bluuebunny/crossref_metadata_2025 huggingface dataset:
Pure apocrine carcinomas of the breast express ER-alpha 36, a novel alternatively spliced variant of human estrogen receptor-alpha (ER-alpha 66).
Authors: Gatalica Z , Deng H , Lee LM , Wang Z
Published: December 2010

Abstract #4035

Background: Pure apocrine carcinomas (PACs) are defined as tumors composed entirely of epithelium showing apocrine differentiation (large cells with prominent eosinophilic, flocculent cytoplasm with sharply defined borders and large nucleus with prominent macronucleolus). PACs do not express classic estrogen receptor alpha (ER-α66) or progesterone receptor (PR) but consistently over-expresses androgen receptor (AR). We have investigated expression of a novel alternatively spliced variant of ER-α66, named ER-α36, which we recently identified and cloned (Wang ZY et al, PNAS 2006;103: 9063) and demonstrated that it mediates membrane initiated steroid signaling (MISS). MISS is dependent on ER interaction with receptor tyrosine kinases, and we hence investigated co-expression of ER-α36 with EGFR and HER2 in PACs.  Methods: 17 patients with breast PAC were studied for expression of ER-α66, PR, AR, HER-2, EGFR and ER-α36 using immunohistochemical methods. ER-α36-specific antibody was custom-made by the Alpha Diagnostic International (San Antonio, TX) against the unique 20 amino acids at the C-terminal of the ER-a36; other antibodies were from commercially available sources. Mammary carcinoma cell line (MDA-MB-231) that lacks expression of ER-α66 but expresses ER-α36 and EGFR, was used as a positive control.  Results: All tumors showed characteristic steroid receptor expression profile of apocrine carcinomas (ERα66 and PR negative; AR strongly positive). ERα36 expression was detected in 16/17 cases (94%) in membranous and cytoplasmic distribution. Co-expression of ER-α36 with either one of the tyrosine kinase receptors (HER2 or EGFR) was detected in 16 cases (100% of ER-α36 positive PACs). In an experimental model (MDA-MB-231 cells), 17β-estradiol (E2) strongly induced rapid phosphorylation of the MAPK/ERK1/2, but had only a weak effect in ER-α36 siRNA knock-down MDA-MB-231 cells.  Conclusion: Despite the lack of classic full length ER-alpha expression (ER-α66) in PACs, a novel alternatively splice variant (ER-α36) is commonly expressed in this aggressive tumor type. This receptor variant is capable of strong E2 signal transduction and responsible for an increased cell growth. This non-genomic estrogen signaling probably involves membranous interaction between a tyrosine kinase receptor (EGFR or HER2) and ER-α36, resulting in activation of mitogen activated protein kinase pathway.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4035.
Histologic markers of mammographic breast density: core-needle biopsy tissue from healthy volunteers.
Authors: Ghosh K , Brandt KR , Reynolds CA , Watson DA , Lingle WL , Pankratz VS , Hartmann LC , Vachon CM
Published: December 2010

Abstract #4037

Background: Mammographic breast density is a strong and consistent risk factor for breast cancer. Women with dense tissue in over 60 to 75% of the breast are at 4 to 6 times greater risk than women with little or no density. However, the biology of breast density is not well understood and studies at the tissue level are limited. We present the first report of a tissue-based study of breast density, sampling mammographically dense and non-dense areas of the breast of healthy women with the goal of examining histologic correlates.  Materials and Methods: Healthy women volunteers aged 40 to 85 years, with no breast symptoms, normal screening mammogram within 6 months, and no personal history of breast cancer were considered eligible. Women with breast-related symptoms, those on endocrine therapy, or with bleeding tendencies were excluded from participation. Sixty consecutive eligible women were enrolled in the study- results are based on the first 34 participants. Eligible women underwent an ultrasound-guided, core-needle breast biopsy of mammographically dense and non-dense areas of the breast, performed by a single experienced radiologist. Quantitative assessment of breast tissue from dense and non-dense areas was performed for epithelium, stroma, and fat. In addition, we assessed the difference in the extent of lobular involution (complete, partial and none) between dense and non-dense areas. We used means and SD to describe distributions in each tissue type. Signed rank test was used to assess within woman differences between dense and non-dense tissue.  Results: The mean age of the participants was 50.1 years (range 40 to 79 years). The histological findings are outlined below.    Dense tissue is comprised of increased stroma and epithelium and decreased fat, consistent with prior reports on breast density. The finding of 'no involution' was greater in dense tissue compared to non-dense tissue (24% versus 8.8%); non-dense tissue had greater proportion of complete involution compared to dense tissue (82.5% versus 35.2%).  Discussion: This report is the first to quantify histology in tissue sampled from dense and non-dense regions of the healthy breast. We find a dramatic difference in tissue composition between dense and non-dense tissue in the breast. Future studies using this tissue to assess molecular markers will further help to characterize pathways through which density may increase breast cancer risk.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4037.
The relationship between tumour NF-kB expression, hormone status, and clinicopathological factors in primary invasive breast cancer.
Authors: Tannahill CL , Obondo C , Al-Murri AM , Doughty JD , Lannigan A , Wilson CR , McMillan DC , Edwards J
Published: December 2010

