bluuebunny/crossref_metadata_2025 huggingface dataset:
The Incidence of Bone Metastases and Skeletal-Related Events in Breast Cancer Patients: A Population-Based Cohort Study in Denmark (1999 – 2007).
Authors: Yong M. , Jensen A. , Jacobsen J. , Nørgaard M. , Fryzek J. , Sørensen H.
Published: December 2010

Background Breast cancer (BrCa) is the most commonly diagnosed cancer among women in the industrialized world. More than half of women presenting with metastatic BrCa develop bone metastases. Bone metastases increase the risk of skeletal-related events (SREs), defined as radiation to bone, pathologic fractures, spinal cord compression, bone surgery, or altered antineoplastic therapy to treat bone pain. Both bone metastases and SREs are associated with unfavorable prognosis and greatly affect quality of life. To date, the epidemiology of the subgroup of BrCa patients who develop bone metastases and/or SREs has not been well-characterized. Our objective was to estimate the one- and five-year incidence of bone metastases and SREs in a large population cohort of newly-diagnosed BrCa patients in Denmark (population ∼ 5.4 million inhabitants). Methods We identified women diagnosed with BrCa (International Classification of Diseases, 10th Revision (ICD-10) code C50.x.) from January 1, 1999 through December 31, 2007, with follow-up through April 2008. We retrieved this data from Denmark's National Registry of Patients (NRP), which includes records from all Danish hospitals. We also identified bone metastases (ICD-10 code C79.5) and recorded SREs. The Kaplan-Meier method was used to estimate time to bone metastases and time to first SRE. We also calculated 1- and 5-year incidence rates (IR) of bone metastases and first SRE in newly-diagnosed BrCa patients. Results We identified 35,941 BrCa patients from the NRP. The median age at diagnosis was 62 years (range, 18-104 years). A total of 1,494 (4%) patients developed bone metastases during follow-up, and of these, 712 developed an SRE. The distribution of SREs by type were 394 (55%) with radiation to the bone, 133 (19%) with pathological or osteoporotic fracture, 42 (6%) with bone surgery, and 143 (20%) with spinal cord compression. The 1-year IR of bone metastases was 13.7 [95% confidence interval (CI): 12.5-15.0] per 1000 person-years (P-Y). The 1-year IR of SREs among patients with bone metastases was 55 times that of the 1-year IR of bone metastases in BrCa patients at 759.2 (95% CI: 662.0-870.5) per 1000 P-Y. After five years of follow-up, the incidence curves plateaued at approximately 4% and 48% for bone metastases and SREs, respectively (Figures 1 and 2). Conclusions Among breast cancer patients with bone metastases, there was a strong tendency towards development of SREs within a year of bone metastases diagnosis; however, this phenomenon stabilized beyond 5 years of bone metastases diagnosis.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2051.
Patient Characteristics Associated with Use of Monoclonal Antibody Treatment in Women with Metastatic Breast Cancer: A Population-Based Analysis.
Authors: McNally D. , Zuckerman I. , Pandya N. , Seal B. , Mullins C.
Published: December 2010

Introduction: Monoclonal antibodies (MoATB) were FDA approved for the treatment of patients with breast cancer (BrCA) whose tumors over expressed the human epidermal growth factor receptor 2 (HER2) in 1998. We sought to determine if certain patient characteristics and co-morbidities influenced MoATB use in a population-based practice setting of elderly women with metastatic BrCA. Methods: We identified female Medicare beneficiaries aged 66+ years diagnosed with incident metastatic BrCA without prior history for any cancer between 1999 and 2005 in the Surveillance, Epidemiology and End Results cancer registries (SEER). Charlson Co-morbidity index (CCI) and separate conditions within the index were created using linked Medicare claims in the year prior to the BrCA diagnosis. We identified both oral and infused chemotherapy (CH) from the Medicare claims from 1999 to 2006. Patients were categorized into three groups: no CH, MoATB+/-CH, and CH w/out MoATB. We performed bivariate statistics to compare the patient characteristics and comorbidities between the three groups, and the treatments groups only. Results: There were 3,820 women with metastatic BrCA, mean age 77 (SD 7.3) years, 81% were white race, 29% were married and 91% lived in an urban setting. 67% of these women (n=2,562) received no CH, 26% received CH w/out MoATB (n=994) and 7% received MoATB+/-CH (n=264). Overall the CCI was lower for women receiving either treatment as compared to no chemotherapy and between treatment groups for the young old (66-75 years) but not those aged 80+ years. The prevalence of congestive heart failure (CHF) and cerebrovascular disease was significantly lower in women receiving MoATB +/-CH, as compared to only CH, and also lower in both compared to no CH (n=2,462). Few women presenting with COPD or dementia were likely to be treated with either CH and/or MoATB compared to No CH. Other co-morbidity conditions within the CCI were not statistically different between the groups or the cell numbers were too small to analyze. Conclusion: MoATB use in the treatment of metastatic breast cancer steadily increased from 5% in 1999 to 23% in 2004. Use in 2005 was slightly lower but will be recalculated once the 2007 claims are available. In 2008, FDA released a black box warning for trastuzumab, the most frequently prescribed MoATB for BrCA, regarding the potential for the development of cardiomyopathy. Our results suggest that co-morbidities in particular CHF and cerebrovascular disease may influence the decision to use MoATB. Further research is necessary to examine the relationship between co-morbidities and the use of MoATB in the treatment of metastatic breast cancer.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2057.
Poor Progress in Breast Cancer Control in the Elderly in the UK.
Authors: Moeller H. , Moran A.
Published: December 2010

