Biomedical Informatics Commons^™

Omics Analyses Of A Somatic Trp53r245w/+ Breast Cancer Model Identify Cooperating Driver Events Activating Pi3k/Akt/Mtor Signaling, Xiaojie Yu, Yun Zhang, Shunbin Xiong, Joy M Mcdaniel, Chang Sun, Gilda P Chau, Jovanka Gencel-Augusto, Dhruv Chachad, Rhiannon L Morrissey, Xiayu Rao, Jing Wang, Guillermina Lozano

Faculty, Staff and Student Publications

Alterations of the tumor suppressor

Lessons From The Failure To Complete A Trial Of Denosumab In Women With A Pathogenic Brca1/2 Variant Scheduling Risk-Reducing Salpingo-Oophorectomy, Meghna S Trivedi, Nadir Arber, Eitan Friedman, Judy E Garber, Kevin Holcomb, Neil S Horowitz, Jason D Wright, J Jack Lee, Lana A Vornik, Saba Abutaseh, Tawana Castile, Edward R Sauter, Eileen Dimond, Brandy M Heckman-Stoddard, Margaret House, Goli Samimi, Powel H Brown, Katherine D Crew

Faculty, Staff and Student Publications

Female carriers of pathogenic/likely pathogenic (P/LP) BRCA1/2 variants are at increased risk of developing breast and ovarian cancer. Currently, the only effective strategy for ovarian cancer risk reduction is risk-reducing bilateral salpingo-oophorectomy (RR-BSO), which carries adverse effects related to early menopause. There is ongoing investigation of inhibition of the RANK ligand (RANKL) with denosumab as a means of chemoprevention for breast cancer in carriers of BRCA1 P/LP variants. Through the NCI Division of Cancer Prevention (DCP) Early Phase Clinical Trials Prevention Consortia, a presurgical pilot study of denosumab was developed in premenopausal carriers of P/LP BRCA1/2 variants scheduled for RR-BSO …

2022 Practice Recommendation Updates From The World Consensus Conference On Bia-Alcl, Fabio Santanelli Di Pompeo, Mark W Clemens, Michael Atlan, Giovanni Botti, Peter G Cordeiro, Daphne De Jong, Arianna Di Napoli, Dennis Hammond, Cara L Haymaker, Steven M Horwitz, Kelly Hunt, Peter Lennox, Patrick Mallucci, Roberto N Miranda, Alexandre M Munhoz, Eric Swanson, Suzanne D Turner, Guido Firmani, Michail Sorotos

Faculty, Staff and Student Publications

BACKGROUND: Laboratory and clinical research on breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is rapidly evolving. Changes in standard of care and insights into best practice were recently presented at the 3rd World Consensus Conference on BIA-ALCL.

OBJECTIVES: The authors sought to provide practice recommendations from a consensus of experts, supplemented with a literature review regarding epidemiology, etiology, pathogenesis, diagnosis, treatment, socio-psychological aspects, and international authority guidance.

METHODS: A literature search of all manuscripts between 1997 and August 2021 for the above areas of BIA-ALCL was conducted with the PubMed database. Manuscripts in different languages, on non-human subjects, and/or discussing …

Use Of Breast Surveillance Between Women With Pathogenic Variants And Variants Of Uncertain Significance In Breast Cancer Susceptibility Genes, Sukh Makhnoon, Minxing Chen, Brooke Levin, Megan Ensinger, Kristin D Mattie, Generosa Grana, Sanjay Shete, Banu K Arun, Susan K Peterson

Faculty, Staff and Student Publications

BACKGROUND: Use of surveillance mammography and magnetic resonance imaging (MRI) has been understudied among women with variant of uncertain significance (VUS) compared to pathogenic and likely pathogenic variants (P/LP).

METHODS: Using data from two cancer settings, we calculated use of risk-reducing mastectomy (RRM) and surveillance during each 13-month span after genetic testing up to 6 years afterwards for a cohort of genetically elevated risk women.

