bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-13-11: Medico-Economic Assessment of the Genomic Grade Index on Adjuvant Treatment Strategy in Elston-Ellis Grade 2, Estrogen Receptor Positive, HER2 Negative, Node Negative, Small Size Breast Carcinomas
Authors: Reyal F , Bollet M , Caly M , Hajage D , Carpentier S , Peyro-Saint-Paul H , Pierga J-Y , Sigal-Zafrani B , Vincent-Salomon A , Sastre X.
Published: April 2011

Background: Elston-Ellis grading (EE) is one of the key criteria for adjuvant therapy decision in ER+/HER2-/pN0/pT1 -2 tumors. The genomic grade index (GGI) is a 97-gene micro-array assay able to identify tumors of high or low genomic grade. GGI has been developed in order to improve the prognosis determination, especially in EE2 tumors which represent a significant proportion of breast carcinomas and where the inter-assessor variability is the highest. The aim of the present study was to model the influence of the GGI on adjuvant treatment decision in EE2 patients, using a cohort of ER+/HER2-/pN0/pT1-2 tumors.

Methods: A randomly selected series of pT1-2, pN0 breast cancers from the Institut Curie 1995-1996 cohort was profiled using Affymetrix HGU133 Plus 2.0 gene chips. The GGI was calculated using Ipsogen Mapßuant Dx®. Treatment decisions were made for EE2 cases based on the Institut Curie adjuvant treatment guidelines (www.curie.fr). The treatment decision algorithm was firstly run using the grade as defined by Elston Ellis, and secondly using the GGI (undetermined cases were classified as grade2).

Results: Out of 72 EE2 tumors, 35 were classified as GGI-1 (49%) and 13 (18%) as GGI-3. Based on EE, 7% of patients would have received adjuvant chemotherapy (ACT) alone (all were ER-/PR-), 50% adjuvant hormonal therapy (AHT) alone, and 43% both. Using the GGI, 7% (n=5) of patients would have been spared AHT and 10% (n=7) ACT. In the ER+/HER2- subgroup of 62 pts, 58% of patients would have received AHT alone and 42% AHT+ACT based on EE; GGI would have lead to a 14% reduction in AHT prescription and to a 26% reduction in ACT prescription. Conclusion: Applying the Genomic Grade Index instead of the Elston Ellis Grade to determine the adjuvant treatment strategy in a series of EE2/ER+/HER2-/pN0/pT1-2 breast carcinomas would lead to a 14% and 27% reduction in the administration of, respectively, adjuvant hormone-therapy and chemotherapy.

Adjuvant treatment decision: models based on Elston-Ellis or Genomic Grading

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-11.
Abstract P5-14-01: The Influence on Upper Limb Function after Sentinel Lymph Node Biopsy or Axillary Lymph Node Dissection
Authors: Miyajima S , Utsumi T , Kobayashi N , Hikichi M.
Published: April 2011

Background

Sentinel lymph node biopsy (SLNB) is accepted as a method in patients with clinically negative axillary lymph nodes because it was assumed to be associated with improvement of upper limb morbidity. The purpose of this study was to investigate that SLNB reduces upper limb morbidity of patients with breast cancer compared with axillary lymph node dissection (ALND). Methods

The study comprised 362 patients with breast cancer who underwent measuring the upper limb mobility before and after surgery (at discharge, 1 month and 3 months after surgery). 241 patients underwent SLNB, 121 patients underwent ALND. In the SLNB group, 148 patients (48.1%) underwent breast conserving surgery (BCS), 67 patients (18.5%) underwent mastectomy. In the ALND group, 68 patients (18.8%) underwent BCS, 53 patients (14.6%) underwent mastectomy. Upper limb mobility was measured by the difference of the angle of the flexion and the angle of abduction between before and after surgery. The recovery defined that the difference of the angle between before and after surgery, is within 10 degree. The recovery rate was investigated by Kaplan-Meier method, and comparisons were evaluated using the log-rank test. Results

The recovery rate of patients in the SLNB group was 85% in measuring flexion, 90% in measuring abduction 3 month after surgery. The recovery rate of patients in the ALND group was 52% in measuring flexion, 58% in measuring abduction. The recovery rate of upper limb function increase by SLNB than by ALND (P<0.001).’

Conclusions

SLNB reduces upper limb morbidity of patients with breast cancer compared with ALND. SLNB can improve activity of daily life (ADL) by improving of the upper limb function.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-01.
Abstract P5-14-02: Immediate Breast Reconstruction: The Effect of Radiation
Authors: Hwang ESS , Sasaki T , Itakura K , Foster R , Fowble B , Tanaka J , Ewing CA , Alvarado MD , Esserman LJ.
Published: April 2011

Background:

Prior history of breast irradiation or anticipated need for postmastectomy radiation have been considered relative contraindications for immediate breast reconstruction. We evaluated the surgical outcomes between three groups of patients: patients without radiation exposure, those with radiation prior to immediate reconstruction, and those with radiation following immediate reconstruction to determine the differences in risk of post-surgical complications among groups. Methods:

