bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-14-08: Responses to Subsequent Anti-HER2 Therapy after Treatment with Trastuzumab-DM1 in Women with HER2-Positive Metastatic Breast Cancer
Authors: Olson EM , Lin NU , DiPiro PJ , Najita J , Krop IE , Winer EP , Burstein HJ. 
Published: April 2011

Abstract
Background: Women with HER2-positive metastatic breast cancer (MBC) can have clinical responses to multiple lines of anti-HER2 therapy. However, it is unknown whether these patients will derive further clinical benefit following treatment with the novel antibody-drug conjugate trastuzumab-MCC-DM1 (T-DM1), which has significant activity in trastuzumab-refractory breast cancer.
Methods: We retrospectively identified patients treated with T-DM1 monotherapy on clinical trials for HER2-positive MBC at Dana-Farber Cancer Institute and characterized clinical outcomes during subsequent lines of anti-HER2 therapy. Response was determined by an independent and blinded radiology review using modified RECIST 1.1 criteria without confirmatory scans; patients without radiologic assessment were considered non-responders. Duration of therapy was defined from initiation of therapy until treatment discontinuation, and for patients continuing on therapy, times were censored at date of last visit; analysis was performed using Kaplan-Meier estimates.
Results: We identified 23 patients treated on protocol-based therapy with single-agent TDM-1 and report on the 20 patients who had discontinued protocol, and hence, T-DM1 therapy. All patients received trastuzumab in the metastatic setting prior to initiation of T-DM1, with a median number of 6 (range 1-14) prior regimens. Most (75%) were taken off study secondary to progressive disease and the remainder discontinued therapy for toxicity. Of these 20 patients, 75% (15 of 20) received further therapy with or without anti-HER2 agents after concluding T-DM1; reasons for not receiving additional treatment after T-DM1 include death (3) and interruption of therapy due to physician or patient request (2). The majority (12 of 15; 80%) of patients treated beyond T-DM1 received a regimen containing either trastuzumab and/or lapatinib at some point during their course. Partial response to either first-or second-subsequent line(s) of therapy was seen in 5 of 15 (33%) treated patients, including 33% (4 of 12) who received a regimen containing trastuzumab and/or lapatinib (Figure 1). Three patients did not have radiographic assessments; however, all 3 demonstrated clinically stable disease (as determined by review of clinical data) to first treatment after T-DM1. Median duration of therapy to first-subsequent regimen after T-DM1 was 5.5 months. Of the 9 patients that received a second-subsequent regimen, the median duration of therapy to the second-subsequent treatment was 6.4 months.
Conclusions: In heavily pretreated HER2-positive MBC patients, prior exposure to T-DM1 does not exhaust the potential benefit of ongoing anti-HER2 therapy with trastuzumab and/or lapatinib-based regimens.
Maximum Decrease in Target Lesion Diameter

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-08.
Abstract P3-14-11: Trastuzumab Cardiac Toxicity and HER2 Polymorphism: A Case-Control Study
Authors: Mailliez A , Révillion F , Ploquin A , Servent V , Bonneterre J. 
Published: April 2011