Abstract #4038

Breast cancer is one of the most common and lethal malignancies in the UK. Conventionally, prognosis is based on hormone status, tumour size, grade and lymph node involvement. Recently it has been proposed that Nuclear Factor Kappa B (NF-kB) is associated with breast cancer development and progression (1). The aim of the present study was to examine the relationship between NF-kB, hormone status and clinicopathological factors in primary invasive breast cancer.  Immunohistochemistry was performed on 168 breast tumour sections, with full clinicopathological characteristics. Antibodies were directed against total NF-kB and NF-kB phosphorylated at serine 536 (phospho NF-kB). Two observers independently scored expression using the weighted histoscore technique and grouped tumours as having high or low expression according to the median value.  Cytoplasmic and nuclear NF-kB expression, either total or phosphorylated did not correlate with grade, size or lymph node involvement. However, nuclear phospho NF-kB expression was inversely associated with Ki67 proliferation index (p<0.05). In addition an association between total nuclear NF-kB (p<0.050) and total cytoplasmic NF-kB (p<0.05) was observed with oestrogen (ER) and progesterone receptor (PR) status, total NF-kB expression was higher in ER and PR positive tumours (n=53) compared with ER negative and PR negative tumours (n=34). This association was also observed for nuclear phospho NF-kB (p<0.001) but not cytoplasmic phospho NF-kB (p=0.292). In addition, ER positive and PR negative tumours (n=78) had reduced nuclear phospho NF-kB (p<0.001) and cytoplasmic phospho NF-kB (p<0.001) expression when compared with ER positive and PR positive tumours (n=53).  These results suggest that reduced tumour expression of phospho NF-kb is associated with increased cell proliferation and PR negativity but not ER negativity in primary invasive breast cancer. The impact of such differential tumour expression of phospho NF-kB on outcome in breast cancer remains to be determined.  1. Cao Y, Karin M. NF-kappaB in mammary gland development and breast cancer.J Mammary Gland Biol Neoplasia. 2003;8:215-23.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4038.
Prognostic significance of GSTP1 and MGMT hypermethylation in invasive ductal breast carcinoma patients.
Authors: Sharma G , Mirza S , Parshad R , Gupta SD , Pandaya P , Ralhan R
Published: December 2010

Abstract #4053

Purpose: Methylation-mediated suppression of detoxification, DNA repair and tumor suppressor genes has been implicated in cancer development, by shifting cells from the normal cellular cycle to a state of high proliferation that favors tumor development and progression. The current study was designed to analyze the methylation status of these genes in sera of breast cancer patients and determine the correlation of promoter hypermethylation of these genes with disease prognosis and patient survival.  Experimental design: To test the hypothesis that promoter methylation of GSTP1 and MGMT is associated with disease prognosis, the methylation status of these genes was analyzed in invasive ductal carcinoma tissues and corresponding sera of breast cancer patients and correlated with disease free survival of these patients.  Results: Promoter methylation of GSTP1 and MGMT was observed in 25% and 38% of breast tumor tissues, respectively and in 23% and 35% of the corresponding sera of breast cancer patients. There was significant association between methylation of GSTP1 and advanced tumor stage. Patients harboring methylated GSTP1 were more likely to have disease progression and reduced overall survival compared with patients who did not have the methylated gene.  Conclusion: GSTP1 methylation in tumor and sera may serve as a poor prognostic marker in patients with invasive ductal carcinoma.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4053.
p38 MAPK is altered transcriptionally, translationally, and post-translationally in inflammatory breast cancer – significance and implications.
Authors: Rosenthal DT , Dambro CR , Brenner JC , Wu Z , Merajver SD
Published: December 2010

Abstract #4061

Inflammatory breast cancer (IBC) is the most lethal form of breast cancer, with a 5-year survival rate below 45%. The disease progresses rapidly, and is typically identified as stage IIIb upon diagnosis. IBC is characterized by widespread invasion of the dermal lymphatics by tumor emboli, which results in lymphatic blockage. It is this blockage that leads to edema, erythema, and the subsequent “peau d'orange” appearance of the breast, and thus the misnomer “inflammatory” breast cancer.  Little is known about the mechanisms of IBC metastasis, and as such the treatments available to patients are limited. Our lab identified RhoC GTPase as an oncogenic driver of the IBC phenotype, as overexpression of RhoC in normal human mammary epithelial cells (HME) leads to increased motility, invasion, and secretion of angiogenic factors. Ensuing studies from our lab revealed that p38 is involved in mediating IBC metastasis and invasion, as demonstrated by the effects of p38 inhibitors on RhoC-transfected HMEs. The aim of the current project was to determine the means by which IBC utilizes p38, and elucidate the contributions of the specific p38 isoforms to IBC metastasis and invasion.  We demonstrate, for the first time, differences in the transcriptional, translational, and post-translational regulation of specific p38 MAPK isoforms in breast cancer, differences which delineate IBC from other invasive breast cancers, and invasive breast cancer from normal mammary epithelia. Furthermore, we show evidence that this upregulation is driven by RhoC overexpression. The contribution of each isoform to metastasis and invasion was then determined using isoform-specific expression vectors and RNA interference (RNAi). The results of this study will be useful in designing new drugs and therapies specific for IBC.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4061.
Reliable data on 5- and 10-year survival in early-stage breast cancer provides accurate estimates of 15-year survival.
Authors: Herold CI , Djulbegovic B , Hozo I , Lyman GH
Published: December 2010

