bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P4-03-05: The Warburg Effect and RUNX2-Regulated Metabolic Switching in Breast Cancer: A New Therapeutic Target?
Authors: Passaniti T , Chumsri S , Girnun G , Brodie A , Choe M.
Published: April 2011

Breast cancer (BC) is the leading cause of cancer deaths among women in North America and Western Europe. Numerous studies have shown that breast tumor progression is associated with a switch from mitochondrial oxidative phosphorylation (OxPhos) to increased utilization of glucose and aerobic glycolysis (Warburg effect). Uncovering underlying mechanisms regulating this progression may lead to innovative approaches for treatment. The RUNX2 DNA-binding transcription factor is expressed in highly aggressive BC and regulates bone metastasis in animal models. We observed increased expression of RUNX2 in primary human ductal carcinoma in situ (DCIS), which correlated with grade and proliferative index (Ki67 staining), decreased estrogen receptor/progesterone receptor expression (ER/PR status), increased glucose uptake values by PET scanning, and increased expression of the glucose transporter, GLUT1. Further, more than 80% (9 out of 11) of triple-negative BC cell lines examined expressed RUNX2. Therefore, to test the hypothesis that RUNX2 may alter the metabolic status of breast cancers and increase their dependence on glycolysis during tumor progression, we have generated a Tet-OFF model system using MCF7 cells with inducible RUNX2 expression. RUNX2-positive MCF7 cells exhibited increased cell death under conditions of glucose depletion or when treated with 2-deoxy-glucose, a competitive inhibitor of hexokinase II. Conversely, RUNX2-positive cells were more resistant to OxPhos inhibitors (rotenone, oligomycin) than RUNX2-negative cells. We also observed higher expression levels of GLUT1 and pAKT in RUNX2-positive MCF7 cells. Hypoxia-inducible factor-α (HIF1α) is a transcription factor that regulates cancer metabolism through its activation of glycolytic genes, while SIRT6, an NAD-dependent deacetylase, is a negative regulator of HIF1α activity. This occurs, in part, via inhibition of HIF1α transcriptional activity. RUNX2-positive or negative cells expressed HIF1α in response to glucose but RUNX2-positive cells exhibited lower SIRT6 expression than RUNX2-negative cells, suggesting that with the loss of SIRT6, HIF1α might be more active in promoting glycolysis in the presence of RUNX2. These results suggest that RUNX2 may have clinical diagnostic value as an indicator of BC metabolic stress and predictor of poor prognosis. Current strategies are utilizing computer-assisted drug design to develop RUNX-specific inhibitors to target BC glycolysis and tumor growth.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-03-05.
Abstract P4-04-02: Isolation and Characterization of Adult Mammary Stem Cells from the Periphery of Breast Cancer
Authors: Shi A , Xu N , Fan Z , Jiang Y , Fu S.
Published: April 2011

Background: Normal adult mammary stem cells (AMSCs) provide promising cell sources for breast reconstruction, especially after the resection of breast tumors. However, the potential targeting by carcinogenic events may convert normal AMSCs to cancer stem cells, posing a safety issue for applying the AMSCs for tissue regeneration in clinic. Objective: In the current study, we characterized a population of AMSCs isolated from the normal tissue at the periphery of human breast tumors and provided evidence that these AMSCs remain normal but not cancerous phenotypes and therefore, could be candidates for breast reconstruction. Methods: A population of AMSCs was isolated from the normal tissue surrounding primary breast tumors using immunomagnetic sorting. The stemness of these cells were examined by differentiation analysis and the gene expression profile compared to that of the cancer cells by microarray, with several differentially expressed candidate genes confirmed by both RT-PCR and Western blot assays. The in vivo tumorigenic capability of these cells were also investigated and compared to that of MCF-7 cell line. Results: The AMSCs were positive for stem cell markers, epithelial specific antigen (ESA) and keratin 19 (K19). When stimulated with the differentiation agent, basic fibroblast growth factor (bFGF), these AMSCs formed lobuloalveolar structure with myoepithelium that are positive for CALLA. The gene expression profiles revealed that compared to the cancer cells, see Table 1,2. AMSCs were low in oncogenes such as c-myc, Ras and c-erbB-2, but high in tumor suppressor genes including Rb1, Pten and CDKN2A, see table 1,2 and fig 1,2. When injected into nude mice, the AMSCs formed no tumors but regular mammary ductal structures. Conclusion: The AMSCs isolated from the normal tissue surrounding the primary breast cancers present features of normal mammary stem cells, therefore, are promising candidates for mammary reconstruction after breast tumor resection.

Gene expression by western blot

(sample 1, 2, 3 were breast cancer; sample 4,5 were mammary stem cells)

CerbB2 rtranscription

(sample 1, 2, 3 were breast cancer; sample 4,5 were mammary stem cells)

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-04-02.
Abstract P4-05-02: Role of the Atr Protein Kinase and Curcumin in Tumor-Stromal Interactions in Breast Cancer
Authors: Aboussekhra A , Al-Ansari MM , Hendrayani S-F , Al-Tweigeri T.
Published: April 2011

