bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal Change in Mammographic Density among ER-Positive Breast Cancer Patients Using Tamoxifen
Authors: Nyante Sarah J. , Sherman Mark E. , Pfeiffer Ruth M. , de Gonzalez Amy Berrington , Brinton Louise A. , Bowles Erin J. Aiello , Hoover Robert N. , Glass Andrew , Gierach Gretchen L. 
Published: November 2015

Abstract
Tamoxifen-associated mammographic density (MD) reductions are linked to improved breast cancer survival. We evaluated MD at six time points to determine the timing of greatest reduction following tamoxifen initiation. We sampled 40 Kaiser Permanente Northwest estrogen receptor (ER)–positive breast cancer patients from a prior study of MD change, according to tamoxifen use duration and age at diagnosis: &lt;4 years tamoxifen and ≤50 years (N = 6) or &gt;50 years (N = 10) old; ≥4 years tamoxifen and ≤50 years (N = 13) or &gt;50 years (N = 11) old. A single reader evaluated percent MD in the contralateral breast on baseline (pre-diagnosis) and five approximately yearly post-diagnostic (T1 to T5) mammograms. Mean MD change was calculated. Interactions with age (≤50 and &gt;50 years), tamoxifen duration (&lt;4 and ≥4 years), and baseline MD (tertiles) were tested in linear regression models. Overall, the largest MD decline occurred by T1 (mean 4.5%) with little additional decline by T5. Declines differed by tertile of baseline MD (Pinteraction &lt; 0.01). In the highest tertile, the largest reduction occurred by T1 (mean 14.9%), with an additional reduction of 3.6% by T5. Changes were smaller in the middle and lowest baseline MD tertiles, with cumulative reductions of 3.0% and 0.4% from baseline to T5, respectively. There were no differences by age (Pinteraction = 0.36) or tamoxifen duration (Pinteraction = 0.42). Among ER-positive patients treated with tamoxifen and surviving ≥5 years, most of the MD reduction occurred within approximately 12 months of tamoxifen initiation, suggesting that MD measurement at a single time point following tamoxifen initiation can identify patients with substantial density declines. Cancer Epidemiol Biomarkers Prev; 25(1); 212–6. ©2015 AACR.
Partnership Status and Socioeconomic Factors in Relation to Health Behavior Changes after a Diagnosis of Ductal Carcinoma In Situ
Authors: Khadanga Sherrie , Lakoski Susan G. , Hart Vicki , Sprague Brian L. , Ba Yi , Hampton John M. , Higgins Stephen T. , Ades Philip A. , Newcomb Polly A. , Trentham-Dietz Amy 
Published: November 2015

Abstract
Background: Change in health behaviors can occur among women newly diagnosed with ductal carcinoma in situ (DCIS). We sought to understand whether partnership status and socioeconomic status (SES) affected behavioral changes in body weight, physical activity, alcohol consumption, and smoking.
Methods: The Wisconsin In Situ Cohort (WISC) study comprises 1,382 women diagnosed with DCIS with information on demographics, SES factors, and pre- and post-DCIS diagnosis health-related behaviors. Logistic regression models were used to determine the association between partnership status, education, and income with change in behavior variables.
Results: Higher educational attainment was associated with lower likelihood of stopping physical activity [OR, 0.45; 95% confidence interval (CI), 0.32–0.63; college vs. high school degree], or starting to drink alcohol (OR, 0.34; 95% CI, 0.15–0.80). Results suggested that higher family income was associated with lower likelihood of gaining &gt;5% body mass index (P = 0.07) or stopping physical activity (P = 0.09). Living with a partner was not strongly associated with behavior changes.
Conclusion: Higher educational attainment and higher income, but not living with a partner, were associated with positive health behaviors after a DCIS diagnosis.
Impact: The associations between higher educational attainment and, to a lesser extent, higher income with positive health behaviors underscore the importance of considering SES when identifying those at risk for negative behavioral change after DCIS diagnosis. Cancer Epidemiol Biomarkers Prev; 25(1); 76–82. ©2015 AACR.
Association of Parity and Time since Last Birth with Breast Cancer Prognosis by Intrinsic Subtype
Authors: Sun Xuezheng , Nichols Hazel B. , Tse Chiu-Kit , Bell Mary B. , Robinson Whitney R. , Sherman Mark E. , Olshan Andrew F. , Troester Melissa A. 
Published: November 2015