Abstract #4076

Background: Evidence-based medicine encourages utilization of empirical evidence from controlled clinical trials in decision making both at the bedside and in health policy. However, the applicability of this approach may be limited by the lack of long-term results from efficacy studies. Decision analytic methods that model outcomes beyond empirically available evidence, typically over the lifetime horizon, have been proposed. There have been few studies of the accuracy of model-based survival projections utilizing reliable but early empiric results for estimating long-term survival. Such results, however, would have direct clinical and health policy implications.  Methods: We took advantage of recently published individual-patient data meta-analysis by Early Breast Cancer Trialists' Collaborative Group (EBCTCG) (Lancet 2005;365:1687-1717) which regularly updates their results at 5-year intervals. A Markov model was built to compare empirical results with those modeled beyond the time horizon for which data was available. We first modeled breast cancer mortality rates comparing the effects of 5 years of tamoxifen versus no treatment. We then modeled the 15-year probability of death from breast cancer using the 5- and 10-year mortality data reported in the overview. Finally, we estimated the effect of breast cancer on life expectancy in women ranging in age from 40 to 70 years by decade.  Results: Verification of the model produced 5-, 10-, and 15-year survival data that were identical to the empirical data reported in the EBCTCG overview. Modeling 15-year survival based on 5- and 10-year empirical data resulted in an average error estimate in breast cancer mortality of 0.75% [range: -0.83 to 2.19%]. Although modeling of differences in life expectancies ranged from an underestimate of -7.93% to an overestimate of 12.64%, in absolute terms over the span of 15 years this corresponded to a loss of 18 days or a gain of 40 days of life, respectively. Regardless of the assumptions used in the model, the decision remained stable: tamoxifen remained the better choice compared to no therapy.  Conclusions: We conclude that reliable data generated at 5 or 10 years may be used to generate models that estimate 15-year survival. Whether 5-year data can be employed over the lifetime horizon remains to be demonstrated.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4076.
Development and validation of Korean breast cancer risk assessment tool.
Authors: Chang M
Published: December 2010

Abstract #4083

Introduction: The NCI breast cancer risk assessment tool of Gail model was used for counseling and chemoprevention of western breast cancer. Because Korean women have different incidence rates and risk factors, the Gail model can not properly estimate the breast cancer risk for Korean women. The author developed and validated a Korean breast cancer risk assessment tool, which would display the absolute breast cancer risks of Korean women.  Methods: A risk model was established from a case-control study of 1687 cases of invasive carcinoma and 1238 controls. The risk factors selected were age, family history of the first and second relatives, body mass index, age at the first delivery, breast-feeding and a special test on the breasts. A baseline risk and individual breast cancer risk were calculated by a competing risk analysis. A discriminatory accuracy of the program was evaluated by a receiver operating characteristic (ROC) curve analysis.  Results: The risk assessment tool was developed in the Internet web page, http://home.dankook.ac.kr/breast/brca/brca-e.htm. It calculated the relative risk and the estimated absolute risks following 5, 10 years and up to age 64, 74. The estimated risks of Korean women using this tool were less than the result of NCI risk assessment tool. The risk of breast cancer was highest in the age of forties. In the discriminatory accuracy, the area under curve (AUC) was 0.587. The curve presented a tendency of high specificity and low sensitivity.  Conclusion: A web-based breast cancer risk assessment tool was developed for Korean women. This program had a limited discriminatory accuracy, but would be useful for the assessment of individual breast cancer risks, the selection of screening tools and preventive options of risk reduction for Korean women.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4083.
Breast complaints and cancer: age stratified predictors of risk from a prospective database.
Authors: Parkinson M , Tsang M , Tilley A , George R
Published: December 2010

Abstract #4086

Surgical clinics are presented with a variety of breast complaints. This study looks at major reasons for referral and correlates them to the likelihood of a benign or malignant disease.  Data comes from a prospective database of new referrals for surgical assessment. Male patients and presentations of recurrent cancer were excluded. Reasons for presentation were sorted into 7 categories defined as breast asymmetry, palpable mass, non-inflammatory skin changes, inflammatory changes, nipple discharge, nipple changes, pain or abnormal imaging. The dominant complaint was applied. Some patients are included twice if they had another problem in the opposite breast, or a second presentation of a new problem. Patient demographics were recorded and all patients were followed to a benign or malignant diagnosis.  Chi-square testing, odds ratios, and confidence intervals were used for the categorical data. Fisher's exact test was employed for categories with a low cell count.  Three hundred and ninety of 1050 patients were found to have breast cancer. The most common presentations of malignancy were a palpable mass and abnormal imaging. Less common presentations that also predicted cancer were persistent inflammation, skin changes, and nipple changes. Breast pain (p=0.00001), breast asymmetry (p=0.00001), and nipple discharge (p=0.00001) were significantly correlated with benign disease. The most common diagnosis varied significantly with age. Fibroadenomas were most common in young women, while cysts were frequent in the peri-menopausal group (p=0.0001). A new mass in a woman over 65 years old was malignant 83% of the time (p=0.000001).  Reason for referral can be significantly correlated with a benign or malignant diagnosis. Breast asymmetry, pain, and nipple discharge were associated with a benign diagnosis, while a new mass in an older woman was more likely to be malignant than benign. This information can be used to help stratify referrals into high and low risk categories, and identify patients for expedited assessment.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4086.
Patient reported causes of fatigue in relation to adjuvant radiotherapy after breast conserving surgery.
Authors: Langkjer ST , Rucinska M
Published: December 2010

