bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-12-02: Use of cytochrome P450 interacting medications in the setting of adjuvant therapy for breast cancer.
Authors: Njiaju UO , Kolesar JM , Johnston SA , Eickhoff JC , Osterby KR , Poggi LE , Tevaarwerk AJ , Millholland RJ , Oliver KA , Heideman JL , Wisinski KB 
Published: August 2014

Abstract
Background: In the current era of personalized medicine, oral targeted therapies are increasingly used in cancer treatment. In breast cancer, oral anti-estrogen agents have historically been part of standard treatment for hormone receptor positive disease. More recently, other targeted agents have been introduced in the metastatic setting, and are being evaluated as adjuvant therapies. Many oral medications, including anticancer therapies, are metabolized by cytochrome P450 (CYP450) enzymes raising possibility of drug-drug interactions that may affect toxicities or breast cancer outcomes. We sought to evaluate concomitant CYP450 medication use among women seeing a medical oncologist to discuss adjuvant systemic therapy for breast cancer.
Methods: We performed an electronic medical record database extraction. Adult women diagnosed with breast cancer from 1/2008-7/2011 were identified from the University of Wisconsin Hospital and Clinics Cancer Registry. Medication lists were extracted from the first encounter with a medical oncologist after the initial breast cancer diagnosis. Non-systemic medications were excluded. Cytochrome P450 (CYP450) enzyme-interacting medications were categorized as inhibitors, inducers, and/or substrates of specific enzymes including CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. CYP450 inhibitors and inducers were further characterized as strong, moderate or weak acting.
Results: A total of 455 women with non-metastatic breast cancer were identified. Mean age was 56.6 years (range of 23–90) and 413 (91%) were Caucasian. Polypharmacy, defined as use of 3–5 medications, was seen in 123 (27.0%) women. A total of 236 (51.9%) women were on 0–4; 109 (24.0%) on 5–10; and 13 (2.9%) on &gt; 10 medications at the time of first encounter with a medical oncologist after a breast cancer diagnosis. 23 (5.05%) women were on strong CYP450 enzyme inhibitors while 72 (15.8%) were on strong inducers. CYP450 enzymes most commonly affected were CYP3A4, CYP2C9, and CYP2D6. Among medications taken on a fixed schedule, levothyroxine and simvastatin were the most commonly used, while simvastatin and ranitidine were the most common CYP450 interacting medications. Further classification of potential CYP450 interactions is ongoing.
Conclusions: A significant proportion of patients were on one or more CYP450 interacting medications in the setting of adjuvant therapy for breast cancer. Given the number of new oral cancer agents that are also CYP450 interacting, the potential for drug interactions should be recognized and appropriate management strategies implemented.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-12-02.
Abstract P6-13-01: Lyso-thermosensitive liposomal doxorubicin + local hyperthermia for radiation-pretreated chest wall recurrence
Authors: Formenti S , Rugo H , Myerson R , Diederich C , Straube W , O'Conner B , Matzkowitz AJ , Goodman RL , Muggia F 
Published: August 2014

Abstract
Background: Chest wall recurrence (CWR) causes much morbidity when not controlled by local measures. Lyso-thermosensitive liposomal doxorubicin (LTLD) provides accelerated release of doxorubicin (Dox) at ≥ 39° C, and is being studied for CWR based on the pioneering thermochemotherapy work of Dewhirst and colleagues at Duke. We now report on its tolerance, pharmacology, and preliminary antitumor effects in a dose-escalation study combined with local hyperthermia (LH) for radiation-refractory CWR. LH selectively increases liposomal permeability in tumor microvasculature, and promotes release of Dox from LTLD, and Dox tumor uptake, in addition to LH anti-tumor effects.
Methods: This phase I study entered patients (pts) with CWRs &lt; 3 cm deep failing all standard Tx including surgery, radiation, and chemotherapy: pts received up to 6 LTLD/LH treatments every 21 days at a starting dose of 40 mg/m2 (cohort 1) and escalated to 50 mg/m2 (cohort 2). LTLD was infused IV over 30 minutes (min); followed within 30 min by microwave or ultrasound LH. The thermal dose goal was 40°C-42°C for 60 min. Pharmacokinetic samples for total plasma Dox and doxorubicinol (Doxol) were taken at 0.5, 5, 10 and 24 hours after starting infusion. Left ventricular ejection fraction was monitored every other cycle.
Results: Eleven pts with a median of 4 prior chemotherapy regimens (range 2 — 12) were enrolled; all but one had prior anthracycline (AC). All pts received ≥ 2 cycles. The within subject variability in Dox and Doxol exposure was small with mean Cycle 2 vs Cycle 1 ratios ranging from 0.99 to 1.06.
Cmax/dose (ng/ml)/(mg/m2) Cycle 1 Cycle 2
Dox 499.82 512.00
Doxol 0.46 0.45
AUClast/dose ((ng*hr/ml)/(mg/m2)
Dox 1338.12 1381.82
Doxol 7.96 8.04
Grade 3 and 4 toxicities included reversible neutropenia in 17 (40.5%) and one case (each) of mucositis (grade 1), chest wall thermal burn, and chest wall cellulitis (both grade 4); these occurred in only ≥ 5% of 42 cycles given. No cardiomyopathy or hand-foot toxicity occurred. The rate of clinically-significant (≥ 6 point) QoL improvement on the FACT-B after 2 cycles was 54.5% (95% CI: 25.1%–83.9%), including 1 lasting &gt; 3 months. The local objective response rate was encouraging: 45.5% (95% CI: 16.1%–74.9%), with 1 complete and 4 partial local responses.
Conclusion: LTLD + LH is safe in CWR after prior radiation and doxorubicin. A phase II study is planned for pharmacologic evaluations and to add pts with less or no anthracycline treatment.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-13-01.
Abstract P6-14-03: Statin and aspirin use is not associated with a reduced risk of VTE's in breast cancer patients
Authors: Shai A , Rennert HS , Ballan Haj M , Lavie O , Steiner M , Rennert G 
Published: August 2014