Background:In 1998 England introduced a national cancer target, to reduce cancer mortality in the under 75 year olds from 1996 to 2010 by 20%. This might potentially lead to inequalities between younger and elderly cancer patients. In this study we assessed progress in breast cancer control in the elderly in the UK by comparing cancer mortality rates in the elderly with younger age groups in the UK and by comparing the elderly in the UK with other similar countries.Material and Methods:Mortality data for the UK, USA, Northern Europe (Denmark, Finland, Iceland, Sweden and Norway) and Western Europe (Germany, Netherlands, Luxembourg, Austria, France Switzerland) was obtained from the WHO mortality database. Age specific cancer mortality rates for the age bands 55-64, 65-74, 75-84 and 85 plus were calculated for the different geographies for the three year periods 1995-97 and 2003-05. Change in the differences between the age bands was assessed as the ratio between the youngest age group 55-64, which was set to 1, and the older age groups. The number of excess deaths in the UK was calculated by applying the lowest rate observed in each age band to the UK population, assuming that the UK could achieve the same rate.Results:Compared to other countries the UK had the highest breast cancer mortality rates in all age bands in 1995-07 and 2003-05 and rates were statistically significantly higher in 2003-05 at the 95% Confidence interval limit. In the younger age groups (55-64 and 65-74) the UK had the biggest decrease from 1995-97 to 2003-05 and is decreasing the gap to the other countries. In contrast the UK was the only geography with an increase in mortality rates in the over 85 year olds and only ranked second after the USA in the 75 to 84 year olds. If the UK had the same mortality rates as the lowest observed in each age band 681 breast cancer deaths could be prevented in the 55 to 74 year olds and 1590 in the over 75 year olds each year. The UK also had the greatest increase in the ratio between the 55-64 year olds and 85plus year olds, with and increase of a 100% from 3.5 to 4.5 from 1995-97 to 2003-05. The USA had the lowest rates in each age group.Conclusion:Little progress has been made in decreasing breast cancer mortality rates in the elderly in the UK. The gap in breast cancer mortality in the elderly compared to the younger age groups as well as the other countries is increasing. The gap with other countries will be closed only if there is a marked decrease in death rates in the over 75s. Future analysis should also look at the causes of higher mortality in the UK, taking the USA as the gold standard.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2059.
Pregnancy after Breast Cancer in Young Patients Does Not Worsen the Outcome of Breast Cancer.
Authors: Cordoba O. , Sabadell M. , Rubio I. , Cortadellas T. , Xercavins J.
Published: December 2010

Background: Pregnancy after breast cancer may worsen the outcome of breast cancer due to associated hormonal changes, especially among young patients. However, prior studies have failed to detect this effect, which may be explained by the selection of patients of older age and those that gave birth to term. The aim of this study is to assess the effects of pregnancy on the outcome of breast cancer in young patients.Patients: One hundred twenty three young patients (≤35 years) with invasive breast cancer or ductal carcinoma in situ treated consecutively at our hospital between 1995 and 2005. Pregnancy was discouraged during the first two years, but not specific recommendation was given thereafter.Methods: We compared the prognostic factors, treatment with adjuvant chemotherapy treatment and follow-up between patients with pregnancy after breast cancer (P) and those who have not had subsequent pregnancy (NP).Results: There were 20 patients that get pregnant (16%). Of them, eight (40%) decided to interrupt pregnancy, and twelve (60%) gave birth to the term. The average time between diagnosis of cancer and pregnancy was four years. Several prognostic factors, such as age at diagnostic (median age 31 years old in both groups), histological type (CDI in P81% NP83.2%), clinical stage(P: 0 9.5%, I 38.1%, IIA 42.9%, IIIA 9.58%; NP: 0 7.9%, I 23.8%, IIA 32.7%, IIB 16.8%, IIIA 8.9%, IIIB 5.9%, IV 1%), positive axillary lymph nodes (P: 44.4% NP: 51.7%), histological high grade (P: 52.9% NP: 50.6%) and use of chemotherapy (P:76.2 NP: 89.2%) were similar among pregnant and non-pregnant women with differences who was not stadistical significance. However, use of hormonal treatment were more frequent in patients without later gestation (P: 33.% NP 68% p=0.003). Ductal Carcinoma in situ is more frequent among patients wit pregnancy but the difference is not statistical significant (P: 14% NP 4% p=0.10). Patients with pregnancy had better disease-free interval at 5 years (P95% vs NP62% p = 0.003) and overall 5 years survival(100% vs. 82% p = 0.008).Conclusions: A significant proportion of patients diagnosed of breast cancer at young age get pregnant, many of them unwillingly. Our study shows that pregnancy does not seem to worsen outcome. Patients should be counselling do not discontinuing her pregnancy.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2062.
Epidemiology of Triple Negative Breast Cancer in China.
Authors: Lin Y. , Yin W. , Yan T. , Zhou L. , Di G. , Wu J. , Shen Z. , Shao Z. , Lu J.
Published: December 2010

