bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiofrequency ablation of breast cancer lumpectomy cavities – a technique intended to increase negative margins after breast conservation surgery. From benchtop to clinical use.
Authors: Rubio IT , Landolfi S , Kylstra JW , Klimberg VS , Coad JE
Published: December 2010

Abstract #4136

INTRODUCTION: Following breast conservation surgery, up to 49% of women require additional surgery due to close or positive lumpectomy margins. This results in significant additional burden for patient and society. This in vivo study assesses the feasibility of using intraoperative radiofrequency ablation (RFA) to treat the lumpectomy cavity walls and in situ extend the final negative margins, with consequent reduced need for re-excision surgery.  METHODS: First, an in vitro study was performed to establish the performance characteristics of a RFA device in 12 mock lumpectomy cavities in fresh human breast or panniculus. These cavities were RFA-treated for 18 minutes with thermocouples recording. Second, an in vivo feasibility study was performed in 10 breast cancer pts (Italy) with clinically less than 2 cm tumors. The patients underwent lumpectomy, followed by in vivo 15 minute RFA cavity treatment, and subsequent quadrantectomy of the treated region. Third, an initial 5 pts (Spain) underwent lumpectomy and RFA only, with 4-5 punch biopsies obtained from the radial resection margin. The devitalized tissue radii around the cavity were measured using triphenyltetrazolium chloride (TTC) viability staining.  RESULTS: In vitro temperatures in excess of 55C for 5 minutes were obtained 3mm from the radiofrequency probe and exceeded 45C at the treatment region edge. The in vitro and in vivo anterior/posterior treatment zone heights were 3.9 ± 0.5 cm and 4.4 ± 1.3 cm, respectively. The in vitro and in vivo distance between the anterior ablation zone edge and adjacent skin dermis measured 1.4 ± 1.1 cm and 0.9 ± 0.6 cm, respectively. The ablation zone edge focally extended to the dermal junction in one in vivo case. The three-dimensional devitalized tissue radii are presented in Table 1. In the 5 patients (Spain) where respective ablation radii were verified by punch biopsies, the devitalized tissue typically extended beyond the 7-14 mm radial depth of the biopsy sample. There were no postoperative complications with the use of RFA.    CONCLUSIONS: This pilot data supports the feasibility of adjuvant radiofrequency lumpectomy cavity treatment to extend final negative tissue margins by approximately 1 cm. The extended margins have the potential to reduce the number of patients requiring re-excision surgery for close or focally positive margins. A multi-center trial aimed at validation of this technique has recently started.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4136.
Intra-operative specimen sonography: a valuable tool to identify tumor free margins during breast-conserving therapy.
Authors: Zarghooni V , Hübbel A , Moers C , Würstlein R , Mallmann P , Warm M
Published: December 2010

Abstract #4146

Background:  Today, breast conserving therapy (BCT) represents the standard of care for the majority of patients with breast cancer. One significant technical difficulty remaining for the surgeon is the intraoperative estimation of tumor size in the attempt to achieve clear margins. We hypothesized that the use of intraoperative ultrasound evaluation of specimen would increase the rate of microscopically clear margins during lumpectomy.  Methods:  All patients who underwent lumpectomy for breast cancer at our hospital during 2007 were eligible. The study was non-randomized with retrospective data acquisition. In cases with positive ultrasound margins, the surgeon was guided to achieve disease- free margins. All cases with intraoperative specimen ultrasound were compared to cases without specimen sonography. We evaluated the technique of intraoperative sonography, the rate of tumor free margins, and the rate of re-excisions.  Results:  Of the 252 patients, 78 patients (31%) were evaluated with intraoperative specimen sonography. Operation times did not show significant differences in both groups.  In the group with intraoperative specimen sonography the rate of microscopically free margins was 96%, compared to 81% in the control group. Intraoperative specimen sonography proved to be a useful adjunct in this series of patients because it significantly reduced the rate of re-excisions.  Conclusion:  Intraoperative specimen sonography proved to be a reliable and helpful tool for detection of tumor free margins in lumpectomy for breast cancer. It significantly reduces the rate of re-excions during breast conserving therapy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4146.
The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36 months follow-up of ZO-FAST.
Authors: Eidtmann H , Bundred NJ , DeBoer R , Llombart A , Davidson N , Neven P , von Minckwitz G , Miller J , Schenk N , Coleman R
Published: December 2010