Abstract
Introduction: Statins and aspirin have been shown to reduce the risk of venous thromboembolic events (VTE's) in the general population in randomized trials.
Aim: To assess whether statins and aspirin reduce the incidence of deep vein thrombosis and pulmonary embolism in patients diagnosed with breast cancer.
Methods: The Breast Cancer in Northern Israel Study (BCINIS) is an on-going population-based case-control study of consecutive breast cancer cases and matched controls diagnosed in the northern part of Israel since 2000.
Only cases insured by the Clalit Health Services (64%) were included in this analysis. Data on medication use and VTE were extracted from the computerized database. Patients taking Warfarin or LMWH were excluded.
Statistical analysis was performed using SPSS (v 18). Use of medications was analyzed as a time dependent covariate in a Cox Regression model.
Results: Of 3552 patients 261 (7.3%) had a VTE during a median follow up of 4.7 years.
In a multivariate analysis age (HR 1.03, 95% CI 1.02–1.04), BMI (HR 2.12, 95% CI 1.43–3.14 for BMI &gt;30), chemotherapy (HR 3.87, 95% CI 2.50–5.98) and metastatic disease (HR 2.27, 95% CI 1.10–6.53) were associated with an increased risk for VTE's.
Statins, mainly simvastatin and pravastatin, were used by 55.7% of the patients, and 45.7% used aspirin. Neither statins nor aspirin were associated with a significantly reduced risk for a VTE. After controlling for age, BMI, stage, chemotherapy and tamoxifen use the HR for statins was 0.80, CI 0.56–1.13, p = 0.2, and the HR for aspirin was 1.004, CI 0.74–1.76, p = 0.98.
Conclusion: In contrast to the findings in the general population, statin and aspirin use were not associated with a reduced risk for VTE's in our cohort of breast cancer patients. Our results might be explained by an alternate mechanism of VTE formation in breast cancer and the use of low potency statins (simvastatin and pravastatin) in this cohort.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-14-03.
Abstract P6-14-04: Rosehip extracts prevent triple negative breast cancer cell proliferation by regulation the phosphorylation of p70S6 Kinase.
Authors: Coburn TL , Cagle PD , Shofoluwe AI , Martin PM 
Published: August 2014