Background:The classification of tumors based on the gene expression may define intrinsic breast cancer subtypes in which the effect of risk factors could be more obvious. We sought to assess the risk factors for triple negative breast cancer on Chinese population.Methods: A retrospective study of 5761 patients was carried out from a large database of breast cancer patients undergoing surgery between January 1, 1991 and June 31, 2008 in Cancer Hospital, Fudan University, Shanghai, China. Univariate analyses were performed by chi-square test of Student's t test and multivariate analyses by logistic regression.Results: A total of 1108 women were identified as having triple negative breast cancer and were compared with the 4653 women with non-triple negative. Regardless the pathological discrepancy, women with triple negative breast cancers were significantly more likely to be younger age(P=0.001; OR=1.615, 95%CI=1.207-2.160), premenopausal (P = 0.003; OR = 1.570, 95% CI = 1.171-2.106) and parous women (P = 0.001; OR = 1.741, 95% CI = 1.269-2.387).There seems no associations with increasing risk of triple negative breast cancer for breastfeeding (P=0.126), younger age at menarche (P=0.129), first degree family history (P=0.111) and oral contraceptive usage (P=0.251).Conclusion:Based on this large population study in Chinese breast cancer patients, the risk factors for triple negative phenotype may be somewhat different from those for Western women. Therefore, a better knowledge of this issue is warranted due to it may have impact on clinical outcomes and may offer some insight into the process of carcinogenesis and therapeutic efficacy.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2065.
The Prognostic Significance of Functional Limitations among Women with Breast Cancer.
Authors: Braithwaite D. , Santariano W. , Moore D. , Hiatt R. , Esserman L. , Castillo A. , Sternfeld B. , Melisko M. , Caan B.
Published: December 2010

Background:With the aging of the population, functional limitations are a growing burden among women with breast cancer. The prognostic impact of functional status among breast cancer survivors is not well understood.Methods:A total of 2270 women diagnosed with breast cancer between 1997 and 2000, and followed in the prospective cohort study, Life after Cancer Epidemiology (LACE) were included. Information on functional limitations, health behaviors, anthropometric and demographic factors was self-reported by participants at enrollment. Tumor characteristics, treatment and outcomes were ascertained from medical records.Associations between functional limitations and survival from all causes, breast cancer specific causes and competing causes were analyzed with delayed entry Cox proportional hazards regression.Results:Thirty-nine percent of the cohort reported one or more limitations at study entry. Compared to women without functional limitations (n=1,345), those with one or more limitations (n = 857) were proportionately more likely to be elderly, less educated and more obese (all p<.0001). Over a mean follow-up of 7 years, breast cancer survivors with functional limitations had higher overall crude mortality than their counterparts with no limitations [137 (50.9%) versus 132 (49.1%) respectively, p<.0001]. When covariates were taken into account, the presence of functional limitations was associated with deaths from all causes [hazard ratio (HR)=1.39, 95% confidence intervals (CI) 1.06-1.83] and those from competing causes (HR=2.60, 95%CI 1.69-3.98) but not with breast cancer specific deaths (HR=.90, 95%CI .71-1.14).Conclusion:More breast cancer cases with functional limitations die of competing causes than of breast cancer. Interventions aimed at regaining physical function should lead to improvements in life expectancy in this population.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2067.
Apparent Decline in Inflammatory Breast Cancer Incidence in Tunisia Associated with Improved Socioeconomic Conditions.
Authors: Boussen H. , Ben Hassouna J. , Khomsi F. , Dhiab T. , Benna F. , Gamoudi A. , Mourali N. , Hechiche M. , Rahal K. , Levine P.
Published: December 2010

Aim: Numerous publications since the 1970s have reported an apparently high frequency of IBC in Tunisia affecting up to 50% of breast cancer patients. In the past 20 years, 3 complete national population-based cancer registries have provided more precise information about breast cancer (BC) incidence. Moreover, IBC diagnostic criteria moved from the French classification of aggressive or rapidly progressing breast cancer (RPBC) also designated as "pousee evolutive" (PEV) to the current system of the American Joint Committee on Cancer (AJCC). In this study we reviewed a series of publications and recent data from the Tunisian Breast Cancer Registries to evaluate the gradual changes in IBC and non-IBC and relate the findings to improvements in the general economic situation in this country.Methods: All indexed Tunisian publications regarding RPBC and IBC since 1970 were compiled and their data were compared to recent data from the Tunisian Cancer Registries. These findings were compared to reports on changing breast cancer patterns in Tunisia overall.Results: Trends in Tunisian BC were compared to the original report of RPBC from Tunisia's National Cancer Institute, the Institut Salah Azaiz, which noted 340 of 581 (58.5%) consecutive breast cancer patients had RPBC which included 282 (48.5%) PEV 3 patients clinically indistinguishable from IBC in the United States. In 6 subsequent series including 700 to 1400 patients affected by BC published from 1985 to 2008, the relative percentage of IBC patients gradually decreased to 30.3%, 6.2% and 5.7% associated with a concurrent increase in the incidence of breast cancer nationwide. Registry data and hospital-based studies have shown also a progressive decrease in mean clinical tumor size in the past four decades from 60mm to 40mm and a discordant tumor size between private patients and public patients, the latter having significantly larger tumors at diagnosis. This trend, compatible with the early observation of a rural predominance of RPBC and a gradual increase in gross national product supports other etiuologic studies indicating a strong environmental determinant. for IBC.Conclusion: These data support a number of studies indicating that environmental factors, including poorer socioeconomic conditions, prolonged breast feeding, and obesity may be risk factors for IBC, and indicate the importance of environmental factors in the etiology of this disease.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2077.
Factors Associated with Aromatase Inhibitor Use in a Large Cohort of Women Cared for in an Integrated Health Plan.
Authors: Haque R. , Schottinger J. , Fisher A. , Avila C. , Guo A. , Zelt S. , Shi J. , Fong E. , Quinn V.
Published: December 2010

