women (91.8%) developed amenorrhea at 1 year post chemotherapy. The mean percent change of BMD in lumbar spine was +0.5% in the ZA group versus -3.6% in the observation group at 6 months (p<0.01) and, -1.0% versus -7.5%, at 12 months (p<0.01). Differences in percent change of BMD from baseline between two groups were 6.5% (95% CI, 5.2 to 7.9%) for the lumbar spine, and 3.6% (95% CI, 2.2% to 5.1%) for the femoral neck (p<0.01). Type I collagen metabolite PINP levels at 12 months were significantly higher in the observation group than in the ZA group; 72.7 mg/l (range 21.8∼250 mg/l) versus 30.8 mg/l (range 14.7∼62.7 mg/l) (p=0.0001). Changes of other bone turnover markers including urinary N-telopeptide, bone alkaline phosphatase, and serum C-telopeptide were also significantly different between two groups (p<0.01). ZA was generally well tolerated, and adverse event profile was similar between two groups.Conclusion: Adjuvant chemotherapy with AC-->T induced amenorrhea in the majority of patients over 40 years in this study. Treatment with two infusions of ZA 4 mg every 6 months effectively prevented bone loss within the first year of adjuvant chemotherapy for early breast cancer in premenopausal women. Regular BMD measurements and early bisphosphonate therapy should be considered for this population.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2104.
Radiofrequency Ablation in Breast Cancer.
Authors: Tzoracoleftherakis E. , Sdralis E. , Maroulis J. , Ravazoula P.
Published: December 2010

Background: Radiofrequency ablation (RFA) of breast tumors is characterized by variable efficiency. Cell viability is principally evaluated by NADH-diaphorase and Hematoxylin-eosin (H&E) staining techniques.Methods: Twenty patients with breast cancer, 20.7 ± 9.14mm in diameter, underwent RFA of the tumor and of the margin of surrounding breast tissue. RFA was based on the radiofrequency impedance-switching algorithm. The algorithm was based on an internally cooled probe, which carried out algorithm-guided deposition of heat in a pulse-cycle fashion and under continuous monitoring of the desiccation status of the ablated site to avoid tissue charring (until its impedance level reached 30Ω above the baseline level or a maximum time interval (tmax) was reached). A minimum time interval of 5 seconds was set as the duration of time that the electrode must be off. If the cycles of power application occurred too rapidly, the power was diverted to the 150Ω resistance load for the remainder of the 5-second interval. Surgical resection was the next step. Sixteen patients underwent quardzantectomy (five with axillary lymph node dissection) and four unilateral total mastectomy. In fifteen patients SLNB was searched and identified (ten negative, four positive and one failure). The ablated tumor tissue was histologically examined and Ki67 immunohistological staining was applied to evaluate cellular proliferation, invasion and survival.Results: The mean time of operation was 119.47 ± 23.35minutes.The mean time of RFA was 12 - 15minutes. One patient had a post-operative complication (trauma infection). All twenty patients had a positive Ki67 immunohistochemical staining mean value of 28.79 ± 21.42, before RFA. The post-RFA Ki67 expression was zero in sixteen patients. In three patients no residual tumor cells were found and in one patient the Ki67 expression was under five percent. Recurrence developed in zero patients, to date (follow up time: 22.5 ± 2.3 months).Conclusion: Ki67 evaluation is a targeting indicator of viability of malignant cells after lesion RFA of breast tumors. RFA is able to provide satisfactory local control in breast cancer.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2106.
Differences in Dielectric Properties between Malignant and Normal Breast Tissue: Preliminary Results of the MicroBlate® Study.
Authors: Chaudhry A. , Baruah B. , Goyal A. , Kink T. , Young P. , Douglas-Jones A. , Mansel R.
Published: December 2010