Carcinoma-associated fibroblasts (CAFs) play important roles in the genesis and thrive of various types of epithelial cancers, including breast carcinomas. Indeed, various genetic and epigenetic variations have been identified in stromal fibroblasts, and we have recently shown that CAFs as well as their corresponding counterparts (TCFs) display neoplastic-specific changes (Hawsawi et al., 2008). We have also shown that the levels of the tumor suppressor proteins p53 and p21 are down-regulated in CAFs as compared to TCFs. During the cellular response to DNA damage these genes are under the control of important proteins such as Atr, a protein kinase essential for the maintenance of genomic integrity. To further elucidate the molecular changes that occur in breast cancer-associated fibroblasts we assessed the expression of Atr and have shown that the level of the Atr protein kinase is lower in 7 out of 10 (70%) CAFs as compared to their corresponding TCFs. Using specific ATR-siRNA we have shown that ATR negatively controls the expression of various proteins involved in the stromal-epithelial interactions. These include the stromal cell-derived factor 1 (SDF1), the vascular endothelial growth factor (VEGF) and the matrix metalloproteinase-2 (MMP2). In addition, the ELISA assay was used to show that the level of these proteins was higher in the conditioned media from stromal fibroblasts expressing specific ATR-siRNA as compared to control cells. Importantly, serum-free conditioned media from ATR-defective cells stimulated the proliferation and invasion/migration of cultured human breast cancer cells in an SDF1-dependent manner. These results clearly show the role of the breast stromal fibroblast Atr protein in suppressing tumoregenesis in the breast. Moreover, we have shown that curcumin can normalize the expression/secretion of these factors and therefore reduces the invasion/migration of breast cancer cells in vitro. This indicates that curcumin has potential use as stromal fibroblastnormalizing factor that can be utilized for the inhibition of both cancer initiation and recurrence.

Hawsawi, N. M., Ghebeh, H., Hendrayani, S. F., Tulbah, A., Al-Eid, M., Al-Tweigeri, T., Ajarim, D., Alaiya, A., Dermime, S., and Aboussekhra, A. (2008). Cancer Res 68, 2717-2725.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-05-02.
Abstract P4-06-02: Systemic Deletion of c-Jun N-Terminal Kinase 1 or 2 Is Protective in Breast Cancer Bone Metastasis
Authors: Nasrazadani A , Van den Berg CL
Published: April 2011

Growth and survival of metastatic breast cancer cells in the bone is enhanced by the release of growth factors during osteoclast mediated bone resorption. In order to facilitate release of bone degradation products, breast cancer cells continually stimulate osteoblasts, which in turn differentiate osteoclast precursors. Mature osteoclasts are then activated to secrete factors such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K to degrade bone matrix. Identification of molecular targets involved in these signaling pathways may prove beneficial for treatment of aggressive tumor types. Results from our previous studies demonstrated that tumor cell expression of c-Jun N-Terminal Kinases (JNKs) mediate lung and bone metastasis. To determine if systemic JNKs play a role in breast cancer progression, jnk1-/- and jnk2-/- Balb/c mice were used to study host related contributions to bone metastasis. The highly metastatic 4T1.2 syngeneic mammary tumor cells were injected intra-cardiac into jnk1-/-, jnk2-/-, and wild-type mice. Both jnk1-/- and jnk2-/- mice survived significantly longer than wild-type controls, (p=0.0034 and p=0.0459, respectively). Wild-type mice succumbed to symptoms of morbidity as early as 10 days post-injection whereas; 60% of the jnk1-/- and 40% of the jnk2-/- mice remained asymptomatic at day 55 and day 70, respectively. Analysis of ribcage metastases post-mortem revealed a significant decrease in bone lesions in jnk1-/- and jnk2-/- mice compared to wild-type mice (P<0.0001 and p=0.0031, respectively). We then evaluated if jnk1 or 2 expression may inhibit osteoclast differentiation and slow tumor related osteolysis, Raw 264.7 osteoclast precursor cells were employed to knockdown Jnk1 or Jnk2 expression to study their proliferation and differentiation into osteoclasts. Proliferation of JNK1and JNK2 deficient osteoclast precursors (Raw shJNK1 and Raw shJNK2, respectively) was slightly decreased compared to wild-type Raw 264.7. In contrast, Receptor Activator for Nuclear Factor κB Ligand (RANKL) induced osteoclast differentiation was impaired in both Raw shJNK1 and Raw shJNK2 cells. Collectively, our results suggest the involvement of JNK1 and JNK2 in osteoclast differentiation, thus playing a vital role in breast cancer metastasis to the bone. These data suggest that therapeutic inhibition of JNKs may improve the morbidity and mortality associated with bone metastasis in breast cancer patients.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-02.
Abstract P4-06-11: Gene Expression Profiling Identifies Potential Precursor Genes in Lobular Carcinoma In Situ
Authors: Andrade VP , Morrogh M , Qin L-X , Olvera N , Giri D , Brogi E , de Alcantara-Filho P , Paik W , Muhsen S , Morrow M , King TA.
Published: April 2011

INTRODUCTION: Historically lobular carcinoma in situ (LCIS) has been considered a risk marker but not a true precursor of invasive breast cancer. Emerging evidence of clonal relatedness between LCIS and synchronous invasive lobular cancers (ILC) has reopened this debate. We hypothesized that gene expression profiling of LCIS and synchronous ILC could identify genes that confer precursor potential in LCIS.

METHODS: Patients with LCIS +/− ILC undergoing mastectomy were prospectively identified. Mastectomies were sampled to collect fresh frozen normal epithelium (N), LCIS and ILC. Laser Capture Microdissection was used to isolate purify cell populations and total mRNA was subject to Affymetrix HU133 2.0 gene expression array. Transcript abundance was compared across samples in a paired analysis (P<0.001) using the R software. Potential precursor genes (PPG) were defined as those with monotonically increasing or monotonically decreasing expression from N to LCIS to ILC. Cellular functions and pathways were identified using the Ingenuity Pathway Analysis.

RESULTS: Patient matched triplets (N, LCIS, ILC) were available from 23 mastectomies. 206 probe sets (178 genes) fit the PPG definition, 154 probe sets (130 genes) displayed monotonically decreasing expression and 52 probe sets (48 genes) displayed monotonically increasing expression. The table shows the top five cellular functions and canonical pathways related to the (PPG).