Abstract #44

Background: Aromatase inhibitors (AI) administered alone or sequentially following tamoxifen are the preferred treatments for hormone-receptor-positive (HRP) early breast cancer (EBC) in postmenopausal women (PMW). As a class effect, long term AI use is associated with an increased loss of bone loss. The primary analysis at 12 months of the Z-FAST and ZO-FAST studies demonstrated that the loss of bone mineral density (BMD) can effectively be prevented by zoledronic acid (ZA). Also, the ABCSG-12 study recently demonstrated a positive impact by ZA on disease recurrence in pre-menopausal women. This 36-months (mo) follow-up for ZO-FAST provides an insight into these issues and longer term safety data as pre-planned secondary endpoints.  Materials and Methods: ZO-FAST has 1064 PMW with HRP EBC receiving Let (2.5 mg qd x 5 yrs). Pts with a BMD T-score >-2 were randomized to immediate ZA arm (IMZA) vs delayed ZA arm (DZA). DZA pts receive ZA when either the post baseline T-score decreases to < -2.0 or if a non-traumatic fracture occurs. All patients underwent a spine x-ray at baseline and at 36-mo to assess for asymptomatic fractures.  Results: The updated primary endpoint continues to demonstrate the benefit of IMZA vs. DZA, with a treatment difference of 9.29(p<0.0001) at the lumbar spine and 5.41(p<0.0001) at the hip. 110 pts (20.5%) in the DZA have started ZA as per protocol at a median of 11.8 mo (range 0.03-38.3). The majority of these (82 pts) for T-score < –2.0. There were 24(4.6%) pts who experienced clinical fractures in the IMZA and 26(4.9%) in DZA (Fisher's exact test:p value=0.88). A total of 676 pts (335 IMZA and 341 DZA) had both baseline and 36-mo spine x-ray reviewed centrally. The log rank test for disease recurrence (22 events-IMZA vs 37-DZA) has a p value of 0.0423. The log rank test for disease free survival (26 vs 43) has a p value of 0.0336. The median duration of Let is 43.3 vs 43.4 mo. Adverse events remain as previously reported, and are consistent with the known safety profile of the study drugs.  Conclusion: The 36-month data continues to demonstrate the efficacy of ZA in preventing BMD loss. The trends in disease events are significant though preliminary at this 36 month analysis. Further follow up is needed to confirm these promising results. These benefits are observed in the context of a favorable safety profile. To date in this relatively small sample size, the rates of fracture are low and similar.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 44.
Chromosome 17 polysomy (Ch17) as a predictor of anthracycline response: emerging evidence from the UK NEAT adjuvant breast cancer trial.
Authors: Bartlett J , Munro A , Dunn J , Hiller L , Jordan S , Twelves C , Cameron D , Thomas J , Campbell F , Rea D , Provenzano E , Pharoah P , Caldas C , Earl H , Poole C
Published: December 2010

Abstract #45

Background: The role of HER2 and Topoisomerase IIα (TOPO2α) as predictors of anthracycline sensitivity remains controversial. To address this we conducted an analysis of HER2, Topoisomerase IIα amplification (TOPO2α-amp) and deletion (TOPO2α-del), chromosome 17 polysomy (C17) and Ki67 as prognostic and predictive markers in the UK National Epirubicin Adjuvant Trial (NEAT) which compared classical CMF with Epirubicin followed by CMF (NEJM 2006;355:1851-62).  Methods: TMAs constructed with 1638/2021 tumors from patients in the NEAT study were analysed for HER2/TopoIIα gene alterations, C17 polysomy, and Ki67. Log-rank analyses explored the prognostic value of markers on relapse-free survival (RFS) and overall survival (OS). Cox-regression models tested independent prognostic value on RFS and OS in the presence of treatment, age, type of surgery, tumor size, nodal status, ER status and grade, and marker x treatment interactions for RFS and OS.  Results: Of 1625 NEAT samples analysed, 806(50%) received anthracycline-containing treatment; 985(61%) were ≤50 years old; 1114(69%) had nodal involvement; 791 (49%) were ER+ve; 961(59%) had G3 tumours; and 893 (56%) had tumour size >2cm. 19% were HER2-amp, 9% were TOPO2α-amp, 9% were TOPO2α-del, 18% were polysomic for C17 and 62% had high Ki67 (>13.0%). HER2-amp and TOPO2α-del were significant poor prognostic factors (P<0.001) for RFS and OS, and were independent variables in multivariate analyses. Other factors did not reach significance at the 1% level. No significant treatment interaction with anthracyclines was seen for HER2-amp (OS p=0.25, RFS p=0.51). Polysomy C17 was not prognostic but exhibited a significant treatment interaction with anthracyclines (RFS p=0.02, HRs 0.96 95%CI 0.73-1.26 vs 0.56 95%CI 0.33-0.97, OS p=0.06, HRs 0.97 95%CI 0.72-1.30 vs 0.60 95%CI 0.33-1.08). Patients with C17 polysomic tumours had significantly greater benefit from anthracyclines.  Conclusions: Analysis of samples from the NEAT trial, which for the first time included HER2, TOPO2α, Ki67 and C17, strongly suggest that the most powerful predictor of benefit from adjuvant anthracyclines is chromosome 17 polysomy, perhaps as a marker of chromosomal instability, with a weak effect for HER2-amp. No effect was observed for differing TOPO2α status. Given the lack of consistency seen in previous studies with respect to HER2 and TOPO2α, we suggest that polysomy C17 could be the unifying predictive marker of anthracycline sensitivity, particularly as these data are confirmed by data from a separate meta-analysis of MA5 and BR9601 trials (SABCS2008).

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 45.
Association of estrogen receptor gene alpha polymorphisms with postmenopausal mammary density.
Authors: Ramos EH , Facina G , Silva ID , Costa AM , Nazario AC , Kemp C
Published: December 2010