Background: Third generation aromatase inhibitors (AI) have been well tolerated in clinical trials and may have fewer side effects than tamoxifen. While national treatment guidelines recommend AI for postmenopausal women with ER+ tumors, the extent to which women are prescribed AIs in community settings in the U.S., and as front-line or extended therapy, remains unknown. Using data from a large non-profit health plan that serves over 3 million residents in Southern California, we report results examining the characteristics of breast cancer (BCa) survivors who were ever prescribed AIs.Methods: This cross-sectional analysis examined a cohort of 25,577 BCa (in situ and invasive cases) diagnosed from 1996-2006. We collected demographic, tumor, and cancer treatment information from automated health plan databases and SEER-affiliated cancer registry files. We identified patient and clinical factors associated with AI use. P-values (2-sided) were based on the chi-square distribution. Adjusted odds ratios (for age and year at diagnosis) and 95% confidence intervals were estimated using logistic regression.Results: In this cohort, nearly 37% ever used AIs (P<0.0001). Use of AIs increased by year (P<0.0001). Compared to non-Hispanic whites, minority women were less likely prescribed AIs (AOR=0.75 for blacks, 95% CI: 0.69-0.81). Although most women who used AI were first diagnosed with early stage disease (2 cm vs. <1cm). Women with positive lymph nodes had twice the odds of AI use (OR=2.27, 95% CI: 2.13-2.42) than those with negative nodes. Women with ER+ or PR+ lesions were more likely to have ever used AI (P<0.0001) as were those with HER- tumors (AOR=1.67, 95% CI: 1.48-1.89). Women who underwent breast conserving surgery without radiation were 36% less likely to use AI (AOR=0.64 95% CI: 0.59-0.69) than those with radiation. Of the total cohort, nearly 64% received adjuvant treatment. Among the 6716 women who received tamoxifen, about 43% (2918/6716) also used AI. Of note, during the 2005-2006 diagnosis years, the percentage treated with tamoxifen dropped among women ever prescribed AI. Of the 6627 women treated with chemotherapy only, 36% also received AI (2354/6627).Conclusions: Odds of AI use were greater among older women (age 60+), white race, higher stage at diagnosis, worse histology, positive lymph nodes, and those with ER+, PR+, or HER- tumors. However, grade and tumor size did not influence AI use. More work is needed to determine how patterns of AI use alone or following tamoxifen, medication changes, and tumor characteristics at initial diagnosis impact long-term breast cancer recurrence in this diverse group of patients in southern California.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2079.
Population-Based Comparison of CEF and AC/T, Two Adjuvant Chemotherapy 'Standards' for Early Stage Breast Cancer.
Authors: Al-Tourah A. , Woods R. , Norris B. , Speers C. , Kennecke H.
Published: December 2010

Introduction: Anthracyclines and taxanes in adjuvant therapy have improved the outcomes of women with early stage breast cancer. The first analysis of the phase III NCIC-MA21 trial comparing the three 6 month adjuvant regimens CEF, AC followed by q3weekly paclitaxel(AC/T) and dose dense EC followed by paclitaxel (EC/T) revealed inferior Relapse Free Survival for AC/Tversus CEF (HR 1.49[1.12,1.99]) and EC/T (HR1.68 [1.25-2.27]). The purpose of this population based analysis is to evaluate the characteristics and outcome of women with high-risk breast cancer treated with CEF vs q3weekly AC/T.Methods: The British Columbia Breast Cancer Outcomes Unit (BCOU) and Pharmacy databases were used to identify patients with node positive or high-risk node negative breast cancer between years 2000-2004 treated with adjuvant chemotherapy with either CEF or AC/T. Both regimens were available and recommended for high risk breast cancer during the time of the study. Patients with cTx, pTx tumours, previous or synchronous breast cancer and those with with locally advanced/inflammatory breast cancer were excluded. Patient and tumour characteristics were compared across study cohorts.Univariate comparisons of overall survival (OS) and breast cancer specific survival (BCSS) were performed using the Kaplan-Meier method. Propensity score models were used to compare outcomes in the two cohorts, adjusting for differences in prognostic and other treatment variables.Results: Between 2000-2004, 774 (CEF=557, AC/T=217)women with breast cancer met the inclusion criteria. Median follow-up for CEF was 4.7 years and for AC-T was 3.0 years. CEF-treated patients had more LVI (p=0.0001) and node +ve disease (p<0.0001), were younger (p<0.0001), more likely ER+ (p<0.0001), less likely to have grade 3 tumours (p<0.0001) and received higher rates of both hormones (p<0.0001) and radiation therapy to regional nodes (p<0.0001). Univariate analyses showed better outcomes for the CEF-treated cohort for both OS (p=0.0056) and BCSS (p=0.0012). Propensity score models also favoured the CEF cohort with adjusted HR's of 0.47 (95% CI: 0.27, 0.83; p=0.0086) and 0.40 (95% CI: 0.22, 0.71; p=0.0020) for OS and BCSS respectively.Conclusion: Between 2000 and 2004, women in British Columbia treated with adjuvant CEF had higher risk breast cancer than patients who received AC/T. However, CEF-treated patients have better outcomes than those receiving AC/T. Both univariate and adjusted analyses favour the CEF cohort. These population-based outcomes are consistent with the finding of the NCIC-MA21 randomized trial.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2084.
Prospective Evaluation of Ovarian Function in Women with Breast Cancer Treated with Anthracyclin-Based Chemotherapy with or without Docetaxel.
Authors: Berliere M. , Malingret N. , Coudyzer P. , Baurain J. , Mazzeo F. , Galant C. , Fellah L. , Piette P. , Machiels J.
Published: December 2010