Background: Minimally-invasive microwave ablation techniques for the management of breast diseases are an emerging technology. These techniques rely, to a certain extent, on the difference in dielectric properties of normal and malignant human tissue. In our unit, we are currently studying the efficacy of a new microwave based technology, MicroBlate®, which has the unique feature of being able to measure tissue impedance and deliver microwave frequency impulse to tissues based on this impedance feedback. In this study we have compared the dielectric properties of normal and malignant breast tissues using this probe to establish proof of principle.Methodology:Impedance of freshly excised mastectomy and reduction specimens were measured ex-vivo using the MicroBlate® probe. This probe was attached to the end of the precision open-ended co-axial cable connected to an Agilent 4-port PNA-L Microwave network analyser (10MHz – 20 GHz). Impedance (Z) was intially recorded as two values which are vector quantities: real (R), which reflects the tissue resistance, and imaginary (X), a measure of tissue reactance. The overall impedance was then calculated using the standard mathematical formula, Z= √(R2+X2). Measurements were performed on adipose, glandular and malignant breast tissue immediately following surgical excision. Differences in the impedance values between these tissue types were calculated and the results analysed using appropriate statistical tests.Results:Our study shows a measurable difference in the dielectric properties of malignant and normal breast tissue. Our data supports the technological basis of MicroBlate®, a minimally invasive microwave ablation technology with impedance feedback, further ex-vivo studies are needed to determine its efficacy in ablating benign and malignant breast tissue. 28 patients undergoing elective mastectomy (n=26) and reduction (n=2) were included in this study between Feb – May 2009. Of the 26 patients undergoing mastectomy, 19 had invasive malignancy and the remaining 7 had in-situ malignancy only. The median age of the patients was 58 years (range 22-80 years). The average impedance of adipose tissue was 29.3 ± 6.9W, glandular tissue was 31.1 ± 6.1W and for malignant tissue was 49.6 ± 9.3W (Mann Whitney U p value <0.001). The average difference between impedance of malignant and glandular tissue in individual patients was 19.6 ± 8.6W.Conclusions:Our study shows a measurable difference in the dielectric properties of malignant and normal breast tissue. Our data supports the technological basis of MicroBlate®, a minimally invasive microwave ablation technology with impedance feedback, further ex-vivo studies are needed to determine its efficacy in ablating benign and malignant breast tissue.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3099.
Evaluation of the Phytochemical Anethole as an Anti-Tumor Agent in MCF-7 Cells.
Authors: Chen C. , De Gasperi M. , Salcedo R. , Cavazos D. , deGraffenried L.
Published: December 2010

Background: Chinese herbal medicines have gained considerable interest from the cancer community as potential anti-tumor agents. Both clinical as well as pre-clinical studies have demonstrated that certain Chinese herbal medicines can improve survival, increase tumor response, improve quality of life, and reduce chemotherapy toxicity. The specific mechanisms by which these compounds mediate their effects remain largely unknown, inhibiting their development as clinical agents. One such compound is anethole. Anethole is an aromatic compound that occurs widely in nature as a component of anise, fennel anise myrtle, licorice, and star anise and is used in traditional Chinese medicine as an anti-inflammatory agent. Anethole has been identified as one of the potential phytochemicals with anti-cancer activities that could be developed into clinical treatments for breast cancers.Objective: In this current study, we evaluated the effect of anethole on physiological responses and specific survival pathways in human breast cancer MCF-7 cells.Results: Cell proliferation and cell survival were suppressed in a dose-dependent manner in response to anethole treatment, but these dosages had differential effect on specific pro-survival pathways. Anethole increased the cleavage of Poly (ADP-ribose) polymerase (PARP), suggesting an increase in apoptotic activity, but concurrently increased the expression of pro-survival proteins Bcl-2 and p21 while decreasing the expression of tumor suppressor protein p53. Phosphorylation of Akt kinase and S6 pro-survival proteins were modulated in an alternating pattern with increasing concentrations of anethole. Studies were also conducted to investigate the effect of anethole on the sensitivity of MCF-7 cells to tamoxifen treatments. The effect of tamoxifen on cell proliferation was not affected significantly by co-treatment with anethole but importantly the suppression of cell survival by tamoxifen was enhanced when anethole is present at a concentration of 10-5 M. Preliminary data suggest that one mechanism by which anethole is mediating some of its suppressive effects is through modulation of ER activity, as measured by luciferase assays. Studies are on-going to evaluate the relevance of this modulation to the inhibitory effects of anethole on the MCF-7 cells, as well as the modulation of the signal transduction pathways indicated on survival.Conclusion: These data suggest that the anethole is a potential anti-tumor agent, and that co-treatment of tamoxifen and anethole is a potential approach to sensitize human breast MCF-7 cells to tamoxifen treatments.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3100.
Oncological Outcome and Patient's Satisfaction of Skin-Sparing Mastectomy and Immediate Breast Reconstruction: A Prospective Observational Study.
Authors: Anderson A. , Burgoyne G. , Mokbel K.
Published: December 2010