All patients undergoing mastectomy and immediate reconstruction with either a tissue expander or implant between January 1, 2005 and June 30, 2009 were entered into an IRB-approved prospective database. Routine institutional protocol consisted of immediate reconstruction with tissue expander, expansion during the1-2 months following surgery, radiation if indicated, followed by implant exchange at 3-6 months after completion of radiation. All complications were collected and recorded within a week of the event, and all patients had a minimum follow-up period of 6 months after implant exchange to allow for sufficient monitoring of complications. Major complications included infection requiring IV antibiotics, unplanned return to surgery, and tissue expander/implant loss. Results:

A total of 446 mastectomies were identified. Of these, 341 had no radiation history, 33 had prior ipsilateral breast radiation, and 72 had post-mastectomy radiation. Overall, there were 160 major complications (36%), including 50 (11%) expander/implant losses. Patient age, BMI, diabetes, and history of tobacco use were not associated with increased risk of major complications in this cohort. However, both prior and postoperative radiation was associated with higher risk of both major complications and implant loss.

Conclusion:

Immediate reconstruction with implant or tissue expander is associated with a 36% risk of major postoperative complications, with the greatest number seen in those patients with history of previous chest wall irradiation. However, most implants were salvaged even in the setting of complications, and the overall implant loss rate was only 8% in unirradiated patients and 22% in those patients with postoperative RT. Although radiation history is not a contraindication to immediate breast reconstruction, patients undergoing this procedure must be well informed of their substantial risk of postoperative complications.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-02.
Abstract P5-14-05: Improved Survival of Patients with Primary Distant Metastatic Breast Cancer in the Period of 1995 — 2007
Authors: Ruiterkamp J , Ernst MF , de Munck L , van der Heiden-van der Loo M , Bastiaannet E , van de Poll-Franse LV , Bosscha K , Tjan-Heijnen VCG , Voogd AC.
Published: April 2011

Introduction

During the last fifteen years, important changes have taken place concerning the sy stemic treatment for patients with metastasized breast cancer. It would be interesting to know whether these improvements have also taken place patients with primary distant metastatic breast cancer. Additionally, several retrospective studies have shown an improvement in overall survival in patients who have received breast surgery. Therefore, we also analyzed the role of surgical resection of the primary breast tumor. Methods

According to the database of the Dutch Cancer Registry 7,358 (5.0%) patients were diagnosed with primary distant metastases between 1997 and 2007. To establish whether improvement of prognosis had taken place, patients were divided into three periods of diagnosis, based on the year of diagnosis of their disease; 1995-1999, 2000-2003 and 2004-2007. The follow-up of these patients was completed until January 1, 2009. Results

The median survival was 1.42 years for patients diagnosed in the period 1995-1999, 1.56 years in the period 2000-2003 and 2.0 years in the period 2004-2007. Only the difference between the periods 2000-2003 and 2004-2007 was statistically significant (P<0.0001). When analyzed according to age group, the improvement of the median survival was most pronounced for patients of 50 years or younger, with an increase of 2.18 to 3.01 years (P<0.0002). The median survival of the patients undergoing surgery was 2.5 years, compared to 1.3 years for the patients without surgical treatment of the primary tumor. Nevertheless, the proportion of patients who underwent a resection of the breast tumor decreased from 31% in the period 1995-1999 to 24% in the last period. In the multivariable analysis, the hazard ratio's (HRs) for mortality in the second and third period as compared to the first period were 0.95 (P=0.13) and 0.86 (P<0.0001), respectively. Older age and larger tumor size were associated with a higher mortality risk. Patients receiving systemic treatment (HR 0.36), locoregional radiotherapy (HR 0.79) or breast surgery (HR 0.65) had a significantly lower risk of death compared to the patients not receiving these treatments. Conclusion

An improvement of six months is seen in the median survival of patients with primary distant metastatic breast cancer, resulting in a median survival of two years in 2007. Maybe, if surgery was more performed in the most recent time period, the improvement of the median survival was even better. However, it seems reasonable to argue that this improvement is due to new developments in systemic treatment.

Figures available in online version.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-05.
Abstract P5-14-10: Risk Factors Associated with Surgical Site Infection after Breast Operations
Authors: Scow JS , Throckmorton AD , Hoskin TL , Boughey JC , Boostrom SY , Holifield AC , Baddour LM , Degnim AC.
Published: April 2011

INTRODUCTION: Surgical site infection (SSI) is a problematic cause of morbidity following breast/axillary surgery. The breast/axilla has a higher rate of SSI than expected for clean wounds. We evaluated risk factors associated with SSI after breast/axillary operations.

Methods: A retrospective review of breast/axillary procedures from July 2004 to July 2006 was performed. SSI was defined using Centers for Disease Control and Prevention criteria, including cases with cellulitis as the only criterion of infection. Data collected included patient demographics, BMI, surgical procedure, ASA class, antibiotic use, drains, and prior radiation (RT).

