bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P6-06-04: Preliminary Studies Characterizing the Prevalence of Mouse Mammary Tumor-Like Sequences in Human Tissues of Pakistani Origin
Authors: Amir S , Bilal S , Ahmed W , Zahid M , Mustafa F.
Published: April 2011

Background: Pakistan has the second highest rate of breast cancer in Asia after Israel with nearly 1 out of 9 women at risk of developing breast cancer at some stage in their lifetime. A potential role of viruses in human breast cancer induction/development is increasingly coming to surface. Several different groups around the world have demonstrated the presence of mousemammary tumor virus (MMTV)-like sequences in tumor but not normal breast tissue. However, these findings are controversial and seem to differ depending upon the geographic location and ethnicity of a population. Some find MMTV-like sequences in tumors of breast cancer patients only, while others believe these results are due to PCR contamination. Yet others believe that these sequences are real and represent endogenous retroviruses that reside within the human genome.

Methods: These possibilities were tested by collecting blood and breast tissue samples from breast cancer and normal individuals after informed consent and ethical approval. A total of 146 blood and tumor samples from cancer patients and 164 blood genomic DNA samples from healthy individuals were collected and subjected to PCR. Primers for different regions of the virus were designed in such a manner that they encompassed regions conserved among different MMTV strains, but were different at their 3’ ends from the human endogenous virus K (HERV-K) that has -50% homology to MMTV.

Results: Single PCR screening of all samples gave sporadic, mostly weak positive results. However, nested PCR of a subset of the samples from normal and cancer patients revealed that for the pol region, over 50-100% of the samples were positive, for env 15-75% of the samples were positive, while for long terminal repeat (LTR) 5-100% of the samples were positive, depending upon whether they were from blood or breast tissue. Sequencing of the PCR fragments further revealed these sequences to be 90-100% homologous to Mtv-8 but not HERV-K, thus identifying these amplified bands to be of MMTV origin. Finally, test of the wild Pakistani Mus musculus revealed that they contain endogenous MMTVs very similar to Mtv-8.

Conclusions: Together, these unexpected results suggest that the Pakistani population may be exposed to MMTV, maybe through zoonotic transmission from mice. These observations need further stringent study and confirmation. Differential expression studies are in the process as well as hunt for viral integration sites. It is only with a positive demonstration of integration sites in normal individuals that one can definitively prove whether MMTV is actually in the human population.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-06-04.
Abstract P6-07-01: CCN3 Impairs Osteoblasts and Stimulates Osteoclast Differentiation To Favor Breast Cancer Metastasis to Bone
Authors: Amir E , Ouellet V , Mourskaia A , Tiedemann K , Fong J , Tran-Tanh D , Clemons M , Perbal B , Komorova S , Siegel PM.
Published: April 2011

Background: The mechanisms underlying the osteotropism of breast cancer are not fully understood. Breast cancer cell lines that aggressively metastasize to bone appear to have increased expression of CCN3 (Nov) compared to those that weakly metastasize to bone. This study aimed to functionally implicate CCN3 in the process of breast cancer metastasis to bone.

Methods: Primary cultures of mouse bone marrow cells were used to assess the effect of recombinant CCN3 protein on RANKL, OPG and on osteoblasts and osteoclasts. To extend data obtained from cell and animal-based models, we have examined CCN3 expression a panel of human breast cancer bone metastases.

Results: CCN3 protein impaired osteoblast differentiation in a dose dependant manner, resulting in an increase in the RANKL/OPG ratio that indirectly favors osteoclast formation. CCN3 also directly induced osteoclast differentiation of RANKL-primer RAW 264.7 monocytes. CCN3 enhanced osteoclast differentiation through its ability to induce calcium mobilization and the subsequent nuclear translocation of NFATc1, a transcription factor essential for osteoclast differentiation. Immunohistochemical staining indicated that CCN3 is readily detectable, both in the breast tumor/stroma and in the majority of breast cancer bone metastasis samples.

Conclusion: Our data support a clinically relevant and important role for CCN3 in modulating the differentiation capacity of bone resident cells to support osteoclast formation and the formation of osteolytic bone metastases.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-07-01.
Abstract P6-08-04: AP-1 Activation and a Functional SNP242 Regulate the LY-6K Gene Expression in Human Breast Cancer Cells
Authors: Kong HK , Park JH
Published: April 2011

Background: Lymphocyte antigen 6 complex locus K(LY-6K), a member of cancer-testis antigen, is a novel breast cancer biomarker. Elevated LY-6K induces cell invasion and metastasis through activating the Raf-1/MEK/ERK signaling pathway. And in a previous study, breast cancer patients have single nucleotide polymorphism (SNP) within promoter of LY-6K. However, the molecular mechanisms that mediate regulation of human LY-6K gene expression are completely unknown. Material and Methods: The human breast carcinoma cells used in these studies include the MCF7 and adriamycin resistant MCF7. Within the pGL3 reporter vector, the -3050/+182 bp fragment and truncated fragment (deleted from -500 to -1 bp and from -1550 to -1050 bp) upstream of the LY-6K gene was subcloned and measured promoter activity. Next, multiple cis elements were identified using several gene tool software (TFSEARCH, TRANSFAC, PROMO and MATCHTM) in the promoter of human LY-6K gene. Substitution of two base pair of transcription factor binding site or single base pair of SNP was subcloned within pGL3 vector using site-directed mutagenesis and measured transcriptional activity. Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA) and supershift assays were used to demonstrate in vitro interactions between the transcription factor and transcription factor binding site within the promoter of LY-6K.