Abstract #5003

Background: With the human genome studies, knowledge about polymorphisms started raising interest in a variety of fields and, in medicine, the evidence of direct action of polymorphisms on the arising and progression of diseases, disclosing the possibility of using them as disease predisposition markers. Substitutions, insertions or deletions which are transmitted through generations and reach frequencies equal or superior to 1% in the population are named polymorphisms. Knowing that the mammographic pattern is a multifactorial character, the objectives of this study were to evaluate a possible association of clinical characteristics and polymorphisms HaeIII, MspI and XbaI of the estrogen receptor gene alpha with postmenopausal mammary density. Materials and Methods: A prospective evaluation was made of 120 women who were not hormone therapy users and had no clinically or mammographically identified breast lesions. All of them underwent bilateral mammography, and the radiological density was determined by three independent observers, with two subjective evaluations based on the ACR-BIRADS® classification of mammographic patterns, 2003, and one computerized evaluation – the grey-scale histogram tool of the Adobe Photoshop® 7.0 software. Peripheral blood samples were obtained for DNA extraction, performed according to the GFX® Kit protocol from Amersham-Pharmacia. After DNA extraction, PCR-RFLP (Polymerase Chain Reaction - Restriction Fragment Length Polymorphism) was carried out for an analysis of the polymorphisms present in intron 1 (HaeIII and XbaI) and in exon 1 (MspI) of the estrogen receptor gene. Results: There was a high degree of concordance among the observers in the determination of mammary density (Kappa, Pearson and Spearman - p<0.001). The associations of clinical characteristics with mammary density were: age (p=0.04), body mass index (p<0.0001), age at menarche (p=0.02), age at menopause (p=0.120), age at first delivery (p=0.120), parity (p=0.09). The relation between the allele distribution of the polymorphisms and the density was: XbaI (p=0.02), HaeIII (p=0.65), and MspI (p=0.65). Conclusion: Polymorphism XbaI and the clinical factors age, menarche and body mass index showed to be associated with postmenopausal mammary density.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5003.
Fetal microchimerism in normal breast in healthy women and women with breast cancer.
Authors: Walline AD , Gadi V
Published: December 2010

Abstract #5048

Introduction: A lasting legacy of a fetus to his mother is a small number of stably persistent allogeneic cells, a phenomenon known as fetal microchimerism. We have been testing the hypothesis that fetal microchimerism is protective against cancer in the mother by participation in immune surveillance. Prior studies demonstrated that fetal microchimerism in the peripheral blood is associated with protection from breast cancer (Cancer Res, 67(19):9035-8 and PLoS ONE, 3(3):e1706). Here we examine whether the same association of fetal microchimerism extends to the tissue of interest, the breast.  Methods: Total genomic DNA was extracted from frozen normal breast tissue adjacent to invasive disease in women with breast cancer. Control tissues were from reduction mammoplasty procedures performed for women with no prior history of invasive breast cancer. The presence of male DNA, presumably from a prior male fetus, was tested with a quantitative PCR assay for the Y chromosome gene, DYS14. Proportions of tissues harboring fetal microchimerism were compared between women with and without prior history of invasive breast cancer.  Results: At present, tissues from 19 women with cancer and 19 without have been tested for the presence and quantity of fetal microchimerism using the DYS14 assay. Fetal microchimerism was detected less frequently in tissues from women with cancer (26%) than without (63%). The odds ratio for this protective association of fetal microchimerism with breast cancer is 0.21 (0.04-1.0 95% confidence interval; p=0.05). A trend towards larger median quantities of fetal microchimerism was noted in control tissues versus normal breast from cancer patients (0.34 versus 0 fetal genomes/million maternal cells, p>0.05).  Conclusions: Preliminary results suggest that the negative association of breast cancer and fetal microchimerism observed previously in the blood is also reflected at the level of the tissue of interest. These results merit further investigation in the breast tissue of controls to identify the phenotype of the cells detected. Furthermore, the findings here provide further support to the overall hypothesis that fetal microchimerism may participate in immune surveillance against breast cancer in healthy women.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5048.
Infiltration of intratumoral T cells and regulatory T cells are associated with p53 expression and ER status in early breast cancer: a Korean breast cancer study.
Authors: Park K , Kim A , Woo O , Ryu W , Yoon S , Suh H , Choi I , Suh J , Kim Y , Kim J , Koo B
Published: December 2010

Abstract #5049

Background: Immune responses, such as rich lymphocyte infiltrate, have shown associated with improved clinical outcomes in patients with breast cancer. Recently, number of tumor-infiltrating regulatory T cell has been identified as a poor prognostic marker. There is, however, not enough data evaluating the associations between the clinicopathologic factors and quantity or quality of TILs in Asian breast cancer patients.  Material and methods: CD4-, CD8-, and Foxp3-positive tumor-infiltrating lymphocytes (TILs) were detected by immunohistochemistry using the paraffin-embedded samples from the 40 patients with early stage (I-III) breast cancer. Expression status of ER, PR, HER-2, p53, and Ki-67 were also evaluated by immunohistochemistry. Clinical data, such as pathologic stage, patient's age, were available for statistical analysis.  Results: Statistically significant correlation between ER expression and CD8/CD4 ratio of the TILs (Spearman r=0.447, p=0.024) was observed. Other clinicopathlogical factors, such as PR, tumor size, nodal metastasis, tumor grade, did not show significant correlation with ratio of the TILs. Additionally, tumors with more dense accumulation of p53 protein were associated with recruitment of higher number of Foxp3-positive regulatory T cells (Spearman r=0.52, p=0.0002). Ki-67, a proliferation index of the tumor cells, was also statistically significantly associated with infiltration of regulatory T cells (Spearman r=0.46, p=0.019).  Discussion: Our data showed that ER-positive tumors had higher ratio of CD8/CD4 TILs, which is opposite result from the previous studies. In addition, p53 overexpression and high proliferation index of the breast cancer were associated with high regulatory T cell infiltration, but not with total TIL. The role of the p53 overexpression of the tumor cells in determining immune balance and its prognostic implication will be evaluated in the future study.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5049.
Evidence that SOM230 can prevent experimental mammary hyperplasia by blocking IGF-I and thus estrogen action in the mammary gland: preliminary evidence for an effect in humans.
Authors: Ruan W , Singh B , Smith J , Axelrod D , Kleinberg DL
Published: December 2010