The candidates PPGs are distributed across all chromosomes, with the highest frequencies on 1 q (9.6%), 16q (7.3%), 2q (5.06%), 5q (5.06%) and 4q (4.49%). All 13 potential precursor genes identified on 16q and the 9 PPG identified on 5q showed monotonically decreasing expression while 13/17 PPGs identified on 1q showed monotonically increasing expression. Among all upregulated PPG, 27.1% are located at 1q while 10% of all downregulated PPGs are located at 16q.

CONCLUSIONS: Gene expression profiling identified 178 candidate genes with monotonically increasing or monotonically decreasing expression across patient matched samples of N-LCIS-ILC. Top cellular functions and canonical pathways represented by the candidate genes are known to be associated with carcinogenesis, suggesting that dysregulation of these candidate genes may confer precursor potential in LCIS. The abundance of potential precursor genes on chromosomes 1 q and 16q is also consistent with the model of lobular carcinogenesis.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-11.
Abstract P4-06-13: c-Jun N-Terminal Kinase 1 (JNK1) Inhibits Tumor Progression and Regulates Embryonic Mammary Development
Authors: Ebelt ND , Ven Den Berg CL
Published: April 2011

Background: Specification of the murine mammary placode in embryonic development involves pathways that are dysregulated in murine and human breast cancers. Beginning with secretion of Neuregulin 3 (Nrg3) and Wingless-Integrated (Wnt) 10b by the dermal mesenchyme, at embryonic day (E) 10.5, a mammary placode will condense over 48 hours due to signaling through the canonical Wnt pathway as well as through the avian ERythroBlastosis oncogene B (ErbB) receptors 4 and 2. By E15.5 placodes will invade the underlying mesenchyme to form the primary duct. The Wnt and ErbB pathways are also known to cause or promote cancer when dysregulated.

Methods and Materials: Number four mammary glands of female, virgin mice (jnk1+/+ or jnk1-/-) were harvested and stained with carmine alum to observe ducts. Wildtype mice were injected with 4T1.2 cells with shRNA targeted to Jnk1 (shJnk1) or non-targeting shRNA (GipZ). Tumors were palpated for growth changes and lungs were stained with India ink to observe lung metastases. RNA from tumors was compared using microarray fro expression of cancer related genes. Results: We have observed that adult glands from jnk1-/- mice contain multiple primary ducts whereas jnk1+/+ mice contain only one, indicating a possible defect during embryonic placode formation. This phenotype mimics what has been previously reported in models of ectopic NRG3 expression. In a 4T1.2 murine mammary cancer model, shJnk1 results in increased tumor growth as well as increased lung metastasis when compared to cells transfected with GipZ. In the tumors grown from the 4T1.2shJnk1 and 4T1.2GipZ cells, a microarray analysis revealed increases in Nrg3, Wnt targets and ligands, and the ErbB2 and Wnt target ETV5 in 4T1.2shJnk1 cells. An increase in the expression of ETV5, Bcl-9, Cox-2 (an ETV5 target), and ErbB2 (a target of ETV5) in 4T1.2shJnk1 cells vs 4T1.2GipZ cells has been confirmed by RT-PCR and western blotting for ErbB2 (Figure 2). I plan to determine how JNK1 affects the Wnt and ErbB pathways in mouse embryos and mammary tumor models. Since Wnt and ErbB pathways are necessary for placode formation, it is likely that these pathways, which are upregulated in our cancer model, are involved in the embryonic phenotype. I hypothesize that JNK1 loss causes increased signaling through these pathways, resulting in the formation of ectopic mammary placodes as well as a more aggressive tumor phenotype. If my hypothesis is supported by these studies then future studies will evaluate if low jnk1 expression is associated with a higher risk of developing breast cancer or a worse prognosis using publically available microarray datasets derived from human tumor samples.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-06-13.
Abstract P4-08-03: False Positive HER-2 Testing by Fluorescence In Situ Hybridization in Human Breast Cancer
Authors: Ramsey B , Hanlon Newell A , Troxell M , Olson S , Keenan E , Luoh S-W.
Published: April 2011

Background: Testing for human epidermal growth factor receptor-2 (HER-2) is routinely performed after breast cancer diagnosis by either immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). FISH is more accurate and reproducible, often considered the gold standard, and a more reliable predictor of a patient's response to HER-2 directed therapies in clinical practice. The growth factor receptor-bound protein-7 gene (GRB7) encodes a multi-domain signal transduction molecule located in close proximity to HER-2 on chromo some 17q11-12 and has been shown to be an independent adverse prognostic marker in breast cancer. Methods: We performed western blotting analysis of protein extracts from 563 annotated frozen breast tumors, collected from 1988 - 1998. GRB7 and HER-2 bands were assigned low or high values compared to specific protein controls, and tubulin bands. HER-2 FISH was performed on a subset of these tumors using an FDA approved Path Vysion kit on 4 μm frozen sections. HER-2 and chromosome 17 centromere (CEP17) signals were enumerated according to ASCO/CAP guidelines. Results: Sixty-six tumors (11.5%) over-expressed HER-2 and GRB7 proteins by Western analysis, 66 (11.5%) over-expressed HER-2 but not GRB7, and 30 (5.5%) over-expressed GRB7 but not HER-2. All 32 tumors (32/32) submitted to FISH analysis that over-expressed both HER-2 and GRB7 proteins demonstrated HER-2 gene amplification, while only one out of thirty-five (1/35) tumors that over-expressed HER-2 without GRB7 protein over-expression were HER-2 amplified. Interestingly, 7 of 28 tumors over-expressing GRB7 but not HER-2 protein were amplified for the HER-2 gene. Clinical laboratory HER-2 IHC testing confirmed the absence of HER-2 protein over-expression in all 7 of these tumors. Conclusions: Our study demonstrates that about ten percent of human breast cancers that test positive with FISH for HER-2 gene amplification do not over-express HER-2 protein, which may influence sensitivity to HER-2 directed therapy. All tumors that show false positive HER-2 gene amplification over-express GRB7 protein, suggesting the presence of GRB7 driven gene amplification in these tumors. Given that the HER-2 FISH probe contains GRB7 sequences, it is possible that HER-2 FISH false positivity may reflect GRB7 gene amplification.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-08-03.
Abstract P4-09-01: Poly (ADP-ribose) Polymerase-1 mRNA Expression in Human Breast Cancer: Correlations with Subtypes and Prognostic Impact
Authors: Gonçalves A , Finetti P , Gilabert M , Sabatier R , Borg J-P , Viens P , Birnbaum D , Bertucci F.
Published: April 2011