INTRODUCTION: The management of early breast cancer with skin-sparing mastectomy (SSM) and immediate breast reconstruction (IBR) is not based on evidence from randomised controlled trials. The purpose of this study is to evaluate the oncological safety, post-operative morbidity and patients' satisfaction with SSM and IBR using the latissimus dorsi (LD) myocutaneous flap and/or breast prosthesis. METHODS: One hundred and twenty five consecutive women underwent 137 SSMs with IBR (12 bilateral), using the LD flap plus implant (n=85) or implant alone (n=42), indications included breast cancer (n=130)and prophylaxis (n=7). Most tumours (99.2%) were Tis, T1, or T2 and only one tumour was T3 stage. Nipple reconstruction was performed in 69 patients, using a small local flap technique (n=61), nipple sharing (n=6), free skin graft (n=1) or Monocryl mesh (n=1). Thirty patients underwent contra-lateral surgery in order to optimise symmetry, including 19 augmentations and 11 mastopexy/reduction mammoplasties. Patient satisfaction with the outcome of surgery was assessed on a linear visual analogue scale ranging from 0 (not satisfied) to 10 (most satisfied). RESULTS: There was no local recurrence (LR) after a mean follow-up of 33.2 months (range=3-98 months). Overall survival was 99.2%, seven patients developed distant disease and one patient died of metastatic breast cancer. No case of partial or total LD flap loss was observed. Morbidities included infection, requiring implant removal in two patients and one patient developed marginal ischaemia of the skin envelope. Significant capsule formation, requiring capsulotomy, was observed in 87% of patients who had either PMR or prior RT compared with 13% for those who did not have RT. Eighty two (65.6%) of 125 patients completed the questionnaire with a median satisfaction scores of 9 (range=5-10). CONCLUSION: SSM with IBR is associated with low morbidity, high levels of patient satisfaction and is oncologically safe for T(is), T1 and T2 tumours without extensive skin involvement.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3113.
Adherence of Adjuvant Hormonal Therapies in Post-Menopausal Hormone Receptor Positive (HR+) Early Stage Breast Cancer: A Population Based Study from British Columbia.
Authors: Chan A. , Speers C. , O'Reilly S. , Pickering R. , Chia S. , Chia S.
Published: December 2010

Background: Adjuvant hormonal therapies for early-stage breast cancer significantly reduce the risk of recurrence, incidence of contralateral breast cancer and death from breast cancer. Optimal compliance to prescribed therapies is associated with improved patient outcomes. However, non-adherence to adjuvant tamoxifen and aromatase inhibitors (AIs) has been reported to range from 17-49% and 19-31% respectively.Objective: To evaluate medication adherence for a large population of post-menopausal women with HR+ early stage breast cancer that were prescribed initial adjuvant hormonal therapies in a publicly funded health care system, and to assess for predictive factors associated with higher rates of non-adherence.Methods: A retrospective cohort of post-menopausal patients diagnosed with HR+ stage I-III breast cancers referred to the BCCA between 2005-2008 whom were prescribed initial adjuvant hormonal therapies (either tamoxifen or an AI) were identified using the British Columbia (BC) Breast Cancer Outcomes Unit database. Cases were matched with the provincial BCCA pharmacy data repository to evaluate patterns of prescription filling. Factors including age, stage, tumor characteristics, use of chemotherapy, hormonal agent prescribed, and prescribing physician were pre-identified as potential factors predicting for non-adherence. Non-adherence was defined as less than 80% of days covered with a prescription.Results: A total of 4,592 patients were prescribed adjuvant hormonal therapies through the BCCA from 2005-2008. 2,414 patients were available for analysis after applying pre-defined inclusion criteria. Overall non-adherence rate was 40%, with non-adherence to tamoxifen and aromatase inhibitors at 42% and 37% respectively. The non-adherence cohort were older, had smaller tumor size, less nodal involvement, lower grade and lower rate of initial chemotherapy (all p<0.001). Non-adherence rates specific to individual physician prescribers ranged from 16% to 67% (p<0.001), and non-adherence rates between specialist provider groups were 34% among medical oncologists compared with 47% in radiation oncologists (p<0.001).Conclusion: Overall non-adherence to adjuvant tamoxifen and AIs in this large population of postmenopausal women with HR+ positive early stage breast cancer was 40%. This likely represents a true reflection of both non-adherence and multiple factors associated with non-adherence given the population size, public health care setting and follow-up strategies. The non-adherent cohort may be the group that is most likely to benefit from hormonal therapy (lower tumor grade) and require hormonal therapy (less adjuvant chemotherapy). Future directions should include interventions directed at physicians in addition to patients given the discrepancy in non-adherence rates among prescribers.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 36.
CYP-2C19*2 Predicts Favorable Outcome of Tamoxifen Treatment for Advanced Breast Cancer.
Authors: Berns P. , Kok M. , Sweep F. , Look M. , Seynaeve C. , Lindemans J. , vantVeer L. , Span P. , Sleijfer S. , Foekens J. , Linn S. , van Schaik R.
Published: December 2010