Abstract
Triple Negative Breast Cancer (TNBC) is an aggressive form of breast cancer, characterized by its lack of the human epidermal growth factor receptor-2 (HER-2), the estrogen receptor (ER), and the progesterone receptor (PR). Due to the lack of these hormone receptors, TNBC has abnormal therapeutic results; leading to the need for unique treatment methods. TNBC has a partial response to chemotherapy, which is associated with the lack of clinically established targeted therapies. Plant extracts have shown to be useful as chemopreventive agents due to their disruption of pro-survival and proliferative mechanisms on cancer cells. Rosehip extracts have shown potential anti-proliferative activity against cancer cells in vitro. This study investigated the effect of rosehip extracts in TNBC cell lines (HCC1806 and MB157) and basal-like breast cancer cell lines (HCC70 and HCC1500). To determine the inhibitory role of rosehip extracts in cell proliferation, MTT assays were conducted, following treatment with varying concentrations of rosehip extracts (1mg/ml, 250ug/ml, 25ug/ml, and 25ng/ml) for 48 hours. The data suggests that rosehip extracts, can significantly decrease cell proliferation in all the breast cancer cell lines assayed. Preliminary studies suggest that this is accomplished without toxic effects. Western blot analysis was used to investigate which signaling pathway rosehip extracts were affecting. Western Blot analysis suggests that rosehip extracts are inhibiting p70 S6 kinase phosphorylation and its ability to act as a kinase for S6 ribosomal protein. Based on these findings, rosehip extracts prevent cell proliferation by interfering with the p70 S6 kinase signaling.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-14-04.
Abstract PD01-02: Increased expression of phosporylated mTOR in metastatic breast tumors compared to primary tumors in patients who received adjuvant endocrine therapy
Authors: Hoefnagel LDC , Beelen KJ , Opdam M , Vincent A , Linn SC , van Diest PJ 
Published: August 2014

Abstract
BACKGROUND: Activation of the PI3K pathway as an adaptive change in response to estrogen depletion results in acquired endocrine therapy resistance in vitro. Metastatic breast cancer patients with previous exposure to endocrine therapy do derive substantial benefit from the addition of an mTOR inhibitor to endocrine therapy compared to endocrine therapy alone. This suggests that compensatory PI3K pathway activation might play a role in the development of clinical resistance to endocrine therapy. We evaluated the activation of the downstream PI3K pathway protein mTOR in primary breast tumors and matched metastatic lesions.
METHODS: From a previously described series of breast cancer patients from whom both primary tumor tissue as well as metastatic tumor tissue was collected, we selected estrogen receptor α (ERα) positive patients who had received endocrine therapy (N = 34) and who did not receive endocrine therapy (N = 37). The difference in expression of phosphorylated mTOR (p-mTOR) between primary and metastatic tumor was assessed by immunohistochemistry, which was scored by using the proportion of tumor cells with sub-membranous p-mTOR expression. We assessed whether this p-mTOR difference between primary and metastatic tumor was associated with clinico-pathological factors (location of metastasis, lymph node status, T-stage, grade, progesterone receptor status) or varied between patients who did and did not receive endocrine therapy, using Mann-Whitney tests. In addition we performed a linear regression model including the same clinico-pathological factors.
RESULTS: In patients who had received endocrine therapy we observed an increase in p-mTOR expression in metastatic tumor lesions compared to the primary tumor (median difference 45%). This was significantly different from the mTOR changes observed in patients who did not receive endocrine therapy (median difference between metastatic and primary lesion 0 %) (p = 0.003). The difference remained significant in the multivariate regression model (p = 0.001). None of the other factors was significantly associated with a differential p-mTOR change.
CONCLUSION: In patients who received previous adjuvant endocrine therapy, the increase in p-mTOR expression in metastatic tumor lesions compared to the primary tumor is significantly higher than in patients who did not receive endocrine therapy. Compensatory activation of the PI3K pathway might therefore be a clinically relevant resistance mechanism resulting in secondary endocrine therapy resistance.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD01-02.
Abstract PD02-05: Comparison of fluorescence in situ hybridization (FISH) and dual-ISH (D-ISH) in the determination of HER2 status
Authors: Mansfield AS , Sakai Y , Walsh FJ , Wiktor AE , Sukov WR , Dogan A , Jenkins RB 
Published: August 2014

