bluuebunny/crossref_metadata_2025_split huggingface dataset:
P3-13-03: Long-Term Symptoms after Radiotherapy of Supraclavicular Lymph Nodes in Breast Cancer Patients.
Authors: Lundstedt D , Gustafsson M , Steineck G , Alsadius D , Sundberg A , Wilderäng U , Holmberg E , Johansson K-A , Karlsson P 
Published: June 2012

Abstract
Background and Purpose: Irradiation of the supraclavicular lymph nodes has historically been shown to increase the risk of brachial plexopathy with neurological problems in the upper limb. The purpose of this study was to compare long-term symptoms after modern radiotherapy (based on 3D dose planning) in breast cancer patients with or without irradiation of the supraclavicular lymph nodes.
Material and Methods: We collected information from 814 recurrence free women consecutively treated with adjuvant radiotherapy for breast cancer at the Sahlgrenska University Hospital in Gothenburg, Sweden, 1999 to 2004. The women had breast conserving surgery or mastectomy with axillary dissection or sentinel node biopsy. The breast area was irradiated to 50 Gy in 2.0 Gy fractions. Women with more than three lymph node metastases had regional radiotherapy to the supraclavicular lymph nodes delivered in 2.0 Gy fractions up to 50 Gy. Systemic treatments were given according to regional guidelines. In this study the women were classified into three groups depending on if they had axillary dissection and regional radiotherapy. The first group had both axillary dissection and regional radiotherapy, the second group had axillary dissection without regional radiotherapy, and the third group had sentinel node biopsy (i.e. no axillary dissection) without regional radiotherapy. Three to eight years after radiotherapy, the women received a questionnaire asking about paresthesia, pain and strength in the upper limb.
Results: Among women with axillary dissection and regional radiotherapy 38/192 (19.8%) reported paresthesia in the hand compared to 68/505 (13.5%) among women with axillary dissection without regional radiotherapy; relative risk (RR) 1.47; 95% confidence interval (95% CI) 1.02 - 2.11, and compared to 9/112 (8.0%) among women with sentinel node biopsy without regional radiotherapy; RR 2.46 (95% CI 1.24−4.90). Type of breast surgery, number of examined axillary lymph nodes, and chemotherapy had no impact on the occurrence of paresthesia. Age was an effect modifier among the women with axillary dissection and regional radiotherapy; up to 49 years of age 26.8% reported paresthesia (RR 2.45; 95% CI 1.05−5.73), between 50 and 59 years of age 19.7% reported paresthesia (RR 1.81; 95% CI 0.73−4.44), and above 59 years of age 10.9% reported paresthesia (RR 1.00 Reference). We found no statistically significant differences between the groups regarding pain or decreased strength.
Conclusions: Radiotherapy to the supraclavicular lymph nodes increases the occurrence of paresthesia in the hand. The effect was mainly seen among younger women. Dose/volume-response analysis regarding paresthesia will be presented at the meeting.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-13-03.
P3-13-10: Does Lapatinip Increase Pulmonary Toxicity When Concurrently Used with Radiation Therapy? An Experimental Study with Wistar-Albino Rats.
Authors: Senel Bese N , Yetmen O , Guzel E , Karaca C , Coban I , Elicin O , Suzer O 
Published: June 2012

Abstract
Purpose: Lapatinib (L) is an oral receptor tyrosine kinase inhibitor which has shown activity in the treatment of metastatic breast cancer. Adjuvant usage of L is being investigated in clinical phase III trials. There is no data regarding the side effects of combination of RT and L which may be a problem when L is used in the adjuvant setting. Lung is the most radiosensitive organ to observe late effects of RT. We evaluated if concurrent administration of L has any impact for the development of radiation induced pulmonary fibrosis in rats (RIPF). Material Methods: 40 female Wistar-albino rats (WAR) were divided into 4 experimental groups (G). G1 (control) did not receive any treatment. G2 (RT) received RT to whole thoracic region. G3 (L) received L without RT. G4 (L+RT) received L with RT. A total dose of 30 Gy in 10 fractions was given to both lungs with an anterior field at 2 cm depth. L equivalent to 1500 mg/day, 60 kg adult dose, were calculated according to the mean weight of rats, orally administrated with a feeding tube twice daily including the week-ends until WAR were sacrificed. WAR were anesthetized and sacrificed 16 weeks after RT which was shown to be a sufficient period for the development of RIPF in rats. Paraffin sections (5 μm thick) of lungs were stained with hematoxylin-eosin and Masson's trichrome. A comparative analysis was performed among 4 groups by scoring the pulmonary injury between 0 and 3 according to the infiltration of inflammatory cells into the alveolar spaces, alveolar wall thickening and architectural deformation across the entire lung section. Normality distribution were tested, then one-way ANOVA followed by post hoc Holm-Sidak testing were used.
Results: In G2 inflammatory cell infiltration, fibrosis with damage to lung structure and formation of small fibrous masses were observed. Alveolar septa was significantly thicker than G1 (p&lt;0.05), which revealed totally normal pulmoner structure. G3 showed minimal alveolar septal thickening and infiltration of inflammatory cells into the alveolar spaces which was not significantly different than G1. Histopathological findings in G4 were similar to those in G2 and statistically different when compared with the G1 and G3(p&lt;0.05). Conclusion: Study shows that addition of L to RT does not increase RIPF in rats.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-13-10.
P3-14-19: Impact of Chemotherapy-Induced Amenorrhea on Response to Neoadjuvant Chemotherapy in Breast Cancer.
Authors: Ahn SK , Moon HG , Kim JS , You JM , Shin HC , Han W , Noh D-Y 
Published: June 2012