Abstract #4094

Background: Fatigue is one of the most frequent symptoms experienced by cancer patients, and it adversely affects the quality of life. Fatigue is multidimensional and associated with the malignancy itself, but also with anti-neoplastic treatment and probably with several other causes. The aim of the study was to assess the level of fatigue during and after adjuvant radiotherapy in breast cancer patients and to uncover the kind of factors believed by patients to play a role in the generation of fatigue in relation to radiotherapy.  Methods: 70 patients (ages 33-76 years, mean 57 years) with early-stage breast cancer were included after breast conserving surgery. Patients were treated with adjuvant radiotherapy (48Gy/24 fractions/5 weeks; 20 patients received boost 10Gy/5 fractions/1 week with tumor-bed). The subjective feeling of fatigue was measured according to the 10-score visual analog scale (VAS). RTOG Acute Radiation Morbidity Scoring Criteria (0-4) were used for the estimation of the acute skin reaction.  Results: 53% of the patients demonstrated no fatigue (VAS 0-1) before the start of adjuvant postoperative radiotherapy. Patients after adjuvant chemotherapy manifested a little higher level of fatigue; there were no differences between patients with or without anti estrogen therapy. Fatigue intensity increased gradually during radiotherapy, but about 1/3 of the patients felt no fatigue. The majority of the patients reported radiotherapy as a cause of fatigue (33 of 47 patients (70%) with fatigue VAS ≥ 2 at the end of radiotherapy). 25% of the patients believed that their fatigue was still associated with previously given adjuvant chemotherapy, but in fact, the patients after chemotherapy did not demonstrate a higher fatigue level at the end of the radiotherapy course. 5 patients (10%) associated their fatigue with the anti estrogen therapy. There was correlation between fatigue level and intensity of radiotherapy-induced skin toxicity – patients with strong acute skin reaction demonstrated a higher fatigue level. But only 8 patients (17%) indicated the skin reaction as a cause of fatigue. Fatigue level was associated with traveling time to the hospital, especially when the journey took 2 hours or more/day. 45% of the patients gave the transport time to the hospital as a reason for fatigue.  Conclusion: Fatigue increased over the course of adjuvant radiotherapy of breast cancer patients after breast conserving surgery. Fatigue seems to be multidimensional, but most of the patients indicate radiotherapy treatment as the cause of fatigue.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4094.
Integrated analysis of efficacy and safety of palonosetron (PALO) 0.75 mg IV for preventing chemotherapy-induced nausea and vomiting (CINV) in anthracycline and cyclophosphamide (AC/EC) combination chemotherapy in Japan: PALO Japanese breast cancer cooperative study group.
Authors: Suzuki Y , Tokuda Y , Inoue K , Aogi K , Saito M , Yanagita Y
Published: December 2010

Abstract #4099

Background: In the treatment of breast cancer, combination chemotherapy of AC/EC has been widely used for neoadjuvant, adjuvant chemotherapy or standard treatment of metastatic breast cancer. AC/EC frequently induces severe nausea and vomiting, that it is important to adequately prevent and control. PALO is the first novel serotonine antagonist approved for prevention of delayed nausea and vomiting in moderately emetogenic chemotherapy in US and other countries. Integrated analysis was done on the data from phase 2 and 3 trials that have been completed in Japan. The purpose of this analysis was to assess efficacy and safety of PALO for preventing CINV induced by AC/EC regimens.  Methods: Three Japanese studies with single/repeated IV dose of PALO in pts receiving AC/EC were used. In all these studies, PALO 0.75 mg IV was administrated 30 min prior to AC/EC. Dexamethasone was administrated before AC/EC on day 1, and also on days 2-3 for the phase 3 trial. This integrated analysis assessed the efficacy and safety by difference in regimens (AC or EC), assessed the efficacy by difference in FEC (EC with 5-FU) or EC regimen and by difference in epirubicin (E) dosage in EC. Apart from the integrated analysis, efficacy of PALO in repeated cycles of chemotherapy was assessed by different regimens (AC or EC).  Results: Total of 266 pts administrated AC/EC were evaluated for efficacy in single dose. Overall CR(CR = no emesis or rescue medication)% for PALO in acute phase was 70.7%. Overall CR% in delayed phase was 61.3%. CR% in acute and delayed phase for (a) AC (n=76) vs EC (n=190), (b) FEC (n=141) vs EC (n=49), (c) low (n=109) vs high (n=81) dosage of E (<=90, >90 mg/m2) in EC were as follows; (a) acute: 80.3 vs 66.8, delayed: 68.4 vs 58.4, (b) acute: 61.7 vs 81.6, delayed: 56.7 vs 63.3, (c) acute: 72.5 vs 59.3, delayed: 61.5 vs 54.3. Total of 155 pts administrated AC/EC were evaluated for efficacy of PALO in repeated cycles of chemotherapy, and similar efficacy between AC and EC was confirmed. Total of 474 pts administered AC/EC were evaluated for safety in all Japanese studies. There was no significant difference in the incidence of adverse drug reactions between AC and EC.  Conclusion: This integrated analysis suggested that high antiemetic activity of PALO in CINV was shown for breast cancer pts receiving either AC or EC. In addition, in the FEC regimen and high dosage of E, all showed CR rate of more than 50% in both acute and delayed phases in the efficacy analysis, revealing a long lasting antiemetic activity of palonosetron.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4099.
Preliminary safety results: addition of bevacizumab to 3 docetaxel regimens as adjuvant therapy for early stage breast cancer.
Authors: Yardley DA , Hart L , Waterhouse DM , Badarinath S , Daniel B , Cook D , Thompson J , Childs BH , Burris HA
Published: December 2010