Results: We found that a novel AP-1 binding site in the LY-6K promoter. The substitution from C to G at the 242 nucleotide position in the promoter region is a functional LY-6K single nucleotide polymorphism (called SNP242), which increase AP-1 transcription binding affinity to LY-6K promoter. Ongoing studies are investigating to identify the relationship between LY-6K transcription and SNP756 which located at the 756 nucleotide position within LY-6K promoter and to find binding partner of LY-6K. We are also manipulating LY-6K transgenic mouse and knock-out mouse to investigate the mechanism of LY-6K in vivo. Discussion: The activity of the AP-1 transcription factor plays an important role in cell mobility of breast cancer cells via the promoting of LY-6K gene expression. LY-6K expression is dependent on not AP-1 transcription factor, but also SNP242 G allele by increasing AP-1 binding affinity. We demonstrated that metastasis of breast cancer cells depend on LY-6K expression turn on ERK signaling. These results suggested that LY-6K SNP242 G allele increases the risk of cancer and metastasis and LY-6K communicate with integrin-GPCR to cell migration via activating Ras/ERK signaling pathway.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-08-04.
Abstract P6-08-13: Alteration of REDD-1 Mediated mTOR Pathway and HIF-1σ Regulation in Human Breast Cancer
Authors: Lee S , Koo JS.
Published: April 2011

A hypoxia-related protein, REDD1 (regulated in development and DNA damage response 1), inhibits the mammalian target of rapamycin (mTOR) signaling pathway in normal cells under hypoxic condition, but a loss of REDD1 causes tumorigenesis in certain tumor cells. The purpose of this study is to investigate REDD 1 -mediated regulation of the mTOR pathway in breast cancer. Tissue microarray included samples from 224 patients with breast cancer, and 30 patients with papilloma were used as control group. The immunohistochemistry (IHC) such as estrogen receptor (ER), progesterone receptor (PR), HER-2, epithelial growth factor receptor (EGFR), cytokeratin (CK) 5/6, Glut-1, HIF-1α, REDD 1, AMPK ≥1, 14-3-3 σ, PTEN, phospho-Akt, phospho-mTOR, phospho-S6, and Ki-67 were performed. Phenotypic classification of breast cancer was performed based on the results of IHC for ER, PR, and HER-2 and fluorescent in Situ Hybridization (FISH) for HER-2: luminal A, luminal B, HER-2 overexpression, and triple negative breast cancer (TNBC). Glut-1and HIF-1 alpha were more highly expressed in TNBC, HER-2 overexpressiontype, and papilloma than luminal A and B (P = 0.000). REDD1 expression was higher in papilloma than breast cancer (P = 0.000), but no difference was found among the 4 breast cancer phenotypes (P = 0.307). HIF-1α expression was an important factor of decreased time to disease free survival and overall survival in univariate analysis (P = 0.003, and 0.000, respectively) and multivariate Cox analysis (P = 0.018, odd ratio: 7.6, and P = 0.002, odd ratio: 13.7, respectively). Among human breast cancer phenotypes, HER-2 overexpression and TNBC type demonstrated down-regulation of REDD1 under hypoxic tumor environment. In HER-2 overexpression and TNBC type, tumor cell proliferation and survival in hypoxic tumor environment could be possible due to dysinhibition of the mTOR pathway and HIF-1α stabilization through down-regulation of REDD1.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-08-13.
Abstract P6-09-02: Risk of Breast Cancer Associated with Hormone Replacement Therapy Use Differs by Age, Race, and Breast Density
Authors: Hong S , Wang W , Huo D , Siddique J , Dignam JJ.
Published: April 2011

Background: Observational studies and randomized trials have demonstrated an association between hormone replacement therapy (HRT) use and increased risk for breast cancer. However, this risk may vary by age and other factors, including breast density and race/ethnicity. Using data from the Breast Cancer Surveillance Consortium (BCSC), we investigate whether self-reported HRT use in the peri-menopausal and immediate post-menopausal age groups is associated with breast cancer, and also whether risk associated with HRT use differs by breast density and race. Subjects and Methods: The BCSC is a longitudinal registry of mammography screening in seven U.S. centers. In the breast cancer risk prediction model developed by Barlow et al (J Natl Cancer Inst 2006 98:1204-14), HRT use and ten other features were identified as risk factorsfor breast cancer. Data for our study consists of 1,642,824 screens and 9,300 breast cancers among the post-menopausal women aged > 44 in this cohort. Logistic regression models were used to estimate odds ratios for breast cancer associated with HRT use within race, age, and density strata, adjusting for other variables from the Barlow model. Multiple imputation methods were used to accommodate missing data for HRT (14%) and other predictors.

Results: Breast cancer risk for HRT use varied by age, with no risk excess among women aged 45-49 and risk excess of 20% or greater for women aged 50-64 (Table 1). Women >64 had a smaller excess risk with HRT use. There was no significant excess risk at any age for Black women, while White women age 50-64 had > 20% excess risk for HRT use. White women with higher breast density had increased risk with HRT use, while Black women did not.

Table 1: Odds ratios (95% confidence interval) for HRT use (yes/no)

Conclusions: In this large cohort of mammography-screened women, HRT use did not increase breast cancer risk in the peri-menopausal period (age 45-49). Women with low breast density had smaller risk increments associated with HRT than those with high density. For Black women, increased breast cancer risk due to HRT was not apparent at any age or breast density category.

Data collection for the BCSC was supported by a NCI-funded Breast Cancer Surveillance Consortium co-operative agreement (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040).

