bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PD3-03: Inhibition of the autocrine IL6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-/HER2+ breast cancers
Authors: Silva J , Rodriguez-Barrueco R , Yu J , Kalinsky K , Maurer M , Califano A 
Published: May 2016

Abstract
Although HER2+ tumors are commonly considered as a single entity there is increasing evidence indicating that important intrinsic differences associated to hormone receptor status (HR) exist. Indeed, while HR+/HER2+ patients benefit from anti-hormonal and HER2 targeted therapies, the outcome of HR-/HER2+ patients strongly depends on their response to chemotherapy as well as anti-HER2 therapy. To identify genes that represent novel mechanistic dependencies in HR-/HER2+ breast cancer cells, we designed an integrative approach that combines functional genomic (RNAi screens) and computational algorithms to interrogate regulatory networks reverse engineered.
Our analysis identified STAT3 as a de novo master regulator (MR) gene associated to HER2 mediated transformation in HR- breast cancer cells. Importantly, we demonstrate that aberrant STAT3 activity is necessary to maintain HR-/HER2+ tumor state, thus representing a non-oncogene dependency. Mechanistically we found that HR-/HER2+ breast tumors secrete high levels of IL-6. This acts in an autocrine way to induce the activation of STAT3 via the canonical JAK2/STAT3 pathway. Aberrant STAT3 activity induces upregulation and secretion of the S100A8/9 complex (Calprotectin) triggering a second autocrine stimulus that enhances proliferation and survival via ERK1/2 and AKT. As a result, disruption of the "IL6-JAK2-STAT3-S100A8/9 cascade" compromises HR-/HER2+ cell viability suggesting that the components of this pathway represent putative therapeutic targets in HR-/HER2 tumors.
Importantly, small molecule inhibitors and blocking antibodies for components of this double autocrine loop are already FDA approved or in clinical trials. Here, we demonstrate in vivo that blocking the IL-6 receptor (IL-6R) with the humanized monoclonal antibody Tocilizumab, STAT3 inactivation with the dual JAK1/2 inhibitor Ruxolitinib or Calprotectin inhibition with the small molecule inhibitor Tasquinimod), alone or in combination with anti HER2 therapies, compromises the viability of HR-/HER2+breast cancer cells. Availability of FDA-approved inhibitors to target this novel mechanism represents an exciting opportunity for rapid translation of these findings to the clinics.
Citation Format: Silva J, Rodriguez-Barrueco R, Yu J, Kalinsky K, Maurer M, Califano A. Inhibition of the autocrine IL6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-/HER2+ breast cancers. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD3-03.
Abstract PD7-02: Multiplex Identification of genetic etiologies among women with bilateral breast cancer using a 25-gene hereditary cancer panel
Authors: Weitzel JN , Blazer KR , Nehoray B , Kidd J , Slavin TP , Solomon I , Niell-Swiller M , Rybak C , Saam J , Lancaster J 
Published: May 2016