Abstract
Background: Parity and time since last birth influence breast cancer risk and vary by intrinsic tumor subtype, but the independent effects of these factors on prognosis have received limited attention.
Methods: Study participants were 1,140 invasive breast cancer patients from phases I and II of the population-based Carolina Breast Cancer Study, with tissue blocks available for subtyping using immunohistochemical markers. Breast cancer risk factors, including pregnancy history, were collected via in-person interviews administered shortly after diagnosis. Vital status was determined using the National Death Index. The association of parity and birth recency with breast cancer–specific and overall survival was assessed using Cox proportional hazards models.
Results: During follow-up (median = 13.5 years), 450 patients died, 61% due to breast cancer (n = 276). High parity (3+ births) and recent birth (&lt;5 years before diagnosis) were positively associated with breast cancer–specific mortality, independent of age, race, and selected socioeconomic factors [parity, reference = nulliparous, adjusted HR = 1.76; 95% confidence interval (CI) = 1.13–2.73; birth recency, reference = 10+ years, adjusted HR = 1.29; 95% CI, 0.79–2.11]. The associations were stronger among patients with luminal tumors and those surviving longer than 5 years.
Conclusions: Parity and recent birth are associated with worse survival among breast cancer patients, particularly among luminal breast cancers and long-term survivors.
Impact: The biologic effects of parity and birth recency may extend from etiology to tumor promotion and progression. Cancer Epidemiol Biomarkers Prev; 25(1); 60–67. ©2015 AACR.
Combination of Photodynamic Therapy and Specific Immunotherapy Efficiently Eradicates Established Tumors
Authors: Kleinovink Jan Willem , van Driel Pieter B. , Snoeks Thomas J. , Prokopi Natasa , Fransen Marieke F. , Cruz Luis J. , Mezzanotte Laura , Chan Alan , Löwik Clemens W. , Ossendorp Ferry 
Published: November 2015

Abstract
Purpose: The efficacy of immunotherapy against advanced cancer may be improved by combination strategies. Photodynamic therapy (PDT) is a local tumor ablation method based on localized activation of a photosensitizer, leading to oxygen radical-induced tumor cell death. PDT can enhance antitumor immune responses by release of antigen and danger signals, supporting combination protocols of PDT with immunotherapy.
Experimental Design: We investigated the local and systemic immune effects of PDT after treatment of established tumors. In two independent aggressive mouse tumor models, TC-1 and RMA, we combined PDT with therapeutic vaccination using synthetic long peptides (SLP) containing epitopes from tumor antigens.
Results: PDT of established tumors using the photosensitizer Bremachlorin resulted in significant delay of tumor outgrowth. Combination treatment of PDT with therapeutic SLP vaccination cured one third of mice. Importantly, all cured mice were fully protected against subsequent tumor rechallenge, and combination treatment of primary tumors led to eradication of distant secondary tumors, indicating the induction of a systemic antitumor immune response. Indeed, PDT by itself induced a significant CD8+ T-cell response against the tumor, which was increased when combined with SLP vaccination and essential for the therapeutic effect of combination therapy.
Conclusions: We show that immunotherapy can be efficiently combined with PDT to eradicate established tumors, based on strong local tumor ablation and the induction of a robust systemic immune response. These results suggest combination of active immunotherapy with tumor ablation by PDT as a feasible novel treatment strategy for advanced cancer. Clin Cancer Res; 22(6); 1459–68. ©2015 AACR.
Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers
Authors: Aparicio Ana M. , Shen Li , Tapia Elsa Li Ning , Lu Jing-Fang , Chen Hsiang-Chun , Zhang Jiexin , Wu Guanglin , Wang Xuemei , Troncoso Patricia , Corn Paul , Thompson Timothy C. , Broom Bradley , Baggerly Keith , Maity Sankar N. , Logothetis Christopher J. 
Published: November 2015

AbstractPurpose: Morphologically heterogeneous prostate cancers that behave clinically like small-cell prostate cancers (SCPC) share their chemotherapy responsiveness. We asked whether these clinically defined, morphologically diverse, “aggressive variant prostate cancer (AVPC)” also share molecular features with SCPC.Experimental Design: Fifty-nine prostate cancer samples from 40 clinical trial participants meeting AVPC criteria, and 8 patient-tumor derived xenografts (PDX) from 6 of them, were stained for markers aberrantly expressed in SCPC. DNA from 36 and 8 PDX was analyzed by Oncoscan for copy number gains (CNG) and losses (CNL). We used the AVPC PDX to expand observations and referenced publicly available datasets to arrive at a candidate molecular signature for the AVPC.Results: Irrespective of morphology, Ki67 and Tp53 stained ≥10% cells in 80% and 41% of samples, respectively. RB1 stained &lt;10% cells in 61% of samples and AR in 36%. MYC (surrogate for 8q) CNG and RB1 CNL showed in 54% of 44 samples each and PTEN CNL in 48%. All but 1 of 8 PDX bore Tp53 missense mutations. RB1 CNL was the strongest discriminator between unselected castration-resistant prostate cancer (CRPC) and the AVPC. Combined alterations in RB1, Tp53, and/or PTEN were more frequent in the AVPC than in unselected CRPC and in The Cancer Genome Atlas samples.Conclusions: Clinically defined AVPC share molecular features with SCPC and are characterized by combined alterations in RB1, Tp53, and/or PTEN. Clin Cancer Res; 22(6); 1520–30. ©2015 AACR.
An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to Vismodegib
Authors: Danial Christina , Sarin Kavita Y. , Oro Anthony E. , Chang Anne Lynn S. 
Published: November 2015

