bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P2-16-13: Phase I dose escalation clinical trial of the PI3K inhibitor BKM120 and capecitabine (C) in metastatic breast cancer (MBC)
Authors: Dees EC , Marcom PK , Snavely A , Noe J , Anders CK , Blackwell K , Kimmick G , Reeder-Hayes K , Rosenstein D , Perou CM , Carey LA 
Published: August 2014

Abstract
Background: PIK3CA is one of the most frequently mutated genes in human breast cancer, and the high expression of a PIK3CA-pathway signature is associated with the poor prognosis Luminal B and Basal-like expression subtypes. BKM120 is an oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, which has shown activity in preclinical and early clinical testing, and synergy with both endocrine and chemotherapy. In this trial we sought to evaluate the safety and estimate the maximum tolerated dose (MTD) of the combination of BKM120 and C in patients (pts) with MBC.
Methods: In a 3+3 dose escalation design, we evaluated four cohorts of BKM 120 daily plus C BID x 14 days in 21 day cycles. Standard definitions for DLT and MTD were used and evaluated on the first cycle. Toxicity was graded by CTCAE version 4. Response was evaluated after 2 cycles by RECIST criteria. Pts with MBC appropriate for treatment with C who had &lt;4 prior chemotherapy regimens and normal organ, bone marrow and cardiac parameters were eligible.
Results: 21 pts (11 hormone receptor (HR)+, 3 HER2+, 9 HR/HER2-negative) were enrolled and treated. All were evaluable for toxicity and 14 for response to date. Median age was 54 (range 35-65). Median prior chemotherapy regimens for MBC was 2 (range 1-4). The following dose levels (DL) were evaluated: BKM120 50 mg/d + C 1000 mg/m2/BID x 14(DL 1-4 pts), BKM120 80 mg/d + C 1000 mg/m2/BID x 14 (DL2-3 pts), BKM120 100 mg/d + C 1000 mg/m2/BID x 14 (DL3-9 pts), BKM120 100 mg/d + C 1250 mg/m2/BID x 14 (DL4-5 pts). Most frequent adverse events (all grades) included: Nausea (12), mood disorders (11), PPE (9), diarrhea (8), fatigue (7), vomiting (5) mucositis (4), rash (4), photosensitivity (3), hyperglycemia (3). Grade 3 or higher AEs in any cycle were transaminitis (3) diarrhea (2) mood disorder (2), hyperglycemia, fatigue, photosensitivity, PPE (1 pt each). DLTs: grade 3 hyperglycemia (1/6 pts at DL3), and grade 3 mood disorder in 1/5 pts DL 4. Additionally 4 of 5 patients at DL 4 required dose reduction or delay prior to C3D1. Thus DL 4 exceeded the MTD and DL 3 was expanded for further safety evaluation. Antitumor activity was seen with best responses of 1 CR (at DL 3), 3 PR (DL1 and 4) and 7 SD.
PK analysis, assessment of tumor PIK3CA mutation status and intrinsic subtype by PAM50 is ongoing.
Conclusions: The combination of BKM120 100 mg po q day and C 1000 mg/m2 / BID x 14 d in 21 day cycles is tolerable and appears active. PK and biomarker analysis are ongoing. A phase II trial is planned.
Acknowledgements: This study was funded by Novartis Pharmaceuticals and by a grant from Susan G. Komen for the Cure (SAC 110044).
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-13.