Abstract #5084

Background: Antiestrogens or aromatase inhibitors are used for breast cancer chemoprevention, however, they are poorly tolerated. We have shown that IGF-I is required to permit estrogen and progesterone action in the mammary gland. A novel somatostatin analog, SOM230, which binds to several somatostatin subtype receptors (SSTR), prevents estrogen action by reducing pituitary growth hormone, and also by a direct IGF-I action inhibitory effect on the mammary gland. Menopausal symptoms have not been observed in acromegalic patients receiving SOM230. Material and Methods: Several approaches have been undertaken. 1) We developed a model of hyperplasia in hypophysectomized and oophorectomized female rats. Hyperplasia was induced by treatment with 600 mcg hGH and follicular phase concentrations of estradiol. 2) To assess translatability to humans we cell proliferation (Ki67) and apoptosis (TUNEL) were measured in normal human breast from reduction mammoplasty and in samples of proliferative fibrocystic change (FCC). 3) We also measured expression of SSTR in atypical ductal hyperplasia and DCIS, and 4) A proof of principal trial with SOM230 has begun accrual to determine whether SOM230 acts in human breast as in rats. Results: 1) hGH and E2 caused florid hyperplasia in rat mammary glands within a week. Twenty-six percent of gland structures exhibited hyperplasia with 50% of those showing florid hyperplasia. SOM230 reduced the number of areas of florid hyperplasia to 7.5 ±0.5 from 18.9±1.3 (p<0.001). This was accomplished by a reduction in cell proliferation and an increase in apoptosis. Interestingly, co-administration with tamoxifen provided no additional benefit over that of SOM230. 2) Proliferative lesions from human breast had 8.09 % of cells stain for Ki67. 3) All 5 somatostatin subtype receptor (SSTR) were present in pathology samples of atypical hyperplasias and DCIS, but SSTR3 and 5 were present in highest concentrations. SSTR 3 is the receptor most likely to mediate the effect of SOM230 with SSTR5 being the next most likely. 4) In the first patient tested we found that SOM230 increased apoptosis and reduced cell proliferation (1000 cells counted).    Discussion: Our data show that SSTR are present in ADH and DCIS and normal breast tissue. Our data also show that SOM230 can prevent cell proliferation and increase apoptosis both in rats and humans. Thus, further clinical trials will be important as SOM230 may have a role in breast cancer chemoprevention.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5084.
Characteristics of carpal-tunnel syndrome in the ATAC trial.
Authors: Sestak I , Cuzick J
Published: December 2010

Abstract #5085

Introduction: Carpal-tunnel syndrome (CTS) is a condition in which the median nerve is compressed leading to pain and muscle weakness in fingers and the hand. Oestrogen depletion has been shown to induce CTS, whereas the use of hormone replacement therapy is associated with a resolution of the symptom. Aromatase inhibitors lead to profound oestrogen suppression and therefore might induce CTS in postmenopausal women.  Methods: The Arimidex Tamoxifen Alone or in Combination (ATAC) trial randomised 9,366 postmenopausal women to anastrozole (1mg/day), tamoxifen (20mg/day) or the combination. Analyses were based on the 100 month median follow-up data in women in the two monotherapy arms who started their allocated treatment (anastrozole=3,092; tamoxifen=3,094). Here, we retrospectively investigate the influence of anastrozole on CTS, clinical outcomes, the relative importance of a range of risk factors for CTS, and examine whether they act differently in the presence of anastrozole treatment.  Results: During the entire active treatment period, 80 (2.6%) cases of CTS were reported in the anastrozole arm compared with 23 (0.7%) in the tamoxifen arm (OR=3.55 (2.22-5.65), P<0.001). In both treatment arms, the majority of CTS were reported as of mild or moderate severity. Most reports of CTS in the anastrozole arm occurred within 18 months of treatment initiation, but incidence remained elevated compared to the tamoxifen arm for the entire treatment period. Median time to resolution of CTS was 8.4 months and none of the women stopped treatment medication due to this adverse event. 13 women underwent carpal-tunnel release surgery (11 anastrozole (1 in 300) vs. 2 tamoxifen (1 in 1500)). Reports of CTS were significantly increased for women who used prior hormone replacement therapy (HRT) (2.3% vs. 1.3%, OR=1.72 (1.16-2.54), P=0.007) or prior chemotherapy (2.5% vs. 1.4%, OR=1.73 (1.14-2.62)). Furthermore, women who were aged 60 years or younger at entry were at greater risk of CTS compared with those aged 61 years or older (2.5% vs. 1.2%, OR=0.48 (0.30-0.76), P=0.002). Body mass index (BMI), hormone receptor status, smoking status, and prior radiotherapy were not found to be risk factors for the development of CTS. When analyses were restricted to only women receiving anastrozole, the same risk factors were identified.  Conclusions: Although the use of anastrozole is clearly associated with a greater incidence of CTS, it is rare and most cases were of mild severity and short duration and did not lead to treatment discontinuation or surgical intervention. Thus, while CTS can be quite debilitating for the few patients who have severe symptoms, this side effect has minimal impact on the overall risk-benefit ratio for the use of anastrozole in postmenopausal women.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5085.
Use of mastectomy in rural versus urban patients: the effects of medical community factors.
Authors: Jacobs LK , Detrani ME , Kelley KA , Rosson GD , Chang DC
Published: December 2010