Introduction: Although poly(ADP-ribose) polymerase-1 (PARP1) inhibition is a recent promising therapy in breast cancer, PARP1 expression in this disease is not known.

Methods. Using DNA microarray and array-based comparative genomic hybridization (arrayCGH), we examined PARP1 mRNA expression and copy number alterations in 326 invasive breast cancer samples and normal breast samples. A meta-analysis was performed on a large public retrospective gene expression dataset (n= 2,485) to analyze correlation between PARP1 mRNA expression and molecular subtypes and clinico-pathological parameters.

Results. PARP1 was overexpressed in 58% of cancers, and its expression was heterogeneous between tumors. ArrayCGH data revealed an association between mRNA overexpression and gain/amplification at the PARP1 locus (p<1.0E-8). Meta-analysis showed that PARP1 expression was higher in basal breast cancers (p<1.0E-72), but overexpression was also found in other subtypes. PARP1 expression correlated with high grade, medullary histological type, tumor size and worse metastasis-free survival (HR=1.12 [1.04-1.22]; p=0.004). In multivariate analysis, PARP1 expression had an independent prognostic value, which was restricted to patients untreated with any adjuvant chemotherapy.

Univariate and multivariate analyses in MFS in patients untreated with systemic adjuvant chemotherapy

Conclusion. These data demonstrate overexpression of PARP1 in a large number of breast cancers and its association with reduced metastasis-free survival. These results further support the development of PARP inhibitors in basal subtype but also potentially in other breast cancer subtypes.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-01.
Abstract P4-09-06: Breast Cancer Prognosis Is Inherited Independently of Patient, Tumor and Treatment Characteristics
Authors: Rapiti E , Hartman M , Usel M , Benhamou S , Schaffar R , Neyroud-Caspar I , Czene K , Vlastos G , Chappuis PO , Bouchardy C , Verkooijen H.
Published: April 2011

Fondation Jean Dausset, Paris, France; Karolinska Institute, Stockolm, Sweden; Geneva University Hospitals, Switzerland Introduction: Several studies have suggested that survival of breast cancer is inherited, but none has assessed if this observation is linked to shared tumor characteristics or type of treatment. We studied the association of survival among first-degree relatives (FDRs) with breast cancer, taking into account characteristics of patients, tumors and treatments. Methods: In the population-based Geneva Breast Cancer Registry, we identified 162 pairs of FDRs diagnosed with breast cancer. Based on the breast cancer specific survival status of their proband (i.e. the mother or older sister), we categorized FDRs into poor, medium and good familial survival risk groups. We compared patient, tumor and treatment characteristics between categories and calculated standardized mortality ratios (SMRs) and adjusted disease specific mortality for each group. Results: Breast cancer patients in the poor familial survival risk group were more likely to be diagnosed at later stages than those in the good familial survival risk group. Similarly, they had higher SMRs than those in the medium and good survival risk groups (18.7, 95% Confidence Interval [CI]: 9.4-33.5 versus 16.5 95% CI: 7.6-31.4 and 9.4, 95% CI: 3.4-20.3, respectively). After adjustment for prognostic factors, women in the poor familial survival risk group were almost five times more likely to die of breast cancer than those in the good survival risk group (adjusted Hazard Ratio 4.8, 95% CI: 1.4-16.4).

Conclusion: This study shows that breast cancer prognosis clusters within families, and suggests that the hereditary component is independent of patient, tumor characteristics and type of treatment.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-06.
Abstract P4-09-08: PTEN Protein Expression in Postmenopausal Steroid Receptor Positive Early Breast Cancer Patients Treated with Adjuvant Tamoxifen
Authors: Milovanovic ZM , Susnjar SV , Plesinac-Karapandzic VS , Juranic ZD , Tatic SB , Dzodic RR.
Published: April 2011

Background: Since one of possible causes of resistance to antiestrogen therapy in SR+BC patients is an alteration of PTEN (Phosphatase and Tensin homolog deleted on chromosome 10) signaling pathways, the aim of this study was to determine the PTEN protein expression in postmenopaual patients with steroid receptor (SR)+ breast cancer (BC) treated with adjuvant tamoxifen, to investigate the association of PTEN protein expression with tumor histology, size and grade, estrogen receptor (ER), progesteron receptor (PR) and human epidermal growth receptor 2 (HER2) statuses and disease outcome, as well.

Patients and methods: This was a retrospective analysis of 78 postmenopausal SR+BC patients treated for stage I/II with adjuvant tamoxifen. PTEN protein expression and ER, PR and HER2 status were determined using immunohistochemistry method.