RESULTS: We identified 389 patients who underwent 678 procedures. Thirty-seven SSI (5.5% of procedures) were identified, of which 24 (65%) had only cellulitis. Median time from surgery to SSI diagnosis was 9 days (range 2-112), with 81% occurring in the first 30 days. Univariate analysis identified prior RT, BMI, type of procedure, operative time, use of drain, and postoperative seroma to be associated with SSI (all P<0.05). With multivariate analysis, procedure type remained significant overall (p=0.04). Specifically, mastectomy with sentinel lymph node biopsy (SLNB) and modified radical mastectomy remained significantly associated with higher risk of SSI, with hazard ratios (HR) of 6.3 and 13.5 fold respectively compared to SLNB alone. Seroma (HR 9.0, 95% CI 2.7-29.3), prior RT (HR 3.4, 1.2-9.9), and BMI >=30 (HR 3.1, 1.6-6.2) also remained significantly associated with SSI.

CONCLUSION(S): SSI are more frequent after breast/axillary operations than other clean wounds and are associated with prior RT, obesity, more extensive and longer procedures, and postoperative seroma.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-10.
Abstract P5-14-12: Management of Phyllodes Breast Tumours: A Review of 165 Cases
Authors: Guillot E , Couturaud B , Reyal F , Curnier A , Ravinet J , Laé M , Bollet M , Pierga JY , Salmon R , Fitoussi A.
Published: April 2011

Aim:The aim of our study was to examine the treatment and outcome of 165 patients with phyllodes tumours and to review the options for surgical management.

Patients and Methods: This is a retrospective study of 165 patients who presented to the Institut Curie between January 1994 and November 2008 for benign, borderline or malignant phyllodes tumours. Results: The median follow-up was 12.65 months [range 0 to 149.8]. The median age at diagnosis was 44 years [range 17 to 79]. One hundred and sixty patients (97%) had breast conserving treatment, of whom 3 patients (1. 8%) had oncoplastic breast surgery. Younger women had a significantly higher chance of having a benign phyllodes tumor (p = 0.0001) or a tumour of small size (< 0.0001). Histological examination showed 114 benign (69%), 37 borderline (22%) and 14 malignant tumours (9%).

The median tumour size was 30 mm [range 5 to 150]. The tumour margins were considered incomplete (< 10 mm) in 46 out of 165 cases (28%) with 52% revision surgery. Only the tumour grade was a significant risk factor for incomplete tumour margins (p = 0.005). Fifteen patients developed local recurrence (10%) and two, metastases. In univariate analysis, the histological grade (p = 0.008) and tumour size (p=0.02) were significative risk factors for local recurrence with an accentuated risk for borderline tumours and tumours of large size. Similar results were obtained using multivariate analysis (p=0.07)

Conclusion: The mainstay of treatment for phyllodes tumours remains excision with a safe surgical margin, taking advantage breast conserving surgery where amenable. For borderline or malignant phyllodes tumours or in cases of local tumour recurrence, mastectomy and immediate breast reconstruction may become the preferred option.Genetic analysis will potentially supplement classical histological examination in order to improve our management of these tumours. The role of adjuvant treatments is unproven and must be considered on a case-by-case basis.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-12.
Abstract P5-14-15: Contralateral Prophylactic Mastectomy: Clinical and Pathological Features of Women Treated at the University of Louisville
Authors: Johnson RR , Barry PN , Kruse B , Dragun AE.
Published: April 2011

Objective: To evaluate the clinical and pathological features of women who underwent contralateral prophylactic mastectomy (CPM) as a component of breast cancer therapy.

Materials & Methods: This is a retrospective review of a prospectively-maintained database of patients treated at the multi-disciplinary breast cancer clinic at the University of Louisville from 2003-2009. Patientswith unilateral pre-invasive and invasive adenocarcinoma who underwent mastectomy as primary surgical treatment for the involved breast with CPM were included. All information from surgical, medical and radiation oncology records were reviewed for this analysis.

Results: A total of 107 patients are included in this analysis. The median age was 48 years (range 26-80). A previous history of breast cancer was noted in 8% of patients, all of whom received lumpectomy and whole-breast radiotherapy. A family history of breast cancer was identified in 46% of patients and 4% of patients possessed a germline BRCA mutation. Ninety-three percent of tumors were invasive. Evaluation of the pathological tumor (T) stage yielded 7% Tis, 48% T1, 36% T2, 3% T3, and 3% T4. Four percent of tumors were pathologically T0 after a complete response to neoadjuvant chemotherapy. Pathological node (N) staging yielded 56% N0, 23% N1, 14% N2, and 7% N3. Two percent of patients had distant metastasis at diagnosis. Twenty-two percent of tumors were negative for the estrogen, progesterone, and HER2/neu receptors (triple negative). Lobular carcinoma in situ was found in 10% of tumors. Five occult tumors were detected in the contralateral breast, of which 4 were carcinoma in situ and 1 was invasive mucinous carcinoma. With a median follow-up of 27 months (range 7-83), 9 treatment failures have been noted. Four patients failed locoregionally, 3 failed distantly, and 2 failed both locoregionally and distantly. Five patients have died of metastatic disease. No contralateral chest wall failures have occurred.