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-09-02.
Abstract P6-09-03: No Increased Breast Cancer Risk with Hormone Replacement Therapy (HRT) in Women with Benign Breast Disease
Authors: McKian KP , Frost MH , Maloney SD , Vierkant RA , Visscher DW , Hartmann LC.
Published: April 2011

The association between hormone replacement therapy (HRT) and breast cancer risk in women with benign breast disease (BBD) is unclear. However, others have shown that HRT use is associated with the development of proliferative breast disease (Rohan et. al, CEBP 2008). To better clarify potential risks associated with postmenopausal hormone use in women with BBD, we performed a nested case control study within the Mayo Clinic Benign Breast Disease Cohort. In the cohort, there are 11,079 women who had benign breast biopsies between 1967 and 1996 and for whom we have outcome and risk factor data, including use of HRT. We studied 947 cases (breast cancer after BBD) and two controls matched to each case based on age and year of BBD. Information on use of HRT was obtained through use of questionnaires and medical record review with a mean time of follow up of 17.4 years. HRT use, histology, involution status, and family history were all evaluated for impact on breast cancer risk in a multivariate model.

As shown in Table 1, when looking at effects of histology, involution, and family history, we confirmed previously reported findings of risk (Hartmann LC et. al, NEJM 2005). Specifically, we saw increased risk in women with AH vs. PDWA or NP, decreased risk with complete involution vs. partial or no involution, and increased risk with strong family history vs. weak or no family history.

Associations of hormone replacement therapy and other relevant clinical variables with risk of breast cancer

Multivariate model simultaneously including all variables listed in the table. HRT=hormone replacement therapy. NP=non-proliferative. PDWA=proliferative disease without atypia. AH=atypical hyperplasia

We found that women who had used HRT had no higher risk of developing breast cancer than women who had not used HRT. Specifically, with Never Users as the reference group, those with 5 years or less exposure had OR 0.80 (0.56-1.15); 6-10 years, 0.85 (0.56-1.28) and 11+ years, 0.51 (0.36-0.72), p =0.002.

In conclusion, we found that HRT use among postmenopausal women with BBD was not associated with an increased risk of breast cancer. In this case-control set, we confirmed previous findings regarding well established risk factors of histology, involution status, and family history. While HRT use may contribute to the development of proliferative breast disease, we do not see that HRT is associated with additional breast cancer risk, beyond that of the proliferative disease itself.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-09-03.
Abstract P6-09-06: Oral Contraceptive Use and Overall Breast Disease Risk: Cross Sectional Retrospective Study
Authors: Hamy AS , Agopian A , Porcher R , Giacchetti S , de Roquancourt A , Espié M.
Published: April 2011

Background: Oral contraception (OC) is one of the most widely used means for birth control in the world. In several studies, OC has been associated with a slightly increased risk of breast cancer in current user, and with a decreased risk of benign disease. Little is known about atypical high risk lesions. Our goal was to investigate whether OC use was a risk factor or a protective factor for benign, high risk or malignant breast lesions. Material and methods : From 2001 to 2007, all non-palpable breast lesions referred to biopsy or cytology in Saint Louis hospital were prospectively registered. Demographic and clinical data including oral contraceptive pill use extent were reported. We defined benign lesions (fibroadenoma, blunt duct adenosis, fibrocystic changes, epithelial hyperplasia, others), high risk lesions (atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ and malignant lesions (ductal carcinoma in situ, invasive ductal or lobular carcinoma). The aim was to analyse the correlation between the duration of OC use and the occurrence of the breast disease classified by histology groups. Patients with previous history of benign breast disease or malignancy were excluded.

Results: The analysis was performed on 1329 breast lesions. The breakdown of the lesions were as follows: 819 benign lesions (fibroadenoma n=155, blunt duct adenosis n=169, fibrocystic disease n=194, epithelial hyperplasia n=132, others n=170), 104 high risk lesions (atypical ductal hyperplasia n=54, atypical lobular hyperplasia n=29, lobular carcinoma in situ n=21), and 406 malignant lesions (ductal carcinoma in situ n=158, invasive ductal or lobular carcinoma n=248). The duration of oral contraception use was not significantly associated with the occurrence of benign, high risk or malignant breast disease. When focusing on benign lesion subtypes, no association was observed either. Older age was significantly correlated to the occurrence of atypia or carcinoma. Significant difference existed in the median age of apparition 55 y.o and 57 y.o respectively, versus 53 y.o for benign lesion (p< 0,0001), as well as menopausal status at diagnosis (57.7% and 68.3%, respectively, versus 53% for benign lesion) (p< 0,0001).

Conclusion: In this cross sectional retrospective study, the duration of OC use was not associated with differential occurrence of benign, high risk and malignant breast lesion. Although a lack of statistical power may be invoked to explain the results, we are called to believe that the magnitude of an effect of OC use is small, if ever it exists.

Results [Table 1]

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-09-06.
Abstract P6-09-09: Dual Estrogen Effects on Breast Cancer: Endogenous Estrogen Stimulates, Exogenous Estrogen Protects. Further Investigation of Estrogen Chemoprevention Is Warranted
Authors: Ragaz J , Wilson K , Muraca G , Budlovsky J , Froehlich J.
Published: April 2011

Introduction

Until the randomized Women Healths Initiative [WHI] trials 1,2, most hormone replacement therapy (HRT) studies showed an association of HRT with higher BrCa risk. However, our recent reviews of the WHI trials suggested that Estrogen alone can be protective while HRT based on Estrogen + Progestin can be carcinogenic 3, 4. In this analysis, we expand this concept to examine the difference between “Exogenous” Estrogen — delivered as part of HRT, versus “Endogenous” Estrogen — i.e. E produced by human tissues. Rationale 1: Endogenous E is carcinogenic.