Abstract
Purpose: To assess the tumor response to the smoothened (SMO) inhibitor, sonidegib (LDE225), in patients with an advanced basal cell carcinoma (BCC) resistant to treatment with vismodegib (GDC0449).
Experimental Design: Nine patients with an advanced BCC that was previously resistant to treatment with vismodegib were given sonidegib in this investigational, open-label study. Tumor response was determined using the response evaluation criteria in solid tumors. SMO mutations were identified using biopsy samples from the target BCC location.
Results: The median duration of treatment with sonidegib was 6 weeks (range, 3–58 weeks). Five patients experienced progressive disease with sonidegib. Three patients experienced stable disease and discontinued sonidegib either due to adverse events (n = 1) or due to election for surgery (n = 2). The response of one patient was not evaluable. SMO mutations with in vitro data suggesting resistance to Hh pathway inhibition were identified in 5 patients, and none of these patients experienced responses while on sonidegib.
Conclusions: Patients with advanced BCCs that were previously resistant to treatment with vismodegib similarly demonstrated treatment resistance with sonidegib. Patients who have developed treatment resistance to an SMO inhibitor may continue to experience tumor progression in response to other SMO inhibitors. Clin Cancer Res; 22(6); 1325–9. ©2015 AACR.
mTOR Inhibitors Suppress Homologous Recombination Repair and Synergize with PARP Inhibitors via Regulating SUV39H1 in BRCA-Proficient Triple-Negative Breast Cancer
Authors: Mo Wei , Liu Qingxin , Lin Curtis Chun-Jen , Dai Hui , Peng Yang , Liang Yulong , Peng Guang , Meric-Bernstam Funda , Mills Gordon B. , Li Kaiyi , Lin Shiaw-Yih 
Published: November 2015

Abstract
Purpose: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease and has the worst outcome among all subtypes of breast cancers. Although PARP inhibitors represent a promising treatment in TNBC with BRCA1/BRCA2 mutations, there is great interest in identifying drug combinations that can extend the use of PARP inhibitors to a majority of TNBC patients with wild-type BRCA1/BRCA2. Here we explored whether mTOR inhibitors, through modulating homologous recombination (HR) repair, would provide therapeutic benefit in combination with PARP inhibitors in preclinical models of BRCA-proficient TNBC.
Experimental Design: We have studied the effects of mTOR inhibitors on HR repair following DNA double-strand breaks (DSB). We further demonstrated the in vitro and in vivo activities of combined treatment of mTOR inhibitors with PARP inhibitors in BRCA-proficient TNBC. Moreover, microarray analysis and rescue experiments were used to investigate the molecular mechanisms of action.
Results: We found that mTOR inhibitors significantly suppressed HR repair in two BRCA-proficient TNBC cell lines. mTOR inhibitors and PARP inhibitors in combination exhibited strong synergism against these TNBC cell lines. In TNBC xenografts, we observed enhanced efficacy of everolimus in combination with talazoparib (BMN673) compared with either drug alone. We further identified through microarray analysis and by rescue assays that mTOR inhibitors suppressed HR repair and synergized with PARP inhibitors through regulating the expression of SUV39H1 in BRCA-proficient TNBCs.
Conclusions: Collectively, these findings strongly suggest that combining mTOR inhibitors and PARP inhibitors would be an effective therapeutic approach to treat BRCA-proficient TNBC patients. Clin Cancer Res; 22(7); 1699–712. ©2015 AACR.
MECP2Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy
Authors: Neupane Manish , Clark Allison P. , Landini Serena , Birkbak Nicolai J. , Eklund Aron C. , Lim Elgene , Culhane Aedin C. , Barry William T. , Schumacher Steven E. , Beroukhim Rameen , Szallasi Zoltan , Vidal Marc , Hill David E. , Silver Daniel P. 
Published: November 2015