RESULTS: Of 889 women, VUS carriers were less likely to undergo RRM compared to those with P/LP (hazard ratio [HR], 0.17; p =

CONCLUSION: The authors found that VUS, whether in high or moderate penetrance …

Comprehensive Multiplexed Immune Profiling Of The Ductal Carcinoma In Situ Immune Microenvironment Regarding Subsequent Ipsilateral Invasive Breast Cancer Risk, Mathilde M Almekinders, Tycho Bismeijer, Tapsi Kumar, Fei Yang, Bram Thijssen, Rianne Van Der Linden, Charlotte Van Rooijen, Shiva Vonk, Baohua Sun, Edwin R Parra Cuentas, Ignacio I Wistuba, Savitri Krishnamurthy, Lindy L Visser, Iris M Seignette, Ingrid Hofland, Joyce Sanders, Annegien Broeks, Jason K Love, Brian Menegaz, Lodewyk Wessels, Alastair M Thompson, Karin E De Visser, Erik Hooijberg, Esther Lips, Andrew Futreal, Jelle Wesseling

Faculty, Staff and Student Publications

Background: Ductal carcinoma in situ (DCIS) is treated to prevent subsequent ipsilateral invasive breast cancer (iIBC). However, many DCIS lesions will never become invasive. To prevent overtreatment, we need to distinguish harmless from potentially hazardous DCIS. We investigated whether the immune microenvironment (IME) in DCIS correlates with transition to iIBC.

Methods: Patients were derived from a Dutch population-based cohort of 10,090 women with pure DCIS with a median follow-up time of 12 years. Density, composition and proximity to the closest DCIS cell of CD20+ B-cells, CD3+CD8+ T-cells, CD3+CD8- T-cells, CD3+FOXP3+ regulatory T-cells, CD68+ cells, and CD8+Ki67+ T-cells was assessed with …

Targeting The Alk-Cdk9-Tyr19 Kinase Cascade Sensitizes Ovarian And Breast Tumors To Parp Inhibition Via Destabilization Of The P-Tefb Complex, Yu-Yi Chu, Mei-Kuang Chen, Yongkun Wei, Heng-Huan Lee, Weiya Xia, Ying-Nai Wang, Clinton Yam, Jennifer L Hsu, Hung-Ling Wang, Wei-Chao Chang, Hirohito Yamaguchi, Zhou Jiang, Chunxiao Liu, Ching-Fei Li, Lei Nie, Li-Chuan Chan, Yuan Gao, Shao-Chun Wang, Jinsong Liu, Shannon N Westin, Sanghoon Lee, Anil K Sood, Liuqing Yang, Gabriel N Hortobagyi, Dihua Yu, Mien-Chie Hung

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated promising clinical activity in multiple cancers. However, resistance to PARP inhibitors remains a substantial clinical challenge. In the present study, we report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes. Conversely, ALK inhibition increases ubiquitination and degradation of CDK9 by Skp2, an E3 ligase. Notably, combination of US Food and Drug Administration-approved ALK and PARP inhibitors markedly reduce tumor …

Lurbinectedin, A Selective Inhibitor Of Oncogenic Transcription, In Patients With Pretreated Germline Brca1/2 Metastatic Breast Cancer: Results From A Phase Ii Basket Study, V Boni, B Pistilli, I Braña, G I Shapiro, J Trigo, V Moreno, D Castellano, C Fernández, C Kahatt, V Alfaro, M Siguero, A Zeaiter, F Longo, K Zaman, A Antón, A Paredes, G Huidobro, V Subbiah

Faculty, Staff and Student Publications

Background: Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer.