Abstract
Background: Multiple primary cancers within an individual is one of the hallmarks of hereditary cancer predisposition. Technical advances in sequencing and identification of additional cancer susceptibility genes have led to multi-gene panel approaches to determine if patient cancers have a heritable cause. Simultaneous testing of multiple breast cancer associated genes to determine the prevalence, spectrum and combinations of mutations has not yet been evaluated in a large set of patients with two breast cancers.
Methods: Patients with two breast cancer diagnoses were identified from 80,748 consecutive cases that underwent a 25-gene hereditary cancer panel test at a commercial diagnostic laboratory. Patient clinical data were obtained by healthcare provider report on test requisition forms.
Results: Of 3,182 patients with two breast cancers, 13.3 % (n=424) had a pathogenic variant (PV) in at least one of 19 genes on the panel. PVs were most prevalent within BRCA1, representing 26.3% of the PVs, followed by BRCA2 (21.9%), CHEK2 (13.5%), PALB2 (11%) and ATM (11%). Fourteen patients had PVs in two different genes, including five with CHEK2/PALB2 in combination, which was the only combination observed more than once. PVs were more common among the 33.8% of patients with synchronous breast cancers compared to those with metachronous diagnoses (10.8% vs. 15%) and in the 58.4% who were first diagnosed younger than 50 years old (15.7% vs. 10%).
Conclusion: Multiplex testing in women with two primary breast cancers identifies a relatively high percentage with a PV, including those whose first diagnosis was older than 50. While still the most prevalent and clear cause, fewer than half of the PVs identified were in BRCA1 or BRCA2. The observation of 5 cases with double CHEK2/PALB2 PVs is statistically unexpected given their individual prevalence in other studies of high risk women with breast cancer, suggesting a possible synergistic or additive effect. This study adds to our understanding of susceptibility to multiple primary breast cancers, and reaffirms the importance of this circumstance as a prompt for genetic testing. Nonetheless, as 66% of cases had metachronous tumors, it would be preferable to identify those at risk with heritable cancer syndromes at their first diagnosis and enable subsequent prevention or early detection.
Citation Format: Weitzel JN, Blazer KR, Nehoray B, Kidd J, Slavin Jr TP, Solomon I, Niell-Swiller M, Rybak C, Saam J, Lancaster J. Multiplex Identification of genetic etiologies among women with bilateral breast cancer using a 25-gene hereditary cancer panel. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD7-02.
Abstract PL2: Clonal Dynamics and Breast Cancer Subtypes
Authors: Aparicio S 
Published: May 2016

Abstract
Breast cancers exhibit inter-patient and intra-tumoural genomic variability which underpins our understanding of intrinsic drivers of the disease. The advent of next generation sequencing methods and informatics approaches has redefined the landscape of primary breast cancer subtypes into many more molecularly defined patient subgroups than had been previously appreciated, thus redefining our understanding of inter-patient variation. These studies have implications for the understanding of driver mutation context in primary cancers and should pattern future clinical and molecular studies of primary breast cancers. Closely linked to inter-patient genomic variability is the notion that most cancers are ecosystems of evolving cellular clones has implications for biological understanding and clinical application. The evolution of clonal composition has particular significance when evidence of positive or negative selection can be associated with the clonal genotype or epigenotype. Over the last 5 years next generation sequencing of tumours and methods for single cell analysis have opened up this approach for solid epithelial malignancies. I will discuss the implications of clonal evolution for cancer medicine and biological studies of cancer with reference to breast cancers. We have developed informatics approaches to population level clonal analysis and extended these to single cell measurements of genotypes. I shall discuss our more recent data from single cell sequencing and clonal analysis applied to clonal evolution of patient derived tumour xenografts, to illustrate the impact of clonal evolution on biological studies of breast cancer in model systems.
Citation Format: Aparicio S. Clonal Dynamics and Breast Cancer Subtypes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PL2.
Abstract S6-03: Anastrozole versus tamoxifen for the prevention of loco-regional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in-situ (IBIS-II DCIS)
Authors: Cuzick J , Forbes JF , Sestak I , Howell A , Bonanni B , Bundred N , Levy C , von Minckwitz G , Eiermann W , Neven P , Stierer M , Holcombe C , Coleman RE , Jones LJ , Ellis I 
Published: May 2016