Abstract
BACKGROUND: Although chemotherapy and ovarian ablation independently improve the outcome of breast cancer, there is controversy about the benefit of chemotherapy-induced amenorrhea (CIA) in breast cancer. We investigated impact of CIA on response to neoadjuvant chemotherapy in breast cancer patients.
METHODS: We reviewed the records of 198 premenopausal patients with breast cancer treated with neoadjuvant chemotherapy between January 2005 and December 2010. Chemotherapy-induced amenorrhea (CIA) was defined as serum FSH level ≥40 IU/L after completion of all scheduled neoadjuvant chemotherapy and prior to definitive surgery.
RESULTS: Among 198 breast cancer patients, 132 pts (66.7%) developed CIA after neoadjuvant chemotherapy. 156 pts (78%) underwent DA chemotherapy. The age of CIA patients was older than non-CIA patients (41.55±5.55 years vs. 38.27 ± 6.86 years, p=0.001). The incidence of CIA after neoadjuvant chemotherapy was significantly higher in responder group (responder vs. nonresponder: 87 pts (74.4%) vs. 45 pts (55.6%); p=0.006). Additionally, FSH level after all scheduled neoadjuvant chemotherapy was significantly higher in responder group (FSH 56.41±32.41 IU/L vs. 45.76±30.31 IU/L; p=0.021). In univariate analysis, CIA (p=0.006) and total number of chemotherapy cycle regardless of chemotherapy regimen (p=0.04) were significantly associated with tumor response. CIA was only independent factor for tumor response after neoadjuvant chemotherapy on multivariate analysis (p=0.012).

CONCLUSION: CIA after neoadjuvant chemotherapy was significantly associated with response to neoadjuvant chemotherapy in locally advanced breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-19.
P3-14-22: Response to Neoadjuvant Chemotherapy in Elderly Patients with Locally Advanced Breast Cancer.
Authors: Vanderhaegen J , Wildiers H , Christiaens M-R , Smeets A , Leunen K , Neven P , Vergote I , Vanlimbergen E , Weltens C , Janssen H , Moerman P , Brouckaert O , Brouwers B , Paridaens R 
Published: June 2012

Abstract
Background
Inoperable, locally advanced breast cancer (LABC) is common in the elderly. Studies have shown good responses with neoadjuvant chemo- and endocrine therapy. However, studies targeting the elderly population are rare.
Aim: To assess complete pathological response rate (pCR) following neoadjuvant chemotherapy (NACT) and to evaluate the effectiveness of this therapeutic option in elderly women with LABC.
Patients: Women (≥70 years) diagnosed at our University Hospital with LABC between 1999 and 2010 and treated with neoadjuvant chemotherapy. After neoadjuvant systemic treatment pCR was assessed if surgery was performed.
Results: 44 women with a mean age of 74.9 (70-93) years were included. Most tumors were ductal (IDA 88.6%), of grade 3 (79.5%) and hormone-receptor (HR) negative (61.4%). Among the 21 tumors (47.7%) that were HER2+ (immunohistochemistry (IHC) 3+ or 2+ and FISH+), all but 3 received neoadjuvant Trastuzumab. Only 4 patients had no surgery (clinical decision or personal choice) while the remaining 40 patients underwent either breast-conserving surgery (17.5%) or mastectomy (82.5%). 23 patients (52.3%) had pathological partial response, 14 patients (31.8%) pCR and 3 patients no response. pCR was more frequently achieved in HR-negative (44.4%) than in HR- positive patients (11.8%). In both groups HER2 positive tumors had better pathological response than HER2 negative tumors. After a mean follow-up of 41 months (5-120) 29 patients (65.9%) had no evidence of disease, 6 patients (13.6%) had (loco)regional recurrence, 12 patients (27.2%) developed metastatic disease and 6 patients (13.6%) died because of breast cancer. Relapse was more frequently seen in patients with a pPR (47.8%) versus patients with a pCR (14.3%).