Abstract
Background: Trastuzumab (T) is a very effective targeted therapy used in breast cancer patients but it can induce cardiac toxicity. Gene polymorphisms of Her 2 have been identified. According to a small report of Beauclair (2007), the polymorphism at codon 655 of the HER2 gene may represent a risk factor for cardiotoxicity induced by T. In this trial, we studied the incidence of the Val655Ile polymorphism in breast cancer patients with cardiac toxicity and in matched contol patients without cardiac toxicity.
Patients and methods: In our institution, between January 1st, 2007 and April 15th, 2010, 26 patients developed cardiac toxicity potentially related to T and were referred to a cardiologist and treated with angiotensinconverting enzyme inhibitors, Beta-blockers. Their cardiac function was monitored. Twenty two control pts without cardiac toxicity were matched according to age, received dose of anthracyclin, BMI, cardiac risk factors, cardiac treatment and initial left ventricular ejection fraction. Her2 gene polymorphism in codon 655 was studied by PCR on lymphocyte DNA from blood samples in both populations. Genomic DNA was extracted from EDTA blood samples (300μl) on the MagNa Pure Compact instrument (Roche Diagnostics, Meylan, France), using the MagNA Pure Compact Nucleic Acid Isolation Kit according to the manufacturer's instructions. The HER2 Ile655Val (rs1163201) polymorphism was detected by sequencing using a 3730 DNA Analyzer (Applied Biosystems, Courtaboeuf, France) with the BigDye Terminator Cycle Sequencing kit and universal primers M13.
Results: The mean age was 54.5 (31-72) and 52.5 (37-73) years respectively in the cardiac toxicity group and in the control group. In the cardiac toxicity group, 17 patients were in an adjuvant or a neoadjuvant setting, 9 were treated for a metastatic disease; 7 had cardiac risk factors (hypertension, diabetes, dyslipidemia or cardiac familial event). The control pts had similar characteristics. In the cardiac toxicity group 3.9% (1 patient) presented a genotype Val/Val at Her 2 codon 655, 42.3% (11)were heterozygous Ile and 53.8% (14) had the wild type. In the control population, the incidence was respectively 4.5% (1 patient), 31.8% (7) and 63.7% (14). No differences were found between the both groups. Discussion-Conclusion: The incidence of mutated, heterogeneous and wild type genotype was similar as the in the literature. We could not confirm the cardiac risk related to the Val allele at Her2 codon 655. Her2 polymorphism cannot be used in clinical practice to predict the risk of cardiac toxicity of Trastuzumab.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-11.
Abstract P3-14-12: High Risk of Recurrence in Japanese Patients with HER2-Positive T1N0 Breast Cancer
Authors: Tanaka K , Kawaguchi H , Koga C , Nishimura S , Yoshiyama T , Yamaguchi H , Nakamura Y , Ohno S. 
Published: April 2011

Abstract
Background: The necessity of adjuvant trastuzumab therapy for patients with T1N0M0 tumors remains controversial. The objective of this study is to determine the risk of recurrence in Japanese women with T1N0 HER2- positive tumors compared with HER2-negative tumors. Methods: Among 1,180 patients with breast cancers diagnosed at our institution between 2001 and 2007, we reviewed 464 T1N0M0 diseases in which HER2 status was evaluated by IHC or gene amplification, who had not received trastuzumab in the adjuvant setting. Recurrence free survival (RFS) was estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards models were used to determine the association of each group with the risk of recurrence. Results: Seventy-nine (17%) of 464 patients had HER2-positive tumors and remaining 385 (83%) were HER2-negative diseases. Patients who had HER2-positive tumors tended to be younger (P=0.015), have more hormone receptor-negative tumors (P&lt;0.001), and have higher histological grade (P&lt;0.001). At a median follow-up of 46 months, 18 patients had experienced recurrences. The 5-year recurrence-free survival (RFS) rates were 88.2% and 97.2% in patients with HER2-positive and HER2-negative tumors, respectively (P&lt;0.001). In patients with T1bN0 tumors and T1cN0 tumors, HER2-positive group had worse RFS than HER2-negative group (P=0.004 and P=0.002, respectively), while there were no differences in the RFS between patients with T1aN0 HER2-positive and HER2-negative tumors (P=0.835). In a multivariate analysis, HER2 status was identified as one of the independent risk factors to predict RFS in patients with T1N0M0 breast cancers (hazard ratio 5.23; 95% CI, 2.07 to 13.21; P&lt;0.001). Conclusion: Japanese women with T1bcN0M0 HER2-positive breast cancer have a significant high risk of recurrence, and adjuvant trastuzmab therapy should be considered for those patients.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-12.
Abstract P3-14-13: Necessity of Confirming the Biological Marker of Distant Metastatic Lesion for Breast Cancer Patients
Authors: Nakamura R , Yamamoto N , Fushimi K , Iwase T , Itami M , Miyazaki M. 
Published: April 2011