Abstract #4107

Background: Docetaxel-containing chemotherapy regimens improve disease-free survival (DFS) and overall survival in early stage breast cancer (BC) patients (pts). Bevacizumab (Bev) improves response rate and DFS in metastatic BC. This trial evaluates the feasibility of adding Bev to 3 adjuvant docetaxel BC regimens. Primary endpoint is cardiac safety (G3/4 congestive heart failure [CHF]).  Materials and Methods: Phase IIb, randomized, non-comparative study. Planned accrual: 225 pts (75/arm) with previously-untreated node-positive or high-risk node-negative BC. Eligibility: operable invasive adenocarcinoma ≥4 wks from surgery, normal cardiac function, known HER2 status. Pts with cardiac disease/risk of cardiac disease were not eligible. HER2 normal pts were randomized to (mg/m2 unless stated otherwise) Arm A (ACT): doxorubicin (A) 60 + cyclophosphamide (C) 600 q3w x 4 followed by docetaxel (T) 100 x 4 or Arm B (TAC): T 75 + A 50 + C 500 q3w x 6. FISH HER2+ pts received Arm C (TCH): T 75 + carboplatin AUC 6 q3w x 6 + trastuzumab (H) 6 mg/kg q3w x 52 wks. Bev 15 mg/kg q3w beginning Day 1 x 52 wks was administered in all arms. Granulocyte growth factor prophylaxis was mandated in all arms.  Results: Safety data are available for the first 138 pts (Arm A=53, Arm B=52, Arm C=33) receiving ≥4 cycles of treatment. Grade 3/4 toxicities (Arms A, B, C) included: neutropenia (n = 24, 22, 2), febrile neutropenia (5, 9, 0), leukopenia (10, 14, 1), thrombocytopenia (3, 7, 0) and fatigue (11, 3, 0). One on-study death occurred in Arm B from neutropenic enterocolitis. Documented CHF was reported in 3 pts (A=1, B=2), 2 occurring at the start of maintenance therapy. No cardiac events have been noted with Bev and H in Arm C. A total of 29 (21%) pts prematurely discontinued study treatment. Radiation therapy prior to study entry was administered in 4 pts (1, 1, 2). Concurrent Bev and adjuvant breast irradiation was administered in: Arm A=7 (13.2%), Arm B=15 (28.8%), Arm C=5 (15.2%). Most common AEs (Arms A, B, C) in these pts were: radiation skin injury (2, 2, 2), arthralgia (6, 4, 1), myalgia (4, 4, 1), bone pain (0, 4, 2), extremity pain (2, 1, 2), and rash (3, 3, 0).  Discussion: Preliminary data show an acceptable early safety profile, with no unexpected toxicity, when Bev was added to docetaxel adjuvant BC regimens. The addition of Bev did not result in increased risk of toxicity from standard radiotherapy administered either prior to or while on-study. Three early CHF events were observed; all occurred in pts receiving anthracyclines. No cardiac events have been identified with the Bev/trastuzumab combination. Accrual to the trial is ongoing. Updated results will be presented.  Support: sanofi-aventis,US.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4107.
Preliminary safety results from a multicenter phase II noncomparative two arm pilot of bevacizumab with anastrozole or fulvestrant as 1st line metastatic breast cancer therapy.
Authors: Yardley DA , Peacock N , Arrowsmith E , Harwin W , Miletello G , Raefsky E , Shipley D , Spigel DR , Hanson S , Greco F
Published: December 2010

Abstract #4113

Background: Estrogen modulates angiogenesis through effects on endothelial cells and by induction of vascular endothelial growth factor (VEGF) expression. Increased VEGF promotes tumor growth and is associated with a poor response to anti-estrogen therapy. This trial evaluates the impact of bevacizumab (B) combined with anastrozole (A) or fulvestrant (F) on progression free survival (PFS) as first line endocrine therapy in metastatic breast cancer (MBC).  Methods: Study design: Two arm nonrandomized, noncomparative trial of A or F in combination with B. Eligibility: 0 prior hormonal or chemotherapy for MBC, measureable or evaluable disease, normal LVEF, postmenopausal, normal organ function. Treatment: Arm 1: Patients (pts) who either were endocrine therapy naïve, ≥ 12 months from adjuvant endocrine therapy, or who had intolerance to or progression on tamoxifen were treated with anastrozole 1 mg po daily. Arm 2: Patients who were ≤ 12 months from adjuvant aromatase inhibitors (AIs), intolerant of or progressed on adjuvant AIs, or at physician's discretion were treated with fulvestrant 500 mg IM loading dose, 250 mg D15 and every q28 days thereafter. B 10 mg/kg q2wks beginning day 1 was administered in both arms. Concurrent trastuzumab (T) was administered in HER2+ patients. Response assessments were performed q8 wks. Pts were treated until disease progression or toxicity.  Results: 44 pts have been enrolled with data available for 29 pts. 18 pts (62%) were treated with anastrozole and 11 pts (38%) with fulvestrant. Median age: 64 yrs (range 44-88), ECOG PS 0-17 pts (59%) and PS 1 -12 pts (41%). 7 pts (24%) presented with de novo stage IV disease. 52% had 2 or more metastatic disease sites with bone metastases predominating 16 pts (55%), 7 pts (24%) with bone only disease. There were no G3/4 heme toxicities. G3/4 non-hematologic events consisted of G3 hypertension in 3 pts (10%), arthralgias 1 pt (3%), and CHF 1 pt (3%). This symptomatic LVEF of 40% occurred in arm 1 during cycle 3 and was noted to recover to 50-55% within 1 wk. This pt did not receive T. A median of 4.5 cycles have been administered. PRs were noted in 7 pts (24%) and 14 pts (48%) demonstrated SD. PD was noted in 3 pts and 5 pts were not yet evaluable. 73% of pts are progression free at 12 months. At a median follow up of 7.5 months, median PFS and overall survival has not been reached.  Conclusions: The combination of bevacizumab with anastrozole or fulvestrant is feasible and well tolerated with adverse events as expected, reflecting standard bevacizumab related toxicities. Bevacizumab in combination with endocrine therapy is promising with early evidence of a high rate of clinical benefit at 72%. Further follow up is warranted.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4113.
Phase I study of sunitinib in combination with metronomic dosing of cyclophosphamide and methotrexate in patients with metastatic breast cancer.
Authors: Lyandres J , Melisko M , Moasser M , Goga A , Park JW , Rugo HS
Published: December 2010