Reducing E levels through oophorectomy, selective oestrogen receptor modulators (SERMs) or with aromatase inhibition is effective at all stages of oestrogen receptor positive breast cancer and is significantly protective against BrCa in high risk women 5. Rationale 2: Exogenous E Protective:

Updates of the WHI trial 2 [women with hysterectomy, randomized to E alone versus Placebo, 1,2 ] with analyses according to prior history of Benign Breast Disease (PH BrD); a first degree relative with BrCa (PH 1st Rel BrCa); or prior HRT use, show:

Results of the WHI trial 2

CONCLUSIONS

These data are compatible with a dual estrogen effect where Exogenous Estrogen is protective, in contrast to the carcinogenic impact of Endogenous Estrogen. The protective effect of Estrogen is comparable in magnitude to that reported with tamoxifen in high risk women. Based on these data, we propose that:

1. In selected women - [i.e. the majority of the WHI HRT trial 2 participants, 71.5 - 80%] - the use of HRT based on Estrogens alone may be appropriate to manage menopausal symptoms, as it is associated with a significant reduction of BrCa rates.

2. The use of Exogenous Estrogen in chemoprevention merits validation, with the optimum Estrogen regimen determination [type of Estrogens; dose; mode of delivery, etc.] high priority.

References:

1. WHI working Group Reports, JAMA 2002; 2004; 2006

2. JCO, June 2010; 16; 2690-97

3. Cancer Res 2009; 69; # 908

4. HRT: A Critical Review. In: Management of Breast Diseases, 2010; Springer, New York, pp, 451-473.

5. Diseases of Breast, the 3rd Edition, 2005

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-09-09.
Abstract P6-09-11: Wide Scale, Automated Breast Cancer Risk Assessment and Decision Support for High Risk Women: www.BreastHealthDecisions.org
Authors: Ozanne EM , Bechtold T , Boortz S , Esserman LJ.
Published: April 2011

Purpose: Despite compelling evidence indicating chemopreventive agents can reduce the risk of developing breast cancer, they remain underused. This is common in elective therapies that hold the possibility of side effects. Effective risk stratification and patient-provider communication are critical for identifying those patients who stand to benefit most from these agents. However, there are few tools available for wide scale breast cancer risk assessment that also integrate decision support. To address this critical gap in healthcare delivery, we developed and performed preliminary evaluations of www.BreastHealthDecisions.org. This tool provides automated risk assessment and internet-based, patient-tailored decision support.

Development Methods: www.BreastHealthDecisions.org was developed to guide informed, value-driven, and patient-centered breast cancer prevention decisions. We implemented four commonly used breast cancer risk prediction models in the form of web-services to provide wide scale automated, individualized breast cancer risk assessments. Our internet-based decision aid is then tailored to individual patients based on risk predictions from these models. The decision aid is designed to integrate patient data from multiple sources including electronic surveys, electronic medical record (EMR), and other databases.

Evaluation Methods: Under Institutional Review Board approval, we evaluated the risk assessment tool and decision aid through patient focus groups, usability testing, and provider interviews (including breast specialist, primary care physicians, and genetic counselors). This included demonstrations and data collection at two scientific conferences (2009 International Shared Decision Making Conference, 2009 San Antonio Breast Cancer Symposium)

Result: Overall, the evaluations were favorable. The patient focus group evaluations and usability testing (N=34) provided qualitative feedback about the format and design of the decision aid; 88% of these participants found the tool useful and 94% found it easy to use. 91% of the providers (N=23) indicated that they would use the risk assessment tool and decision aid in their clinical setting.

Conclusion: www.BreastHealthDecisions.org represents a new approach to breast cancer prevention care and a framework for high quality preventive healthcare. The ability to integrate wide scale risk assessment and decision support in real time will allows for informed, value-driven, and patient-centered breast cancer prevention decisions. The tool is being further evaluated in a randomized controlled trial designed to determine the optimal mode of delivery in the primary care setting.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-09-11.
Abstract P6-10-04: Outcome of Triple Negative Breast Cancer in Patients with or without Deleterious BRCA Mutations
Authors: Arun BK , Gutierrez-Barrera AM , Akar U , Litton JK , Albarracin C , Gonzalez-Angulo AM , Hortobagyi GN.
Published: April 2011

Background: Triple-negative breast cancer (TNBC) affects 10-17% of all breast cancers and is associated with a poor prognosis. The biology of TNBC is poorly understood; however, it has been shown that up to 60% of BRCA1 mutation carriers develop TNBC. The aim of this study was to determine if there were differences in the progression-free survival (PFS) and overall survival (OS) rates of BRCA mutation-associated TNBC and Non-BRCA mutation-associated TNBC.