Tamoxifen is metabolised by cytochrome P450 (CYP) enzymes to active metabolites. CYP2D6 and CYP2C19 genotypes have been reported to be associated with therapy outcome of adjuvant tamoxifen for breast cancer. Effects, however, were inconsistent and no data for advanced disease is available.We studied the association of functional polymorphisms in CYP2C19 and CYP2D6 with outcome of tamoxifen for advanced breast cancer.This multicenter study was performed on genomic DNA of 499 estrogen receptor (ER)-positive, retrospectively collected, primary breast tumor specimens of patients treated with first-line tamoxifen therapy for advanced disease.Primary endpoint was the time to treatment failure (TTF). Genomic DNA was analysed with Taqman allele-discrimination assays.A pooled analysis of three independent patient cohorts showed a longer TTF for CYP2C19*2 carriers, encoding lower enzymatic activity, compared to non-carriers (Hazard ratio (HR) (95% Confidence Interval (CI)): 0.71 (0.57-0.90), p=0.004). Neither the ultra-active CYP2C19*17 nor the inactive CYP2D6*4 allele were associated with TTF.In a pooled multivariable analysis, stratified for centre and time between primary diagnosis and occurrence of metastases, corrected for menopausal status at treatment start, adjuvant chemotherapy and CYP2D6*4 status, CYP2C19*2 was independently associated with TTF (HR (95% CI): 0.73 (0.58-0.91), p=0.007).CYP2D6*4 and CYP2C19*2 gene status were not prognostic for breast cancer outcome.In conclusion, CYP2C19*2 is associated with a longer time to treatment failure in breast cancer patients treated with tamoxifen for advanced disease.Our finding on the involvement of CYP2C19 in tamoxifen metabolism opens new avenues for further treatment individualisation and new management strategies.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4036.
Outcome Prediction in Node-Negative Breast Cancer Based on ASCO-Recommended Biomarkers uPA/PAI-1 Using the Final 10-Year Analysis of the Randomized Multicenter Chemo N0 Trial Compared to Adjuvant Online™.
Authors: Harbeck N. , Meisner C. , Ravdin P. , Kates R. , Friedel C. , Schmidt M. , Untch M. , Lisboa B. , Jaenicke F. , Schmitt M. , Thomssen C. ,   on Behalf of Chemo N0 Study Group
Published: December 2010

Background: Based on interim analysis of Chemo N0, the first prospective multicenter randomized clinical trial using biomarkers uPA/PAI-1 for risk stratification and chemotherapy selection in N0 breast cancer, uPA/PAI-1 are now recommended for routine use by ASCO and AGO guidelines. Final 10-year follow-up of Chemo N0 has validated the clinically relevant long-term prognostic and predictive impact of uPA/PAI-1 in N0 breast cancer. To quantify the clinical utility of this impact, outcomes in subgroups defined by these biomarkers were compared to predictions of Adjuvant Online™, the leading validated tool based on established clinical factors. Methods: In Chemo N0, patients (n=647, 1993-98) were prospectively stratified according to uPA/PAI-1: High-risk patients were randomized (6x CMF vs. observation), low-risk patients observed. Retrospectively, we divided recruited patients into two groups (chemotherapy vs. no adjuvant therapy) and stratified using uPA/PAI-1 (low vs. high). Individual 10-year OS was calculated by www.adjuvantonline.org (Version 7.0); these estimated values were compared to the observed Chemo N0 10-year OS. Results: 383/647 patients have complete 10-year follow-up data. Median 10-year OS estimated by Adjuvant Online™ was 80.5% taking into account administered adjuvant therapy; 10-year Chemo N0 follow-up revealed observed 10-year OS of 74.7% (97/383 died). 77.8% (298/383) did not receive chemotherapy: In high-risk, untreated patients (n=137), 10-year OS was 72.3% vs. estimated 81.1%. In CMF-treated patients (all high-risk, n=85), observed OS was 61.2% vs. estimated 76.4%. Conclusions: For the first time, risk assessment by novel biomarkers is compared to that by Adjuvant Online™ in final data from a randomized prospective clinical trial. In patients with high uPA/PAI-1, the individual 10-year risk calculated by Adjuvant Online™ seems to be underestimated compared to observed patient outcome. Tumor-biological information provided by validated biomarkers thus has the potential of enhancing epidemiology-based risk estimation using only established factors.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4038.
Prognostic and Predictive Impact of Intrinsic Biological Classification by Immunohistochemistry (IHC) and QPCR for Adjuvant Tamoxifen in Pre-Menopausal Breast Cancer: Results from the NCIC CTG MA.12 Trial.
Authors: Chia S. , Ung K. , Bramwell V. , Tu D. , Perou C. , Ellis M. , Bernard P. , Vickery T. , Mardis E. , Cheang M. , Pritchard K. , Shepherd L. , Nielsen T.
Published: December 2010