Abstract #4119

Background  Antiangiogenic therapy targeting VEGF with bevacizumab in combination with taxanes is effective in the treatment of metastatic breast cancer (MBC). Sunitinib (S) is a potent multitargeted tyrosine kinase inhibitor and has activity against VEGFR, PDGFR, c-Kit, and Flt-3. S has demonstrated activity in a variety of tumors and is approved at a dose of 50mg 4 wks on/ 2 wks off. Single agent continuous dosing (CD) at 37.5 mg/d is safe in phase II trials and may avoid a flare in angiogenesis with drug withdrawal. The effects of metronomic chemotherapy in preclinical studies are enhanced in combination with antiangiogenic agents, and cyclophosphamide and methotrexate (CM) have demonstrated limited efficacy in MBC. We combined S with CM in a phase I dose escalation study to evaluate an all oral regimen with CD. Serial measurements of circulating tumor cells (CTC) and endothelial cells (CEC) were performed in patients receiving study therapy.  Methods  Eligible patients (pts) have measurable or evaluable progressing MBC. Study treatment includes a two week lead-in course of S, followed by CD of S combined with CM. The primary endpoint is to determine the MTD of S + CM, secondary endpoints include toxicity and response. Quantitative analysis for CTC and CEC is performed at baseline, before starting CM then every 3 weeks. 3 patients are enrolled in each cohort starting at 12.5mg/d of S; 6 patients will be enrolled at the MTD followed by a phase II trial. Efficacy is assessed at week 8 then every 6 weeks.  Results  15 pts have been treated to date (median age 57 (range 36-86); PS 0-2; median number prior chemo regimens 5 (range 2-9) in three dose cohorts (12.5, 25, 37.5 mg/d). 3 pts discontinued during the “run-in” due to symptomatic PD. 3 of 6 evaluable pts at 25 mg/d had asymptomatic grade 3 neutropenia responding to a dose reduction in CM. 4 pts had grade 2 neutropenia. One pt receiving 37.5 mg/d of S developed grade 4 thrombocytopenia. Other adverse events (all grade 1/2 ) included fatigue (7/12), elevated LFTs (5/12), nausea (5/12), mucositis (5/12) and thrombocytopenia (3/12). One pt had grade 2 fingertip desquamation resolving in two weeks off all study therapy. At week 8, 4/6 evaluable pts at 25 mg/d S with CM had stable disease (SD), 1 pt had a PR at week 14 and one pt had SD for 47 weeks. Enrollment to the third cohort at 37.5 mg S and CM is complete and tumor response is pending.  Conclusion  The combination of S with CM is well tolerated in heavily pretreated pts with MBC and has shown preliminary evidence of efficacy. Final phase I data, including the third cohort, CTC and CEC data will be presented.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4119.
Bevacizumab (BEV) and paclitaxel (PAC) every two weeks as first-line treatment for advanced breast cancer (ABC). Preliminary results.
Authors: Ardavanis A , Doufexis D , Kountourakis P , Malliou S , Karagiannis A , Kardara E , Sykoutri D , Rigatos G
Published: December 2010

Abstract #4121

Background: Targeting angiogenesis is nowadays one of the most promising approaches for breast cancer. BEV, an anti- VEGF monoclonal antibody, was recently approved in combination with PAC for first-line treatment of ABC. Preliminary of a biweekly regimen of the combination are presented here.  Patients-treatment: P with ABC were to receive, after appropriate premedication, BEV 10 mg/kg and PAC 135 mg/m2 with growth factors where necessary, q2weeks for six months; responders and stabilized P had to receive maintenance with BEV 15 mg/kg q3weeks until progression. This regimen was chosen instead of the established one standard ( PAC weekly ) for better patient convenience, while maintaining the same dose intensity for both drugs (for PAC the DI of the 3-weekly 175/m2 schedule).  Results: Thirty one ( 31 ) , HER 2 negative women aged 39-63 ( average 55 )were enrolled. Toxicity was in general acceptable: Neutropenia/leucopenia grade III/IV, anaemia I/II, neuropathy grade III and manageable hypertension in 5, 3, 7, 6 P ( 16%, 9%, 22%, 19% ) respectively were observed. Efficacy: Two P experienced a complete response, 12 responded partially, 12 P with stable disease and 5 progressed. Overall response and disease control rates were 45% and 83% respectively. Results for PFS and OS are still immature.  Conclusion: This biweekly BEV/PAC combination seems to be active with acceptable toxicity in ABC. The activity observed in the small-size population of this study should be assessed in a larger number of patients; if confirmed, BEV/PAC/q2w might represent an interesting alternative option for this group of patients as it has a clear advantage for patient's convenience over the weekly regimen contributing to QoL preservation and saving of resources.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4121.
HER-2 and topoisomerase IIa gene alterations in male breast cancer.
Authors: Rudlowski C , Wardelmann E , Merkelbach-Bruse S , Buettner R , Kuhn W , Schildhaus H
Published: December 2010