Conclusions: CPM has become more popular over the past 6 years and patients present with a diverse array of clinical and pathological features. Occult disease in the contralateral breast is rare and was not encountered in our series. The pattern of failure is determined by the primary disease and the clinical utility of CPM therefore remains uncertain.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-15.
Abstract P5-14-16: Resection of Breast Cancer Liver Metastases: Single Institution Experience
Authors: Nikolic S , Tomasevic Z , Inic M , Zegarac M , Pupic G.
Published: April 2011

Background

Metastatic breast cancer (MBC) is considered incurable and systemic treatment is usually given, even when liver metastasis is solitary and the only metastatic site. However, occasionally in selected, for surgery highly motivated patients, liver metastases resection is performed. The definitive disease outcome for those patients is rarely reported. The aim of this analysis is to evaluate outcomes for patients after breast cancer liver metastases resection. Patients and methods

From December 2002-March 2010, 36 MBC patients were referred to surgery for liver metastases resection. Median age at MBC was 48 (range 29-71), median DFI from breast cancer diagnosis to metastases development was 36 (0-144 months).

Steroid receptor status was positive (defined as ER and or PGR Qucik score ≥4) in 20 primary BC (74%), negative (Quick score<4) in 6 primary BC (22%), and unknown for 7 pts (22.5%).

HER2 status was known for 24 pts (77.4%), and was positive (IHC 3+, and CISH+ for HER2 2+) in 5 pts. (21%), and negative in 19 pts (79%) Results

Five pts were excluded because metastases in other organ sites were detected.

In 3/31 pts who underwent surgery, inoperable multiple, metastases were intra-operatively confirmed despite initial diagnostic procedures indicate solitary lesions. Outcome for those patients is not shown in this analysis. In 3 pts, metastases were ruled out by biopsy during laparatomy. In 25 pts who underwent liver resection median number of liver metastases was 1 (range 1-5), median size 25 mm (7-50). All pts received systemic, postoperative chemotherapy, +/− treatment according to molecular characteristics of metastases (reported elsewhere). Outcome after liver resection: 7/25 (28%) patients are lost of follow-up;

3/25 (12%) died; NED stage (no evidence of disease) is achieved in 16/25 pts and 5/16 (31.5%) are still free of disease, for median 36 months.

Conclusion

Median 36 months after metastases resection,5/16 (31.5%) of patients remained in NED stage.

That percentage of durable response is et least equal to systemic treatments response.

It seems that there is a subgroup of patients who could benefit of metastases resection achieving long lasting NED stage. Still, the most important characteristics of this subgroup in not well recognized.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-16.
Abstract P5-15-04: A Randomized Trial Comparing Intermittent Pneumatic Compression with Manual Lymphatic Drainage for Treatment of Lymphedema in Patients with Breast Cancer
Authors: Ozkan Gurdal S , Kostanoglu A , Cavdar I , Ozbas A , Cabioglu N , Ozcinar B , Muslumanoglu M , Igci A , Ozmen V.
Published: April 2011

Aim: Lymphedema is a serious complication associated with axillary surgery and/or radiotherapy in patients with breast cancer. The aim of this randomized study was to assess the efficacy of two different treatment modalities of lymphedema by comparing the manual lymphatic drainage and compression bandage with intermittent pneumatic compression and self-lymphatic drainage.

Material and Methods: Thirty patients diagnosed with lymphedema after treatment for breast cancer were randomized to either manual lymphatic drainage (MLD)by physicotherapists with compression bandage-group (n=15) or to the intermittent pneumatic compression (IPC)-group with self-lymphatic drainage massage (n=15). In both groups, treatment program was performed three days a week, every other day for 6 weeks. To determine the efficacy of the treatment modalities, arm circumferences were measured from wrist to shoulder girdle with 10 cm distance before and after treatment for lymphedema at the 1st, 3rd, and 6th weeks of the therapies. Tests evaluating the quality of life including EORTC-QLQ and ASES-test were also performed before and after treatment at 6th week.

Results: The median age of patients was 54.5 years (31-74) and lymphedema occured after a median time of 18 months following surgery (range, 6-72 months). Patients in both groups had similar demographic and clinical characteristics. At the 6th week, even though both treatment modalities resulted in significant decreases (p< 0.001) in the total arm volume (12.2% decrease in IPC-group versus 14.9% decrease in MLD-group), no significant difference could be found in the therapeutic efficacy between the IPC-and MLD-groups. Furthermore, significant improvements of ASES scores were detected after both IPC-and MLD-therapies (p=0.001), but there was no statistically significance between two groups. In the EORTC-QLQ-C30 quality of life test, however, global health status, functional and cognitive functioning scores appeared to be improved only after MLD-therapy, whereas emotional functioning scores, fatique and pain scores significantly improved after MLD-or IPC-therapy. Conclusion: Both treatment modalities by MLD and IPC appear to be effective in the treatment of lymphedema with similar therapeutic efficacy in patients with breast cancer. MLD-therapy seems to be superior to IPC-therapy since there is a trend of an improvement in the quality of life in patients treated with MLD. However, IPC might still be the preferred treatment for some patients who work at the day time since it could be performed easily at home by themselves without a need for a physicotherapist at the hospital.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-15-04.
Abstract P6-01-06: Identification of Molecular Subtypes of DCIS and Invasive Breast Cancer Using Computerized Image Analysis for Data Integration
Authors: Adeyanju OO , Khramtsov A , Verma A , Liu L , Wang X , Sattar H , Olopade OI , Huo D.
Published: April 2011

Background: Breast cancer is a heterogeneous disease with different putative therapeutic targets based upon the particular subtype. The particular subtype can have profound implications for therapy, as in the case of basal-like carcinomas which tend to be more aggressive with less therapeutic options. Although many studies have examined the transition from Ductal Carcinoma in-situ (DCIS) to Invasive Breast Cancer (IBC), the mechanisms involving the transformation are poorly understood. DCIS cases that are more likely to progress to IBC can be treated more aggressively. This study used image analysis to examine the association between predictive molecular biomarkers between pure DCIS, DCIS associated with IBC and IBC.