Patients and methods: This phase II basket multitumor trial (NCT02454972) evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 21 patients with pretreated germline BRCA1/2 breast cancer. Patients with any hormone receptor and human epidermal growth factor receptor 2 status were enrolled. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival …

Mri-Based Digital Models Forecast Patient-Specific Treatment Responses To Neoadjuvant Chemotherapy In Triple-Negative Breast Cancer, Chengyue Wu, Angela M Jarrett, Zijian Zhou, Nabil Elshafeey, Beatriz E Adrada, Rosalind P Candelaria, Rania M M Mohamed, Medine Boge, Lei Huo, Jason B White, Debu Tripathy, Vicente Valero, Jennifer K Litton, Clinton Yam, Jong Bum Son, Jingfei Ma, Gaiane M Rauch, Thomas E Yankeelov

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) is persistently refractory to therapy, and methods to improve targeting and evaluation of responses to therapy in this disease are needed. Here, we integrate quantitative MRI data with biologically based mathematical modeling to accurately predict the response of TNBC to neoadjuvant systemic therapy (NAST) on an individual basis. Specifically, 56 patients with TNBC enrolled in the ARTEMIS trial (NCT02276443) underwent standard-of-care doxorubicin/cyclophosphamide (A/C) and then paclitaxel for NAST, where dynamic contrast-enhanced MRI and diffusion-weighted MRI were acquired before treatment and after two and four cycles of A/C. A biologically based model was established to …

Bet Inhibition Induces Vulnerability To Mcl1 Targeting Through Upregulation Of Fatty Acid Synthesis Pathway In Breast Cancer, Gonghong Yan, Augustin Luna, Heping Wang, Behnaz Bozorgui, Xubin Li, Maga Sanchez, Zeynep Dereli, Nermin Kahraman, Goknur Kara, Xiaohua Chen, Caishang Zheng, Daniel Mcgrail, Nidhi Sahni, Yiling Lu, Ozgun Babur, Murat Cokol, Bora Lim, Bulent Ozpolat, Chris Sander, Gordon B Mills, Anil Korkut

Faculty, Staff and Student Publications

Therapeutic options for treatment of basal-like breast cancers remain limited. Here, we demonstrate that bromodomain and extra-terminal (BET) inhibition induces an adaptive response leading to MCL1 protein-driven evasion of apoptosis in breast cancer cells. Consequently, co-targeting MCL1 and BET is highly synergistic in breast cancer models. The mechanism of adaptive response to BET inhibition involves the upregulation of lipid synthesis enzymes including the rate-limiting stearoyl-coenzyme A (CoA) desaturase. Changes in lipid synthesis pathway are associated with increases in cell motility and membrane fluidity as well as re-localization and activation of HER2/EGFR. In turn, the HER2/EGFR signaling results in the accumulation …

Tumor Immune Microenvironment Changes By Multiplex Immunofluorescence Staining In A Pilot Study Of Neoadjuvant Talazoparib For Early-Stage Breast Cancer Patients With A Hereditary Brca Mutation, Tapsi Kumar, Evie Hobbs, Fei Yang, Jeffrey T Chang, Alejandro Contreras, Edwin Roger Parra Cuentas, Haven Garber, Sanghoon Lee, Yiling Lu, Marion E Scoggins, Beatriz E Adrada, Gary J Whitman, Banu K Arun, Elizabeth A Mittendorf, Jennifer K Litton

Faculty, Staff and Student Publications

PURPOSE: The immunological profile of early-stage breast cancer treated with neoadjuvant PARP inhibitors has not been described. The aim of this study was to delineate the changes in the tumor immune microenvironment (TiME) induced by talazoparib.

PATIENTS AND METHODS: Patients with operable germline BRCA1/2 pathogenic variant (gBRCA1/2+) breast cancer were enrolled in a feasibility study of neoadjuvant talazoparib. Thirteen patients who received 8 weeks of neoadjuvant talazoparib were available for analysis, including 11 paired pre- and post-talazoparib core biopsies. Treatment-related changes in tumor-infiltrating lymphocytes were examined and immune cell phenotypes and their spatial distribution in the TiME were identified and …

Integrated Imaging And Molecular Analysis To Decipher Tumor Microenvironment In The Era Of Immunotherapy, Jia Wu, Aaron T Mayer, Ruijiang Li