Abstract
Background: Third generation aromatase inhibitors are a more effective treatment option than tamoxifen for hormone receptor positive invasive breast cancer in postmenopausal women. However, it is not known whether anastrozole is more effective than tamoxifen in preventing the recurrence of breast cancer in women with hormone receptor (HR) positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole versus tamoxifen in postmenopausal women with HR positive DCIS.
Methods: A multi-centre randomised placebo-controlled trial of 1mg/day anastrozole (oral) vs. 20mg/day tamoxifen (oral) for five years was conducted in 2980 postmenopausal women with locally excised HR positive DCIS. The primary endpoint was to determine if anastrozole is at least as effective as tamoxifen in loco-regional control and prevention of contralateral disease. Secondary endpoints included breast cancer mortality, other cancers, cardiovascular disease, fractures, adverse events and non-breast cancer deaths. All analyses were done on an intention-to-treat basis and Cox proportional hazard were used to compute hazard ratios and corresponding confidence intervals for recurrence.
Results: Between 2003 and 2012, a total of 2980 postmenopausal women were recruited into the IBIS-II DCIS trial. 1471 women were randomly assigned to receive anastrozole and 1509 women tamoxifen. Median follow-up for this first analysis is 6.8 years and 131 breast cancer recurrences have been recorded. Median age was 60.3 years (56.1-64.6), median BMI was 26.7 (23.6-30.7), and 45.6% of women had used hormone replacement therapy (HRT) before joining the trial. Of the 131 women with recurrent disease, 77 had a loco-regional recurrence and 51 reported contralateral disease. A total of 61 deaths were recorded. We will present a comprehensive analysis of the efficacy of anastrozole and tamoxifen for preventing loco-regional/contralateral breast cancer and major adverse events by intention to treat (ITT).
Conclusions: To follow.
Citation Format: Cuzick J, Forbes JF, Sestak I, Howell A, Bonanni B, Bundred N, Levy C, von Minckwitz G, Eiermann W, Neven P, Stierer M, Holcombe C, Coleman RE, Jones LJ, Ellis I. Anastrozole versus tamoxifen for the prevention of loco-regional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in-situ (IBIS-II DCIS). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S6-03.
Abstract B26: Leptin affects proliferation, stem cells and chemotherapeutic treatment outcome of pancreatic cancer: A link to health disparity
Authors: Harbuzariu Adriana , Daley-Brown Danielle S. , Harmon Tia L. , Garrison Robin C. , Beech Derrick J. , Cason Frederick D. , Klug Christopher , Gonzalez-Perez Ruben R. 
Published: May 2016

Abstract
Background: Pancreatic cancer (PC) is an aggressive disease that is in most cases advanced at the time of diagnosis. The overall 5-year survival rate for PC patients is less than 5 %. African-Americans show the highest incidence of obesity and PC as well as mortality rate. How obesity is associated to PC incidence and health disparity is still an unanswered question. High levels of leptin shown by obese African American patients could impact negatively on PC. We hypothesize that leptin signaling induces PC proliferation, stem cells (PCSC) and drug resistance.
Methods: Human PC cell lines derived from primary pancreatic adenocarcinoma (Panc-1 and MiaPaCa-2-highly aggressive, BxPC-3-less aggressive) and from metastatic tumor (AsPC-1) were challenged with leptin and chemotherapeutic agents. Cell proliferation, apoptosis rate, and the expression levels of molecular markers were analyzed. PCSC markers were determined in cell lines and tumor biopsies. Effects of leptin and chemotherapeutics on PC-tumorsphere formation were also determined.
Results: Leptin stimulated proliferation of PC cells, induced the expression of PCSC markers and increased tumorsphere formation. Moreover, leptin impaired the efficacy of chemotherapeutics on PC cells.
Conclusions: Present data suggest leptin is a proliferative and survival factor for PC that reduces chemotherapeutic effectiveness. These observations are of paramount importance for obese African American PC patients, who show the highest levels of leptin, poor prognosis and outcome of chemotherapeutic treatment.
Acknowledgements: this work was supported by the DOD W81XWH-13-1-0382; NIH/SBIR 1R41CA183399-01A1; Pilot Project Award from MSM/Tuskegee University/UAB Cancer Center Partnership grant 5U54CA118638; PC SPORE Grant from UAB to RRGP, and facilities and support services at Morehouse School of Medicine (1G12RR026250-03; NIH RR03034 and 1C06 RR18386).
Citation Format: Adriana Harbuzariu, Danielle S. Daley-Brown, Tia L. Harmon, Robin C. Garrison, Derrick J. Beech, Frederick D. Cason, Christopher Klug, Ruben R. Gonzalez-Perez. Leptin affects proliferation, stem cells and chemotherapeutic treatment outcome of pancreatic cancer: A link to health disparity. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B26.
Abstract B82: Predictors of intention to obtain colorectal cancer screening among African American men in a state fair setting
Authors: Rogers Charles R. , Goodson Patricia , Dietz Lindsey R. , Okuyemi Kola S. 
Published: May 2016