Abstract P2-16-24: Folate targeted SMDC’s: A possible new treatment alternative for folate receptor expressing TNBC patients
Authors: Leamon CP , Reddy JA , Nelson M , Bloomfield A , Dorton R , Vetzel M 
Published: August 2014

Abstract
Triple negative breast cancer (TNBC) is a subtype characterized by lack of gene expression for the estrogen receptor, progesterone receptor and the Her2/neu protein. Hence, the lack of hormonal or Her2 targeted therapy options makes TNBC difficult to treat, resulting in a death rate which is disproportionately higher than for other breast cancer subtypes. Recently, the folate receptor (FR) was shown to be highly expressed in TNBC, and expression significantly correlated with the higher grades of malignancy as well as poor outcomes. These observations suggest that TNBC patients may benefit from treatment with an FR-targeted therapy. To address this question, an established FR-positive subcutaneous TNBC pre-clinical model (MDA-MB-231) was chosen to evaluate a panel of FR-targeted small molecule drug conjugates (SMDC) with high potencies and varying mechanisms of action. Thus, EC1456 (folate-tubulysin B; IC50 ∼ 1 nM) and EC1744 (a folate-DNA cross-linking agent; IC50 ∼0.1 nM) were dosed intravenously at 2 μmol/kg following a three times per week, two week schedule in tumor-bearing mice. Both FR-targeted agents were found to be highly active against the MDA-MB-231 tumors, with 80-100% cure rates. In all cases, the observed anti-tumor activity was not accompanied by any significant weight loss in the test animals. These findings suggest that folate-targeted SMDCs may be active against TNBC and that further preclinical studies are warranted.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-24.
Abstract P2-19-02: Do older women benefit from post-mastectomy breast reconstruction?
Authors: Sisco M , Johnson DB , Wang CE , Yao KA 
Published: August 2014

Abstract
Purpose: Despite evidence that post-mastectomy breast reconstruction (PMBR) decreases psychological morbidity and improves body image, older women (aged 65 and above) receive it six times less often than younger women. It is unclear whether this difference represents a disparity or reflects informed patient choices since the outcomes of PMBR in older women have never been rigorously studied. We hypothesized that in older women, the use of PMBR is associated with greater psychosocial well-being and breast satisfaction than mastectomy alone.
Patients and Methods: The Dillman method was used to survey 299 older women with stage 0-III breast cancer who underwent a mastectomy from 2006-2011. The response rate was 75.3%. The survey incorporated demographic questions and measured satisfaction and health-related quality of life outcomes using the Duke health profile and the BREAST-Q mastectomy module. Patients who underwent PMBR were compared to those who did not (no-PMBR) to determine differences in patient characteristics, satisfaction, and quality-of-life outcomes between groups. Satisfaction and outcome results were risk adjusted using multivariable logistic regression to account for differences between PMBR and no-PMBR groups.
Results: The median age of respondents was 72. Of these, 77/214 (36%) elected to undergo PMBR. Marital status, education level, race, and tumor stage were similar in PMBR and no-PMBR groups. Those in the PMBR group were generally younger and more affluent than those in the no-PMBR group (p&lt;0.001 and p&lt;0.05, respectively). There were no significant differences in age-adjusted physical health, anxiety, or depression scores between PMBR and no-PMBR groups. Both groups reported high levels of decisional satisfaction. However, after adjusting for age and income, PMBR was associated with greater breast satisfaction (BREAST-Q score 69 vs. 57, p&lt;0.001) and greater psychosocial well-being (BREAST-Q score 83 vs. 76, p&lt;0.001). These differences in scores compared favorably to those seen in younger women.
Conclusions: This is the first study to compare psychosocial outcomes and breast satisfaction between older women who undergo PMBR and those who do not. These findings show that older women have the potential to benefit from PMBR at least as much as younger women do. PMBR can be performed in a significant proportion of older women with high levels of satisfaction. Older women who are appropriate candidates should be encouraged to consider breast reconstruction, and efforts should be made to narrow the disparity in the delivery of PMBR between older and younger women.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-19-02.
Abstract P2-19-04: Latissimus dorsi muscle onlay patch alternative to acellular dermal matrix is useful for implant-based breast reconstruction
Authors: Lee J , Bae Y , Lee S 
Published: August 2014

Abstract
Introduction: The implants-based breast reconstruction is very useful method for breast conserving surgery in breast cancer. Recently, acellular dermal matrix (ADM) is applied to release the inferior pectoralis muscle for maintaining breast contour and to prevent burst out from the implant pocket. Authors applied latissimus dorsi (LD) muscle onlay patch instead of ADM for implant-based breast reconstruction.