Abstract
Background
The systemic management of metastatic breast cancer patients is usually based on biological marker of the primary tumor. However, characteristics of hormone status or HER2 over expression may change with metastatic site due to long term treatment for metastatic cancer with endocrine therapy, chemotherapy or biologic agents. The first purpose of this study was to investigate the concordance in HER2 over expression between primary tumor and distant metastases. The second purpose was to evaluate the efficacy of biologic agents for the patients with positive changes in HER2 status.
Material and methods One hundred forty-one patients had biopsy or operation of their metastatic site from 2000 to December 2009 at the Chiba Cancer Center Hospital. Specimen of operation or biopsies of suspected metastatic site were obtained from breast cancer patients. Specimen were analyzed pathologically to confirm metastatic disease and secondly to evaluate
HER2 by immunohistochemistry or FISH.
Results
Specimen of metastatic site were 67 local lesion (breast or lymph node), 27 brain, 16 liver, 12 bone and 5 others organs (stomach, intestine, ovary or uterus. Negative, positive or no change in HER2 status was observed in 4%, 6%, and 90% respectively. Positive changes of HER2 in metastatic site were 3(4%) local lesion, 3(11%) brain, 1 (7%) lung, 0(0%) liver, 2(17%) bone, and 0(0%) others, respectively. Three patients with positive change in HER2 status of metastatic site were treated to trastuzumab. Two of 3 patients with HER2 positive change were assessed to responded to trastuzumab-based treatment schedules.
Conclusions This study demonstrates the presence of substantial discordance in HER2 overexpression between primary tumor and metastases site.Metastatic tissue confirmation might be considered in patients with suspicious metastatic recurrence or resistance trastuzumab treatment.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-13.
Abstract P3-15-06: No Correlation between Endocrine Symptoms and Musculoskeletal Symptoms in Women Receiving Adjuvant Aromatase Inhibitor Therapy
Authors: Cigler T , Singer O , Moore A , Chuang E , Vahdat L , Reichman B , Levine AB , Do HT , Mandl LA. 
Published: April 2011

Abstract
Background:
The etiology of Aromatase Inhibitor (AI) associated musculoskeletal symptoms remains unclear. It has been proposed that musculoskeletal side effects are related to the estrogen depletion achieved on AI therapy. Estrogen depletion with AI therapy is known to result in endocrine side effects. The 18-item Functional Assessment of Cancer Therapy Breast Cancer-Endocrine Subscale (FACTB-ES) is a reliable and well validated quality of life questionnaire shown to be sensitive to changes in endocrine symptoms in breast cancer patients. The objective of this study was to determine whether among women with breast cancer treated with adjuvant AI therapy, self reported musculoskeletal side effects correlate with increased hormonal side effects as measured by the FACTB-ES. Methods:
In this 6 month, single center, prospective cohort study, post-menopausal women with hormone-sensitive, non-metastatic breast cancer prescribed AIs by their treating oncologist were evaluated by a rheumatologist at baseline (before starting the AI) and at 6 months. Women who reported new or worsening musculoskeletal symptoms since starting the AI were classified as symptomatic. The FACTB-ES was administered at each visit.
Changes in scores between baseline and 6 months were compared between
the symptomatic and asymptomatic groups
Results:
Thirty-five subjects completed the 6 month follow up period. Nineteen (54%) were symptomatic and n=2 (5.7%) discontinued the AI due to these musculoskeletal symptoms. Mean time to onset of symptoms was 6 weeks (range 2 to 18 weeks). Baseline characteristics including age, ethnicity and body mass index did not differ between the groups. There was no significant difference in hormonal symptoms between groups. Both groups had equivalent worsening of their endocrine symptoms as seen by the reduction in their FACTB-score. The mean change in FACTB-ES score was -2.52 (range: -31.00, 23.00) in the symptomatic women versus -2.06 (range: -19.00, 22.21) in the asymptomatic women (Wilcoxon rank sum p=0.95). Conclusions:
These data suggest that endocrine symptoms as measured by the FACTB-ES do not correlate with the development of musculoskeletal pain in women treated with adjuvant AI therapy for breast cancer. Though larger studies are necessary to confirm these results, the musculoskeletal symptoms associated with AI use may not be estrogen-dependent.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-15-06.
Abstract P4-02-07: A Progesterone Receptor Modulator, CDB-4124, Inhibits Mammary Carcinogenesis by Suppressing Cell Proliferation In Vitro and In Vivo
Authors: Wiehle RD , Lantvit DD , Yamada T , Christov K. 
Published: April 2011