Abstract #5089

Background: Disparity exists in surgical treatment of breast cancer patients living in rural versus urban counties. Past studies evaluating this used patient level data. We examine county-level medical community factors that potentially impact the geographic variation of mastectomy versus breast-conserving therapy.  Methods: Data from 137,303 patients and 200 counties were analyzed combining the 2006 SEER and 2004 ARF (Area Resource File) databases. Inclusion criteria identified in SEER were: stage I, II, or III disease, female, diagnosis after 1992. Patients were linked to county level data from the ARF based on their county of residence. Medical community variables analyzed with ARF are seen in Table 1.  Results: A total of 9.58% of the patients reside in a rural county, and 59.90% of these received a mastectomy, compared to 44.92% of the urban patients. Multivariate analysis of the medical community factors was calculated by both land area and population with calculation by population accounting for the disparity in mastectomy use (Table 1). Of the medical community factors in this analysis, the screening hospital density was highly significant, accounted for the difference in rural versus urban mastectomy rates, and resulted in an increased likelihood of receiving mastectomy (OR 1.009, 95% CI 1.004-1.014). Bivariate analysis also revealed a higher density of screening hospitals in rural counties (57.62) than in urban counties (18.22).  Conclusions: Analysis using land area versus population to estimate availability of services suggests that disparity in the rural community is most affected by availability of providers and not to required travel distance. Density of screening hospitals was found to be the most important factor resulting in disparity between rural versus urban mastectomy rates. Rural counties have a higher density of screening facilities, yet they also have a higher mastectomy rate. This may represent a volume/quality issue that will require further investigation.   

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5089.
Multicentric study with neoadjuvant endocrine therapy for breast conserving surgery. Experience in Mexico.
Authors: De la Garza JG , Bargallo E , Solorio C , Ramirez T , Salazar F , Sanchez J
Published: December 2010

Abstract #5119

Background: In patients with large, operable breast tumors who are ineligible for Breast-conserving surgery (BCS), neoadjuvant therapy is a useful option for reducing tumor size and for increasing the proportion of candidates to BCS. Neoadjuvant chemotherapy has been widely studied, but little has been published on neoadjuvant endocrine therapy. This study analyzes the use of neoadjuvant endocrine therapy with aromatase inhibitors in postmenopausal women with hormone receptor-positive locally advanced breast cancer (LABC).  Material and Methods: The study was designed as a multicenter study and was conducted in four centers in Mexico between July 2005 and August 2006. Thirty six patients were assigned to receive letrozole 2.5 mg, daily, for 4 months prior to schedule surgery. This group was compared with a group of 36 patients who received conventional chemotherapy as neodjuvant treatment. At baseline none of these patients were considered to be candidates for BCS. Primary end points were response rate (ORR) defined as the percentage of patients with a complete response (CR) or partial response (PR) as determined by breast palpation and the percentage of patients who underwent BCS. Standard descriptive statistics were performed.  Results: All patients were postmenopausal, median age was similar in both groups (64 (50 86) years vs. 59 (50 – 77) years; P = 0.1). At baseline 75% of tumors in endrocrine group were T2 (median (range) 4 (2 – 5) cm) while 25% were T3 (median (range) 7.6 (5.5 – 10) cm) and in chemotherapy group 83% were T2 (median (range) 3.9 (2 - 5) cm) and 17% T3 (median (range) 6.8 (5.5 – 9.5) cm). Clinical response was similar between groups. The ORR was 70% for endocrine group versus 80% for chemotherapy group (P = 0.3). In terms of clinical progression, 8% of patients in the endocrine group progressed vs. none in the chemotherapy group, while 22% of endocrine- and 19% of chemotherapy-treated patients had stable disease. The proportion of patients able to undergo BCS was significantly higher in the endocrine group than in the chemotherapy group (36% vs. 19%, respectively; P = 0.0008).  Discussion: Over third of patients become BCS-eligible within 4 months of preoperative endocrine therapy. Neoadjuvant therapy with aromatase inhibitors could be an effective treatment option for highly selected postmenopausal women who are unwilling or unable to undergo BCS or preoperative chemotherapy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5119.
A prospective nonrandomize study comparing electron intraoperative boost radiotherapy versus postoperative interstitional brachytherapy in patients having breast conserving surgery and adjuvant external beam radiotherapy.
Authors: van Dam PA , Weytjens R , DeMaeyer L , van Dam AM , Alberty J , Verstraeten H , Huget P , Verkinderen L , Prove A , Vermeulen P , Dirix LY
Published: December 2010