Methods: With approval by the Institutional Review Board, we evaluated tissue microarrays comprising 453 tissue cores from 149 patients. Five immunohistochemical biomarkers were utilized: estrogen (ER), progesterone (PR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin 5/6 (CK-5/6). We then employed the Automated Cellular Image Analysis (ACIS) to score the biomarker status. We compared regional scoring (rated 0, 1, 2, or 3) between an experienced pathologist's subjective assessment and an automated score derived from ACIS. An image library was generated and integrated to our Translational Data Mart (TraM: http://tram.uchicago. edu). Statistical analyses included a comparison of histological grade, race, age, tumor size, and lymph node status associated with the prevalence of subtypes between pure DCIS tumors and those that advanced to IBCs. Results: The concordance between ACIS-based and pathologist-based scoring was moderate (kappa = 0.38). There was more variability in the pathologist's scoring with a standard deviation of 1.14 as compared to 0.85 for ACIS. Subtypes associated with IBC were also present in DCIS. In the pure DCIS cases, there was a higher proportion of the luminal A subtype (74.1%, n = 54) as compared to DCIS adjacent to IBC (54.2%, n=24) or pure IBC cases (57.4%, n = 115) (p=0.05). In contrast, there was more basal-like subtypes in DCIS juxtaposed with IBC (20.8%) and IBC (27.8%) than in pure DCIS tumors (9.3%).

Discussion: Molecular subtype analysis of DCIS could be useful in predicting DCIS with high risk of progressing to invasive cancer. The resemblance between subtypes bolsters the hypothesis that IBCs and DCIS originate from the same precursor lesion. Although the automated scoring featured by ACIS would be useful in expediting readings, it must be validated by a pathologist's assessment.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-01-06.
Abstract P6-02-03: The Use of Charcoal Suspension Labeling as an Adjunct in the Detection of Non-Palpable Breast Lesions
Authors: Santos Cavalcanti TC , Budel VM , Gasperin P.
Published: April 2011

Introduction and Objectives: Inert charcoal suspension is used as a tissue marker, which provides innumerous advantages over other labeling methods and techniques, such as dyes and metallic needles. In addition, the use of charcoal does not present problems with regards to its diffusion, labeling the trajectory from the lesion to the skin, being easily identified by both the surgeon and pathologist. The occurrence of morphological alterations due to the use of charcoal is very rare. In contrast, there are still doubts and questions concerning the interference of charcoal labeling with regards to the anatomopathological diagnosis accuracy. The main objectives in this study are to analyze the efficiency of labeling impalpable breast lesions with inert charcoal suspension; to evaluate the morphological alterations associated with its use and to determine whether the use of charcoal labeling hampers with the diagnostic interpretation of the pathologist. Materials and Methods: The study evaluated a total of 135 cases of impalpable breast lesions, previously labeled with charcoal suspension. Histological H/E stained slides containing charcoal pigments were analyzed using optical microscopy, by which both quantitative and qualitative evaluations with regards to inflammatory response and interference in diagnosis were performed. Lymphocyte, giant cells and neutrophils were evaluated and quantified. Moreover, the distribution of the charcoal suspension present in the lesions was evaluated. Results: As to the quantitative and qualitative evaluation of the inflammatory response caused by the use of charcoal labeling, it was observed that granulomas were present in all samples, regardless of the quantity of injected charcoal. Lymphocytic inflammatory response was absent in 5.19% of the samples only, were 82.22% demonstrated discrete intensity and 12.59% was moderate. With regards to acute inflammatory response, 42.96% showed total absence of neutrophilic exudate, were as 42.22% demonstrated discrete and 11.11% moderate, and only 3.7% of cases were intense. Conclusion: This study corroborates the utility and easiness of the charcoal method as a means of efficient labeling of impalpable breast lesions. In addition, this technique is easy to use, has a low cost, high efficiency and does not interfere with the histological analysis. Moreover, it is comfortable for the patient and is of great help in finding and localizing the lesions to both the surgeon and pathologist.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-02-03.
Abstract P6-04-02: Profiling of BRCA1 Mutated Breast Tumours Using a Breast Cancer Specific Microarray To Identify a Profile of BRCAl-Deficiency
Authors: Irwin G , Lamers E , McDyer F , Mulligan J , Couch F , Kennedy R , Harkin P , Quinn J.
Published: April 2011

Background

The BRCA 1 tumour suppressor gene is mutated in a significant proportion of hereditary breast cancer cases. Additionally, downregulation of BRCA1 mRNA and protein expression is reported in approximately one third of sporadic breast cancers. BRCA1 is strongly implicated in the maintenance of genomic stability by its involvement in multiple cellular pathways including: DNA damage signalling, DNA repair, cell cycle regulation, protein ubiquitination, chromatin remodelling, transcriptional regulation and apoptosis. To date, gene expression profiling has identified: (1) at least five breast cancer subtypes and (2) that BRCA1 mutant tumours segregate with basal-like breast cancers. These studies also provide evidence that breast cancers with germline mutations in BRCA1 are different from non BRCA1-related tumours. The main aim of this study is to investigate the underlying biology of BRCA1-mutated breast cancer. Methods