Methods: Patients with TNBC who were referred between 1997 and 2010 for genetic counseling were included in the analysis. Data was collected from a prospectively maintained IRB-approved research database. All patients with one primary breast cancer and negative expression of ER, PR, and Her2 were included in this study. A Kaplan-Meier survival analysis was performed to determine survival outcomes. Results: Out of 98 TNBC patients, 48 (48 %) were BRCA negative, and 47 (49%) were found to have a deleterious BRCA mutation (42 BRCA1 and 5 BRCA 2); 3 (3%) patients had a variant of uncertain significance in BRCA2 and were removed from study. The median age of diagnosis for BRCA positive TNBC was 42 years (range, 21-71) and for BRCA negative TNBC was 40.5 years (range, 21-64). There were no significant differences between age at diagnosis, nuclear grade, stage (I-III), or tumor histology of BRCA positive and BRCA negative TNBCs. The PFS for BRCA positive patients was 230.7 (range, 2-271) months and for BRCA negative was 203.1 (range, 2-258) months (p = 0.19). The overall survival (OS) for BRCA positive patients was 263.4 (range, 2-292) months and for BRCA negative 236.2 (2-279) months (p = 0.39). Conclusion: Outcome of triple-negative breast cancer is not different in BRCA mutation carriers versus non carriers. Further studies need to evaluate whether different therapies will change the outcome in these subgroups of TNBC.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-10-04.
Abstract P6-10-06: Metachronous Contralateral Breast Cancer (CBC) Has More Aggressive Biology and Clinical Characteristics Compared to Synchronous Bilateral Breast Cancer (BBC)
Authors: Pistamaltzian NF , Papadimitriou C , Panopoulos C , Koumakis G , Demiri S , Tsoukalas N , Yannoukakos D , Apostolikas N , Panagopoulos E , Efremidis A.
Published: April 2011

Purpose: Bilateral breast cancer is an uncommon clinical entity. There is no specific treatment strategy and controversial issues concerning diagnostic criteria, management and classification exist.

Method: In order to address some of these issues, a prospective analysis (data recorded upon patients first presentation) of an electronic breast cancer database at a tertiary cancer centre was performed. Patients’ epidemiologic characteristics, clinical profile, genomic analysis information and the tumours’ histopathology were analyzed.

Results: Out of 900 patients treated for breast cancer between 2006 and 2009, 44 diagnosed with bilateral disease (5% of total)having a median age of 53 years(range 32-73). 16 of them (36%)suffered from synchronous disease and 28 (64%)from metachronous { >3 months apart between the initial diagnosis and subsequent contralateral breast tumour).

Genetic analysis revealed 3 patients with inherited breast cancer syndromes (2 with BRCA1 and one with CDH-1 mutation). Among those with synchronous BBC 63% (10/16)were postmenopausal, 50% (8/16)had a positive family history for breast cancer and upon initial diagnosis 80% (13/16)of them presented with early stage disease (stages I,II).Contralateral disease was diagnosed incidentally. In contrast to these patients with synchronous BBC,57% of the patients (16/28)with metachronous CBC were premenopausal and 68% (19/28)had advanced disease (stages III,IV) upon the second diagnosis. Etrogens’ use didn't differ among the two groups, obesity was more common in patients with metachronous CBC, and smoking in the synchronous BBC patients.

Of the 88 tumours, 81(92%) were invasive, with ductal adenoCa being the more common (53% of specimens).

Of synchronous BBC tumours 12/16 (75%)were HR+ positive and 80%(13/16) expressed the same biologic features bilaterally. Of the metachronous tumours, upon initial diagnosis,26% were triple negative and only 7% were found with HER2 amplification, compared with 41% and 26% respectively in the second diagnosis. Conclusions: Synchronous BBC is less prevalent than Metachronous CBC, has more favourable characteristics (earlier stage at diagnosis, hormonal receptor positivity), and occurs mainly among postmenopausal women with positive family history.

Metachronous CBC is more common in premenopausal women and has a tendency to change its biological and clinical characteristics to a more aggressive phenotype (triple negative, HER2 amplification) between initial and latter diagnosis.

If this phenomenon is a result of previously given chemo/radio-therapy or it reperesents the natural evolution to a second primary, remains a challenging question to be answered.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-10-06.
Abstract P6-11-10: Full-Oral, Metronomic Schedule of Vinorelbine (VNB) and Capecitabine (CAPE) in Locally Advanced or Metastatic Breast Cancer (BC) Patients (Pts): A Single Institution, Dose-Finding Study
Authors: Cazzaniga ME , Torri V , Villa F , Giuntini N , Zeppelini A , Cortinovis D , Bidoli P.
Published: April 2011

BACKGROUND: Choice of chemotherapy is a major problem in locally advanced (LABC) or metastatic BC pts already treated with anthracyclines and taxanes, or not suitable for these drugs. VNB and CAPE are two valid options, both tested as single agents or in combination in this setting of pts. Different studies have demonstrated that the metronomic treatment could achieve a significant rate of clinical response with an acceptable toxicity profile. Based on the results of metronomic Phase I/II trial, which fixed the dose of VNB at 60 mg/tot thrice a week and considering that the two drugs have a different safety profile, we designed a dose-finding study, aiming to determine the optimal dose of oral VNB in combination with CAPE, both administered in a metronomic way. PATIENTS AND METHODS: Fixed dose of CAPE was 500 mg thrice a day, continuously. Level I dose of VNB was 20 mg/tot, three times a week for 3 weeks (1 cycle); subsequent cohorts started with 30 mg/tot Level II), 40 mg/tot (Level III) and 50 mg/tot (Level IV), respectively, if no Grade 3-4 toxicity was observed in the same dose level of the previous cohort.

Results: Twelve consecutive pts were enrolled. Median age was 67.5 years (49-81), 4 pts were LABC or metastatic at diagnosis, HR status was positive in 11/12 pts (91.6%), 2 pts were HER2+ but could not or no longer receive antiHER2 agents due to cardiac failure. All pts but 2 (83.3%) received anthracyclines, taxanes or both. Mean number of metastatic sites was 3 (1-5). At the 50 mg level of dose, 1 pt developed G3 neurological toxicity during the 3rd week of cycle 1 and 1 pt G4 neutropenia in the 2nd week of cycle 2. No pts treated with the 40 mg level of dose experienced G3 toxicity. The Maximum Tolerated Dose (MTD) was fixed at 40 mg thrice a week.