Results: The distribution of PTEN protein expression according to tumor histology was as follows: PTEN+ status in 27/43 (62,8%) patients with ductal and in 26/35 (74,3%) patients with lobular carcinomas and PTEN-status in 16/43 (37,2%) patients with ductal and in 9/35 (25,7%) patients with lobular carcinomas. Disease relapse was observed in 38/78 pateints: 14/53 (26.4%) of PTEN+BC subgroup and 24/25 (96%) of PTEN-BC subgroup. There were no significant association between PTEN protein expression and tumor histology, size and grade, and ER, PR and HER2 expression, as well. Patients with PTEN-BC had significantly shorter disease-free interval and overall survival (for both Log rank test, P<0.01) compared to PTEN+BC pateints.

Conclusion: Our results suggest that PTEN protein expression might be of prognostic significance in postmenopausal SR+ BC patients treated with ajduvant Tamoxifen.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-08.
Abstract P4-09-12: The Effect of Age on Breast Cancer Outcomes in Women with Her-2 Positive Breast Cancer: Results from the HERA Trial
Authors: Partridge AH , Gelber S , Piccart M , Focant F , Scullion M , Winer E , Gelber R
Published: April 2011

Background: Previous research has suggested that young age at diagnosis is an independent risk factor for breast cancer recurrence and death. However, young women are more likely to develop more aggressive subtypes of breast cancer and no prior studies have adequately controlled for Her-2/neu status or anti-Her-2 treatment. We sought to evaluate whether age is a prognostic factor in the HERA trial, which is a large randomized phase III trial of women with Her-2 positive early stage breast cancer who were randomized to receive trastuzumab (for one or two years) or observation following (neo)-adjuvant chemotherapy.

Methods: We used 2 year median follow-up data from the HERA trial and conducted Cox proportional hazards models. Age was dichotomized at ≥40 years versus > 41 years to evaluate its prognostic effect on outcomes in women who received trastuzumab and those who did not. Only patients included in the 1-year trastuzumab and observation arms were included in the present analysis.

Results: Of the 1703 women randomized to one-year of trastuzumab and 1698 to observation, 722 (21%) were age 40 or younger at study entry. Younger women were more likely to have node negative (33% vs 37%), estrogen receptor (ER)-negative (56 % vs 49%), and progesterone receptor (PR)-positive disease (41% vs 32%). In separate Cox models controlling for T and N stage, grade, ER and PR status, chemotherapy, endocrine therapy, and menopausal status at randomization, disease-free survival (DFS) hazard ratios were consistent for women ≥40 years compared with > 41 years old patients, regardless of whether they were assigned to observation or to receive trastuzumab. DFS were as follow: observation group: HR (younger/older) = 1.09, p-value = 0.62; trastuzumab group: HR (younger/older) = 1.05, p-value = 0.84. There was no statistically significant interaction between age and treatment (p=0.94).

Conclusions: In women with early stage Her-2/neu positive breast cancer in a large RCT, age was not an independent predictor of risk of early recurrence. Future research to investigate whether age is a predictor of later risk of recurrence or is a predictor among women with other tumor subtypes is warranted.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-12.
Abstract P4-09-17: Case-Matching Study Comparing Outcome of Unilateral and Synchronous Bilateral Breast Cancer
Authors: Nichol A , Yerushalmi R , Tyldesley S , Lesperance M , Bajdik C , Speers C , Gelmon K , Olivotto I.
Published: April 2011

Background: Several retrospective studies have demonstrated worse outcomes for patients with synchronous bilateral breast cancer (SBBC) compared to unilateral breast cancer. This study aimed to determine whether SBBC outcomes can be estimated accurately from the characteristics of the higher-risk cancer.

Material and Methods: In the province of British Columbia, Canada, women newly diagnosed with invasive breast cancer between 1989 and 2000, without metastatic or inflammatory presentation, were identified: 207 with SBBC (< 2 months apart) and 15,497 with unilateral breast cancer. Their breast cancer-specific survival (BCSS) outcomes were compared. Using 10-year BCSS estimates, the higher-risk cancer of each SBBC was determined. The priority sequence of matching of the prognostic and predictive variables was: positive lymph node number, primary tumor size, age, grade, lymphovascular invasion status, estrogen receptor status, type of local therapy, margin status, treating clinic, diagnosis year and systemic therapy use. A software program was employed on the 15,497-case cohort to select three unilateral cases that matched the maximum number of variables for the higher-risk cancer of each SBBC case, thereby generating a matched 621-case unilateral cohort.

Results: At a median follow-up of 10.2 years, the 10-year BCSS was significantly lower for the SBBC cohort, 71% (95%CI 63 — 77) than for the 15,497-case unilateral cohort, 81.1% (95%CI 80.5 — 81.8) (p < 0.001). However, the SBBC cohort had significantly higher median age and stage at presentation. After the matching, there was no significant difference for the eleven variables between the SBBC cohort and the 621-case unilateral cohort. The 10-year BCSS was 71% (95%CI 63-77) for the SBBC cohort and 74% (95%CI 69-77) for the matched 621-case unilateral cohort. Discussion: BCSS was similar between the SBBC cohort and the unilateral cohort matched to the higher-risk SBBC. Therefore, the outcome of women with SBBC is best estimated from their higher-risk cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-17.
Abstract P4-10-06: 10-Years Results of Intraoperative Electron Radiotherapy (IOERT) in Boost Modality in Breast Cancer Patients Treated with Breast Conserving Surgery
Authors: Reitsamer R , Kopp M , Fastner G , Menzel C , Glueck S , Merz F , Kopp P , Deutschmann H , Sedlmayer F.
Published: April 2011

Introduction:

The aim of this nonrandomized study was to compare the ipsilateral breast tumor recurrence rates in patients with invasive breast cancer, who had been treated with breast conserving surgery and whole breast irradiation and conventional boost or intraoperative electron radiotherapy boost (IOERT).