Extensive gene expression profiling and data analysis were performed on a cohort of 70 FFPE (Formalin Fixed Paraffin Embedded) derived BRCA 1 mutated breast tumours and matched sporadic controls using the Almac Breast Cancer DSATM research tool. Functional analysis was performed with DAVID and METACORE. Validation of gene targets was performed by qRT-PCR and Western blotting. Results

A list of differentially expressed transcripts has been derived from the comparison of these BRCA1 mutant breast tumours and matched sporadic controls. Functional analysis of this gene list has identified the key genes and molecular pathways that are deregulated in these tumours. BRCA1 deficiency was associated with deregulation of pathways involved in: (1) immune response, (2) metastasis and invasion, (3) cytoskeletal remodelling, (4) spindle assembly and chromosome separation, (5) apoptosis and survival. Validation of the key genes underlying this BRCA1-deficient breast cancer profile has been performed. Conclusions

This approach has revealed a set of transcripts that could potentially be used to identify both hereditary and sporadic breast cancer patients with BRCA1- deficiency. The ability to perform gene expression profiling from FFPE derived breast tissue could also have significant clinical application.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-04-02.
Abstract P6-04-08: Microarray Characterization of 24 Cases of Pure Mucinous Carcinoma of the Breast
Authors: Sanchez-Salazar AJ , Gunn SR , Yeh I-T.
Published: April 2011

Background: Mucinous carcinoma of the breast has been shown to be a distinct histological entity with a better clinical prognosis than invasive ductal carcinoma, NOS. Only a few cases have thus far been studied by molecular analysis. The purpose of this is study is to further evaluate the genomic changes in mucinous carcinoma of the breast. Design: 24 pure mucinous breast carcinomas with available fresh frozen tissue were retrieved from our files. The cases were reviewed for histologic grade (SBR), mitoses, percent mucin, intracytoplasmic mucin, type A or B mucinous carcinoma, and estrogen receptor (ER) and progesterone receptor (PR) expression. Follow-up was available for 13 patients and included 4 recurrences. Representative sections of the tumors were dissected from the normal tissue present in the blocks and were assayed by Agilent (Santa Clara, CA, USA) human genome CGH microarray kit 105A. Analysis was performed using Agilent (Santa Clara, CA, USA) genomic workbench 5.0 software.

Results: The 24 mucinous carcinomas were composed of 19 type A and 5 type B mucinous carcinomas, including 21 with >60% mucin and 3 with <60% mucin. Seven cases contained intracytoplasmic mucin. Tumors were grade 1 in 20 cases and grade 2 in 4 cases. Mitotic count per 10hpfs was 0 or 1-2 in 19 cases and >3 in 5 cases. ER was positive in all cases, and PR was positive in all but 4 cases. Analysis of the genome arrays showed that 17 of the cases had a complex level of genetic instability with three or more (up to 15) of the chromosomes showing instability while four show only one or two chromosomes affected. On the other hand, there are no abnormalities found in four of the cases. The most frequently affected chromosome is chromosome 1 which is involved in 12 of the cases, with three cases showing 1p partial loss/full loss, and nine cases showing 1q partial gain/full gain. Gains were also commonly seen in 8p, 8q, 11q, 16p, 17q and 20q. Losses were most frequently seen in 6q, 11q, 16q and 17p. Four of five Type B tumors exhibited a complex pattern, and all four grade 2 tumors had a complex pattern. Of the tumors that recurred, three of four had a complex pattern of genetic instability.

Conclusions: Evaluation of pure mucinous carcinomas studied showed a high level of genomic complexity with multiple chromosomal changes in most cases. Tumors that were grade 2 and mucinous type B tumors tended to be of higher complexity than grade 1 and type A mucinous tumors. The most commonly affected chromosomes include chromosomes 1, 6, 8, 11, 16, and 17.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-04-08.
Abstract P6-04-16: Molecular Profiling of Stage II and III Breast Cancer in Latin American Women Receiving Standard-of-Care Treatment
Authors: Gomez J
Published: April 2011