Abstract
CDB-4124 (Proellex or Telapristone acetate) is a modulator of progesterone receptor (PR) signaling which has been employed in preclinical studies for the treatment of uterine fibroids and endometriosis. Here we provide evidence for its action in breast cancer from both in vitro and in vivo studies. When CDB-4124 is given to rats at 200 mg/kg for 24 months it prevents the development of spontaneous mammary hyperplastic and premalignant lesions. In a second set of experiments, we found that CDB-4124, given as subcutaneous pellets at two different dose suppressed MNU-induced mammary carcinogenesis in rats in a dose dependent manner (see table below). The high dose (30 mg over 84 days) increased tumor latency from 66 to 87 days (P&lt;0.02), decreased incidence from 85% to 35% (P&lt;0.01), and multiplicity, from 3.0 to 1.1 tumors/animal (P&lt;0.01). Tumor burden (total of all tumor weights in an animal) decreased from 2.6 g to 0.26 g/animal (P&lt;0.01). Moreover in suport of our observations, CDB-4124 significantly suppressed Ki-67 positive cells from 30.5±7.1% in placebo-treated to 25.4±14.4% in low-dose and further to 10.3±4.5% (P&lt;0.001) in the high-dose treated animals.
CDB-4124 increased latency and inhibited the incidence, multiplicity and burden of mammary tumors
CDB-4124 inhibited cell proliferation and induced apoptosis in these mammary tumors and this correlated with decreased proportion of PR+ tumor cells. Serum progesterone was lowered but there were no effects on estradiol. This progesterone receptor modulator appears to exert its effects in the presence of estrogen. In a mechanistic study employing human T47D breast cancer cells we found that CDB-4124 suppressed G1/0-S transition by inhibiting cdk-2 and cdk-4 expression and this correlated with inhibition of ER expression. Taken together, these data indicates that CDB-4124 can suppress the development of spontaneous and carcinogen-induced ER+ mammary tumors in rats and thus newer progesterone receptor modulators may have implications for prevention and treatment of human breast cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-07.
Abstract P4-02-14: Tailoring Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A CYP2D6 Multiple-Genotype-Based Modeling Analysis and a Validation
Authors: Yu K-D , Shao Z-M 
Published: April 2011

Abstract
Purpose
Previous studies have suggested that postmenopausal breast cancer women with wild-type CYP2D6 might actually have similar or superior recurrence free survival outcomes when they take tamoxifen rather than an aromatase inhibitor (AI). The present study established a CYP2D6 multiple-genotype-based model to determine the optimal endocrine therapy for patients harboring wild-type CYP2D6.
Methods
We created a Markov model to determine whether tamoxifen or AIs maximized 5-year disease-free survival (DFS) for extensive-metabolizer (EM) patients using annual hazard ratio (HR) data from BIG 1-98 trial. Then we replicated the model by evaluating 9-year event-free survival (EFS) using HR data from ATAC trial. We also employed two-way sensitivity analyses to explore the impacts of HR of decreased-metabolizer (DM) and its frequency on survival by studying a range of estimates.
Results
The 5-year DFS of tamoxifen-treated EMs was 83.3%, similar to that for genotypically unselected patients receiving an AI (83.7%). In the validation study, we further demonstrated that EMs could get comparable survival benefit from tamoxifen relative to an AI (9-year-EFS, 81.4% vs. 83.2%). Two-way sensitivity analyses showed the robustness of results.
Conclusions
Our modeling analyses indicate that among EMs, the DFS/EFS outcome of patients receiving tamoxifen is similar to that of patients receiving an AI. Further prospective clinical trials are needed to scrutinize the value of CYP2D6 genotype in the selection of endocrine therapy.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-14.
Abstract P4-02-18: Antiprogestins as Possible Therapeutic Agents for Breast Cancer Patients Showing a High Expression of the Progesterone Receptor Isoform A
Authors: Rojas PA , Sequeira G , Gonzalez P , Bagnati A , Urrutia A , Medel J , Martinez Vazquez P , Gass H , Lanari C. 
Published: April 2011