Conclusion: In a selected population of elderly patients with LABC and treated with neoadjuvant chemotherapy, a reasonable percentage of pCR can be achieved. Concordant with younger populations, this percentage is higher in HR-/HER2 positive breast cancer. Neoadjuvant chemotherapeutic treatment can thus be as beneficial for the older patient as for younger ones. In fit elderly patients, neoadjuvant chemotherapy should therefore not be omitted solely on the basis of advanced age.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-22.
P3-15-02: The Change of Bone Turnover Markers during Neoadjuvant Anastrozole Versus Exemestane: A Randomized Single-Center Study.
Authors: Jinno H , Shimada K , Takahashi M , Hayashida T , Hirose S , Ikeda T , Kitagawa Y 
Published: June 2012

Abstract
Background: Non-steroidal aromatase inhibitors including anastrozole and letrozole have been reported to increase the rate of bone turnover, accelerate loss of bone, and increase the incidence of fractures. Although steroidal inactivator exemestane has similar inhibitory effect on the aromatization, animal studies have shown a weak but potentially important anabolic effect of exemestane metabolites, which might lead to decreased bone resorption. This randomized trial was conducted to compare the effect of exemestane and anastorozole on bone turnover markers.
Patients and Methods: Fifty-two postmenopausal women with ER-positive, HER2−negative, invasive, nonmetastatic, and operable breast cancer were randomly assigned to neoadjuvant exemestane (25 mg daily) or anastrozole (1 mg daily) for 4 months. The primary endpoint was change in bone turnover markers including resorption markers urinary and serum N-telopeptide (NTX) and the formation markers serum bone alkaline phosphatase (BAP). The secondary endpoint was tumor objective response (OR) assessed by both caliper and ultrasound. Comparisons were also made of breast conservation rate and adverse events.
Results: The changes in serum NTX from baseline to week 16 were not statistically different between anastrozole and exemestane. The changes in urinary NTX from baseline to week 16 were also not statistically different between both groups .BAP did not show any significant increase in the exemestane group (10.8%; p=0.21), whereas the increase in BAP from baseline to week 16 in the anastrozole group was 15.0% and marginally significant (p=0.05). There were no significant differences in OR in the intent-to-treat population between patients receiving anastrozole or exemestane (45.8% vs. 39.2%; p=0.63). The OR was similar between the patients with a baseline Ki67 index of ≥15% and &lt;15% in exemestane group (37.5% vs. 41.2%; p=0.86). In anastrozole group the OR in patients with a baseline Ki67 index of ≥15% and &lt;15% was 44.4% and 53.8%, respectively(p=0.66). Breast conservation rate was similar between anastrozole and exemestane (62.5% vs. 67.9%; p=0.68). Treatment was well tolerated and much the same for both groups.
Conclusions: There is no significant differences of the change in bone turnover markers between anastrozole and exemestane. These results indicate exemestane had no anabolic effects which would lead to fewer adverse effects on bone.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-15-02.
P3-16-01: Safety Profile and Clinical Activity of Single-Agent BKM120, a Pan-Class I PI3K Inhibitor, for the Treatment of Patients with Metastatic Breast Carcinoma.
Authors: Rodon J , Bendell JC , Abdul Razak AR , Homji N , Trandafir L , Quadt C , Graña-Suárez B , Siu LL , Di Tomaso E , Demanse D , Massacesi C , Hirawat S , Burris III HA , Baselga J 
Published: June 2012