Faculty, Staff and Student Publications

Radiological imaging is an integral component of cancer care, including diagnosis, staging, and treatment response monitoring. It contains rich information about tumor phenotypes that are governed not only by cancer cellintrinsic biological processes but also by the tumor microenvironment, such as the composition and function of tumor-infiltrating immune cells. By analyzing the radiological scans using a quantitative radiomics approach, robust relations between specific imaging and molecular phenotypes can be established. Indeed, a number of studies have demonstrated the feasibility of radiogenomics for predicting intrinsic molecular subtypes and gene expression signatures in breast cancer based on MRI. In parallel, promising results …

A Multi-Institutional Prediction Model To Estimate The Risk Of Recurrence And Mortality After Mastectomy For T1-2n1 Breast Cancer, Sarah M C Sittenfeld, Emily C Zabor, Sarah N Hamilton, Henry M Kuerer, Mahmoud El-Tamer, George E Naoum, Pauline T Truong, Alan Nichol, Benjamin D Smith, Wendy A Woodward, Tracy-Ann Moo, Simon N Powell, Chirag S Shah, Alphonse G Taghian, Ibrahim Abu-Gheida, Rahul D Tendulkar

Faculty, Staff and Student Publications

Background: Post-mastectomy radiation therapy (PMRT) in women with pathologic stage T1-2N1M0 breast cancer is controversial.

Methods: Data from five North American institutions including women undergoing mastectomy without neoadjuvant therapy with pT1-2N1M0 breast cancer treated from 2006 to 2015 were pooled for analysis. Competing-risks regression was performed to identify factors associated with locoregional recurrence (LRR), distant metastasis (DM), overall recurrence (OR), and breast cancer mortality (BCM).

Results: A total of 3532 patients were included for analysis with a median follow-up time among survivors of 6.8 years (interquartile range [IQR], 4.5-9.5 years). The 2154 (61%) patients who received PMRT had significantly more …

Modeling The Prognostic Impact Of Circulating Tumor Cells Enumeration In Metastatic Breast Cancer For Clinical Trial Design Simulation, Lorenzo Gerratana, Jean-Yves Pierga, James M Reuben, Andrew A Davis, Firas H Wehbe, Luc Dirix, Tanja Fehm, Franco Nolé, Rafael Gisbert-Criado, Dimitrios Mavroudis, Salvatore Grisanti, Jose A Garcia-Saenz, Justin Stebbing, Carlos Caldas, Paola Gazzaniga, Luis Manso, Rita Zamarchi, Marta Bonotto, Angela Fernandez De Lascoiti, Leticia De Mattos-Arruda, Michail Ignatiadis, Maria-Teresa Sandri, Daniele Generali, Carmine De Angelis, Sarah-Jane Dawson, Wolfgang Janni, Vicente Carañana, Sabine Riethdorf, Erich-Franz Solomayer, Fabio Puglisi, Mario Giuliano, Klaus Pantel, François-Clément Bidard, Massimo Cristofanilli

Faculty, Staff and Student Publications

Despite the strong prognostic stratification of circulating tumor cells (CTCs) enumeration in metastatic breast cancer (MBC), current clinical trials usually do not include a baseline CTCs in their design. This study aimed to generate a classifier for CTCs prognostic simulation in existing datasets for hypothesis generation in patients with MBC. A K-nearest neighbor machine learning algorithm was trained on a pooled dataset comprising 2436 individual MBC patients from the European Pooled Analysis Consortium and the MD Anderson Cancer Center to identify patients likely to have CTCs ≥ 5/7 mL blood (StageIVaggressive vs StageIVindolent). The model had a 65.1% accuracy and …

Alyref, A Novel Factor Involved In Breast Carcinogenesis, Acts Through Transcriptional And Post-Transcriptional Mechanisms Selectively Regulating The Short Neat1 Isoform, Christiane Klec, Erik Knutsen, Daniela Schwarzenbacher, Katharina Jonas, Barbara Pasculli, Ellen Heitzer, Beate Rinner, Katarina Krajina, Felix Prinz, Benjamin Gottschalk, Peter Ulz, Alexander Deutsch, Andreas Prokesch, Stephan W Jahn, S Mohammad Lellahi, Maria Perander, Raffaela Barbano, Wolfgang F Graier, Paola Parrella, George Adrian Calin, Martin Pichler