Abstract
Near 75 percent of breast cancer patients express progesterone (PR) and estrogen (ER) receptors and are potential candidates to receive an endocrine therapy. Most of the endocrine therapies available have been designed to target ER and there is not much information about PR as a therapeutic target for breast cancer treatment. However, extensive clinical and experimental evidence suggest that progestins are associated with the induction and maintenance of the neoplastic phenotype in the mammary gland. Moreover, different antiprogestins including ZK 98299, ZK 230211 and RU-486 proved to exert excellent therapeutic effects in murine mammary carcinomas from the MPA-breast cancer model which express high levels of PR with an increased PR-isoform A/PR-isoform B ratio (PR-A/PR-B) (Lanari C et al, Endocrine Related Cancer, 2009 Feb, Jun;16(2):333-50).
The main goal of this study is to validate these experimental results using human breast cancer samples and to identify breast cancer patients that might benefit from an antiprogestin therapy. In the first part of this study our aim was to set up primary cultures from each breast cancer sample and to evaluate the in vitro response to antiprogestins, correlating this response with the PR-A/PR-B ratio. Tumor samples were obtained at surgery from patients diagnosed with breast cancer at the Magdalena V. de Martinez Hospital from General Pacheco and at the Rivadavia Hospital of Buenos Aires after signing the informed consent (n=70; median age 53.9 years). All tumor samples were processed by mechanical and enzymatic disaggregation and epithelial cells were purified by differential sedimentation techniques. Only 10 percent of the tumor samples succeeded in tissue culture and could be subcultured for further studies in 24 well plates. Cells were grown in culture medium in the presence of 10% fetal calf serum with or without RU-486 (10-8 M) or Tamoxifen (10-8 M). After one week of treatment, the cells were trypsinized and the total number of cells in each well was counted. Treatment with RU-486 or with Tamoxifen induced a decrease in the number of cells as compared to the controls (n=4, P&lt;0.05). In these patients PR-A expression was the same or higher than PR-B as observed by Western Blot. Our results suggest that RU-486 might be an alternative therapy to treat breast carcinomas showing a high expression of PR-A. We still need more successful cultures in order to correlate the in vitro responsiveness with the PR isoform ratio.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-18.
Abstract P4-03-01: Inhibition of Fatty Acid Synthase (FASN) Sensitizes Breast Cancer Cells to Chemotherapy and Disrupts the Lipid Rafts
Authors: Espinoza I , Cheol Hong P , Busby R , Ruth L. 
Published: April 2011

Abstract
MN
Background: Breast cancer is the second leading cause of cancer death of women worldwide. One of the major challenges for a better prognosis of breast cancer patients is the ineffectiveness of chemotherapy and drug resistance. To investigate the mechanisms of drug resistance, resistant cancer cell lines have been established with various anticancer agents. We found that FASN, an important metabolic enzyme overexpressed in aggressive carcinomas, is t responsible in part for the drug resistance phenotype of breast cancer cells. Our findings show that blockage of FASN augments the cytotoxicity of the anti-mitotic drug Taxol in breast cancer cells. Moreover, C75 and Taxol have a synergistic effect both drugs are combined. The in vivo effect of C75 and Taxol and the mechanism by which blockage of FASN sensitizes the cells to chemotherapy are unknown. Material and Methods: In this study first we show the effect of C75 plus Taxol in breast tumor growth. BT474 cells were injected into the mammary fat pad of nude mice to generate the tumors. When the tumors were measurable we treated the mice with C75, Taxol or with a combination of both drugs. Second we studied the lipid rafts disruption after treatments by sucrose gradient and immunofluorescence. Results: We found that C75 plus Taxol extensively inhibited the tumor growth 9 fold and reduced the tumor size in 4 fold comparedn to the control mice (no treatement). In comparison C75 alone reduced the tumor growth in 1.5 fold only; and Taxol 2.5 fold compared to the control mice. These results show for first time that blockage of FASN (with C75) sensitizes breast cancer tumors to Taxol treatment in vivo. In addition, we studied the possible mechanism involved in the sensitization of breast cancer cells to Taxol by FASN blockage. Previous studies reported that blockage of FASN or Taxol treatment decrease the sphingolipids synthesis. Sphingolipids and cholesterol are the most abundant fatty acid in the lipid rafts in the plasma membrane. Disruption of lipid rafts has been shown to induce apoptosis in different carcinoma cell lines. Based in these findings, we studied lipid rafts in BT474 cells treated with C75, Taxol or combination of both with sucrose gradient and immunofluorescence microscopy. Discussion: Our results show that C75 and Taxol disrupt the lipid rafts. Thesefindings show that FASN is a new mechanism of drug resistance and may be an ideal target for chemosensitization in breast cancer chemotherapy.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-03-01.