CONCLUSION: MTD of metronomic full-oral schedule of VNB in combination with fixed dose of CAPE was 40 mg thrice a week and was the recommended dose for the further ongoing Phase II study.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-10.
Abstract P6-11-11: Trastuzumab beyond Progression in HER2-Positive Advanced Breast Cancer: The Royal Marsden Experience
Authors: Waddell T , Kotsori A , Constantinidou A , Yousaf N , Ashley S , Parton M , Johnston S , Smith I.
Published: April 2011

Background: Routine clinical practice and a growing body of evidence support the continuation of trastuzumab (T) in patients with HER-2 positive (+ve) advanced breast cancer progressing on previous T-based therapy. Despite this, recent UK clinical guidance advises against continuing T on evidence of disease progression (PD) in the absence of brain metastases. This retrospective study therefore evaluated the outcome of patients (pts) with HER-2+ve locally advanced (LA) or metastatic breast cancer (MBC) who continued T beyond PD, treated in our Unit. Patients and methods: HER-2+ve pts receiving T for LA or MBC were identified from our prospectively maintained database and pharmacy records. Those receiving T beyond PD after adjuvant or one line of T for advanced disease were assessed for response and outcome. From thetimepoint of T continuation beyond PD we calculated the overall disease control rate (response or stable disease), time to progression (TTP), and overall survival (OS).

Results: 114 pts with HER-2+ve LA or MBC treated with T beyond PD were identified. At the time of analysis 35 (31%) pts were still alive with a median follow up of 20 months (mo). The main site of disease was visceral in 84 (74%) pts, including 37 (32%) pts with CNS involvement. 30 (26%) pts had soft tissue or bone metastases only. Fifty nine (52%) pts had received adjuvant chemotherapy and 13 (11%) pts had received adjuvant T. Seventy six (66%) pts had 1 line of chemotherapy prior to continuation of T beyond PD and 21 (19%) had 2 or more lines. Fifty three (46%) pts had previously received taxanes + T for their LA or MBC. Post-progression, 66 (58%) pts received T combined with chemotherapy; 12 (11%) taxane-based, 32 (28%) capecitabine and 22 (19%) vinorelbine. Information regarding response was not available in 21(18%) pts. Of the ninety three (82%) pts with documented clinical (n=16) or radiological (n=77) response evaluation, 68 (60%) pts were considered as having stable disease (SD) or better and 25 (22%) as having PD. The median duration of T was 10 mo (95% CI: 8-11 mo), the median TTP was 24wks (95% CI: 21-28 wks) and the median OS was 19 mo (95% CI:12-24mo). In a sub-group analysis of the 81(71%) pts who received T as first-line Rx or relapsed within 12 wks of adjuvant T, overall disease control was achieved in 50 (61%) pts, the median TTP was 25wks (95% CI:18-33 wks) and the median OS was 22 mo(95% CI:17-27mo). In terms of safety, only 6 (5%) pts overall had to discontinue T secondary to decline in left ventricular ejection fraction.

Conclusion: Our results from an unselected group of patients are supported by positive results from other studies and provide additional evidence that continuation of trastuzumab beyond disease progression is of clinical benefit.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-11.
Abstract P6-11-14: Long-Term Disease Control with Vinorelbine, Cisplatin and Continuous Infusion of 5-Fluorouracil -ViFuP Regimen-in Metastatic Triple Negative Breast Cancer Patients
Authors: Sciandivasci A , Munzone E , Aurilio G , Adamoli L , Botteri E , Locatelli M , Esposito A , Minchella I , Cullura’ D , Curigliano G , Goldhirsch A , Nole’ F.
Published: April 2011

Background: Triple negative breast cancers (TNBCs) are characterized by lack of estrogen, progesterone, HER-2-neu receptors expression and comprise 15% to 20% of all breast cancers. Studies have suggested that

TNBCs may be more sensitive to DNA damaging agents like cisplatin. Our previous experience had identified a combination chemotherapy -the ViFuP regimen-with noteworthy efficacy and safety as a first or subsequent line treatment for metastatic breast cancer (MBC) patients (pts). In this view we retrospectively examined the activity of ViFuP regimen in 2 cohorts (A and B) of metastatic TNBC pts.

Material and Methods: From January 2000 to December 2008, 115 pts with MBC were treated with ViFuP regimen, at the European Institute of Oncology, Milan, Italy. Among these, 35 pts (30%) had TNBC. Pts received continuous infusion 5-fluorouracil 200 mg/m2/day, vinorelbine 20 mg iv on days 1 and 3 and cisplatin 60 mg/m2on day 1. Therapy was given every three weeks. In A 22 pts (63%) were triple negative on primary tumor and in B 13 pts (37%) were triple negative in metastatic site. Median age was 54 years (range 35-73), 11 pts (31%) were pre-treated for MBC and 21 pts (60%) had ≥3 metastatic sites.

Results: Thirty three pts were evaluable for response and 34 pts were assessable for toxicity. Median duration of treatment was 3.57 months (range 1-5.7). Four pts (12%) had complete responses, 14 pts (42%) had partial responses and 11 pts (33%) had stable disease with a clinical benefit (CB) of 73% (95% CI, 55%-87%). Four pts (12%) had progressive disease. Median time to progression was 6 months (95% CI, 5-8 months). Main toxicity was haematological with 62% of the pts showing grade 3/4 leuco-neutropenia. Alopecia was almost absent.