Faculty, Staff and Student Publications

The RNA-binding protein ALYREF (THOC4) is involved in transcriptional regulation and nuclear mRNA export, though its role and molecular mode of action in breast carcinogenesis are completely unknown. Here, we identified high ALYREF expression as a factor for poor survival in breast cancer patients. ALYREF significantly influenced cellular growth, apoptosis and mitochondrial energy metabolism in breast cancer cells as well as breast tumorigenesis in orthotopic mouse models. Transcriptional profiling, phenocopy and rescue experiments identified the short isoform of the lncRNA NEAT1 as a molecular trigger for ALYREF effects in breast cancer. Mechanistically, we found that ALYREF binds to the NEAT1 …

Molecular Characterization And Prospective Evaluation Of Pathologic Response And Outcomes With Neoadjuvant Therapy In Metaplastic Triple-Negative Breast Cancer, Clinton Yam, Nour Abuhadra, Ryan Sun, Beatriz E Adrada, Qing-Qing Ding, Jason B White, Elizabeth E Ravenberg, Alyson R Clayborn, Vicente Valero, Debu Tripathy, Senthilkumar Damodaran, Banu K Arun, Jennifer K Litton, Naoto T Ueno, Rashmi K Murthy, Bora Lim, Luis Baez, Xiaoxian Li, Aman U Buzdar, Gabriel N Hortobagyi, Alistair M Thompson, Elizabeth A Mittendorf, Gaiane M Rauch, Rosalind P Candelaria, Lei Huo, Stacy L Moulder, Jeffrey T Chang

Faculty, Staff and Student Publications

PURPOSE: Metaplastic breast cancer (MpBC) is a rare subtype of breast cancer that is commonly triple-negative and poorly responsive to neoadjuvant therapy in retrospective studies.

EXPERIMENTAL DESIGN: To better define clinical outcomes and correlates of response, we analyzed the rate of pathologic complete response (pCR) to neoadjuvant therapy, survival outcomes, and genomic and transcriptomic profiles of the pretreatment tumors in a prospective clinical trial (NCT02276443). A total of 211 patients with triple-negative breast cancer (TNBC), including 39 with MpBC, received doxorubicin-cyclophosphamide-based neoadjuvant therapy.

RESULTS: Although not meeting the threshold for statistical significance, patients with MpBCs were less likely to experience …

Risk Of Peritoneal Carcinomatosis After Risk-Reducing Salpingo-Oophorectomy: A Systematic Review And Individual Patient Data Meta-Analysis, Miranda P Steenbeek, Majke H D Van Bommel, Johan Bulten, Julia A Hulsmann, Joep Bogaerts, Christine Garcia, Han T Cun, Karen H Lu, Heleen J Van Beekhuizen, Lucas Minig, Katja N Gaarenstroom, Marielle Nobbenhuis, Mateja Krajc, Vilius Rudaitis, Barbara M Norquist, Elizabeth M Swisher, Marian J E Mourits, Leon F A G Massuger, Nicoline Hoogerbrugge, Rosella P M G Hermens, Joanna Inthout, Joanne A De Hullu

Faculty, Staff and Student Publications

Purpose: After risk-reducing salpingo-oophorectomy (RRSO), BRCA1/2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO.

Methods: Unpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA-PV with and without …

Signal Detection Of Adverse Events Associated With Trastuzumab In A Cohort Of Elderly Patients With Breast Cancer, Efstathia Polychronopoulou, Sharon H Giordano, Lin-Na Chou, Xiaoying Yu, Yong-Fang Kuo

Faculty, Staff and Student Publications

AIM: Utilization of signal detection methods in longitudinal claims data can improve post-marketing drug surveillance, but to date there has been limited application. The aim of this study is to use 3 approaches, the proportional reporting ratio, Gamma Poisson Shrinker, and tree-based scan statistic in detecting adverse drug events (ADEs) attributed to trastuzumab using an administrative claims dataset.