Patients and Methods:

378 patients were included in the study, 188 patients in group 1 (conventional boost) and 190 patients in group 2 (IOERT boost). Patients were comparable with regard to age, menopausal status, tumor size, histological type, grading and axillary lymph node status. Included were patients with invasive breast cancer pT1 and pT2, N0, N1, N2, M0, and breast conserving surgery with clear margins >3mm. Excluded were patients with DCIS only, patients with invasive breast cancers larger than pT2, patients after primary systemic therapy and patients with multicentric disease. All patients (group 1 and group 2) received postoperative whole breast irradiation of 51-56.1 Gy. Group 1 received postoperative electron boost irradiation of 12 Gy after whole breast irradiation and group 2 received one intraoperative electron boost of 9 Gy in a single fraction during surgery before whole breast irradiation. Results:

The 10-years actuarial rates of ipsilateral breast tumor recurrence (IBTR), true local recurrence (TLR), distant recurrence (DR) and disease free survival (DFS) were 7.1% (95%CI, 3.2-11.0%), 4.8% (95%CI, 1.5-8.0%), 14,2% (95%CI, 9.1-19.4%) and 82.4% respectively in group1 and 2.7% (95%CI, 0.0-5.9%, P=0.062), 0.7% (95%CI, 0.0-2.0%, P=0.016), 13.6% (95%CI, 5.0-22.2%, P=0.90) and 84.0% (P= 0.76) respectively in group 2.

Conclusion:

Patients treated with IOERT boost and whole breast irradiation achieve excellent local control rates at 10 years and exhibit statistically significant decreased true local recurrence rates compared to patients treated with whole breast irradiation and conventional electron boost.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-10-06.
Abstract P4-10-09: An Oncoplastic Surgical Planning Tool Based on Tumor Location Improves Breast Conservation Outcomes
Authors: Kaufman GJ , Clough KB , Oden S , Nos C , Safarti I.
Published: April 2011

OBJECTIVE

Oncoplastic Surgery is an evolving field in breast cancer surgery. Considerable variations in oncoplastic surgery (OPS) for breast conservation (BCS) have developed as the interest and utilization by both breast surgeons and plastic surgery teams continues to increase. Our goal is to assess the effectiveness of an oncoplastic surgical planning tool for BCS. The tool is a surgical atlas and guide that matches oncoplastic procedure recommendations for a specific tumor location.

BACKGROUND

Oncoplastic surgery for the treatment of breast cancer has been validated compared to standard BCS in terms of rate of re-excision, preservation of the natural breast shape, complications and 5-year local recurrence rates. Oncoplastic surgery incorporates plastic surgery techniques for the purpose of breast conservation. A bi-level OPS classification system and guide for patient selection was created to improve both patient outcomes and enable all breast surgeons to choose a safe and effective oncoplastic approach.

METHODS

This is a single institution prospective study of patients with breast cancer that had an oncoplastic level II procedure for breast conservation between 2005 and 2009 at the Paris Breast Center. The corresponding level II OPS technique was chosen for each patient based on the principals of patient selection and tumor location described in the atlas. A set of objective outcomes as well as an aesthetic evaluation was recorded based on tumor location and choice of procedure.

Results

A total of 151 patients met the criteria for performing a level II OPS for breast conservation based on the selection process outlined in the oncoplastic Atlas. The overall adherence rate for selection of procedure based on tumor location was 90%. The reexcision rate was 4% with greater then 80% of patients achieving a margin width exceeding .5cm and an average specimen weight of 144 grams. The conversion rate to mastectomy approached 12%. We found a good to excellent aesthetic outcome in 95% of evaluated patients. The rate of deformity in this level II OPS series was 0%. The early complication rate was 11% resulting in a delay of treatment for adjuvant therapy in less then 2% of patients.

Tumor Location and OPS Level II Procedure

Complications and Delay in Treatment

CONCLUSIONS

Adherence to the oncoplastic surgical guide resulted in an acceptable reexcision rate with the elimination of the risk of deformity for patients undergoing large volume resections for breast conservation. This initial assessment validates the efficacy of the atlas and provide surgeons with a reliable system to correctly choose the most appropriate oncoplastic procedure based on tumor location and avoids the complications associated with a one technique fits all approach for OPS.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-10-09.
Abstract P4-11-04: The Influence of Radiation on Survival in Patients with Triple Negative Stage II Breast Cancer
Authors: Hinton B , De Los Santos J , Keene K , Meredith R , Carpenter J , LoBuglio A , Falkson C , Krontiras H , Bland K , Wang C , Kim Y , Forero A.
Published: April 2011

Background: Prospective trials of locally advanced breast cancer patients treated with adjuvant radiation (RT) have demonstrated a survival advantage; however, use of postmastectomy RT in stage II patients is controversial. This study explores the possibility that patients with aggressive variant molecular subtypes [triple receptor negative (TN)] treated with modern chemotherapy, may experience a survival benefit from adjuvant RT.

Methods: Billing codes for all breast cancer patients treated with chemotherapy between 1/1998 and 5/2005 at the University of Alabama at Birmingham were reviewed to comprehensively capture all Stage II and III patients with intact data. Patient, tumor, and treatment related variables were recorded and patients were divided into 3 molecular subtypes based on receptor status: hormone receptor (HR) positive, Her2 negative; HR+/− , Her2+; and TN. Kaplan Meier curves to assess survival were performed by dividing the TN group into 2 groups: those who did or did not receive adjuvant RT.