Background: Aside from the estrogen receptor (ER), there is no other validated predictive biomarker for the magnitude of benefit from tamoxifen. Gene expression profiling has clearly demonstrated that breast cancer is a heterogeneous disease, and has re-classified breast cancer into intrinsic subtypes. We have utilized material from a prospective randomized trial of tamoxifen versus placebo in pre-menopausal women with primary breast cancer who have completed adjuvant chemotherapy (NCIC CTG MA.12 Trial) in order to evaluate the prognostic and predictive significance of intrinsic subtypes as classified by both IHC and qPCR.Methods: A tissue microarray (TMA) was constructed from 492/672 (72%) of the study population. A panel of six IHC antibodies (ER, PR, HER2, EGFR, CK 5/6 and Ki67) was utilized with established cut-offs to define the intrinsic subtypes of luminal A, luminal B, HER-2 and basal. Total RNA from 403/672 (60%) patients was sufficient for intrinsic subtyping with a 50 gene predictor (PAM50) by qPCR. In 354 cases intrinsic subtyping was performed by both methods.Results: There were no significant differences between the initial study population and the TMA series in baseline characteristics. Within the TMA series 39% (n=190) were classified as luminal A, 31% luminal B (n=143) [20% by Ki67 and 11% by HER2], 7% HER2-enriched and 17% basal-like by IHC. Intrinsic subtypes were prognostic with luminal A (5 year 93% OS) having the best outcome and basal-like (5 year 71% OS) the worst (p=0.0086 Wilcoxon). Tamoxifen appeared to benefit the luminal B cancers most (5 year DFS HR 0.67; 95% CI 0.39-1.16: p=0.077) when compared to placebo, however no subtype, nor ER status alone, predicted benefit of tamoxifen in this correlative study. Data for concordance for subtyping by IHC and qPCR as well as prognostic/predictive impact by qPCR subtyping will be presented.Conclusions: Intrinsic biological classification of breast cancer is important for prognosis and may have predictive value for relative benefit to tamoxifen. Further validation of these results are required.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4056.
High Frequency of BRCA1 Founder Mutations in the Bahamas.
Authors: Donenberg T. , Lunn J. , Turnquest T. , Curling D. , Krill-Jackson E. , Royer R. , Narod S. , Hurley J.
Published: December 2010

The frequency of mutations in the BRCA1 and BRCA2 genes differs among ethnic groups, due to regional founder effects. The Bahamas is an island nation of 305,000 people, with a complex history of immigration from the 1600s-1800s including English, Americans and African slaves. An initial survey by our group demonstrated that 48% of breast cancers in the Bahamas are diagnosed in women under 50 suggesting an inherited cause for many. In a follow up study, we identified four distinct BRCA1 mutations in 9 of 19 high risk Bahamian breast and ovarian cancer families (47.36%). A fifth mutation has been previously published in a Bahamian family and is a confirmed African founder mutation. In the current study, we sought to estimate the prevalence of these mutations among unselected breast and ovarian cancer patients from the Bahamas. We have enrolled 135 unrelated women with breast (n = 133) or ovarian cancer (n=2) attending public and private clinics in the Bahamas and Miami. A detailed family history was obtained from each patient and a saliva sample was obtained for DNA analysis. DNA samples were tested by mutation specific assay for the presence of five BRCA1 mutations (IVS13+1G>A, M1775R, IVS16+6A>C, 4730insG and 943ins10). Twenty-three mutations were detected, representing 17% mutation prevalence in this population, including IVS13+1G>A (14 times), IVS16+6A>C (two times), M1775R (three times), 4730insG (three times) and 943ins10 (once). This reflects a very high rate of genetic breast cancer in this population with a strong founder effect. This important finding raises the possibility of developing an inexpensive genetic screen for inherited susceptibility to breast cancer in the Bahamas and the need to mount an effective cancer prevention strategy for this population at high risk.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4078.
Breast Cancer in Young Women: The University of New Mexico Cancer Center (UNMCC) Experience.
Authors: Movva S. , Ballinger L. , Saiki J. , Royce M.
Published: December 2010

Background: While only a small proportion of breast cancer is attributable to hereditary susceptibility, identifying high-risk individuals is essential for appropriate medical management. Furthermore, identifying individuals with inherited breast cancers have significant impact on both patient and their family. Beyond early age of onset, family history of multiple cancers may warrant a referral to cancer genetics professional. However, in a busy oncology practice, documentation of a full family history can be time consuming and referral opportunities for genetic counseling may be missed. In this study, we evaluated the strength of family history documentation in breast cancer patients' charts, and whether or not appropriate referrals to the Hereditary Cancer Assessment Program (HCAP) were made. Racial differences in these referral patterns were also assessed.Materials and Methods: All charts of patients last known to be living as of 03/29/06 per the UNMCC Tumor Registry with an invasive breast cancer who were 40 years old or younger at the time of diagnosis were reviewed. Baseline data included patient age at diagnosis, self-reported ethnicity, histology, bilaterality and cancer status. The presence or absence of family history of breast and other cancers, and referral to the HCAP was documented. Descriptive statistics were performed on baseline data. Correlative analyses were conducted to note any racial differences in referral to HCAP.Results: A total of 211 women met inclusion criteria. Patients in the Tumor Registry were seen at diagnosis at UNMCC from 01/01/67 through 12/31/04. Mean age was 35. Racial distribution was similar to that of the New Mexican population: 44% Caucasian, 41% Hispanic, 10% Native American (NA) and 3% African American. Predominant histology was infiltrating ductal carcinoma (79%); 10% of women had a second breast primary. 63% of women had a positive family history of cancer; however, family history was not recorded in 17%. After HCAP was established, 109 women were eligible for referral, yet 68 (62%) of women had not been referred for genetic counseling. Only 39% of Caucasian, 40% of Hispanic and 34% of NA eligible women were referred.Discussion: Women under the age of 40 at time of breast cancer diagnosis are more likely to have a hereditary cancer syndrome. In our population, 17% of women had no documentation of family history, and almost 70% were never referred for hereditary counseling. There was no difference in referral patterns among different racial/ethnic backgrounds. On the basis of this review, quality improvement initiatives were undertaken to improve referral patters of young women with breast cancer for genetic counseling and potential genetic testing.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4079.
Study of Neurobehavioral Symptoms and Impairments in Breast Cancer Patients Receiving Adjuvant Aromatase Inhibitor Therapy.
Authors: Weaver J. , Stark S. , Stark S. , Shahverdi K. , Jeter S. , Zorzi J. , Skolasky, Jr R. , Skolasky, Jr R. , Andrejczuk M. , Stearns V. , Gordon B. , Gordon B.
Published: December 2010