METHODS: Using data from the Texas Cancer Registry and SEER linked to Medicare from 2010 to 2013, we conducted 1:2 propensity score matching. Breast cancer HER2+ patients treated with trastuzumab in addition to standard chemotherapy were matched to HER2- patients treated with …

Dedifferentiation-Mediated Stem Cell Niche Maintenance In Early-Stage Ductal Carcinoma In Situ Progression: Insights From A Multiscale Modeling Study, Joseph D Butner, Prashant Dogra, Caroline Chung, Javier Ruiz-Ramírez, Sara Nizzero, Marija Plodinec, Xiaoxian Li, Ping-Ying Pan, Shu-Hsia Chen, Vittorio Cristini, Bulent Ozpolat, George A Calin, Zhihui Wang

Faculty, Staff and Student Publications

We present a multiscale agent-based model of ductal carcinoma in situ (DCIS) to study how key phenotypic and signaling pathways are involved in the early stages of disease progression. The model includes a phenotypic hierarchy, and key endocrine and paracrine signaling pathways, and simulates cancer ductal growth in a 3D lattice-free domain. In particular, by considering stochastic cell dedifferentiation plasticity, the model allows for study of how dedifferentiation to a more stem-like phenotype plays key roles in the maintenance of cancer stem cell populations and disease progression. Through extensive parameter perturbation studies, we have quantified and ranked how DCIS is …

Ezh2 Engages Tgfβ Signaling To Promote Breast Cancer Bone Metastasis Via Integrin Β1-Fak Activation, Lin Zhang, Jingkun Qu, Yutao Qi, Yimin Duan, Yu-Wen Huang, Zhifen Zhou, Ping Li, Jun Yao, Beibei Huang, Shuxing Zhang, Dihua Yu

Faculty, Staff and Student Publications

Bone metastases occur in 50-70% of patients with late-stage breast cancers and effective therapies are needed. The expression of enhancer of zeste homolog 2 (EZH2) is correlated with breast cancer metastasis, but its function in bone metastasis hasn't been well-explored. Here we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFβ) signaling. EZH2 induces cancer cell proliferation and osteoclast maturation, whereas EZH2 knockdown decreases bone metastasis incidence and outgrowth in vivo. Mechanistically, EZH2 transcriptionally increases ITGB1, which encodes for integrin β1. Integrin β1 activates focal adhesion kinase (FAK), which phosphorylates TGFβ receptor type …

Ndrg1 In Aggressive Breast Cancer Progression And Brain Metastasis, Emilly S Villodre, Xiaoding Hu, Bedrich L Eckhardt, Richard Larson, Lei Huo, Ester C Yoon, Yun Gong, Juhee Song, Shuying Liu, Naoto T Ueno, Savitri Krishnamurthy, Stefan Pusch, Debu Tripathy, Wendy A Woodward, Bisrat G Debeb

Faculty, Staff and Student Publications

BACKGROUND: N-Myc downstream regulated gene 1 (NDRG1) suppresses metastasis in many human malignancies, including breast cancer, yet has been associated with worse survival in patients with inflammatory breast cancer. The role of NDRG1 in the pathobiology of aggressive breast cancers remains elusive.

METHODS: To study the role of NDRG1 in tumor growth and brain metastasis in vivo, we transplanted cells into cleared mammary fat pads or injected them in tail veins of SCID/Beige mice (n = 7-10 per group). NDRG1 protein expression in patient breast tumors (n = 216) was assessed by immunohistochemical staining. Kaplan-Meier method with 2-sided log-rank test …

Chromosomal Imbalances Detected Via Rna-Sequencing In 28 Cancers, Zuhal Ozcan, Francis A San Lucas, Justin W Wong, Kyle Chang, Konrad H Stopsack, Jerry Fowler, Yasminka A Jakubek, Paul Scheet

Faculty, Staff and Student Publications

Motivation: RNA-sequencing (RNA-seq) of tumor tissue is typically only used to measure gene expression. Here, we present a statistical approach that leverages existing RNA-seq data to also detect somatic copy number alterations (SCNAs), a pervasive phenomenon in human cancers, without a need to sequence the corresponding DNA.