Abstract
Introduction: The appropriate assessment of HER2 amplification status is critical to determining which patients should receive HER2-directed therapy. An alternative to FISH is D-ISH (Ventana Medical Systems Tucson, Arizona) which utilizes chromogenic HER2 and chromosome 17 probes. Both FISH and D-ISH utilize formalin-fixed, paraffin-embedded (FFPE) human breast cancer tissue specimens. D-ISH has two principle advantages over FISH: it can be visualized using light microscopy and after analysis the specimens can be archived.
Methods: We tested 250 samples with FISH and with D-ISH. Fifty specimens were controls: 25 cases with no HER2 or CEP17anomaly and 25 cases with HER2 amplification. There were also 200 test subjects of 50 cases each of chromosome 17 aneusomy, HER2 deletion (HER2/CEP17 ratio &lt;0.8), HER2 duplication (HER2/CEP17 ratio 1.3–1.8), and equivocal results (HER2/CEP17 ratios between 1.8 and 2.2). FISH (Abbott Molecular) and D-ISH analysis were performed using methods described in the appropriate clinical kit package inserts, with the following exception: Four cases with CEP17 and HER2 co-amplification were also included and for FISH analysis these cases were reflexed to the use of chromosome 17 control probe (D17S122).
Results: Four samples failed testing by D-ISH. There was a 63% (155/246) concordance between FISH and D-ISH by anomaly (aneusomy, duplication, deletion, etc.) and an 83% concordance by amplification status (non-amplified, equivocal, and amplified). D-ISH detected 18 (62%) of F-ISH-amplified cases. D-ISH resulted in lower estimates of HER2/CEP17 ratios than FISH, and many cases that were equivocal by FISH were normal by D-ISH. D-ISH did not detect HER2 amplification in any of the four HER2 and CEP17 co-amplified cases.
Conclusions: We observed a lower concordance rate between FISH and D-ISH than the ∼95% rate in the D-ISH package insert. This lower concordance rate is likely a result of how this study was designed: it was biased toward common chromosome 17 anomalies and difficult specimens. Such specimens comprise about 60% of our current clinical HER2 biomarker practice. D-ISH may underestimate the HER2/CEP17 ratio, or FISH may overestimate this ratio. D-ISH also does not reliably detect HER2 amplification when the centromere of chromosome 17 is also co-amplifed. Compared to FISH, in this study cohort D-ISH had a significant false negative rate for the detection of HER2 amplification.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD02-05.
Abstract PD03-02: Evidence for the anti-cancer action of metformin mediated via tumor AMPK, Akt and Ki67, in a preoperative window of opportunity trial
Authors: Hadad SM , Dowling RJO , Chang MC , Done SJ , Purdie CA , Jordan LB , Dewar J , Goodwin PJ , Stambolic V , Thompson AM 
Published: August 2014

Abstract
Background: Metformin reduces the overall risk of cancer incidence by 31%, improves cancer-related mortality and enhances response to neoadjuvant chemotherapy in type 2-diabetics receiving metformin. There is evidence that metformin works through activation of Adenosine Monophosphate Protein Kinase (AMPK), an energy-sensing kinase that maintains cellular energy homeostasis. In a pre-operative window-of-opportunity randomized trial we have demonstrated that metformin significantly reduces proliferation and blunts the insulin response in primary operable breast cancer. This study further analysed cancer tissue from the trial to dissect the molecular mechanisms involved.
Methodology: Non-diabetic women with operable invasive breast cancer were randomised to receive pre-operative metformin or no drug. Forty seven patients had core biopsy at diagnosis then were randomized to metformin (metformin 500mg o.d. for 1 week increased to 1g b.d for a further week continued to surgery) or no drug, and 2 weeks later had core biopsy at surgery. Insulin receptor, phospho-AMPK (pAMPK), phospho-Akt (pAkt) and Ki67 immunohistochemistry was performed on formalin-fixed paraffin-embedded cores and scored blinded to treatment. Paired t-test was used for analysis.
Results: Significant up-regulation of pAMPK (p = 0.04) and down-regulation of pAkt (p = 0.04) in metformin treated patients was demonstrated compared to the control group. No change in insulin receptor expression was identified but, as previously reported, there was a fall in ki67. Changes were independent of Body Mass Index. Seven patients (7/24) receiving metformin withdrew because of gastro-intestinal upset and were excluded from the immunohistochemical analyses.
Conclusion: These findings suggest that metformin works in vivo in breast cancer patients via up-regulation of tumor pAMPK and down-regulation of pAkt and proliferation. Since down-regulation of pAMPK is a feature of breast cancer, this suggests mechanistic evidence for the therapeutic effect of metformin.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-02.
Abstract PD05-01: Next generation genomic sequencing (NGS) identifies molecular targets in inflammatory breast cancer (IBC)
Authors: Cristofanilli M , Alpaugh KR , Ross J , Binghman C , Wu H , Stephens P , Lipson D , Palmer G 
Published: August 2014