Abstract
Background
Phosphatidylinositol 3-kinase (PI3K) is critical to cancer cell growth, survival, and metabolism. BKM120 is an oral pan-class I (α, β, γ, δ) PI3K inhibitor that has demonstrated in vitro and in vivo tumor cell growth inhibition in a range of cancer types including breast cancer.
Materials and methods: The Phase I study CBKM120X2101 investigating single-agent daily BKM120 in patients (pts) with advanced solid tumors has been recently completed with the maximum tolerated dose established at 100 mg/day. Here, we report the analysis of metastatic breast carcinoma (MBC) pts enrolled in this study.
Results: Overall, 83 pts have enrolled, 21 of whom have MBC. At the cut-off date of 25th February 2011, 20 MBC pts were evaluable: 1 pt at 80 mg, 1 pt at 150 mg and 18 pts at 100 mg. Patient characteristics were as follows: median age 55 years (range 37–71); performance status ECOG 0/1/2 for 7/12/1 pts, respectively; visceral disease was reported in 16 pts, including liver, 10 pts (50%); lung, 9 pts (45%); and pleura, 5 pts (25%); all pts had &gt;3 lines of systemic therapy (3-12). The median time from last treatment and study entry was 46 days (29-235). The median duration of BKM120 treatment administered was 7.5 weeks (1.0−96.4). The most frequent grade 3 drug-related adverse events (AEs) were: transaminases increase, 4 pts; psychiatric disorders, 3 pts, consisting of anxiety, affective disorder, and mood alteration (1 pt each); diarrhea, 2 pts; fatigue, 2 pts; and hyperglycemia, 1 pt. The only grade 4 drug-related AE was hyperglycemia, reported in 1 pt at 150 mg. Most AEs were manageable with treatment interruption and dose reductions. Eighteen pts were evaluable for objective tumor response by RECIST. Two pts (11%) exhibited partial responses, which were confirmed in a triple-negative MBC pt, and unconfirmed in an ER+ HER2− MBC pt. For these 2 pts, the treatment duration was 29+ (ongoing) and 6 months, respectively. An additional 9 pts (50%) had stable disease, lasting &gt;4 months in 7 pts (35%).
Conclusions: This preliminary analysis showed that BKM120 has single-agent activity in heavily pretreated pts with MBC, and an acceptable safety profile. Molecular profiling and updated pharmacokinetic results will be presented at the meeting.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-01.
P3-16-03: Enhancing Anti-IGF Directed Therapeutics by Co-Targeting Autophagy.
Authors: Oh AS , LaPara K , Yee D 
Published: June 2012

Abstract
Autophagy (macroautophagy) is a cellular mechanism that maintains homeostasis and cell growth by regulating the turnover of damaged proteins. Autophagy has a critical role in maintaining cellular viability during nutrient starvation and metabolic stress by recycling intracellular proteins for nutrient reallocation. Whether the autophagy pathway utilized by breast cancer cells has a survival mechanism or is a feature of cell death is not fully understood. Since the IGF/insulin signaling maintains cellular growth, nutrient utilization, and survival, increased autophagy or autophagic flux might be induced with IGF-I inhibitors as a compensatory survival mechanism. In breast cancer cells treated with anti-IGF1R kinase inhibitors, we observed an increase in autophagic flux; similar to levels induced by nutrient deprivation.
Objective: In this study, we examined whether IGF1R inhibitor -induced autophagy is cytoprotective or cytotoxic. If autophagy has a protective role in nutrient-depleted conditions it could reduce the long term efficacy of IGF1R inhibition by making cells refractory to blockade of this signaling system. In this study, we hypothesized that blocking autophagy in combination with anti-IGF1R therapies (antibodies or small molecules) would further enhance growth inhibition in a panel of breast cancer cells types (luminal and basal-like/triple negative).
Results: We initially examined whether autophagy inhibitors (chloroquine or bafilomycin A1) had a differential growth effect on breast cancer cells that varied in their sensitivity to IGF1R stimulated growth. We found that low-to-moderate IGF growth dependent MDA-MB-231 and MDA-MB-435A breast cancer cells were more sensitive to chloroquine alone. However, sensitivity to bafilomycin A1 differed between breast cancer cell lines compared to chloroquine. In conditions of cellular stress when autophagy is normally triggered, co-treatment with IGF inhibitor (OSI-906) and chloroquine, increased growth inhibition in all breast cancer cell lines. Further, basal-like breast cancer cells (i.e. low-to-moderate IGF growth dependent cells) had a higher baseline autophagic flux compared to luminal MCF-7L breast cancer cells (i.e. highly IGF-I dependent). Using MCF-7L cells selected for long-term resistance to IGF1R kinase inhibitor (AEW-541), we found that these cells were not sensitivite to chloroquine or Bafilomycin A1 compared to wild type MCF-7Ls. Inhibiting autophagy in combination with anti-IGF therapies could offer benefit over single therapy alone if autophagy inhibitors are given together with IGF1R inhibitors, but not in IGF1R inhibitor resistant cancers. Additionally, targeting autophagy as a single agent therapy may be more beneficial in triple negative breast cancer compared to other subtypes of breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-03.
P3-16-16: Overcoming EGFR Resistance Using Dasatinib in Combination with Cetuximab and Cisplatin in Triple Negative Breast Cancer Cell Lines.
Authors: Kim EMH , Gartner E , Choi L , Boerner J 
Published: June 2012