Abstract #4128

Background:  In accordance to the guidelines for female breast cancer and due to more advanced tumor stages at diagnosis primary male breast cancer (MBC) is treated predominantly with anthracycline-based chemotherapeutic regimens. However, amplification of the HER2 and topoisomerase IIalpha (TOPO2A) genes has been linked to the effects of anthracyclines in female breast cancer. Presently no data are available reporting the percentage of TOPO2A amplification/deletion and its potential clinical impact on MBC. Here we present first data about HER2 and TOPO2A genomic alteration in MBC.  Patients and Methods:  We studied HER2 amplification and TOPO2A amplification/deletion (by fluorescence in situ hybridization) and HER2 protein expression (by immunohistochemical analysis) in 96 primary invasive MBC's using tissue microarrays. A gene copy number/chromosome 17 copy number ratio of 2.0 respectively 1.8 or higher indicated amplification of HER2 and TOPO2A. A TOPO2A/chromosome 17 ratio of less than 0.8 indicated gene deletion. In addition, HER2 protein expression was scored according to standard HercepTest guidelines (DAKO, Carpenteria, CA). Tumor characteristics and follow-up data were available and correlated with HER2/TOPO2A gene alterations and HER2 protein expression.  Results:  91/96 cases were evaluable for TOPO2A/HER2 assessment. HER2 gene amplification were found in 6 cases (6,25%) of which 3 were classified as 3+, 2 as 2+ and 1 as 1+ positive for protein expression. TOPO2A amplification/deletion showed 3 patients (3.1%), 2 with amplification and one with a deletion. Only one patient had both HER2 and TOPO2A gene amplification. HER2/TOPO2A gene alterations were not related to the tumor characteristics, response to therapy or the patients survival.  Conclusion:  In female breast cancer recent studies have suggested that deletions or amplifications of the TOP2A gene are associated with poor prognosis and predictive of greater response to anthracycline-containing than to non-anthracycline-containing regimens. In this study group both HER2 and TOPO2A gene alterations were rare events. A simultaneous amplification was observed in only one case. Our data for MBC suggest that due to the low number of TOPO2A gene amplification/deletion the clinical significance of TOPO2A is of limited value. Based on these findings the role of anthracycline-containing regimens for MBC has necessarily to be defined.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4128.
Matched-pair analysis of female and male breast cancer: a comprehensive cohort study.
Authors: Foerster R , Foerster FG , Wulff V , Schubotz B , Lange R , Habeck J , Baaske D , Rudlowski C
Published: December 2010

Abstract #4129

Introduction:  Male breast cancer (MBC) is a rare disease accounting for approximately 1% of all breast carcinomas. Due to the low incidence treatment guidelines based on prospective studies are lacking. Presently treatment recommendations are derived from the standards for female breast cancer. However, those approaches might be inadequate because of distinct gender specific differences in tumor biology of breast cancer. This study was planned in order to elucidate potential differences between female and male breast cancer in both tumor biological behavior and clinical practice.  Patients and Methods:  MBC diagnosed 1995-2007 (region Chemnitz/Zwickau, Saxony, Germany) was retrospectively analyzed. Tumor characteristics, treatment and follow-up of the patients were documented. In order to highlight potential differences matched-pairs of female and male breast cancer patients were created. Each MBC was matched with a female counterpart (FBC) that showed accordance in at least 5-7 tumor characteristics (age, TNM, grade, hormone receptors, HER2 stage).  Results:  FBC and MBC (n=113 patients each) were evaluable for this analysis. For MBC the following tumor characteristics were documented: >60% advanced stages (T2-4), only 6% well differentiated, 42.5% nodal-positive, 86% hormone-sensitive (ER-positive 79.2%, PR-positive 76.9%), 6.2% HER2 positive.  83.2% of MBC had a mastectomy/axillary dissection (FBC 49.0%), 55% adjuvant radiotherapy (FBC 66.7%), 64% adjuvant systemic therapy (FBC 80.6%), 32.7% chemotherapy (FBC 49.5%) and 47.8% endocrine treatment (FBC 60.1%). 31% of MBC had a relapse (FBC 25.9%), 68.1% overall survival (OS) (FBC 70.4%), 98 months (FBC 76 months) median survival time. In univariate analyses reduced OS of MBC was significant associated with advanced tumor stages (p<.005), poor histological grade (p<.05), receptor negative (p<.05) and nodal-positive tumors (p<.05). Furthermore adjuvant radiotherapy showed survival benefit. However, in multivariate analysis only tumor stage showed statistical significance (p<.01). Regarding these tumor characteristics no OS differences could be observed between FBC and MBC. However, MBC showed a trend to a shortened survival for receptor negative tumors in comparison to FBC (p=.055).  Discussion:  1. Delayed diagnosis of MBC; 2. Our study showed more advanced and undifferentiated tumors with a high percentage of nodal positivity; 3. In our analysis these unfavorable tumor characteristics were not related to a poor OS; 4. We found no significant differences regarding disease outcome between FBC and MBC; despite of a more aggressive adjuvant treatment for FBC.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4129.
Local-regional and distant recurrence rates in skin-sparing mastectomies compared with non-skin-sparing mastectomies.
Authors: Yi M , Hunt KK , Meric-Bernstam F , Kronowitz SJ , Nayeemuddin KM , Feig B , Hwang RF , Symmans W , Lucci A , Ross MI , Ames FC , Bedrosian I , Singletary E , Kuerer HM
Published: December 2010