Patients and methods: From January to December 2012, a total of 20 patients with breast tumor underwent 22 cases of implant-based breast reconstruction with ADM or LD muscle onlay patch. The cosmetic outcome is assessed with 4-point scoring system at 4 weeks after from chemotherapy or radiotherapy. And the statistical analysis was evaluated between 2 groups.
&lt;Surgical technique&gt; After conventional breast conserving surgery was done, the origin of the pectoralis major muscle are released and the window is checked pectoralis major muscle medially, rectus sheath inferiorly, and serratus anterior muscle laterally. Then, LD flap is sutured to cover this window with avoiding the vessel injury. The implant is inserted in the subpectoral pocket and breast reconstruction is finished with LD flap.
Results: Mean operation time of ADM group and LD muscle onlay patch group was 153.9 and 299.7 minutes, respectively. (p = 0.054).
Demographic characteristicsCharacteristicsADM (n = 10)LD muscle onlay patch (n = 12)p-valueAge (years)36.8±10.145.8±12.50.820BMI (kg/m2)19.0±2.023.4±3.430.065Volume loss (g)153.9±120.29299.7±116.030.030OP time (minutes)198±86.06342.5±54.70.054Hospital stay (days)6.9±1.528.7±1.560.059Follow-up period (Mo)6.2±2.668.7±1.560.232Interval period (days)19.9±6.2427.9±7.580.516Chenotherapy5110.056Radiotherapy590.378Complication 0.571Inflammation10 Seroma11 Cosmetic outcome 1.000Excellent34 Good55 Fair23
There were no significant differences between 2 groups; postoperative complication, cosmetic outcomes, and tumor characteristics.
Tumor characteristicsCharacteristicsADM (n = 10)LD muscle onlay patch (n = 12)p-valueTumor type 0.088Atypical ductal hyperplasia20 Carcinoma in situ31 Invasive carcinoma511 Dermal invasion011.00Tumor size2.0±1.453.8±2.270.586Multicentricity310.293Stage 0.440031 I21 IIA24 IIB13 IIIA01 IIIB02 Microcalcification230.594Differentiation 0.038Well20 Moderate35 Poor06 Perineural invasion 0.706Positive01 Negative1011 Lymphovascular invasion 0.261Positive04 Negative108 Estrogen receptor 0.770Positive87 Negative05 Progesterone receptor 0.013Positive85 Negative07 c-erbB2 protein 0.074Positive04 Negative88
However, ADM was found to be much more expensive than LD muscle onlay patch.(p&lt;0.001)
Conclusion: Implant-based breast reconstruction with LD muscle onlay patch would be a feasible surgical technique alternative to ADM, when LD flap is planned for breast reconstruction.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-19-04.
Abstract P3-02-02: Cyclin D1 overexpression increases the risk for breast cancer death 4-fold in hormone receptor positive and node negative breast cancer
Authors: Ahlin C , Grönberg M , Valachis A , Zhou W , Amini R-M , Blomqvist C , Fjällskog M-L 
Published: August 2014

Abstract
Background: Cyclin D1 has a central role in cell cycle control, but also directly affects the estrogen receptor. It has been shown that cyclin D can activate the estrogen receptor in a ligand-independent way and studies are implying that cyclin D overexpression may be linked to tamoxifen resistance. We wanted to explore the prognostic value of cyclin D overexpression in node negative breast cancer.
Patients and methods: We examined the expression of cyclin D1 using immunohistochemistry on tissue micro array (TMA) sections from a case control study (1:1) consisting of 380 patients with T1-2N0M0 breast cancer. Adjuvant radiotherapy and endocrine treatment was allowed, but not chemotherapy. Event was defined as breast cancer death. Breast cancer specific survival was analyzed in univariate and multivariate models using conditional logistic regression.