AbstractAn unbiased genome-scale screen for unmutated genes that drive cancer growth when overexpressed identified methyl cytosine-guanine dinucleotide (CpG) binding protein 2 (MECP2) as a novel oncogene. MECP2 resides in a region of the X-chromosome that is significantly amplified across 18% of cancers, and many cancer cell lines have amplified, overexpressed MECP2 and are dependent on MECP2 expression for growth. MECP2 copy-number gain and RAS family member alterations are mutually exclusive in several cancer types. The MECP2 splicing isoforms activate the major growth factor pathways targeted by activated RAS, the MAPK and PI3K pathways. MECP2 rescued the growth of a KRASG12C-addicted cell line after KRAS downregulation, and activated KRAS rescues the growth of an MECP2-addicted cell line after MECP2 downregulation. MECP2 binding to the epigenetic modification 5-hydroxymethylcytosine is required for efficient transformation. These observations suggest that MECP2 is a commonly amplified oncogene with an unusual epigenetic mode of action.Significance: MECP2 is a commonly amplified oncogene in human malignancies with a unique epigenetic mechanism of action. Cancer Discov; 6(1); 45–58. ©2015 AACR.This article is highlighted in the In This Issue feature, p. 1
Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer
Authors: Russo Mariangela , Misale Sandra , Wei Ge , Siravegna Giulia , Crisafulli Giovanni , Lazzari Luca , Corti Giorgio , Rospo Giuseppe , Novara Luca , Mussolin Benedetta , Bartolini Alice , Cam Nicholas , Patel Roopal , Yan Shunqi , Shoemaker Robert , Wild Robert , Di Nicolantonio Federica , Bianchi Andrea Sartore , Li Gang , Siena Salvatore , Bardelli Alberto 
Published: November 2015

Abstract
Entrectinib is a first-in-class pan-TRK kinase inhibitor currently undergoing clinical testing in colorectal cancer and other tumor types. A patient with metastatic colorectal cancer harboring an LMNA–NTRK1 rearrangement displayed a remarkable response to treatment with entrectinib, which was followed by the emergence of resistance. To characterize the molecular bases of the patient's relapse, circulating tumor DNA (ctDNA) was collected longitudinally during treatment, and a tissue biopsy, obtained before entrectinib treatment, was transplanted in mice (xenopatient), which then received the same entrectinib regimen until resistance developed. Genetic profiling of ctDNA and xenopatient samples showed acquisition of two point mutations in the catalytic domain of NTRK1, p.G595R and p.G667C. Biochemical and pharmacologic analysis in multiple preclinical models confirmed that either mutation renders the TRKA kinase insensitive to entrectinib. These findings can be immediately exploited to design next-generation TRKA inhibitors.
Significance: We provide proof of principle that analyses of xenopatients (avatar) and liquid biopsies allow the identification of drug resistance mechanisms in parallel with clinical treatment of an individual patient. We describe for the first time that p.G595R and p.G667C TRKA mutations drive acquired resistance to entrectinib in colorectal cancers carrying NTRK1 rearrangements. Cancer Discov; 6(1); 36–44. ©2015 AACR.
See related commentary by Okimoto and Bivona, p. 14.
This article is highlighted in the In This Issue feature, p. 1
Validation of Intratumoral T-bet+ Lymphoid Cells as Predictors of Disease-Free Survival in Breast Cancer
Authors: Mulligan Anna Marie , Pinnaduwage Dushanthi , Tchatchou Sandrine , Bull Shelley B. , Andrulis Irene L. 
Published: November 2015

AbstractWe previously observed T-bet+ lymphocytes to be associated with a good prognosis in a cohort of women with familial breast cancer. To validate this finding, we evaluated lymphocyte T-bet expression in an independent unselected prospectively accrued series of women with lymph node–negative breast carcinoma. T-bet and clinicopathologic data were available for 614 women. Hormone receptors, HER2, Ki-67, CK5, EGFR, p53, and T-bet status were determined using IHC and/or biochemical methods. Tumors were assigned to luminal A, luminal B, HER2, and basal subtypes based on the expression of IHC markers. Multiple cutpoints were examined in a univariate penalized Cox model to stratify tumors into T-bet+/high and T-bet−/low. Fisher exact test was used to analyze T-bet associations with clinicopathologic variables, IHC markers, and molecular subtype. Survival analyses were by the Cox proportional hazards model. All tests were two sided. A test with a P value &lt; 0.05 was considered statistically significant. T-bet+/high tumor status was significantly associated with large tumor size, high grade, hormone receptor negativity, CK5, EGFR and p53 positivity, high Ki-67, and basal subtype. With a median follow-up of 96.5 months, T-bet−/low tumor status was associated with a reduced disease-free survival compared with T-bet+/high tumor status in multivariate analysis (P = 0.0027; relative risk = 5.62; 95% confidence intervals, 1.48–50.19). Despite being associated with adverse clinicopathologic characteristics, T-bet+ tumor-infiltrating lymphoid cells are associated with a favorable outcome. This supports their role in Th1-mediated antitumor activity and may provide insight for the development of new therapeutic strategies. Cancer Immunol Res; 4(1); 41–48. ©2015 AACR.
Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model
Authors: Reardon David A. , Gokhale Prafulla C. , Klein Sarah R. , Ligon Keith L. , Rodig Scott J. , Ramkissoon Shakti H. , Jones Kristen L. , Conway Amy Saur , Liao Xiaoyun , Zhou Jun , Wen Patrick Y. , Van Den Abbeele Annick D. , Hodi F. Stephen , Qin Lei , Kohl Nancy E. , Sharpe Arlene H. , Dranoff Glenn , Freeman Gordon J. 
Published: November 2015