Background: to determine prospectively the incidence of chemotherapy-related amenorrhea and the recovery of ovarian function in premenopausal women with breast cancer undergoing adjuvant or neoadjuvant anthracyclin-based chemotherapy with or without docetaxel.Material and methods: we studied the incidence and the reversibility of clinical amenorrhea induced by different chemotherapy regimens: i) 6 cycles of 5-fluorouracil 500mg/m2, epirubicin 100mg/m2 and cyclophosphamide 500mg/m2 on day 1 every 3 weeks (6FEC) and ii) 3 cycles of FEC 100 followed by 3 cycles of docetaxel 100 mg/m2 on day 1 every 3 weeks (3FEC/3D) and iii) 4 cycles of FEC 100 followed by 4 cycles of docetaxel on day 1 every 3 weeks (4FEC100/4D) .Recovery of ovarian function was defined as recovery of premenopausal hormonal values :luteinizing hormone (LH <17mIU/ml),follicle-stimulating hormone (FSH <45.7mIU/Ml) and oestradiol (E2>50pg/ml).This recovery of ovarian function did not need to be associated with regular menses.Hormonal dosages were performed every 3 months starting at the beginning of chemotherapy and during the year following the end of chemotherapy.After, dosages were performed every 6 months.Results: 170 premenopausal patients were included between january 2005 and january 2008: 62 patients received 6FEC, 66 patients 3FEC/3D and 42 patients 4FEC/4D. The median age was 41 years (range: 25-51) in 6FEC, 42.8 years (range: 27-52.8) in 3FEC/3D and 40.2 years (range: 24-49.5)in 4FEC/4D. The incidence of chemotherapy-related amenorrhea at the end of chemotherapy was similar in the 3 groups: 90.3% in the 6FEC arm, 89.4% in the 3FEC/3D arm and 92.8% in the 4FEC/4D arm. However in the year following the end of chemotherapy, more patients recovered ovarian function in the 3FEC/3D arm (51.5%)(p=0.017) and in the 4FEC/4D arm (50%)(p=0.046)compared with the 6FEC group (30.6%). The difference was statisticaly significant for patients > or=40 years but not for patients < 40 years.Importantly, among the 23 patients with premenopausal hormonal values and treated with tamoxifen, 12/23 did not mention any menses recovery during the first year of follow-up.Conclusion: our prospective study confirms our previous retrospective data showing that 3FEC/3D and 4FEC/4D induce less definitive amenorrhea than 6FEC. Age is the most important predictor of ovarian function recovery, independently of chemotherapy regimen.Anamnestic data, especially in patients treated with tamoxifen are insufficient to determine pre-or postmenopausal status. Therefore, hormonal values must be followed regularly during and after chemotherapy. Since the menopausal status has an impact on the endocrine therapy choice.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2086.
Incidence of Febrile Neutropenia with Taxane-Based Systemic Therapy in Women with Early Stage Breast Cancer.
Authors: Alkhayyat S. , Dent S. , Verreault J. , Robinson A. , Germond C. , Vandenberg T.
Published: December 2010

Background: Febrile neutropenia (FN) is one of the most significant toxicities experienced by patients treated with systemic therapy. Taxanes now play an integral role in the systemic therapy for women with early stage breast cancer. The most common taxane-containing regimen utilized in Ontario, Canada is 5-Fluorouracil/Epirubicin/Cyclophosphamide x 3 followed by Docetaxel x 3 (FEC-D). PACS 01 reported a febrile neutropenia (FN) rate of 11.2% in the FEC-D arm. In our clinical practice, clinicians have noted a much higher rate of FN. We report the FN rate with the use of FEC-D in women with early stage breast cancer treated at tertiary care centers in Ontario.Methods: All women with early stage breast cancer who were treated with FEC-D from three tertiary care cancer centers in Ontario, Canada (London, Sudbury, Ottawa) between June 2006 and December 2008 were included in this retrospective analysis. Data included: demographics, staging, hormone receptor status, primary prophylaxis use with growth factors, FN rate, admission to hospital and duration of hospital admission.Results: Median age of 630 women is 52 years (r: 24-77). Staging was: I (88), IIA (243), IIB (159), IIIA (94), IIIB (23), IIIC (14) and 9 unknown. A total of 474 (75.2%) were ER positive. Primary prophylaxis with growth factor support was given to 222 patients (35%) and 408 patients (65%) did not have upfront prophylaxis. Of the 222 patients who were given primary prophylaxis, 14 patients (6.3%) were diagnosed with FN. Of the 408 patients who did not receive primary prophylaxis, 120 patients (29.4%) were diagnosed with FN. All patients (n=120) diagnosed with FN received secondary prophylaxis with growth factor support. A total of 126 patients (20%) were admitted to hospital for FN. The median duration of hospital admission was 3.9 days (r: 1-65 days). The impact of risk factors, the use of filgastrim versus pegylated filgastrim on FN rates and the clinical ramifications of febrile neutropenia (ICU admissions/deaths) will be reported.Conclusions: The results of this retrospective analysis demonstrate a much higher risk of FN (29.4%) with FEC-D than has been previously reported. More complete reporting of primary prophylaxis is required. This rate of FN would warrant use of primary prophylaxis for patients prescribed FEC-D, particularly in high risk subgroups.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2087.
Relationship of Anthracycline-Free Interval to Outcomes in a Phase 3 Trial of Pegylated Liposomal Doxorubicin Plus Docetaxel Compared with Docetaxel Monotherapy in Patients with Advanced Breast Cancer Treated with Adjuvant Anthracycline.
Authors: Sparano J. , Zhuang S. , Londhe A. , Lantz K. , Lowery C.
Published: December 2010