Discussion: Treatment with ViFuP regimen was effective and safe in metastatic TNBC providing long-term disease control in a high proportion of pts. The prolonged CB supports this regimen as an additional therapeutic opportunity in this category of pts.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-14.
Abstract P6-12-04: Patterns of Trastuzumab-Based Treatment in Advanced Breast Cancer — Results from a Large GERMAN Non-Interventional Study
Authors: Jackisch C , Hinke A , Schoenegg W , Soeling U , Stauch M , Thomas G , Kuehn W , Gerhard K , Reichert D.
Published: April 2011

Background: In an ongoing, prospective observation study, treatment pattern of HER2 antibody-based treatment in metastatic breast cancer (MBC) in clinical routine is evaluated in Germany since 2001. Material and methods: A total of 1.687 patients (pts), presenting with Her2neu overexpressing MBC either pretreated (39%) or naïve to palliative chemotherapy (CT), were recorded in 202 German institutions. The median duration of fully documented therapy was 51 weeks. Additional information on trastuzumab (T) treatment beyond progression (TBP) was retrieved, as well as long-term outcomes, progression-free and overall survival (PFS, OS) in a subgroup of 940 pts, in which the treatment documentation had been finalized before July 2007.

Results: According to the most recent recommendations the majority of pts received T concurrently with chemotherapy (74%), 14% received T in combination with endocrine therapy (ETO). and 12% T as single agent therapy (SAT). In a multivariate logistic model, the choice of a non-cytotoxic regimen (ETO/SAT) was independently associated with the following pts characteristics: no visceral metastasis (p = 0.0000002), and positive hormone receptor status (p = 0.0018), while higher patient age (> 65 y) (p = 0.061), and number of metastatic sites < 2 showed a clear trend. No major correlation was observed between administration of cytotoxic treatment and relapse-free interval after initial diagnosis of breast cancer, adjuvant chemotherapy, adjuvant hormone therapy, and metastatic disease at initial diagnosis. After a median follow-up of more than 30 months (mo), median PFS (840 events) was 11.1, 9.9 and 19.1 mo and median OS (530 deaths) was 32.7, 39.6 and 48.8 mo in the CT, SAT and ETO group, respectively. Overall best response rates were 64%, 47%, and 45%.

Trastuzumab TBP was applied with a growing tendency over time and could be analyzed in a subgroup of 376 first-line patients with progression within approximately one year. The prolongation of trastuzumab remains to be strongly associated with longer survival after first progression in this updated analysis (medians: 15.1 vs. 20.6 mo; HR = 0.66, 95% CI: 0.49 - 0.88; p = 0.0045).

Conclusion: This large non-interventional trial reveals that 74% of all included patients were treated with trastuzumab plus CT which is considered standard of care for 1stline HER2+ MBC. The decision for not choosing a CT-based regimen was associated with good prognostic factors (no visceral metastasis, positive hormone receptor status, only one metastatic site) or higher age. Trastuzumab beyond progression is used increasingly in routine clinical practice and results in a prolonged survival.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-12-04.
Abstract P6-13-02: Survival Outcomes with Eribulin Mesylate vs. Treatment of the Physician's Choice (TPC) in Heavily Pretreated Subjects with Locally Recurrent or Metastatic Breast Cancer in North America, Western Europe, and Australia: Results of the Phase III EMBRACE Study
Authors: Vahdat LT , Twelves CJ , Seegobin S , Akerele C , Wanders J , Cortes J.
Published: April 2011

Background: Eribulin mesylate (E7389) is a nontaxane microtubule dynamics inhibitor. We conducted a randomized, controlled, open-label, phase III study to compare the efficacy and safety of eribulin vs. TPC in heavily pretreated subjects with locally recurrent or metastatic breast cancer. This report focuses on outcomes for participants enrolled in North America, Western Europe, and Australia (Region 1).

Methods: Eligible subjects had locally recurrent or metastatic breast cancer and had received 2-5 prior chemotherapy regimens, including an anthracycline and a taxane, with ≥2 of the regimens given for locally recurrent or metastatic disease. Subjects were stratified by geographic region, HER2/neu status, and prior capecitabine treatment. They were randomized 2:1 to receive eribulin 1.4 mg/m2 intravenously over 2-5 minutes on Days 1 and 8 every 21 days or an approved TPC. The primary endpoint was overall survival (OS); progression-free survival (PFS) was a secondary endpoint.

Results: A total of 762 subjects in 135 centers worldwide were enrolled. Subjects had a median age of 55 years, 92% were white, 76% were postmenopausal, and 81% had taxane-refractory disease. The median time since original diagnosis was 6.7 years. The majority of subjects (488 [64%]) were from Region 1, of whom 325 received eribulin and 163 received TPC. The most common treatments received by subjects from Region 1 in the TPC arm were vinorelbine (28%), gemcitabine (17%), capecitabine (13%), taxanes (20%), and anthracyclines (12%). 9% of subjects in this region received other therapies. Among the intent-to-treat population in Region 1, median OS was significantly prolonged with eribulin (13.3 months) vs. TPC (10.2 months) (HR: 0.724; 95% CI: 0.568-0.924; p=0.009). Median PFS was also prolonged with eribulin (3.3 months) vs. TPC (2.2 months; HR: 0.843; 95% CI: 0.666-1.066; p=0.153) in this population, as assessed by independent reviewers.