Background: Whether treatment with aromatase inhibitors (AI) may be associated with the development of cognitive or other mental impairments is under debate. Few studies have carefully assessed AI-associated changes in cognitive function, and none have assessed differences between the three third-generation AIs – anastrozole, letrozole, and exemestane. We initiated a prospective clinical trial to compare baseline and 1-year change in neurophysiological testing in women initiating adjuvant AI.Patients and Methods: Women with a hormone receptor-positive stage 0-III breast cancer who were about to begin AI treatment were eligible for enrollment. We compared intra-individual neurophysiological testing results at baseline (Session I) and following one year of AI (Session II). Cognitive/behavioral assessment included standardized tests sensitive to 8 neuropsychological domains: General Intelligence, Attention, Perceptual-motor Performance, Working Memory, Visual Long-term Memory, Verbal Long-term Memory, Language, and Executive Functioning. Scoring was based upon age- and education-adjusted normative data. In addition, participants completed several subjective reports of cognitive, physical, and emotional functioning.Results: To date, 53 subjects enrolled in Session I, and 30 completed Session II. Analysis of the 30 women who completed both sessions revealed statistically significant differences (with the significance level set at p=0.05, test-wise), including: impairment from Session I to Session II on the PASAT Trial I (p=0.005) and improvement from Session I to Session II on the following tests: FAS Total (p<0.001); Animal Naming (p=0.025); RAVLT I-V, B, Delay, and Immediate (p<0.001 for all); RAVLT 5-1 (p=0.017); RAVLT % (p=0.022); Logical Memory I (p=0.005) and II (p<0.001); WMS-Faces I & II (p<0.001 for both); WAIS-Picture Completion (p=0.027); and WAIS-Vocabulary (p<0.001).Discussion: Only a few studies have examined the effect of AI treatment on cognitive functioning. Findings from the present study suggest that, following the administration of AI for 1 year, women as a group appear to exhibit impairments in attention (as evidenced by PASAT performance) and possibly in executive functioning. However, there was also improved performance in the areas of language, verbal long-term memory, and visual long-term memory. These preliminary results suggest a need to be sensitive to the possibility that AI treatment may have mixed effects on cognitive and related behavioral functions.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4084.
A Randomised Study Comparing the Effects of Adjuvant Anastrozole (A), Letrozole (L) and Exemestane (E) on Lipid Metabolism.
Authors: McCaig F. , Renshaw L. , Williams L. , Young O. , Murray J. , Macaskill E. , McHugh M. , Riermersma R. , Evans D. , Dixon J.
Published: December 2010