Results: Cyclin D1 was inversely correlated to Elston grade (rho = 0.2; p = 0.000); moderately correlated to PgR status (rho = 0.3, p = 0.000) and strongly correlated to ER status (rho = 0.4, p = 0.000). Cyclin D1 overexpression did not increase the risk for breast cancer death analyzing the whole patient population. However, subgroup analyses of hormone receptor positive patients showed an increased risk for breast cancer death (OR 4.2; 95% CI 1.4-12.6) and (OR 3.9; 95% CI 1.3-12) when adjusted for tumor size and age at diagnosis.Conclusion: Cyclin D1 is an independant prognostic factor of outcome in hormone receptor positive and node negative breast cancer with overexpression increasing the risk for breast cancer death 4-fold.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-02-02.
Abstract P3-02-03: The phosphatase function of the eyes absent (EYA) homolog is required for the induction of breast cancer cellular proliferation via cyclin D1
Authors: Pestell RG , Wu K , Li Z , Tian L , Chen K , Wang J , Hu J , Sun Y , Li X , Ertel A 
Published: August 2014

Abstract
The Drosophila Eyes Absent Homologue 1 (EYA1) is a component of the retinal determination gene network (RDGN) and serves as an H2AX phosphatase. The cell fate determination gene network includes the dachshund (dac), twin-of-eyeless (toy), eye absent (eya), teashirt (tsh) and sine oculis (So). In Drosophila, mutations of the RDGN leads to failure of eye formation, whereas, forced expression induces ectopic eye formation. EYA functions as a transcriptional co-activator being recruited in the context of local chromatin, but lacking intrinsic DNA binding activity. EYA family members EYA 1-4 are defined by a 275 amino acid carboxyl-terminal motif that is conserved between species, referred to as the EYA domain (ED). The human homologs EYA 1-4 are highly conserved in their EYA domain and amino termini, with the exception of a small tyrosine rich residue region named EYA domain II.
Altered expression or functional activity of the RDGN has been documented in a variety of malignancies. DACH1 expression is reduced in breast, prostate, endometrial and brain cancer. EYA2 is up regulated in ovarian cancer, promoting tumor growth. EYA1 and EYA2 enhanced survival in response to DNA damage producing agents in HEK293 cells. Eya2 was required for Six1/TGFb signals that govern a prometastatic phenotype and epithelial mesenchymal transition (EMT). Although EYA proteins are expressed in human breast cancer, the relationship to molecular genetic subtype, prognosis and the molecular mechanisms governing contact-independent growth are not known.
The cyclin D1 gene encodes the regulatory subunits of a holoenzyme that phosphorylates and inactivates the pRb protein. Herein, comparison with normal breast demonstrated EYA1 is overexpressed with cyclin D1 in luminal B breast cancer subtype. EYA1 enhanced breast tumor growth in mice in vivo requiring the phosphatase domain. EYA1 enhanced cellular proliferation, inhibited apoptosis, and induced contact-independent growth and cyclin D1 abundance. The induction of cellular proliferation and cyclin D1 abundance, but not apoptosis, was dependent upon the EYA1 phosphatase domain. The EYA1-mediated transcriptional induction of cyclin D1 occurred via the AP-1 binding site at -953 and required the EYA1 phosphatase function. The AP-1 mutation did not affect SIX1-dependent activation of cyclin D1. EYA1 was recruited in the context of local chromatin to the cyclin D1 AP-1 site. The EYA1 phosphatase function determined the recruitment of CBP, RNA polymerase II and acetylation of H3K9 at the cyclin D1 gene AP-1 site regulatory region in the context of local chromatin. The EYA1 phosphatase regulates cell cycle control via transcriptional complex formation at the cyclin D1 promoter.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-02-03.