Background: An earlier report showed that pegylated liposomal doxorubicin (PLD) + docetaxel (D) improved time to progression (TTP) vs D alone in patients (pts) with advanced breast cancer (ABC) who had relapsed at least 1 year after adjuvant or neoadjuvant anthracycline therapy. (Sparano et al., SABC 2008, #80) This analysis evaluated whether the time between completion of adjuvant anthracycline therapy until relapse impacts overall outcome. We retrospectively examined outcomes in pts with an anthracycline-free (A-F) interval of 1 to 2 years and pts with an A-F of >2 years.Methods: 751 pts were randomly assigned to receive either D 75 mg/m2 (N=373) or PLD 30 mg/m2 followed by D 60 mg/m2 (N=378) every 21 days. Treatment was continued until disease progression or the occurrence of unacceptable toxicity. The primary endpoint was TTP and secondary endpoints included overall survival (OS), progression free survival (PFS), objective response rate (ORR), and safety. Pts were categorized into groups by anthracycline-free interval of 1-2 years or >2 years. Relationship between the interval and outcomes was examined by proportional hazards model for TTP, OS (updated as of 1-Dec-2008), and PFS.Results: Approximately 60% of pts in both treatment groups had A-F intervals of >2 years. Median TTP, OS, and PFS (months) by A-F interval groups are listed in the Table. A-F interval 1-2 years  A-F interval >2 years   D, n=151PLD+D, n=155HR (CI)*; P**D, n=221PLD+D, n=221HR (CI)*; P**TTP5.77.80.67 (0.52, 0.87); .0027.710.60.63 (0.50, 0.79); <.001OS15.817.90.90 (0.69, 1.16); .40424.722.91.10 (0.86, 1.40); .448PFS5.57.70.67 (0.52, 0.87); .0027.710.00.65 (0.51, 0.81); <.001ORR25%34%P=.086†27%36%P=.042† A-F interval 1-2 years, N=306  A-F interval >2 years, N=442 HR (CI)***; P**TTP6.6  8.9 0.74 (0.63, 0.88); .001OS17.2  23.4 0.63 (0.52, 0.75); <.001PFS6.5  8.7 0.74 (0.62, 0.87); <.001ORR30%  31% P=.826†*Proportional hazard model for PLD+D vs D; **Log-rank test; ***Proportional hazard model for >2 years vs ≤2 years A-F; †Cochran-Mantel-Haenszel test.Overall, HFS and stomatitis occurred more often in pts treated with PLD+D. The overall incidence of CHF was 1%.Conclusions: An A-F interval of >2 years reduced the risk for TTP, OS, and PFS, regardless of treatment. However, similar to results of the overall study, treatment with the combination PLD+D resulted in statistically significant improvement of TTP and PFS, but not OS, compared with D among pts with ABC, regardless of A-F interval. The addition of PLD to a D-based regimen is an active option for pts with ABC previously treated with adjuvant anthracycline regimens.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2095.
Oral Bisphosphonate and Breast Cancer: Prospective Results from the Women's Health Initiative (WHI).
Authors: Chlebowski R. , Chen Z. , Cauley J. , Rodabough R. , McTiernan A. , Lane D. , Manson J. , Snetselaar L. , Yasmeen S. , O'Sullivan M. , Stafford M. , Hendrix S. , Wallace R.
Published: December 2010

Background: Emerging clinical evidence suggest intravenous bisphosphonates may directly inhibit breast cancer (Gnant SABCS 2008) while oral bisphosphonates in US clinical practice have received limited evaluation regarding breast cancer influence.Methods: To investigate associations between oral bisphosphonates and invasive breast cancer we examined data for 151,592 postmenopausal women enrolled in the WHI. Information was collected on breast cancer risk factors and oral bisphosphonate use. To control for bone mineral density (BMD) we employed a published hip fracture prediction model which did not incorporate BMD (Robbins 2007) against the 10,296 WHI participants who had baseline total hip BMD determination. Breast cancers were centrally adjudicated by pathology report review. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs).Results: Of the 151,592 participants, 2,216 were oral bisphosphonate users at entry (90% alendronate, 10% etidronate). An analysis comparing hip fracture risk score to BMD in those with both found a significant correlation (regression line = .79-.0478 log predicted hip fracture, r=0.43). As a result, the hip fracture risk score was used to control for potential BMD group differences. HRs for invasive breast cancer by bisphosphonate use are outlined below after 7.8 (1.7) mean years (SD).  Bisphosphonate Use     NoYesBreast Cancer Incidence ** Invasive Breast CancerNRate*NRateHR95% CIP-valueTotal50924.38643.290.68(0.52-0.89)< .01ER positive38293.28502.560.70(0.52-0.95)0.02ER negative7170.6180.410.66(0.31-1.39)0.27 * Rate/1000 women years of follow-up**Cox proportional hazards analyses adjusted for age, ethnicity, smoking, alcohol use, physical activity, BMI, mammograms, prior hormone use, calcium, vitamin D, hip fracture risk score, Gail risk score and stratified on WHI trial randomization arm.Conclusion: There was a statistically significant association between oral bisphosphonate use and lower invasive breast cancer incidence with fewer ER positive breast cancers and a non-significant trend for ER negative breast cancers in bisphosphonate users. This result suggests oral bisphosphonates may have direct inhibiting effects on breast cancer.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 21.
Paclitaxel-Related Peripheral Neuropathy Associated with Improved Outcome of Patients with Early Stage HER2+ Breast Cancer Who Did Not Receive Trastuzumab in the N9831 Clinical Trial.
Authors: Moreno-Aspitia A. , Dueck A. , Patel T. , Hillman D. , Tenner K. , Dakhil S. , Rowland K. , McLaughlin S. , Perez E. ,   TBCI Breast Cancer Intergroup of North America
Published: December 2010