Abstract
Racial disparities in health among African American men in the United States are appalling: African American men have the highest mortality and incidence rates from colorectal cancer (CRC) compared to all other ethnic, racial, and gender groups. Juxtaposed to their white counterparts, African American men have CRC incidence and mortality rates 25% and 50% higher, respectively. CRC is a treatable and preventable condition when detected early, yet the intricate factors influencing African American men's intention to screen remain understudied. Employing a non-experimental, on-line survey research design at the Minnesota State Fair, the purpose of this study was to explore whether male role norms affect knowledge, attitudes, and intention to screen for CRC directly, or mediated by perceived barriers, among 297 African American men. As hypothesized, these Minnesota men (ages 18-65) lacked appropriate CRC knowledge: only 33% of the sample received a “passing” knowledge score (85% or better). In a logistic regression model, the three factors significantly associated with a higher probability of obtaining CRC screening were age, perceived barriers, and perceived subjective norms. Findings from this study provide a solid basis for informing health policy and designing health promotion and early-intervention CRC prevention programs that are responsive to the needs of African American men in Minnesota and beyond.
Citation Format: Charles R. Rogers, Patricia Goodson, Lindsey R. Dietz, Kola S. Okuyemi. Predictors of intention to obtain colorectal cancer screening among African American men in a state fair setting. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B82.
Abstract C60: Injectable, biodegradable micro- and nano-particles loaded with prodigiosin-based drug for localized anticancer drug delivery
Authors: Obayemi John D. , Malatesta Karen A. , Odusanya Olushola S. , Yiporo Danyuo , Yu Wei , Uhrich Kathryn E. , Soboyejo Winston O. 
Published: May 2016

Abstract
This paper presents the synthesis and physicochemical characterization of injectable, multi-functional, biodegradable poly (D,L-lactide-co-glycolide) (PLGA)-loaded micro- and nano-particles. These particles were loaded with an anticancer drug from prodigiosin (PG), which was obtained from bacteria, Serratia marcescens subsp. Marcescens. The release of paclitaxel (PT) was also tested as a control. The PG and PT were encapsulated using a single-emulsion solvent evaporation technique with PLGA as a polymer matrix and poly-(vinyl alcohol) (PVA) as an emulsifier. The dependence of particle size and morphology on processing conditions was also evaluated. In vitro release studies were used to elucidate drug loading efficiency, encapsulation efficiency and microparticle morphology using a combination of UV-visible (UV-Vis) spectrophotometry, optical Microscopy, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and atomic force microscopy (AFM). The implications of the results are then explored using MDA-MB-231 cells (breast cancer cells) for the development of injectable, multi-functional, polymeric micro- and nano-particles for the controlled release of cancer drugs and the localized treatment of cancer.
Citation Format: John D. Obayemi, Karen A. Malatesta, Olushola S. Odusanya, Danyuo Yiporo, Wei Yu, Kathryn E. Uhrich, Winston O. Soboyejo. Injectable, biodegradable micro- and nano-particles loaded with prodigiosin-based drug for localized anticancer drug delivery. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C60.
Abstract A14: Hedgehog inhibition delays cancer growth in C3(1)/Tag transgenic murine mammary carcinoma model
Authors: Makarova Anastasia M. , KC Subheksha , Dolorito John A. , Khaimskiy Yefim I. , Epstein Ervin H. 
Published: May 2016