Abstract #4138

Background: Although skin-sparing mastectomies (SSMs) are becoming more common, there are few data regarding the local-regional and distant recurrence rates. The aim of this study was to examine the incidence of local-regional recurrence, distant recurrence, and survival in breast cancer patients who underwent SSMs or non-skin-sparing mastectomies (NSSMs) at our institution.  Methods: We reviewed records of patients with primary breast carcinoma stage 0 to III who underwent total mastectomies with or without complete axillary dissection at our center from January 2000 to December 2005. After excluding patients with bilateral breast cancer, mastectomies for recurrent breast cancer, and patients with less than two-year follow-up, there were 1623 patients for study. Patient and tumor characteristics were evaluated and comparisons undertaken between the SSM and NSSM groups with univariate and multivariate logistic analyses. Kaplan-Meier curves and log-rank test were used to evaluate the overall and disease-free survival in the two groups.  RESULTS: Of the 1623 patients, 465 (28.7%) patients underwent SSM and 1158 (71.3%) underwent NSSM. Patients who underwent NSSM were older (55.6 vs. 48.9, p<0.0001) and had more advanced stage tumor (stage II or high: 48.3% vs. 28%, p<0.0001). Significantly more patients in the NSSM group received systemic chemotherapy (p=0.045), radiation therapy (p<0.0001), and endocrine therapy (p=0.002). At a median follow-up of 24.4 months (range 1.1-95.3), 138 patients (4.6%) had local-regional or distant recurrence. Specifically, 7 patients (1.5%) in the SSM group and 34 patients (2.9%) in the NSSM group had local-regional recurrences (p=0.097). The distant recurrence rate in patients undergoing SSM or NSSM was 14 (3.0%) and 110 (9.5%) patients (p<0.0001) at median follow-up time of 29.2 and 25.4 months, respectively. There is no difference in disease-free survival between the SSM group and NSSM after adjusting for tumor TNM stage and final nodal status at a median follow-up time of 54.3 months and 53.2 months, respectively.  CONCLUSIONS: SSM is safe and effective in appropriately selected patients with breast carcinoma.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4138.
Fibrin sealant for the prevention of axillary seroma formation after axillary lymph node disection. A prospective randomized study.
Authors: Sanchez-Mendez JI , Lopez-Rodriguez MJ , Sanchez-Martinez C , Martinez-Garcia MT , Iniesta Doñate MD , Ordas Santotomas J
Published: December 2010

Abstract #4139

Background  The most frequent postoperative complication after axillary limph node dissection is the axilary seroma (AS) formation. Currently accepted practice includes insertion of one or more drainage system for fluid evacuation. Several methods have been proposed to decrease AS formation, such as closed suction catheters, shoulder immobilisation, tetracycline sclerotherapy, talc podrage and closure of dead space; however no of them have reduced the incidence of AS. Seromas are associated with wound infection, wound dehiscence and skip flap necrosis, which prolong the recovery and can extend patient´s stay in Hospital.  The aim of this prospective randomized controlled trial was to evaluate the efficacy of fibrin sealant (FS) on the prevention of AS.  Material and Methods  Sixty-two patients undergoing axillary lymph node dissection were randomized to treatment with drainaje alone (arm A, n=49), drainage plus FS (arm B, n=12), or FS alone (arm C, n=53). Arm B was cancelled after primary results. Efficacy was evaluated in terms of lengh of hospital stay, volumen of fluid drainage and rate of wound related complications (seroma, hematoma, infection, dehiscence) in each arm.  Results  No significative differences are detected neither type of surgery, nor histlogycal characteristics.    The mean result is a difference of almost minus 3 days in postoperative stay in the FS group.    Conclusions  1- Application of fibrin sealant reduces the amount of serosanguinous drainage and the length of postoperative stay in patients who have undergone axillary lymph node dissection.  2- Fibrin sealant allows to avoid the insertion of an axillar drainage system  3- It is very important the correct preparation and application of the fibrin sealant and it should be performed by a qualified surgeon.  4- Future clinical trials toasses the role of fibrin sealant seroma are warranted.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4139.
Complications of methylene blue dye infiltration for sentinel lymph node biopsy in breast cancer.
Authors: Piscatelli N , Crawford S , Larkin A , Robert Q , Layeequr Rahman R
Published: December 2010

Abstract #4140

Background: Isosulfan blue has proven invaluable for sentinel lymph node identification in breast cancer. However, an intermittent supply shortage of this agent over the last few years has led to alternative usage of methylene blue. Worldwide, methylene blue is traditionally viewed as a less expensive and safer equivalent to isosulfan, with few reports of significant side effects. Its increased usage has led to anecdotal reports of local skin reactions. This study serves to review the rate of local complications observed following subareolar infiltration of methylene blue for sentinel lymph node identification in breast cancer staging.  Material Methods: This is a retrospective review of prospectively collected data in a university based surgical oncology practice. Records of all patients undergoing sentinel lymph node biopsy for breast cancer between August, 2007 and April, 2008 were reviewed (the switch from Isosulfan to Methylene blue was made in August of 2007). Local complication of fat necrosis was recorded. Tumor stage, neoadjuvant therapy, volume and dilution of dye used were analysed for association with fat necrosis.  Results: One hundred and three patients underwent sentinel node biopsy for breast cancer during the study period. Seven (7%) patients developed fat necrosis at the site of injection. The rate of injection site fat necrosis is associated with the volume of methylene blue [0% for <3cc and 7.2% for > 3cc (p = 0.0071)]; there was no association with tumor stage [3.2% for stage <1, 13.1% for stage 2 and 0% for stage 3 (p=0.343)] and tumor type [7.3% for invasive ductal cancer, 8.3% for invasive lobular and 0% for in situ cancer (p=1.000)].  Discussion: While methylene blue has typically been viewed as an inert agent for sentinel node biopsy, our study documents a 7% rate of fat necrosis. This is clinically significant in terms of painful symptoms and also the work-up that it may necessitate as a new mass in a breast cancer patient which has suspicious appearance on traditional imaging studies.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4140.