Background: Microtubules are crucial for spindle formation during mitosis and for cellular proliferation. The antineoplastic effect of paclitaxel is mainly related to its ability to bind the beta subunit of tubulin, thus preventing tubulin chain depolarization and inducing apoptosis. Tubulins are expressed in human peripheral nerves and the binding of paclitaxel to tubulin may lead to neuropathy. Peripheral neuropathy is a common dose limiting toxicity of paclitaxel. We hypothesized that the occurrence of peripheral neuropathy may correlate with outcome (disease-free survival; DFS).Methods: This analysis sought to describe incidence of peripheral neuropathy following paclitaxel and its association to outcome (DFS) in patients who received paclitaxel (weekly x 12) in the adjuvant HER2+ intergroup trial N9831. Only eligible pts who initiated paclitaxel and did not have peripheral neuropathy at initiation of paclitaxel that were randomized to arms A (955 pts; chemotherapy alone) and C (889 pts; chemotherapy plus concurrent trastuzumab) of N9831 were included. Cox regression analysis stratified by ER/PR status and nodal status was used to compare DFS within arm between patients with and without peripheral neuropathy.Results: Out of 1844 eligible pts, 379 developed neuropathy (20.5%). For pts in arm A, those who developed neuropathy had better DFS than pts who did not (3 yr DFS: 86.2% vs 81.8%; HR 0.65; p=0.01), despite lower doses of paclitaxel in the pts with neuropathy. Grade of neuropathy did not appear to impact DFS. No statistical difference was noted for pts treated in the trastuzumab-containing arm (3 yr DFS: 92.8% vs 91.1% for pts with neuropathy vs not; HR 0.79; p=0.34). There were no differences in paclitaxel dose intensity between arms A and C.Conclusion: Patients with early stage HER2+ breast cancer who received adjuvant paclitaxel-containing chemotherapy in arm A and developed peripheral neuropathy had a better DFS than pts who did not develop neuropathy. This effect was possibly abrogated by the use of trastuzumab in Arm C. This side effect may represent effective bindings of paclitaxel to the target tubulin, lack of point mutations in tubulin at the paclitaxel binding site and/or lack of selective overexpression of β-III tubulin. This is a hypothesis generating study and additional analysis needs to be conducted from other large taxane-based trials.Partial support from Genentech and the Breast Cancer Research Foundation

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2100.
Influence of Treatment Conforming to Guidelines on Recurrence Free Survival (RFS) and Overall Survival (OS) in Triple Negative Breast Cancer.
Authors: Atassi Z. , Wischnewsky M. , Wöckel A. , Kurzeder C. , Wolters R. , Novopashenny I. , Kreienberg R.
Published: December 2010

Introduction: The triple negative(TN) breast cancer subtype (ER neg, PR neg, HER 2 neg) represents about 10 to 15% 0f all breast cancer types. It characterizes an aggressive phenotype with significantly worsened RFS, OS as well as specific clinical and pathological properties. The aim of this study was: 1.To assess the efficacy of guideline conforming conventional chemotherapy, local recurrence rate, distant recurrence rate, as well as overall survival. 2.To ask for subgroups that show the greatest benefit from conventional chemotherapy and 3. to ask for impact of guidelines violation on RFS and OA.Patients and methods: 3658 breast cancer Patients that were first diagnosed between the years 2000 and 2005 were analyzed in a multicentric retrospective study. A total of 371 (10,1%) were triple negative. Results: Median age was 62 years(26-101) TN: 60years.(28-97). 13,8% of all included patients are triple negative. 90,3% of all TN patients are at intermediate/high risk according to Nottingham risk classification. 76,5 have G3 tumors. The 5 year DFS is 74,8% (95%CI 68,8% - 80,8%) and for none TN 86,5%(95%CI 84,6% - 88,4%) (logrankp<0,0001). The 5 year OS is 75,8%(95%CI:69,9%- 81,8%) and for none TN 86%(95%CI:84,1%-87,9%). (logrank p < 0,0001). The essential parameters for RFS and OS were guidelines conforming surgery and radiation therapy, when chemotherapy conforming to guidelines was provided. The 5 year RFS for TN patients undergoing a 100% guideline according adjuvant therapy is 86.1%(95%CI:78.9%-93.4%), with 1-2 violations 76.0% (95%CI:69.0%-83.1%) and with ≥3 violations 50.6%(95%CI:20.1%-81.1%) (logrank p<0.0001). In total a 66,8% of all TN patients were not treated according to guidelines (ranking of violations: Chemotherapy, radiation therapy, surgery). 18% had 2 or more violations. Summary: The Results show a significant improvement of outcomes in TN breast cancer patients when treatment is conducted in accordance to guidelines. There are subgroups of TN breast cancer patients that profit from therapy according to guidelines. The leading guideline violation was noted for radiation therapy.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2101.
Three-Year Follow-Up of Survival and Progression in a Phase II Trial of Gemcitabine Plus Carboplatin (Plus Trastuzumab in HER2+ Patients) in Metastatic Breast Cancer Patients.
Authors: Loesch D. , Loesch D. , Asmar L. , McIntyre K. , McIntyre K. , Orlando M. , Zhan F. , Boehm K. , O'Shaughnessy J. , O'Shaughnessy J. , O'Shaughnessy J.
Published: December 2010