Abstract
In 1941 Apperly hypothesized that differential sunlight exposure is the cause of the latitudinal gradient in breast cancer mortality, and subsequently the effect was postulated to be due to the tumor inhibitory properties of skin produced vitamin D3. We first tested this latitudinal hypotheses using the C3(1)/Tag transgenic murine mammary carcinoma model and found that ultraviolet radiation (UVR) significantly prolongs tumor-free and overall survival but that dietary D3 has no such effect. The mechanism of this anti-mammary carcinogenesis effect of UVR is unclear but there is evidence that D3 is a potent inhibitor of the hedgehog (HH) - signaling pathway. To test this mechanistic hypothesis we compared the effects of the small molecule Smo-acting HH pathway inhibitor (HHI) BMS-833923/XL139 with those of UVR on breast cancer development in C3(1)/Tag mice. We have found that oral administration of the pharmacologic HHI delays Tag mammary carcinogenesis with an efficacy similar to that of UVR treatment (350 mJ/cm2, 3x/week), thus, time to first palpable tumor was delayed by 9 days by UVR treatment (p=0.016) and by 14 days by HHI treatment (p=0.009), compared control mice. Overall survival was delayed by 9 days by UVR treatment (p=0.19) and by 15 days by HHI treatment (p=0.011). And, we have found that HHI, like UVR, acts at an early stage of carcinogenesis (i.e. reduction of histologic changes at age 12 weeks), and initial studies of UVR + HHI treatments suggest that HHI and UVR have overlapping effects. Taken together our results are consistent with (albeit by no means proof of) our hypothesis that inhibition of mammary carcinogenesis by UVR-produced vitamin D3 underlies the latitudinal gradient and is mediated via HH inhibition. Moreover, our results suggest more broadly that HHI treatment before tumors develop may have more of an anti-cancer effect than does HHI treatment after tumors already have become clinically apparent.
Note: This abstract was not presented at the conference.
Citation Format: Anastasia M. Makarova, Subheksha KC, John A. Dolorito, Yefim I. Khaimskiy, Ervin H. Epstein, Jr. Hedgehog inhibition delays cancer growth in C3(1)/Tag transgenic murine mammary carcinoma model. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A14.
Abstract A32: MCL1 gene amplification in breast cancer is associated with TNBC status and can respond to a sorafenib/vorinostat regimen
Authors: Ross JS , Wang K , Johnson A , Watson J , Hatzis C , Pusztai L , Chmielecki J , Yelensky R , Lipson D , Elvin JA , Vergilio J , Suh J , Miller VA , Dicke K , Stephens PJ , Ali SM 
Published: May 2016

Abstract
Background: MCL1 encodes the induced myeloid leukemia cell differentiation protein Mcl-1, a member of the BCL-2 family which functions to inhibit apoptosis. Mcl-1 over-expression has been associated with high tumor grade and adverse prognosis in triple negative breast cancer (TNBC) but therapies specifically leading to inhibition of MCL-1 have not been identified.
Methods: Comprehensive genomic profiling (CGP) using hybridization capture of 3,769 exons from 315 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to ≥50ng of DNA extracted from 2,824 consecutive BC and sequenced to high, uniform median coverage (&gt;600X). The original primary BC was assayed in 44% of cases and a sample from a metastatic focus was assayed in 56% of cases.
Results: Of 2824 consecutive BC cases, 200 (7.1%) cases harbored MCL1 amplification. Of these MCL1-amplified cases, 146 (73%) were TNBC and 54 were non-TNBC (p&lt;0.0001). Twelve of the latter cases (22%) were ERBB2 (HER2) amplified and slide-based HER2 status concordance with CGP was 99%. MCL1 amplification was also observed in the TCGA dataset for 32/123 (26%) of TNBC (p=0.008). Of the MCL1 amplified TNBC cases, 88% were high grade and 98% were stage IV at the time of CGP. Genes co-altered within MCL1 amplified TNBC included TP53 (86%), MYC (41%), MYST3 (21%), LYN (20%), CCNE1 (19%), PIK3CA (18%), and AKT3 (15%). Two MCL1 amplified TNBC patients were treated with a multi-drug regimen based on sorafenib and vorinostat and experienced significant clinical benefit.
Conclusions: MCL1 amplification is a frequent feature in advanced stage and high grade TNBC, and correspondingly such MCL1 amplified tumors very seldom harbor co-amplifications of ERBB2. Clinical observation suggests that treatment with sorafenib and vorinostat in heavily pre-treated MCL1 amplified patients may be correlated with clinical benefit, consistent with historic preclinical investigation. These preliminary findings suggest that MCL1 amplified TNBC may be able to benefit from combination targeted therapy, and warrant further systematic investigation.
Citation Format: JS Ross, K Wang, A Johnson, J Watson, C Hatzis, L Pusztai, J Chmielecki, R Yelensky, D Lipson, JA Elvin, J Vergilio, J Suh, VA Miller, K Dicke, PJ Stephens, SM Ali. MCL1 gene amplification in breast cancer is associated with TNBC status and can respond to a sorafenib/vorinostat regimen. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A32.