Abstract #5140

Purpose: to compare the surgery and radiotherapy related outcomes, toxicities and cosmesis of patients undergoing breast conserving surgery and adjuvant external beam radiotherapy having intraoperative electron boost radiotherapy (IEBR) versus postoperative boost interstitinal brachytherapy (PIB).  Materials and methods: Between January 2007 and June 2008, 80 women with a diagnosis of early breast cancer ( pT1: 69, pT2: 11, pN0: 66, pN1: 14) were treated with lumpectomy, sentinel node biopsy, with (N=14) or without (N=66) axillary lymphadenectomy. During surgery an electron boost of 9 Gy (4-12 Mev) was administered to the tumor bed using a Mobetron (Intraop, USA). Adjuvant treatment was completed with whole breast external beam radiotherapy (WBEBR, 45 Gy in 25 fractions) and systemic therapy if necessary (group 1). The outcomes in these patients was compared propectively to 100 stage-matched patients treated in the same period having similar breast conserving surgery, systemic treatment and WBEBR, and receiving a boost by means of postoperative interstitional brachytherapy (192Iridium, 15 Gy, Nucletron Afterloader, USA) implanted under general anesthesia according to the Paris system (group 2)  Results: Median netto (= incision to closure) and bruto (= total time spend in the operating theatre) time in the operating theatre at primary surgery was significantly higher in group 1 (respectively 96 vs 62 min, p < 0.01, and 118 and 80 min, p <0.01). Netto and bruto time to implant the iridium wires respectively was 27 and 50 min. This means that the total theatre time was comparable in both groups (netto 96 vs 89 minutes, and bruto 148 vs 130 minutes, NS). Perioperative morbidity was slightly higher in group 1 due to a higher amount of postoperative wound infections (9/80 vs 4/100, p< 0.05). Median total surgery and radiotherapy related hospital stay for the entire treatment was 2.5 days in group 1 and 4.0 days in group 2 (p < 0.01). Patient satisfaction was significantly higher in patients receiving IEBR. Acute skin toxicity at the end of the entire treatment was significantly lower in group 1. Out of 48 evaluable patients after 6 months there were no patients with grade 4 skin toxicity in group 1. No tumor recurrences were seen in both groups after a median follow-up 10 months.  Conclusions: Intraoperative radiotherapy is feasible and well tolerated in selected patients with early breast cancer. Total hospital stay is lower and patient satisfaction is higher in women having IEBR compared to PIB. Our study suggest it may be considered to give patients undergoing IEBR prophylactic antibiotic treatment.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5140.
Tumor angiogenesis imaged by optical tomography can accurately diagnose early-stage invasive breast cancers.
Authors: Zhu Q , Kane M , Tannenbaum S , Cronin E , Hegde P , Iyers M , DeFusco P , Ardeshirpour Y , Xu C , Baccaro N , Kurtzman S , Deckers P
Published: December 2010

Abstract #52

Background: Our initial clinical results obtained from a novel ultrasound(US)-guided diffusive-wave optical tomography have shown that early-stage invasive breast cancers may be distinguished from benign lesions with an average of two-fold angiogenesis contrast. However, breast cancer is a heterogeneous disease with different growth and metabolic rates that result in a wide range of functional differences. In this report, we present a spectrum of breast lesion angiogenesis distributions from benign lesions, early-stage invasive cancers to advanced cancers. The objective is to investigate the feasibility of optical tomography with US localization in differentiating malignant from benign breast masses.  Materials and Methods: 123 patients underwent US-guided biopsy and were imaged with a combined imager consisting of a commercially available US system and a near infrared (NIR) imager. A hand-held probe with a centrally located US transducer and NIR sensors surrounding it was used to simultaneously acquire co-registered US images and optical data. The lesion location provided by US was used to guide optical imaging reconstruction. Light absorption was measured at multiple wavelengths. From this, tumor angiogenesis was assessed based on calculated total hemoglobin concentration.  Results: There were 23 stage I carcinomas, 21 stage II to IIII carcinomas, and 112 benign lesions. The mean maximum and average values of total hemoglobin concentration (tHb) of the stage I malignant group were 102.0 μ mol/liter (±30.7) and 72.3 μ mol/liter ( ±18.1), and the values of the state II to IIII malignant group were 114.4 μ mol/liter (±38.4) and 75.4 μ mol/liter (±25.2), respectively. The mean maximum and average values of the benign group were 54.0 μ mol/liter (±22.3) and 38.2 μ mol/liter (±14.8), respectively. Both maximum and average of tHb level were statistically significantly higher in the malignant groups than the benign group (P<0.01). An example of a six mm stage I cancer imaged by US (Fig.1(a)) and the NIR imager (Fig.1(b) is given in Figure 1.    The detection sensitivity and specificity of the stage I cancer group were 91% and 94%, and 76% and 94% for the stage II to IIII cancer group.  Discussion: The tumor angiogenesis distributions are complex and the angiogenesis contrast holds great promise for distinguishing early-stage invasive breast cancers from benign lesions. For advanced cancers, the angiogenesis distribution is heterogeneous and often presents periphery enhancement and/or shadow effect which can be used to assist US diagnosis.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 52.
Risk of distant recurrence using oncotype DX in postmenopausal primary breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study.
Authors: Dowsett M , Cuzick J , Wales C , Forbes J , Mallon L , Salter J , Quinn E , Bugarini R , Baehner FL , Shak S ,   on Behalf of the ATAC Trialists' Group
Published: December 2010