Breast cancer, though genetically and clinically heterogeneous, still lacks reliable prognostic and predictive markers. Gene expression profiling studies have correlated with long-term survival and response to therapy. Multiple variables thought to modify gene expression (i.e., ancestry, socio-economical and cultural factors) are not always controlled when correlating molecular markers with clinical outcome. Breast cancer rates are lower in Latin America than in other countries; molecularly, variations in gene expression should reflect different genetic and epigenetic levels there. The United States-Latin America Cancer Research Network (US-LA CRN) launches its first breast cancer pilot study in 2010 in over 20 hospitals and research facilities across Argentina, Brazil, Chile, Mexico, and Uruguay, primarily to characterize molecular profile distribution (luminal A, luminal B, HER2-like, and basal) in Latin American women with non-metastatic stage II or III breast cancer. Molecular profiles determined by microarray will be correlated with epidemiological, histological, and clinical data, including pathologic response to standard neoadjuvant chemotherapy; a molecular signature that predicts response to neoadjuvant therapy in breast cancer will be defined. This prospective cohort study will not dispense investigational drugs. Part A characterizes molecular profiles of breast cancer in Latin America; Part B examines associations between response to neoadjuvant therapy and molecular profiles. Tissue samplesfor gene expression profiling will be collected during routine core biopsies or during surgery. Core biopsies and surgical resection specimens from participants will undergo histopathologic evaluation, tumor ER, PgR, HER2, and Ki67 status assessment. During Part B, patients will be sorted by hormone receptor and HER2 status and receive standard neoadjuvant chemotherapy. Tissue samples will be re-assessed to evaluate residual cancer burden for pathologic response to neoadjuvant treatment and gene expression. Five-year patient follow-up will determine associations between molecular profiles and disease evolution after standard treatment. Besides providing data on the effectiveness of standard chemotherapy in Latin American women, study infrastructure includes establishing biobanks in participating countries to conduct additional clinical trials incorporating complex genomic and pathologic biomarkers, including trials to evaluate investigational therapies.

Studying the molecular profile of breast cancer in Latin America will improve diagnosis and treatment, correlate molecular subtypes with long-term survival and response to therapy, and identify indolent-disease subpopulations of cancer patients, perhaps enabling future personalized cancer management.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-04-16.
Abstract P6-05-05: Signaling Pathways Activated in Her 2 and ER Negative Breast Cancers
Authors: Song D , Gao L , Cui M , Han B , Zhao G , Fu T , Li P , Ye F , Fan MZ , Pelletier G , Zhang DY.
Published: April 2011

Introduction: Breast cancer is the most common cancer in women (192,370 new cases in 2009) and the second leading cause of cancer death (40,000) among women in USA. Current multimodality treatment of breast cancer is based on the level of ER expression and Her 2 gene amplification. However, no effective treatment is currently available for breast cancers with low level expression of ER and no amplification of Her 2 gene. The aim of this study is to identify protein pathways activated in the breast cancer with negative expression of ER and Her 2. Method: Protein Pathway Array was used to assess the level of protein expression and phosphorylation in 71 paired fresh frozen breast samples (tumor and adjacent benign tissue). A total 159 antibodies were evaluated which represent most important signal transduction pathways involved in proliferation, apoptosis, angiogenesis, invasion and metastasis. Several potential therapeutic kinase proteins were also assessed. Results: A total 20 proteins (PCNA, phospho-PTEN, cyclin B1 cyclin E1, CDK6, E-cadherin, NFkB, ect) were differentially expressed between normal and tumor tissues based on the statistical analysis. In Her 2 negative tumors (n=37), 3 proteins were differentially expressed and among them, 2 were up-regulated (CDK6 and HSD1) and 1 was down-regulated (IGF). In ER negative tumors (n=18), 4 proteins (HSD, SK, TDP and Slug) was up-regulated and 1 proteins were down-regulated (E-cadherin). In triple negative tumors (n=13), one protein (E-cadherin) down-regulated and 2 proteins (TDP and HSD) were up-regulated. Furthermore, based on the expression pattern of these proteins, tumors negative for both ER and Her 2 (n=15) can be clustered into 3 groups

Figure 1: Subclassification of breast cancers negative for ER and Her-2 based protein pattern.

Hierarchical clustering analysis of 20 differentially expressed proteins in

15 ER/Her-2 negative breast cancers. The cancers can be separated into 3 subtypes. Red indicates overexpression, green underexpression, black no change, and gray no expression. Each column represents a protein. Each row represents a sample.

Conclusion: Our study showed that distinct sets of signaling pathways activated in ER and Her 2 negative breast cancers. The increased expression of cell cycle progression proteins in Her 2 negative tumors suggests activation of cell proliferation via different growth promotion pathway. Similarly, different cell proliferation pathways are also activated in ER negative tumors. This finding may be used to design future clinical trial based on the activation of different signaling pathways.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-05-05.
Abstract P6-07-02: A Systems Analysis of Oscillations in the MAPK Pathway Reveals New Mechanisms of Feed-Forward and Feedback Signaling Control
Authors: Hu H , Faratian D , Goltsov A , Bown J , Langdon SP , Harrison DJ.
Published: April 2011