Results: 409 patients with stage II-III disease with were identified. Out of this group, 81 patients had TN breast cancer (60 Stage II and 21 Stage III). RT data was known in 79 of these patients. Median age was 49 years. Median follow-up was 72 months. Thirty-seven stage II and 18 stage III patients received adjuvant RT. Of the stage II patients who received radiation, 25 underwent lumpectomy and 11 underwent mastectomy. Stage II patients who received adjuvant RT had a statistically significant improvement in DFS (p=0.03), and had a trend towards improvement in OS (p=0.07) when compared with those who did not receive adjuvant RT. There was no significant difference in survival for the stage III patients with use of RT, however numbers in this group were small. Conclusion: Adjuvant RT was associated with an improvement in DFS and a trend towards improvement in OS in patients with Stage II, TN breast cancers treated with modern chemotherapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-04.
Abstract P4-11-10: A Study of Intraoperative Radiotherapy with Electrons in Breast-Conserving Surgery in China: 3 Year Results
Authors: Zhou S , Sun C , Meng D , Shi W , Lv Q , Jing J , Zhao Y.
Published: April 2011

Background:The standard treatment for most localised breast cancer patients is the breast-conservating sugery followed by postoperative radiation worldwide. Preliminary studies of intraoperative radiotherapy with electrons(ELIOT) in selected patients, mainly in Europe since 1999, have shown good local control, less toxicity and satisfatory cosmetic apperance. However few studies have been conducted among non-western populations. To investigate the feasibility of ELIOT in China, we introduced ELIOT in selected early breast cancer patients. Risk of local relapse is the main outcome objective, toxicity and cosmetic results are also studied.

Patients and Methods:From June 2007 to May 2010, 51 patients diagnosed with unifocal breast carcinoma up to a diameter of 3cm received a wide excision of the primary tumor followed by a radiotherapy of 21Gy delivered to the breast tissue at the surface of the tumor bed, biologically equivalent to 58 to 60 Gy in standard fractionation.

The median age of the treated patients was 47 years, with 38/51(74.5%) patients younger than 50. 8 patients(15.7%) were found to have positive axillary I-nodes(six patients had one node involved, one patient had two and one had three positive nodes). Pathologic free margins ≥10 mm were obtained in all patients. Patients were evaluated semiannunally after surgery, and thereafter every 6 months for cosmetic results, complications and other events.

Results: After a follow-up from 4 to 36 months(median time12 months), 3 patients developed fat deliquescence, 16 patients showed wound edema and excess fluid and no one had incision infection or hematoma. Two patients developed local relapses. One was comfirmed unrecognised multi-focal cancer in other quadrants of the breast remain dormant. The other patient was confirmed ipsilateral positive axillary III-nodes and no relapse was found in the same quadrant. Neither contralateral breast cancer nor distant metastases were observed. No replase was found in patients aged <50. Accodring to the JCRT standard, cosmetic result was excellent in 73.1% and 90.9% patients at one year and two year checkup respectively, and good was found in 15.4% and 9.1% patients.

Conclusion:The incidence of breast cancer remains to increase in China with the aging of society and changes of lifestyle, and the highest incidence is found in the age group 45-50 years.Our study suggested the toxicity and cosmetic evalution were good. Data on local control were encouraging, especially for those under 50. ELIOT of 21Gy was a well-tolerated treatment in early stage Chinese breast cancer patients. And further follow up is still needed.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-10.
Abstract P4-11-13: A Multi-Institutional Assessment of the Feasibility, Implementation, and Early Clinical Results with Noninvasive Image-Guided Breast Brachytherapy for Tumor Bed Boost
Authors: Hamid S , Ackerman S , Arthur D , Benda R , Cavanaugh S , Kuske R , Prestidge B , Quiet C , Sha S , Wazer DE.
Published: April 2011

Background: Noninvasive image-guided breast brachytherapy (NIIGBB) is an FDA-approved, commercially available (AccuBoost®, Billerica, MA) mammography-based, breast brachytherapy system whereby the treatment applicators are centered on the planning target volume (PTV) to direct 192Ir emissions along orthogonal axes. This study evaluates the feasibility, implementation, and early results of NIIGBB for breast tumor bed boost in combination with external beam whole breast radiation therapy (WBRT), as part of post-lumpectomy radiation.

Material and Methods: A privacy-encrypted online data registry was created to collect clinical and technical information from 8 independent academic and community-based institutions. Data were collected from consecutive 110 individual women with early stage breast cancer after breast conserving surgery, who received adjuvant WBRT (mean dose 48.3 ± 2.5 Gy) and tumor bed boost with NIIGBB between July, 2007 and March, 2010. Of the patients, 74% had invasive cancer, with 80% ER+ and 34% HER2+. NIIGBB was delivered before, during, or after WBRT in 57%, 39%, or 4% of the patients. Patient age and lumpectomy cavity size ranged from 32-88 yrs and 0.1-5.3 cm, respectively. Boost dose was delivered in 1.9 ± 0.3 Gy/fx for a total of 12.9 ± 3.4Gy. Toxicity and cosmesis were evaluated after radiation therapy and graded according to the Common Toxicity Criteria (v3.0) and the Harvard scale. Median follow up was 6 months (1-17 months).