Abstract
Inhibition of immune checkpoints, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and its ligand PD-L1, has demonstrated exciting and durable remissions across a spectrum of malignancies. Combinatorial regimens blocking complementary immune checkpoints further enhance the therapeutic benefit. The activity of these agents for patients with glioblastoma, a generally lethal primary brain tumor associated with significant systemic and microenvironmental immunosuppression, is not known. We therefore systematically evaluated the antitumor efficacy of murine antibodies targeting a broad panel of immune checkpoint molecules, including CTLA-4, PD-1, PD-L1, and PD-L2 when administered as single-agent therapy and in combinatorial regimens against an orthotopic, immunocompetent murine glioblastoma model. In these experiments, we observed long-term tumor-free survival following single-agent anti–PD-1, anti–PD-L1, or anti–CTLA-4 therapy in 50%, 20%, and 15% of treated animals, respectively. Combination therapy of anti–CTLA-4 plus anti–PD-1 cured 75% of the animals, even against advanced, later-stage tumors. In long-term survivors, tumor growth was not seen upon intracranial tumor rechallenge, suggesting that tumor-specific immune memory responses were generated. Inhibitory immune checkpoint blockade quantitatively increased activated CD8+ and natural killer cells and decreased suppressive immune cells in the tumor microenvironment and draining cervical lymph nodes. Our results support prioritizing the clinical evaluation of PD-1, PD-L1, and CTLA-4 single-agent targeted therapy as well as combination therapy of CTLA-4 plus PD-1 blockade for patients with glioblastoma. Cancer Immunol Res; 4(2); 124–35. ©2015 AACR.
Epicardial Catheter Ablation Using High-Intensity Ultrasound
Authors: Nazer Babak , Salgaonkar Vasant , Diederich Chris J. , Jones Peter D. , Duggirala Srikant , Tanaka Yasuaki , Ng Bennett , Sievers Richard , Gerstenfeld Edward P. 
Published: November 2015

Background—
Epicardial radiofrequency catheter ablation of ventricular tachycardia remains challenging because of the presence of deep myocardial scar and adjacent cardiac structures, such as the coronary arteries, phrenic nerve, and epicardial fat that limit delivery of radiofrequency energy. High-intensity ultrasound (HIU) is an acoustic energy source able to deliver deep lesions through fat, while sparing superficial structures. We developed and tested an epicardial HIU ablation catheter in a closed chest, in vivo swine model.

Methods and Results—

The HIU catheter is an internally cooled, 14-French, side-facing catheter, integrated with A-mode ultrasound guidance. Swine underwent percutaneous subxyphoid epicardial access and ablation with HIU (n=10 swine) at 15, 20, and 30 W. Compared with irrigated radiofrequency lesions in control swine (n = 5), HIU demonstrated increased lesion depth (HIU 11.6±3.2 mm versus radiofrequency 4.7±1.6 mm; mean±SD) and epicardial sparing (HIU 2.9±2.1 mm versus radiofrequency 0.1±0.2 mm) at all HIU powers, and increased lesion volume at HIU 20 and 30 W (
P
<0.0001 for all comparisons). HIU ablation over coronary arteries and surrounding epicardial fat resulted in deep lesions with normal angiographic flow. Histological disruption of coronary adventitia, but not media or intima, was noted in 44% of lesions.

Conclusions—
Compared with radiofrequency, HIU ablation in vivo demonstrates significantly deeper and larger lesions with greater epicardial sparing in a dose-dependent manner. Further development of this catheter may lead to a promising alternative to epicardial radiofrequency ablation.