Background:Aromatase inhibitors (AIs) reduce circulating oestrogen which may have a detrimental effect on lipid metabolism and subsequently ↑ cardiovascular risk. This study compares the effects of adjuvant A, L and E on lipid metabolism.Patients and Methods:This was an open, randomised pharmacodynamic study. Plasma lipids were measured in 120 postmenopausal women with invasive ER +ve breast cancer. As part of their adjuvant hormone therapy, patients were randomized to receive either:• 4 months of A or• 4 months of L or• 4 months of EFasting blood and urine samples were collected at the same time of day on each of (a) the day of entry, (b) after 3 months and (c) after 4 months. Patients were then switched to tamoxifen (T) and further samples collected after 12 months.• Triglycerides, cholesterol, ApoB and cLDL were measured.↑ levels are associated with ↑ cardiovascular risk.• ApoA-1 and HDL were also measured.↑ levels are associated with ↓ cardiovascular risk.Analyses were performed using repeated measures or analysis of covariance.ResultsDifferences between A vs L vs ETriglycerides E significantly ↓ triglycerides. There was a borderline significant difference between the drugs (p=0.055).Cholesterol E significantly ↓ cholesterol (p=0.03).ApoB No significant changes were detected.cLDL No significant changes were detected.ApoA-1 There were no significant differences detected between A or L although the fall with E was less but not significantly different to A or L (p=0.08).HDL E significantly ↓ HDL (p=0.008).Differences between steroidal vs non-steroidal AIsTriglyceride and ApoA-1 levels fell significantly more with E compared to the non-steroidal A+L (p=0.02, p=0.045 respectively).Effects of tamoxifenChanges from baseline after treatment on AIs and subsequent treatment with TFollowing T there was no evidence to suggest that the changes from baseline were influenced by the type of AI that patients received.Changes from end of treatment on AIs and subsequent treatment with TT increased HDL by a statistically significant greater amount following E than it did after A or L (p=0.009). From the end of treatment with AIs, T produced significant rises in triglyceride (p=0.0001), HDL (p=0.006) and ApoA1 (p=0.0003), and significant falls in cholesterol (p=0.03) and cLDL (p<0.0001).Conclusions:There were no significant differences between letrozole, anastrozole and exemestane and their effects on cholesterol, HDL, cLDL or ApoB.There was a significant difference between steroidal and non-steroidal in their effect on triglycerides and ApoA1.Tamoxifen had significant effects on lipids lowering cholesterol and cLDL and increasing triglycerides HDL and ApoA-1.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4086.
Letrozole in Combination with Trastuzumab Is Superior to Letrozole Monotherapy as First Line Treatment in Patients with Hormone-Receptor-Positive, HER2- Positive Metastatic Breast Cancer (MBC) – Results of the eLEcTRA Trial.
Authors: Huober J. , Fasching P. , Paepke S. , Kubista E. , Barsoum M. , Wallwiener D. , Harbeck N.
Published: December 2010

Background: Letrozole (LET) and trastuzumab (TRA) are established agents for the treatment of hormone-receptor (HR) positive metastatic breast cancer (MBC) patients and HER2 positive disease, respectively. The “eLEcTRA” trial was designed to compare the efficacy and safety of LET combined with TRA to LET alone in patients that are both HER2 and HR positive. Furthermore, LET alone was compared in patients with HER2 and HR positive disease vs. those with HER2 negative, HR positive tumors.Methods: In this multicenter trial, 92 pts from 32 sites in 7 countries were enrolled from 2003 to 2007. Initially, enrollment of 370 pts was planned, however, due to slow recruitment the trial was prematurely closed in 2007. Patients with HER2 and HR positive MBC were randomized to either LET alone (Arm A, n=31) or LET + TRA (Arm B, n=26) as first-line treatment. In addition, 35 patients with HER2 negative and HR positive tumors were assigned to receive LET alone as first-line treatment (Arm C). Tumor response assessments were based on RECIST. Primary endpoint was time to progression (TTP), secondary endpoints were overall response rate (ORR) and clinical benefit rate (CBR).Results: Median age in the three arms was 61 (arm A), 61,5 (arm B), and 70 years (arm C), respectively. Median TTP in the LET alone arm (A) was 3.3 months compared to 14.1 months in the LET + TRA combination arm (B) (hazard ratio=0.67; p=0.23) and 15.2 months in arm C (hazard ratio=0.71; p=0.03). CBR was 39% for arm A compared to 65% in arm B (odds ratio 3.15, CI 1.07-9.26) and 77% in arm C (odds ratio 5.34, CI 1.83-15.58), respectively. ORRs were 13% for arm A, 27% for arm B, and 11% for arm C.LVEF as cardiac safety parameter showed no change from baseline to the minimum value during the treatment for arms A and C and a slight decrease by 5% for arm B.The incidence of other cardiac adverse events was comparable in all arms (10%, 8%, and 9%). Gastrointestinal disorders or musculoskeletal and connective tissue disorders were slightly more frequent for patients receiving LET and TRA (arm B).Conclusion: The results of the eLEcTRA trial show that the combination of letrozole and trastuzumab can be safely administered and is superior to letrozole alone as first-line therapy in patients with HER2 and HR positive MBC. Our results also confirm earlier evidence that aromatase-inhibitor therapy alone is only associated with a rather short TTP in HER2 and HR positive MBC. In contrast, outcome in letrozole-treated patients with HER2 negative HR positive tumors is significantly better compared to that associated with tumors with both HR and HER2 expression.(Trial was sponsored by Novartis Pharmaceuticals)

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4094.
A Retrospective Analysis of Primary Tumour Histology and Survival in Breast Cancer Patients Developing Symptomatic Brain Metastases Treated with Whole Brain Radiotherapy (WBRT) at Mount Vernon Cancer Centre (MVCC).
Authors: Miller R. , Assoku M. , Assoku M. , Krell D. , Sasieni P. , Mulholland P. , Mulholland P.
Published: December 2010