Background: We have previously reported (Loesch, et al. Clin Breast Cancer, 2008) the efficacy and safety of gemcitabine and carboplatin with or without trastuzumab in patients with metastatic breast cancer. We now report time-to-progression (TTP) and overall survival (OS) after up to 3.5 years of extended follow-up.Patients and Methods: Patients were stratified into 3 groups at registration; Group 1: HER2 positive (+) regardless of prior taxane; Group 2: HER2 negative (–) and taxane naïve or remote (no taxanes within the past 2 years); and Group 3: HER2– and taxane pretreated. Women ≥18 years of age, with ECOG performance status 0-2, with RECIST-defined measurable disease, and either HER2– or HER2+ (3+ score) by immunohistochemistry or fluorescence in situ hybridization were enrolled. Treatment: Day 1 gemcitabine 1500 mg/m2 over 30 minutes followed by carboplatin AUC=2.5 repeated every 14 days up to Cycle 9. Group 1 also received trastuzumab 8 mg/kg in Cycle 1 followed by 4 mg/kg in Cycles 2-9, followed thereafter by 6 mg/kg every 21 days until progression or intolerable toxicity.Results: A total of 150 patients were registered (50, 51, and 49 in Groups 1, 2, and 3, respectively). Median follow-up for surviving patients, calculated from registration, was 31.3, 27.1, and 25.4 months, respectively. Median TTP (calculated as progression-free survival), was 7.2, 5.6, and 4.6 months, respectively. Median OS (range) has not been reached for Group 1 (range, 1.2-46.9); for Group 2 was 21.7 months (<1-44.3); and, for Group 3 was 11.9 months (<1-33.6). At 24-months, survival rates were 73.3%, 41.4%, and 20.5%, respectively; at 36-months, survival rates were 60.6%, 25.7%, and ≤8.3%, respectively. For Group 1 only, the remaining 3 responding patients were followed for 3.5 years, at which time they were relapse-free.Conclusions: Gemcitabine plus carboplatin with or without trastuzumab has been shown to be highly active in metastatic breast cancer. HER2+ patients receiving trastuzumab had the highest TTP and survival rates of all treatment groups. As expected, taxane-pretreated patients had shortened TTP and decreased OS rates compared to taxane-naïve patients.Research support was provided, in part, by Lilly USA, LLC; Indianapolis, IN.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2105.
Subgroup Analyses in Contemporary Phase III Trials in Advanced Breast Cancer (ABC).
Authors: Calabrich A. , Katz A. , Saad E.
Published: December 2010

Objective: Subgroup analyses of treatment effects according to baseline patient characteristics are often performed in phase III trials in oncology. However, the frequency and determinants of this practice in ABC have not been described in the literature.Methods: We used the medical subject headings “breast neoplasms” and “drug therapy” to search PubMed for phase III trials on systemic antineoplastic therapies published between 01/00 and 12/07 in one of 10 leading medical journals (Ann Oncol, BCRT, Br J Cancer, Cancer, Eur J Cancer, JCO, JNCI, Lancet Oncol, Lancet and NEJM). We excluded factorial trials and studies on high-dose chemotherapy. When a subgroup analysis was not reported in the main article for each trial, a PubMed search was conducted using the names of first and last authors (separately) and the experimental drug(s). All variables were analyzed as reported by the authors of trials.Results: The initial search yielded 58 trials enrolling a total of 23,371 patients in 122 trial arms. For 31 trials (53.4%), a subgroup analysis was reported in the main article. Another 7 trials reported a subgroup analysis in a companion paper, for a total of 38 out of 58 trials reporting a subgroup analysis (65.5%; 95% CI, 51.8 – 77.2%). Such analyses were reportedly pre-planned in only 11/38 cases (28.9%), and only two trials reported a formal test for interaction. The number of factors considered in subgroup analyses ranged from 1 to 14. In 21/38 cases (55.3%), none of these factors was used for stratification before randomization. The results of the subgroup analysis were mentioned in the main article abstract in 13/31 cases (41.9%), 5 of which in the conclusions. There was no difference in the proportion of positive (70.4%) and negative (61.3%) trials (regarding their primary endpoints) for which a subgroup analysis was reported (P=0.53). Likewise, financial support (pharmaceutical industry [N=36] vs others [N=22]) was not predictive of subgroup analysis (P=0.17). However, trials published between 2000 and 2003 were more likely (P=0.03) to report a subgroup analysis (79.3%) than trials published between 2004 and 2007 (51.7%).Conclusion: Our review suggests that subgroup analyses are frequently performed in phase III trials in ABC. In the vast majority of cases, no formal test for interaction is presented. There seems to be a temporal trend for decrease in reporting of subgroup analyses. Other potential predictors of subgroup analysis are currently being sought.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2107.
Prognostic Significance of Molecular Subtypes in Male Breast Cancer.
Authors: Foerster R. , Foerster F. , Foerster F. , Wulff V. , Schubotz B. , Lange R. , Habeck J. , Baaske D. , Baaske D. , Kuhn W. , Rudlowski C.
Published: December 2010

INTRODUCTIONThe relatively unfavorable outcome in male breast cancer has been attributed to more advanced local tumor stage and high incidence of lymph node invasion at the time of diagnosis. This study aimed to classify the molecular subtypes of male breast cancers based on the expression profile of immunomarkers and to evaluate their association with clinicopathological features and patients outcome.METHODSTo define molecular subtypes a total of 174 cases of male breast carcinoma were examined retrospectively using immunostains for hormone receptors (HR) and cytokeratin 5/6 (CK5/6). Human epidermal growth factor receptor 2 (HER2) expression was evaluated by immunostaining and confirmed by fluorescent in situ hybridization. Tumor characteristics and overall survival (OS) data were available and correlated with protein expression and the molecular subtype.RESULTSThe luminal A subtype (HR+/HER2-) was the most common subtype in male breast cancer (82.8%; n=144) with a median patients OS of 122 month. Luminal B tumors (HR-/HER+) were found in 6.2% (n=11), basal-like (HR-/HER2-/CK5/6+) in 9.6% (n=17) and HER2+/HR- carcinomas in 1.1% (n=2). Basal like male breast carcinoma showed a statistically significant reduced overall survival (median: 51 month; p<0.01). Due to the low number of patients prognostic significance of HER2 positivity (luminal B and HER2+/HR-subtype) was not evaluable.CONCLUSIONSIn our study group, luminal A was the predominant subtype of male breast carcinoma and showed an excellent patients outcome. However, like in females tumors with a basal like subtype which were known to show minor chemotherapy response had a worse prognostic outcome. Therefore, new therapeutic options have to be defined.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2110.