Oscillations occur in diverse areas of cellular biology, from mechanotransduction to circadian control. Their physiological, pathological, and therapeutic significance in breast cancer remains undetermined, and their existence has yet to be described in the key oncogenic signaling pathways. Mathematical modeling lends itself to detailed study of these complex dynamic phenomena. We observed damped oscillations in pERK with approximately 20 minute periodicity in MCF7 breast carcinoma cell lines after stimulation with heregulin or epidermal growth factor (EGF). In order to establish mechanisms by which these oscillations might occur, we used an ordinary differential equation-based mathematical model of MAPK/PI3K signaling to simulate oscillatory behaviour in MAPK signaling. Both modification of feed-forward (HER2 overexpression) and feedback (abrogation of early gene transcription, EGFR phosphorylation by pERK, crosstalk between pAKT and RAF, and binding of pERK with SOS) loops resulted in the emergence of sustained oscillations in phospho-ERK. When these simulations were tested experimentally, MCF7 cells stably transfected with HER2 (MCF7/HER2-18) showed sustained oscillations in pERK when stimulated with heregulin, which were abrogated by inhibition of HER2 heterodimerisation with pertuzumab. Likewise, suppression of transcriptional feedback with cycloheximide resulted in sustained oscillations in pERK of increased amplitude. We have therefore described oscillations in MAPK signalling for the first time in breast cancer cell lines. Since the duration and amplitude of these oscillations is altered both by addition of the HER2 oncogene, and by inhibition of feedback control, the functional consequences of changes in oscillations may have fundamental consequences both in oncogenesis and therapeutic efficacy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-07-02.
Abstract P6-08-02: Comparative Analysis between Primary and Secondary in Breast Tumors by Polymorphysim of Androgen Receptor Gene and Mitochondria D-Loop Somatic Mutation
Authors: Umemura SM , Kadowaki T , Kumaki N , Tang X , Takekoshi S , Yoshimura S , Suzuki Y , Tokuda Y , Osamura RY.
Published: April 2011

Background: It has not been fully understood how we can differentiate a new primary breast cancer from a recurrent tumor, when second tumor arises in ipsilateral breast after the surgery for primary breast cancer. To address this research question, we estimate the usefulness of a method analyzing polymorphism of androgen receptor gene and mitochondrial D-loop somatic mutation.

Materials and methods: 1) Select patients: Among the 558 patients who received the breast conservative surgery in Tokai University Hospital (1991∼2004), 9 ipsilateral breast tumors and 11 contralateral breast tumors were submitted for the analysis. 2) Formalin-fixed paraffin-embedded (FFPE) sections of non-neoplastic lymph node were examined whether polymorphism of AR gene present or not. 3) When polymorphism of AR gene in non-neoplastic lymphoid tissue were demonstrated, ipsilateral and contralateral breast cancers were further examined. 4) When AR gene in breast cancers on same allele in primary and secondary tumors, FFPE sections were further analyzed by mutaion analysis of mitochondrial D-loop region.

Results: 1) Polymorphism of AR was demonstrated in 8/9 (88.9%) and 9/11 (81.8%) non-neoplastic lymph nodes obtained from the patients who had ipsilateral and contralateral breast tumor, respectively. 2) Only 2 of 8 ipsilateral breast cancers demonstrated AR polymorphism different from primary cancer. In contrast, 6 of 9 contralateral breast cancers had different polymorphism for AR from primary breast cancers. 3) Analysis of mitochondrial D-loop mutation showed that 8 seconary ipsilateral cancers had different mutation in 3/8 (37.5%), identical mutation in 3/8 (37.5%), and no mutation in 2/8 (25.0%).

Results of analysis for ipsilateral secondary breast cancers

Conclusion: Half of the ipsilateral in breast secondary tumors were estimated as new primary lesions by molecular estimation. Combination analyses of AR gene polymorphism and mitochondrial D-loop somatic mutation unable us to distinguish between true recurrent or new primary cancers.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-08-02.
Abstract P6-08-03: MYC Amplification and Overexpression Discriminate Secondary from Primary Angiosarcoma of the Breast
Authors: Hadj-Hamou NS , Kirova YM , Laé M , Sastre-Garau X , Malfoy B.
Published: April 2011

Background: Secondary angiosarcoma of the breast is defined as a sarcoma developed in the irradiated field in patients previously treated for breast carcinoma. These tumors represent 25% to 50% of sarcomas developed after irradiation for breast cancer and are of poor outcome. Up to now, there are no criteria to distinguish primary from secondary angiosarcomas. The aim of this work was to identify molecular features able to discriminate these two types of tumors.

Material and Methods: Our study was mainly based on the use of whole genome (SNP array) and whole transcriptome (mRNA and miRNA microarray) approaches. Others methods included quantitative PCR, reverse transcription quantitative PCR, fluorescence in situ hybridization and immunohistochemistry.

All patients’ records were reviewed and the clinical information about the primary and secondary sarcomas was recorded. For all radiation-induced sarcomas, the patients’ radiotherapy plans were reviewed and it was confirmed that the tumors respected the classic Cahan's criteria to confirm their secondary nature.

Results: Amplification (5 to 50 fold) of the MYC oncogene was found in all breast secondary angiosarcomas (19 cases) but in none of primary angiosarcomas (6 cases) (p-value = 2.353e-05). MYC amplification was associated with mRNA and protein overexpression of this gene. In tumors with a MYC amplification, numerous genes corresponding to MYC targets and coding for mRNA or miRNAs were found to be deregulated as compared with expression levels observed in tumors without amplifications. These data point to the pathways preferentially involved in the pathogenesis of secondary angiosarcomas of the breast. The relationships between clinical, pathological and biological features are studied.

Conclusions: MYC is amplified and overexpressed in secondary angiosarcomas of the breast. We suggest to exploit these characteristic features as a diagnostic criteria to distinguish primary from secondary angiosarcomas of the breast. Furthermore, those newly identified characteristics of secondary angiosarcomas could serve as a basis for tailored therapeutic approaches.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-08-03.