Background: The purpose of this study was to determine the influence of primary tumour histology on survival following WBRT for brain metastases in patients with breast cancer.Methods: From treatment records we identified 294 patients with brain metastases and a diagnosis of primary breast cancer who were treated with WBRT at MVCC from January 2000 until December 2008. We obtained information from case notes and original pathology reports regarding TNM staging and receptor status: Estrogen (ER), progesterone (PR) and human epidermal growth factor receptor-2 (HER-2). Dates of diagnosis and death were sourced from records at MVCC, the Thames Cancer Registry and GP practices.Results: We obtained receptor status, TNM staging and dates of death for 294 patients; 19 were excluded as date of death could not be verified. The dates of primary diagnosis for the study cohort ranged from 1983 to 2008. The median age at diagnosis was 52 (range 24-81, interquartile range 42-62).Analysis of age at primary diagnosis expressed as < 50 or ≥ 50 demonstrated improved survival in the younger age group (HR 0.64 95% CI 0.50-0.83). Time to brain relapse amongst patients receiving WBRT was not related to initial tumour size (p=0.8) but was related to the number of affected nodes (reduced by 9 months per node, p=0.038) and women with (non-brain) metastatic disease at diagnosis had WBRT on average 2.4 years earlier than those that did not (p=0.004). TNM staging did not affect post WBRT survival. After adjusting for age at diagnosis (<,≥50), post WBRT survival was not affected by age at treatment. Controlling for the influence of age at diagnosis, Cox regression analysis of survival post WBRT demonstrated improved survival for ER positive patients (HR 0.66 95% CI 0.49-0.90). Survival post WBRT was not significantly influenced by HER-2 (HR 0.81 95% CI 0.55-1.19) or PR (HR 0.91 95% C.I. 0.63-1.33) status. Patients who experience late brain relapse (> 4 years post diagnosis) have slightly better survival post WBRT (HR 0.77, p=0.054). ER positive patients in this study developed brain metastases on average 1.8 years later than ER negative patients (95% CI 0.9-2.8).Conclusions: In this cohort ER positive patients who relapse in the brain do so later and live longer following WBRT (figure 1). Our data suggests that HER-2 status has little effect on post WBRT survival.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4110.
Evidence for Unique Mechanisms of Estrogen Receptor Degradation Elicited by Estradiol and ICI 182,780 (Fulvestrant).
Authors: Casa A. , Casa A. , Lazard Z. , Thorne C. , Ouspenskia M. , Zhang P. , Lee A. , Lee A. , Lee A.
Published: December 2010

Selective estrogen receptor down-regulators (SERDs), such as ICI 182780 (Fulvestrant), comprise a class of drugs that has been developed to inhibit estrogen receptor alpha (ER) activity in breast cancer. ICI is a pure antagonist that competitively binds to the ligand-binding domain of ER. The binding of ICI is thought to reduce the receptor's half-life by increasing protein turnover. However, the exact mechanism of ICI action, including whether or not receptor degradation is actually required for its antiestrogenic action, is currently unknown. Our laboratory has shown that a cytoplasmic ER mutant (ERΔNLS) lacking a nuclear localization sequence (NLS) is completely resistant to ICI-mediated degradation in both MCF-7 breast cancer cells and their ER-negative derivatives, C4-12 cells. Immunofluorescence and confocal microscopy were performed to assess localization of all ER proteins. These cells were also treated for different lengths of time with varying concentrations of both estradiol (E2) and ICI. Immunoblotting was performed to determine levels of ER protein. A competitive radioligand binding assay was also conducted to assess the ligand-binding capability of the ERΔNLS mutant receptor. Immunofluorescence and confocal imaging of stably transfected C4-12 cells has confirmed distinct subcellular localization of each ER protein. Wild-type ER localizes mainly to the nucleus, while ERΔNLS is cytoplasmic. As expected, treatment of either wild-type MCF-7 cells or C4-12 cells expressing wild-type ER with E2 or ICI caused degradation of ER protein. Treatment of MCF-7/ ERΔNLS or C4-12/ ERΔNLS cells with E2 caused degradation of ERΔNLS protein. In stark contrast, increasing concentrations of ICI failed to cause degradation of ERΔNLS. Furthermore, experiments performed in the presence of cycloheximide have shown that ICI does not modulate ERΔNLS half-life. The inability of ICI to degrade ERΔNLS is not due to an inability of ERΔNLS to bind ligand, since results from competitive radioligand binding assays show that the affinity of ERΔNLS for both E2 and ICI is equal to the affinity of wild-type ER for both ligands. We have recently cloned the SV40-NLS onto ERΔNLS, and confocal microscopy has confirmed that the SV40-NLS is sufficient to force ERΔNLS into the nucleus. I am currently using this construct to determine if it is the NLS domain itself or merely subcellular localization of ER that is important for ICI-mediated degradation. In conclusion, ER is a critical marker for response to antiestrogen therapy. Treatment with ICI is not without its shortcomings. A better understanding of the mechanism by which ICI degrades ER may lead to the development of better antiestrogen therapies to inhibit ER action with less toxicity and greater specificity.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4137.