Abstract #53

Background: The Recurrence Score (RS) has been validated for estimating residual risk of distant recurrence (DR) in ER+ node negative (N-) primary breast cancer patients receiving adjuvant tamoxifen. Aromatase inhibitors (AIs) are widely used for adjuvant treatment of ER+ disease in postmenopausal women. The RS has not been evaluated in patients treated with an AI.  Method: Tumour blocks were collected retrospectively from patients in the monotherapy arms of the ATAC trial under the TransATAC protocol yielding 1308 hormone receptor positive (HR+) blocks in UK patients for analysis (1). Cox proportional hazards model was used to test the significance of adding RS to a clinical model (age, tumour size, grade, treatment) and to Adjuvant! Online.  Results: 65 patients received chemotherapy, 4 were centrally HR negative and 8 did not start adjuvant therapy leaving 1231 evaluable patients of which 872, 306 and 53 were N-, N+ and N unknown in whom there were 72, 74 and 6 DRs, respectively. In the prospectively-defined primary multivariate analysis tumour size, grade and RS were each separately statistically significant in predicting time to DR in N- patients (p<0.001, 0.003 and <0.001, respectively). Similar results were seen in N+ patients. The 9-year rates of DR by nodal status for the pre-specified RS groups are shown in the table. RS showed statistically significant prognostic value beyond that provided by Adjuvant! Online in both N- (p<0.001) and N+ patients (p=0.003).    Conclusions: Oncotype DX RS is an independent predictor of the risk of distant recurrence in N- and N+ HR+ patients treated with anastrozole or tamoxifen. The data are not predictive of a differential benefit between anastrozole and tamoxifen.  (1) Dowsett et al JCO 2008, 26, 1059.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 53.
Clinicopathological factors affected no 18FDG uptake in 18FDG-PET CT: only invasive ductal cancer.
Authors: Seo H , Bae Y , Park B
Published: December 2010

Abstract #6007

Background: Positron emission tomography with fluorine-18 fluoro deoxy-glucgose (18FDG-PET CT) recently used is suggested more useful tool for accurate, non-invasive imaging modality of the prediction of prognosis and staging of breast cancer. The aim of this study was to evaluate whether no enhanced 18FDG uptake would be associated with the biological non-aggressiveness of invasive ductal carcinoma and suggest limitation of using 18FDG-PET CT for preoperative evaluation.  Materials and Methods: The patients were consisted of 124 female patients raging in age from 29-80 years (average 51.1 years) with primary invasive ductal carcinoma. All patients had histologically or cytologically proven invasive ductal carcinoma before performing 18FDG-PET CT sacn. All patients were examined with 18FDG-PET CT sacn before neoadjuvant chemotherapy. Patients undergoing excisional biopsy were excluded from this study.  Results: 20 patients had primary tumor with no enhanced 18FDG uptake and 18FDG-PET CT showed hypermetabolic axillary foci in 25 patients. In these 25 patients, two was false positive findings. Histologic examination was confirmed 56 patients had axillary lymph node metastasis. The mean tumor diameter was 2.2 cm (range 0.4-6 cm). With regard to histopathologic grading, 117 were grade 1 and 2, and 7 were grade 3. It was correlation with no enhanced 18FDG uptake (p=0.003). No enhanced 18FDG uptake in invasive ductal carcinoma depended on presence of axillary lymph node metastases (p=0.014). Small tumor (< 2.0cm) also was significantly correlated with no enhanced 18FDG uptake. The relationship between no enhanced 18FDG uptake and presence of lymphovascular invasion, necrosis and calcification was not significant. The immunohistochemical stain of ER/PR/p53/c-erbB2 did not correlate with no enhanced 18FDG uptake. Triple negative tumor also was not significant (p=0.072). 123 specimens were examined with Ki-67. Ki-67 positivity ranged from 0% to 60% (mean 15%). 67 specimens showed immunoreactivity to Ki-67 antigen in < 10% of tumor cell. This revealed a significant correlation between no enhanced 18FDG uptake and Ki-67 (p=0.003). Logistic regression analysis between these factors was shown that histologic grade, status of axillary lymph node metastases and Ki-67 were correlated with no enhanced 18FDG uptake.  Discussion: The our results demonstrated that an association exists between no 18FDG uptake and good prognostic factors in invasive ductal cancer, such as low histologic grade (1 & 2), no axillary lymph node metastases and low Ki-67 (<10%). Although further studies are needed, 18FDG-PET CT may be suggested more useful tool for accurate, non-invasive imaging modality of the prediction of prognosis and we purpose the limitation of using 18FDG-PET CT for follow-up study in these patient.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6007.
Metabolomics of basal breast carcinomas: a potential target for treatment intervention.
Authors: Thor AD , Edgerton SM , Fan Z , Lind SE , Liu B
Published: December 2010

Abstract #6026

Breast cancers of the basal subtype (ER, PR and HER2 negative; EGFR and/or CK5/6 positive) are typically high grade, rapidly proliferative, associated with a poor outcome and are resistant to many chemotherapeutic regimens. They occur more frequently in women with BRCA-1 mutations, African Americans and obese individuals. At the molecular level, basal cancers have impairment of BRCA-1 and p53 signaling and are driven, in part, through EGFR which activates the PI3K/AKT/mTOR pathways. Treatment of basal carcinoma cell lines with the FDA approved anti-diabetic drug metformin significantly reduces cellular proliferation, induces cell cycle arrest (late G1/S phase) and apoptosis in vivo and in vitro. Similar effects were not observed in breast cancer cells of the luminal A, B or HER2 subtypes. Metformin induces a wide spectrum of metabolic and molecular changes in basal carcinoma cell lines in vitro, including: a reduction in glucose uptake, enhanced lactate release, a decrease in cellular proliferation and colony formation, a decrease in EGFR, phospho-EGFR and downstream signaling including pAKT, pMAPK and psrc, inhibition of cyclins D1 and E, reduced E2F1, PARP cleavage and activation of caspases 3, 8 and 9 in a dose and time dependent manner. Nude mice with basal cell line MDA-MB-231 xenografts treated with metformin showed significantly reduced tumor growth and prolonged survival as compared to control untreated mice. Pre-treatment with metformin prior to xenograft inoculation reduced both tumor formation and growth as compared to mice treated with metformin after implantation or untreated control mice, suggesting that metformin may have some use in basal cancer prevention. Epidemiologic data has shown that women treated with metformin have a reduced rate of breast cancer and, for those patients with breast cancer, an improved disease free and overall survival. In aggregate, these data suggest that further study of metformin to prevent or treat breast cancer in some patient subgroups may be indicated.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6026.
Expression of prostaglandin metabolizing enzymes in correlation with vitamin D receptor in benign and malignant breast cell lines and breast tissue and regulation of prostaglandin metabolism by calcitriol.
Authors: Thill M , Fischer D , Becker S , Tim C , Diedrich K , Friedrich M
Published: December 2010