Abstract
Background: Patients presenting with triple negative breast cancers (TNBC's) have a poorer prognosis compared to those with other subtypes of breast cancer, and effective therapeutic targets have yet to be identified. The majority of TNBC's overexpress EGFR, however studies have demonstrated that EGFR inhibition as a monotherapy is ineffective. Interestingly, adding the EGFR inhibitor, cetuximab to cisplatin chemotherapy doubled both the response rate and time to progression compared with patients only on cisplatin. c-Src tyrosine kinase plays a critical role in signal transduction downstream of growth factor receptors, and has been found to contribute to the resistance of TNBC cell lines through the phosphorylation of EGFR. We hypothesize that dasatinib, a c-Src inhibitor, may help overcome EGFR resistance and in combination therapy enhance the cytotoxic activity.
Material and Methods: A panel of breast cancer cell lines, including 7 triple negative cell lines, were tested using increasing doses of dasatinib (1 nM to 10 μM), cetuximab (1 μg/ml to 100 μg/ml), and cisplatin (10 nM to 10 μM) alone and in combination. Growth inhibition was determined after 3 days of treatment using the MTT colorimetric assay, and apoptosis was assessed through Caspase-3 activation and TUNEL assays.
Results: All cell lines were generally resistant to cetuximab, with 100 μg/ml required to decrease cell viability. Two TNBC lines, SUM149 and SUM229, showed an additional decrease in cell viability with dasatinib added to cetuximab, while SUM102 and BT20 cells showed an additional decrease in viability using the dasatinib and cisplatin combination, compared to single agents. In 4 out of 7 TNBC lines, the combination of dasatinib, cisplatin, and cetuximab showed a significant decrease in cell viability compared to the combination without dasatinib (p-value &lt; 0.02). The decrease in proliferation using the combination of dasatinib, cisplatin, and cetuximab was due to an increase in apoptosis. In contrast, this combination did not increase the loss of cell viability or apoptosis in ER/PR+ and HER2+ breast cancer cell lines.
Discussion: Targeting c-Src family kinases with dasatinib may help overcome the resistance to EGFR inhibition in triple-negative breast cancer. This may have significant clinical implications in treating TNBC patients, and hence further investigation into the mechanism of this effect is warranted.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-16.
P3-17-11: Dovitinib (TKI258), a Dual Inhibitor of FGFR and VEGFR, Induces Tumor Growth Suppression in Xenograft Models of Primary Human Breast Cancer.
Authors: Shi MM , Linnartz R , Versace R , Graus Porta D , Kay A , Dugan M 
Published: June 2012

Abstract
Introduction: The objective of this study was to evaluate the efficacy of dovitinib (TKI258), a small-molecule dual inhibitor of fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) in mouse models of human breast cancer. Molecular epidemiological studies have implicated that FGFR1 and FGFR2 gene amplification plays a critical role in breast cancer tumorigenesis. FGFR1 gene amplification correlates with gene expression and is associated with poor prognosis in patients with estrogen receptor-positive (ER+) tumors. Dual FGFR/VEGFR inhibitory activities of dovitinib make it an attractive molecule for targeting breast cancer.
Experimental Design: Dovitinib was evaluated in 3 primary human breast carcinoma xenograft models with different histological and molecular profiles: a triple-negative breast cancer model (HBCx-15), a HER2+ model (HBCx-5), and an ER+ model (HBCx-3). Dovitinib was administered orally at 20- and 40-mg/kg dose levels (n = 8–10/group), once daily for 21 consecutive days.
Results: At a dose of 40 mg/kg, dovitinib demonstrated strong antitumor efficacy as a single agent, particularly in the ER+ HBCx-3 and the HER2+ BCx-5 tumor models (ΔT/T0 = −26.42% and ΔT/ΔC = 5.09%, respectively), whereas the response was less significant in the triple negative breast cancer HBCx-15 model (ΔT/ΔC = 31.7%).
Conclusion: Dovitinib showed significant antitumor effect in human breast cancer xenograft mouse models. This study provides a strong rationale for clinical investigation of dovitinib in patients with advanced breast cancer, particularly in patients with ER+ and HER2+ disease.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-17-11.