Abstract P3-02-04: QM-FISH analysis of the genes involved in the G1/S checkpoint signaling pathway in triple-negative breast cancer
Authors: Zhang J , Zhang S , Hou G , Shao Y , Zhang X 
Published: August 2014

Abstract
OBJECTIVES: To analyze copy number alterations(CNAs) of the genes involved in the G1/S checkpoint signaling pathway of triple-negative breast cancer (TNBC) and non- triple-negative breast cancer(non-TNBC) and in order to find specific CNAs associated with overall survive for TNBC.In all,to provide an effective target for future treatment.
METHODS: We selected the samples randomly form Tianjin Cancer Hospital between August, 2006 and August, 2007,which contained one hundred TNBC cases and one hundred non-TNBC cases. Quantitative mμlti-gene fluorescence in situ hybridization (QM-FISH) was used to study CNAs of the genes involved in the G1/S checkpoint signaling pathway, including CCND1,c-Myc,p21, CHEK2, p16, Rb1, Mdm2and p53.
RESULTS: The amplification rates of c-Myc and the deletion rates of p53 in TNBC tended to be higher than those in non-TNBC, whereas the amplification rates of CCND1 and Mdm2 in non-TNBC tended to be higher than those in TNBC. In Kaplan-Meier analysis, the amplification of CCND1 (P = 0.02) and c-Myc (P = 0.02) as well as the deletion of p53 (P = 0.01) predicted worse survival in the TNBC group. While in the non-TNBC group, the amplification of CCND1 (P = 0.01) and Mdm2 (P = 0.04) as well as the deletion of p53 (P = 0.049) were associated with worse survival. The amplification of c-Myc and the deletion of p53 in TNBC were associated with higher mortality risk (HR,2.87;95%CI,1.14-7.21[P = 0.03]; HR, 3.34;95%CI, 1.22-9.09 [P = 0.02]), whereas the mortality risk tended to be higher in the patients with amplification of CCND1 (HR, 4.35;95%CI,1.23-15.39 [P = 0.02])in non-TNBC.
CONCLUSIONS: The amplification rates of c-Myc and deletion rates of p53 in TNBC tended to be higher than those in non-TNBC, whereas the amplification rate of CCND1 and Mdm2 tended to be higher in non-TNBC. c-Myc and p53 were independent prognostic factors for TNBC, while CCND1 was the independent prognostic factors for non-TNBC.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-02-04.
Abstract P3-05-03: HER2-CONNECT® pathologist-assisted image analysis algorithm for HER2 IHC interpretation improves correlation with HER2 FISH results
Authors: Miller DV , Stender H , Kristensen T , Min RK , Isaac J , Hansen J , Seaman J , Grunkin M , Vyberg M 
Published: August 2014

Abstract
Background: HER2 testing by immunohistochemistry (IHC) is prone to inter-observer variability and subjective interpretation. Pathologist-assisted digital image analysis is recommended in the CAP/ASCO guidelines to improve interpretive consistency. As a quality benchmark, HER2 IHC results should correlate with HER2 fluorescence in-situ hybridization (FISH) in &gt;95% of positive and negative cases. HER2-CONNECT® (Visiopharm, Hoersholm Denmark) is a digital analysis algorithm that scores stained membrane interconnectivity rather than relying solely on staining of individual cells. As such, it can be thought of as a surrogate for the so-called “chickenwire” pattern characteristic of true HER2 positive tumors. In this study we applied HER2-CONNECT® analysis with pathologist quantitative interpretation (HC+PQI) to a set of breast tumors with known HER2 FISH status to assess concordance.
Design: Breast carcinoma tissue sections previously stained with HER2 IHC (HercepTest) and interpreted manually were retrospectively re-submitted for HC+PQI. These included core and excisional biopsies from primary and metastatic sites. Fixation times were documented within recommended guidelines. HER2 FISH (PathVysion) was performed on all cases. Using connectivity scores on a scale of 0 - 1.0 from the analyzed regions, a pathologist determined the overall% of HER2 positive tumor cells in the sample (since HER2-CONNECT reports connectivity, but not tumor cell quantitation) and reported a final score per CAP/ASCO guidelines (&lt;10% = 1+, 10-30% = 2+, &gt;30% = 3+).