Results: Grade 1-2 skin toxicity was observed in 18%, 7%, and 0% during the acute (1-3wks), intermediate (4-26 wks), and late-intermediate (>26wks) periods. There were no Grade 3 or higher skin toxicity events. At 6 months, for the entire cohort, cosmetic grading was excellent, good, fair/poor in 52%, 48%, and 0%. The breast compression achieved for each treatment session was remarkably consistent with a mean mammographic plate separation of 6.4 ± 0.3 cm. Breast compression was scored as “uncomfortable” when NIIGBB was delivered before or during WBRT. The mean total duration of set-up and treatment per fraction was 16.7 ± 2.1 min. For each patient, the fraction-to-fraction variability in estimated PTV was low as 69% of treatments were completed with the same applicator size.

Discussion: These data indicate that NIIGBB is feasible and can be consistently implemented in a broad array of practice settings. Preliminary evaluation suggests that NIIGBB is associated with acceptably mild normal tissue toxicity and favorable early cosmetic results. The application of

NIIGBB before completion of WBRT may be associated with better patient tolerance at the expense of slightly less favorable short-term cosmetic outcome.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-13.
Abstract P4-11-14: Pulsed Reduced Dose-Rate Radiotherapy: A Re-Irradiation Strategy for Breast Cancer Patients with Brain and Spinal Cord Metastasis
Authors: Howard SP , Richards GM , Robins HI , Mahler PM , Wolfgang TA.
Published: April 2011

Background: Radiotherapy delivered at reduced dose-rates has the potential to preferentially reduce normal tissue toxicity, while still yielding almost identical tumor cell kill due to the superior repair capacity of late responding normal tissue. In conventional radiotherapy a 2 Gy dose is delivered at a dose-rate of 4-6Gy/min. A reduced dose-rate can be obtained by dividing a standard treatment fraction into a number of sub-fractions delivered in a pulsed manner separated by a fixed time interval. This increases the overall treatment time, allowing normal tissue repair during these sessions. Radiobiological modeling shows that a 2 Gy fraction can be delivered in a series of 0.2 Gy pulses separated by 3-minute intervals, creating an effective dose-rate of 0.0667 Gy/min. We have termed this re-irradiation technique pulsed reduced dose-rate radiotherapy (PRDR).* Methods: Between November 2000 and April 2010, 21 previously irradiated and heavily pretreated patients (pts) with progressive metastatic breast cancer were re-irradiated with PRDR to the whole brain (WB) (15) or spinal cord (SC) (6). The mean prior RT dose to the whole brain was 34.5 Gy (range 30-40 Gy) and the spinal cord was 39.9 Gy (range 30-50 Gy). A mean PRDR dose to the WB of 27.8 Gy (range 18-36 Gy) and SC of 31.3 Gy (range 28-40 Gy) was delivered in 1.8 or 2.0 Gy per fraction. Results: Mean overall survival (OS) of pts treated to the WB was 5.9 months (M) (range 0.5-21.3 M) and for pts treated to the SC was 18.9 M (range 5.6-43 M); 2 pts remain alive as of this report. Treatment was well tolerated: no grade 4 or 5 acute toxicities or grade 3 or 4 late toxicities were observed. Despite a mean cumulative dose of 64.9 Gy (range 54-80 Gy), there was no clinical or radiographic evidence of radionecrosis and/or neurological sequela. There appeared to be a correlation between KPS and OS. Conclusions: PRDR is a well-tolerated and effective radio-therapeutic method for the treatment of breast cancer patients with progressive metastatic CNS disease that have received prior radiotherapy.

* Reirradiation of Large-Volume Recurrent Glioma with Pulsed Reduced-

Dose-Rate Radiotherapy. Adkison JB, Tome W, Seo S, Richards GM,

Robins HI, Rassmussen K, Welsh JS, Mahler PA, Howard SP.

Int J Radiat Oncol Biol Phys. 2010 May 14. [Epub ahead of print] PMID:

20472350

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-14.
Abstract P4-11-22: The Role of Postmastectomy Radiation in Breast Cancer Patients with One to Three Positive Axillary Lymph Nodes
Authors: AboTouk NA , Zayed DH , Abdulla MM , Younies SG.
Published: April 2011

Background: Adjuvant radiotherapy in T1-T2 invasive breast carcinoma and 1-3 positive lymph nodes is controversial due to discrepancies in the reported locoregional recurrence risks and survival data. Purpose: This work aims to explore the effectiveness of postoperative radiation therapy in patients with 1-3 positive axillary lymph nodes treated by modified radical mastectomy with systemic chemotherapy with or without hormonal treatment on locoregional recurrence and survival rates. Patients and methods: One hundred and thirteen breast cancer patients with T1 or T2 tumors and 1-3 positive axillary lymph nodes, treated by modified radical mastectomy were registered in Clinical Oncology and Nuclear Medicine Department of Mansoura & Tanta University Hospitals in the period between January 1995 and December 1998. Of the 113 patients, 55 patients received postoperative radiotherapy while 58 patients did not receive it. Results: Postoperative radiotherapy reduced the incidence of locoregional recurrence from 18.2% to 5.2% (P=0.03). Distant metastases was 22.4% in the radiotherapy group of patients in comparison to 40% (P= 0.04). Disease free survival and overall survival were prolonged with postoperative radiotherapy received group (P= 0.03, 0.05) respectively. The risk factors including tumor size, grading and number of dissected axillary lymph nodes were of statistically significant value regarding both locoregional recurrence rates and survivals on the univariate analysis. On multivariate analysis they were statistically significant regarding disease free and overall survivals. Conclusion: Postoperative radiotherapy significantly reduces locoregional recurrence and survival in patients with 1 -3positive axillary lymph nodes. Patients with high risk factors including tumors ≥2cm, grade III and inadequate lymph node dissection are more likely to benefit from radiotherapy.

Key words: breast cancer, postmastectomy radiation, Positive lymph nodes, locoregional recurrence, risk factors.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-22.