Abstract
BACKGROUND: Inflammatory breast cancer (IBC) is the most aggressive form of invasive breast cancer and is associated with poor outcome in spite of optimal multidisciplinary management. The disease is associated poor response to neoadjuvant chemotherapy and a peculiar pattern of recurrence (chest wall, nodes, CNS). There currently few distinct molecular alterations for effective therapeutic targeting in the advance setting. The availability of comprehensive cancer genomic testing using Next-Generation Sequencing (NGS) technology may identify a number of genomic alterations not assessed by traditional methods and provide opportunities for more effective treatment selection particularly in aggressive and uncommon diseases such as IBC.
METHODS: Twenty-three patients with refractory metastatic IBC were included in this analysis. All patients underwent confirmatory biopsy and/or tissue collection. Tissue from metastastic lesions of patients with recurrent IBC was submitted as slides or FFPE blocks. NGS was performed by Foundation Medicine, Cambridge, MA. The entire coding sequence of 182 cancer-related genes (3,230 exons) plus 37 introns from 14 genes often rearranged in cancer were sequenced to high depth (&gt;500X) All classes of genomic alterations were detected.
RESULTS: The site distribution and frequency of disease recurrence included: soft tissue (19) lung (4), bone and liver (3), and brain (2). The disease subtype classification based on the expression of ER, PR and HER-2 were as follow: ER−, PR−, Her-2−, Basal-like or TN (65%); ER+ and/or PR+, HER-2− (grade3) or HER-2+, Luminal B (22%); ER−, PR−, HER2+ (13%). Genomic alterations were identified in all patients with various frequencies. Genetic mutations included: P53 (DNA-binding domain, splice site), PI3KCA (H1047R, R441N, E545K, K111E,); RB1; PTEN (D107Y); EGFR (L858R); ERBB2 (V777L, S310F) in a patient with TN disease; ESR1 D538G. Gene amplifications included: MYC (26%); CCND1 (22%); ERBB2 (in a patient with TN disease), MLC-1, CCNE1, CK4, K-RAS. One patient had evidence of discordant genomic abnormalities in two simultaneous sites of recurrence (skin and pleura) suggesting disease heterogeneity. Three patients were effectively treated with genomic alterations-guided therapies.
CONCLUSIONS: Genomic sequencing of advanced IBC is feasible, identifies potential therapeutic targets and can advance our understanding of the molecular alterations of this aggressive disease.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD05-01.
Abstract PD05-03: What is the appropriate sample (s) on which to perform sequencing for mutational analysis to guide the selection of targeted therapy?
Authors: Alpaugh RK , Bingham C , Fittipaldi P , Banzi M , Palmer G , Cristofanilli M 
Published: August 2014

Abstract
BACKGROUND: Success of targeted therapy requires expression of the protein. Tumor tissue source can include diagnostic biopsy, surgical samples from initial or follow-up surgeries, fluids e.g. pleural or ascites and circulating tumor cells (CTC). The goal of using CTCs was 1. To determine whether CTC can be used as a “liquid” tumor biopsy and enable gene sequence information at the single cell level and 2. To determine the heterogeneity represented in the circulation compared to that seen in solid tumor by examining single cells (or a small cluster of cells) for the presence of a specific mutation which was detected in tissue tumor source.
METHODS: We performed sequencing for mutational analysis on tissue(s) from patients with inflammatory breast cancer (IBC). Tumor sources varied from mastectomy tissue, metastatic site(s) e.g. liver or skin from chest wall disease, pleural fluid and CTC isolated into pure single cell populations (or groups of cells) using Silicon Biosystems DEPArray. Ampli1™ WGA kit was used for CTC amplification. Of the 22 patients sequenced, mastectomy primary tumor was examined in 3, metastatic site skin chest wall disease in 15, other metastatic site in 4, pleural fluid in 2 and CTC collected to investigate p53 mutations in 8.
RESULTS: To date 22 patients have had mutational data performed, 14/22 had mutations in p53, 4/22 in RB1, 2/22 in each PI3K and ERBB2, 1/22 in each of BRAC1, BRAC2, ATM, KRAS, Notch 1, MEN1 and ESR1. Numerous amplifications were noted including AKT1, RPTOR, MLC1, MYC, CCND1 and ERBB2. For one patient's chest wall biopsy compared to two single CTCs and a cluster of 10 CTCs the same TP53C229fs*10 mutation was detected revealing the same 2bp deletion. No 2bp deletion was found in single white blood cells. Whereas, another patient which showed a TP53 S215G mutation in her skin biopsy of chest wall disease, only amplifications of AURKA, CCND1, IGF1R, MDM2 and SRC in pleural tumor cells were detected and no mutations in three single CTC, two single pleural tumor cells and in single white blood cells were seen. Primary tumor tissue is being sort for both of these patients. Mutational data reviewed to date suggest that IBC is not one disease but a multiplicity of diseases, revealing a variety of target(s). Aberrations are not consistent across tissue source.
CONCLUSIONS: Successful treatment outcomes using standard of care chemotherapy combined with target therapies will require not one, but a panel, of tissue sources for sequencing to guide the selection of appropriate targeted therapies.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD05-03.