Results: 190 cases comprised the analysis set, including 77 3+, 73 2+, and 40 0/1+ as scored in the original reports. 66 cases were HER2 FISH amplified (64/77, 83% of the original 3+ cases and 2/73, 2.7% of 2+ cases) and 6 cases were FISH equivocal. None of the 0/1+ cases were HER2 FISH amplified. Using HC+PQI, the new scores were 67 3+, 68 2+, and 55 1+. Correlation between HC+PQI and HER2 FISH was 95.5% (64/67) for 3+/amplified and 100% (55/55) for &lt;2+/nonamplified (overall concordance 97.5%). Using FISH as the gold standard, the HC+PQI interpretation reduced the false positive rate from 13% (15/108) to 3% (4/108). 17 of 63 HER2 nonamplified samples originally scored 2+ were changed to 1+ on HC+PQI (i.e. reduction of FISH testing by 27% (17/63)).
Conclusions: Relative to the original report scores, HC+PQI improved correlation with HER2 FISH and reduced the overall number of 2+ results (potentially reducing the number of FISH tests required). These data also objectively highlight the importance of the “chickenwire” pattern in positive result interpretation for HER2.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-05-03.
Abstract P3-07-08: Breast cancer in China reveals transcriptomic likeness to Caucasian breast cancer
Authors: Huang X , Dugo M , Callari M , Sandri M , DeCecco L , Carcangiu ML , Iorio M , Xue J , Daidone MG , Ménard S , Tagliabue E , Wu J , Orlandi R 
Published: August 2014

Abstract
The incidence of breast cancer among Chinese women has been historically much lower than that of Caucasian women but has increased dramatically over the past 30 years in urban areas of China, an increase likely to continue in the next decades across China with progressive urbanization and economic development. However, it is still unclear whether differences in breast cancer incidence between Chinese and Caucasian women reflect differences in disease biology in addition to environmental factors. To address this question, we compared consecutive cohorts of Chinese and Italian breast cancer patients who underwent surgical resection in the years 2005-2007 at Fudan Cancer Center of Shanghai (China) and Fondazione IRCCS Istituto Tumori of Milan (Italy), respectively, two comprehensive cancer centers with similar inpatients and outpatients recruited in a large area. Analyses of clinico-pathological characteristics of 1563 Chinese and 1052 Italian consecutive breast cancer patients revealed that 50% of patients in the Chinese cohort were younger than 50 years versus 29% of Italian patients, indicating that Chinese women develop breast cancer earlier than Italian patients, with a peak of frequency at 50-60 years. Among Chinese breast tumors, 63% were estrogen receptor (ER)-positive versus 85% of the Italians, and the prevalence of ER-positive tumors was equivalent in pre- and postmenopausal Chinese cases, suggesting the same hormonal features in tumors of younger and older patients, consistent with findings in the Italian cohort.
Microarray-based gene and miRNA expression profiling was then conducted on 80 Chinese and 97 Italian samples using Illumina Gene and MicroRNA expression technologies. To minimize potential bias and artifact due to variability in specimen collection, storage, processing and analysis of high-throughput results, samples initially collected in the Chinese and Italian hospitals were all stored, randomly processed and analyzed in the Italian center. Analysis revealed a comparable pattern of gene and miRNA expression in the 2 cohorts with unsupervised hierarchical clustering of 12,338 genes and 858 miRNAs, and similar expression of intrinsic and extracellular matrix (ECM) genes led to a similar partition in intrinsic and ECM subtypes, indicating molecular similarity among Chinese and Caucasian breast cancers.
Supported by Ministero Affari Esteri (Italy-China significant bilateral project).
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-07-08.