Conclusion: OS was significantly prolonged in eribulin-treated patients participating in the EMBRACE trial in the North America, Western Europe, and Australia region. When assessed by independent review, PFS was also prolonged with eribulin, although this difference did not reach statistical significance for this geographic region.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-13-02.
Abstract P6-13-03: Local Treatment Strategies in Young and Elderly Stage IV Breast Cancer Patients in the USA and The Netherlands
Authors: van de Water W , Bastiaannet E , van de Velde S , Dekkers OM , Margenthaler JA , Deshpande AD , Jeffe DB , de Craen AJM , van de Velde CJH , Liefers GJ.
Published: April 2011

Introduction

Approximately 5-10% of breast cancer patients present with stage IV at diagnosis. The appropriate treatment is still under debate. This study focused on differences in treatment regimens between the United States (USA) and the Netherlands (NL) within age groups.

Methods

As we included data from NL and the USA, we were able to construct an instrumental variable as a substitute for randomization and get around selection bias. We compared Dutch and USA treatment strategies; restrictive versus more often extensive local therapy. Data from the NL Cancer Registry and the US Survaillance, Epidemiology and End Results Program were used to construct a database for analyses. All primary stage IV breast cancer patients diagnosed in 1995-2003 were included. Follow up cutoff date was 12- 31-2005 (USA) and 12-31-2008 (NL). Analyses were stratified by age (<65, 65-75 and ≥75 years). Chi Square Tests were performed for therapy rates, overall survival was calculated by Cox Proportional Hazard Analyses.

Results

A total number of 11030 patients were included (5354 NL, 5676 USA). Within each age category, surgery was applied more often in the USA (<65: NL37%-USA52%, P<0.001. 65-75: NL28%-USA42%, P<0.001. ≥75: NL21%-USA39%, P<0.001).

Similar results were observed for use of radiotherapy after surgery (<65: NL30%-USA47%, P<0.001. 65-75: NL26%-USA44%, P<0.001. ≥75: NL 17%-USA36%, P<0.001). Rate of radiotherapy without surgery did not differ between the two countries. With increasing age, use of surgery and use of radiotherapy after surgical treatment decreased (NL, USA each P<0.001). Use of radiotherapy without surgical intervention however increased with age in both countries (NL p=0.002, USA p=0.001). Although unadjusted analysis showed enhanced overall survival for patients <65 years of age in the USA compared to NL (HR 0.92 (0.86-0.98), p=0.006), these results were not confirmed in multivariable analyses. Patients ≥75 years of age in the USA compared to NL, however, had worse overall survival, confirmed in multivariable analyses (HR 1.17 (1.08-1.27), P<0.001).

Conclusion

Surgery and radiotherapy after surgical treatment for stage IV breast cancer patients was applied more often in the USA compared to NL in all age categories. Use of local therapy decreased with increasing age. In multivariable analyses, patients ≥75 years of age had a worse overall survival in the USA. This finding suggests that a more extensive local treatment strategy does not improve overall survival in this group of elderly patients. The opposite was true for young patients, although these results were not confirmed in multivariable analyses.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-13-03.
Abstract P6-14-01: Effect of Denosumab Versus Zoledronic Acid Treatment in Patients with Breast Cancer and Bone Metastases: Results from the Extended Blinded Treatment Phase
Authors: Stopeck A , Martin M , Ritchie D , Body J-J , Paterson A , Viniegra M , Jassem J , Takano T , Van Poznak C , Bourgeois H , Fan M , Dansey R , Braun A.
Published: April 2011

Background: Denosumab is a fully human monoclonal antibody which inhibits RANKL, a key mediator of osteoclast activity. Results from the primary analysis of this pivotal phase 3 trial showed that denosumab was superior to zoledronic acid (ZA) in delaying the time to first on-study skeletal-related events (SRE) in patients with breast cancer and bone metastases. We now report results including an additional 4 months of blinded treatment.

Methods: Randomized patients received either subcutaneous (SC) denosumab (120 mg) and intravenous (IV) placebo or IV ZA (4 mg, adjusted for renal function) and SC placebo every 4 weeks. No dose adjustments were made for SC denosumab. All patients were advised to take daily calcium (≥500 mg) and vitamin D (≥400 IU) supplements. The primary endpoint was time to first on-study SRE (predefined as pathologic fracture, radiation or surgery to bone, or spinal cord compression). Time to first and subsequent SRE (multiple event analysis) and safety endpoints were also evaluated. Analyses for the extended treatment phase are considered exploratory.

Results: Overall, 2046 patients enrolled: 1026 were randomized to denosumab and 1020 were randomized to ZA. Denosumab was superior to ZA in delaying the time to first on-study SRE by 18%, and the time to first and subsequent on-study SRE by 22% (Table). The median time to first on-study SRE was 5 months longer for the denosumab group (32.4 months) than the ZA group (27.4 months). Overall survival and disease progression were similar for both treatment groups. Similar percentages of subjects reported adverse events (AEs; 96.2% denosumab, 97.4% ZA) and serious AEs (47.9% denosumab, 50.2% ZA). Positively adjudicated cases of osteonecrosis of the jaw were reported in 2.5% (n=26) of denosumab-treated patients and 1.8% (n=18) of ZA-treated patients (P=0.29). Hypocalcemia was reported by 62 (6.1 %) patients in the denosumab group and 37 (3.7%) patients in the ZA group.

Conclusion: Among patients with breast cancer and bone metastases, denosumab was superior to ZA in delaying or preventing SREs, and continued treatment with denosumab resulted in a median time to first SRE that was 5 months longer than treatment with ZA. Denosumab, with its novel mode of action, may represent a potential treatment option for patients with breast cancer and bone metastases without the need for dose adjustment or renal monitoring.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-01.