Abstract #6028

Backround: The antiproliferative effects of calcitriol [1,25(OH)2D3] make the biologically active form of vitamin D to a promising target in breast cancer therapy. It is well known, that these effects are mediated via the vitamin D3 receptor (VDR). Furthermore breast cancer is associated with inflammatory processes based on an upregulation of cyclooxygenase-2 (COX-2) expression, the prostaglandin E2 (PGE2) synthesizing enzyme. The PGE2 metabolizing enzyme, 15 hydroxyprostaglandin dehydrogenase (15 PGDH) is described as a tumor suppressor in cancer. First references suggest a correlation between vitamin D and prostaglandin metabolism through the impact of 1,25(OH)2D3 on the expression of COX-2 and 15 PGDH. Thus we evaluated the expression of COX-2 and 15 PGDH with VDR and the influence of calcitriol on COX-2 and 15 PGDH.  Materials and methods: The Expression of VDR, COX-2 and 15 PGDH in MCF10F, a human benign epithelial cell line and the breast cancer cell line MCF-7 was determined by real time PCR and western blot analysis. Furthermore, we determined mRNA level of COX-2 and 15 PGDH and VDR in healthy and malignant breast sample tissues. In addition we examined the effect of calcitriol on COX-2 and 15 PGDH mRNA levels.  Results: Although our data from real time pCR were divergent from those obtained from the western blot analysis, we showed, that COX-2 protein expression is increased in MCF-7 2-fold compared to MCF10F. These data were confirmed in breast cancer tissue samples, where COX-2 mRNA level increased to 1,44 in comparison to healthy tissues. No correlation of 15 PGDH was detected in both cell lines, but in malignant tissues 15 PGDH expression increase dramatically compared to healthy tissue samples. The expression of VDR we found differs in protein and mRNA level in benign and malign cell lines. VDR protein levels were inverse correlated to 15 PGDH expression and reveal that the benign tissue as well as the MCF10F cells have the highest VDR expression. Furthermore we demonstrated a downregulation of cyclooxygenase and an up-regulation of 15 PGDH by calcitriol.  Conclusion: We found a basically inverse correlation between VDR and 15 PGDH protein level expression. These findings suggest a possible link between VDR, associated target genes and the prostaglandin metabolism. The influence of calcitriol on COX-2 and 15 PGDH might lead to an additional novel pathway of calcitriol action mediating its antiproliferative effects in breast cancer and might open new therapeutic approaches in breast cancer therapy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6028.
HOXB13 protein expression predicts the benefit of tamoxifen treatment in breast cancer patients.
Authors: Jerevall P , Jansson A , Fornander T , Skoog L , Nordenskjöld B , Stål O
Published: December 2010

Abstract #6038

Background: The two-gene expression ratio HOXB13:IL17BR, originally from a microarray analysis, has been shown to be indicative of clinical outcome in the setting of adjuvant tamoxifen monotherapy of breast cancer, with a high ratio associated with decreased disease-free survival. Analysis of a cohort of breast cancer patients randomized to 2 or 5 years of adjuvant tamoxifen therapy showed that the two-gene ratio and expression of the HOXB13 gene alone were predictive of the benefit of prolonged tamoxifen treatment. Patients with tumors expressing HOXB13 at high levels were unresponsive to prolonged adjuvant treatment, suggesting that this gene is involved in tamoxifen resistance. It is suggested that a high two-gene ratio may indicate impaired ER signaling, which is known to predict resistance to tamoxifen. To our knowledge, there are no studies investigating the HOXB13 protein levels in breast cancer.  Methods: We have analyzed the protein expression of HOXB13 with immunohistochemistry in tumor samples from 912 postmenopausal node negative breast cancer patients randomized to 2 years of tamoxifen or no endocrine treatment. After 2 years, recurrence-free patients were randomized to 3 more years of tamoxifen, or no further therapy. This selection enabled us to investigate the treatment predictive value of HOXB13.  Results: Data on HOXB13 protein expression were obtained from 866 patients (see table). Tamoxifen treated patients with estrogen receptor (ER) positive tumors expressing none or low levels of HOXB13 had a clear benefit from tamoxifen in terms of longer distant recurrence-free survival (hazard ratio (HR) 0.37, 95% CI 0.23-0.60, p=0.000048). However, for patients with a high or intermediate HOXB13 tumor expression, tamoxifen did not prolong the distant recurrence-free survival compared to the untreated patients (HR=0.83, 95% CI 0.45-1.54, p=0.55). The interaction between HOXB13 expression and benefit from tamoxifen was statistically significant (p=0.046). HOXB13 did not have any prognostic value among systemically untreated patients.    Conclusions: HOXB13 protein level may be used as a predictive marker for tamoxifen treatment, but does not have any prognostic value. Patients with a high expression of HOXB13 do not seem to benefit from tamoxifen.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6038.