Results: We present an analysis of 4942 participant samples from 28 cancers in The Cancer Genome Atlas (TCGA), demonstrating robust detection of SCNAs from RNA-seq. Using genotype imputation and haplotype information, our RNA-based method had a median sensitivity of 85% to detect SCNAs defined by DNA analysis, at high specificity (∼95%). As an …

Breast Radiation Therapy-Related Treatment Outcomes In Patients With Or Without Germline Mutations On Multigene Panel Testing, Bhavana V Chapman, Diane Liu, Yu Shen, Oluwafikayo O Olamigoke, David S Lakomy, Angelica M Gutierrez Barrera, Shane R Stecklein, Gabriel O Sawakuchi, Scott J Bright, Isabelle Bedrosian, Jennifer K Litton, Benjamin D Smith, Wendy A Woodward, George H Perkins, Karen E Hoffman, Michael C Stauder, Eric A Strom, Banu K Arun, Simona F Shaitelman

Faculty, Staff and Student Publications

PURPOSE: Multigene panel testing has increased the detection of germline mutations in patients with breast cancer. The implications of using radiation therapy (RT) to treat patients with pathogenic variant (PV) mutations are not well understood and have been studied mostly in women with only BRCA1 or BRCA2 PVs. We analyzed oncologic outcomes and toxicity after adjuvant RT in a contemporary, diverse cohort of patients with breast cancer who underwent genetic panel testing.

METHODS AND MATERIALS: We retrospectively reviewed the records of 286 women with clinical stage I-III breast cancer diagnosed from 1995 to 2017 who underwent surgery, breast or chest …

Construction And Validation Of Prognostic Nomogram For Metaplastic Breast Cancer, Yongfeng Li, Daobao Chen, Haojun Xuan, Mihnea P Dragomir, George A Calin, Xuli Meng, Meng Chen, Hongchuan Jin

Faculty, Staff and Student Publications

In this study we aimed to develop nomogram models for predicting the overall survival (OS) and cancer-specific survival (CSS) of patients with metaplastic breast cancer (MBC). Data of patients diagnosed with MBC from 1973 to 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox analyses were performed to identify independent prognostic factors for OS and CSS of MBC patients. The obtained prognostic variables were combined to construct nomogram models for predicting OS and CSS in patients with MBC. Model performance was evaluated using concordance index (C-index) and calibration plots. Data from 1125 patients …

Transcribed Ultraconserved Regions Are Associated With Clinicopathological Features In Breast Cancer, Erika Pereira Zambalde, Douglas Adamoski, Daniela Fiori Gradia, Iris Rabinovich, Ana Carolina Rodrigues, Cristina Ivan, Enilze M S F Ribeiro, George Adrian Calin, Jaqueline Carvalho De Oliveira

Faculty, Staff and Student Publications

Ultraconserved regions (UCRs) are 481 genome segments, with length longer than 200 bp, that are 100% conserved among humans, mice, and rats. The majority of UCRs are transcriptionally active (T-UCRs) as many of them produce non-coding RNAs. In a previous study, we evaluated the expression level of T-UCRs in breast cancer (BC) patients and found that 63% of transcripts correlated with some clinical and/or molecular parameter of BC. In this study, we delved into the expression levels of 12 T-UCRs and correlated them with clinicopathological parameters, immunohistochemical markers, and overall survival in two breast cancer cohorts: TCGA and Brazilian patients. …

Cell-Directed Aptamer Therapeutic Targeting For Cancers Including Those Within The Central Nervous System, Jun Wei, Renduo Song, Aria Sabbagh, Anantha Marisetty, Neal Shukla, Dexing Fang, Hinda Najem, Martina Ott, James Long, Lijie Zhai, Maciej S Lesniak, Charles David James, Leonidas Platanias, Michael Curran, Amy B Heimberger

Faculty, Staff and Student Publications

Osteopontin (OPN) is produced by tumor cells as well as by myeloid cells and is enriched in the tumor microenvironment (TME) of many cancers. Given the roles of OPN in tumor progression and immune suppression, we hypothesized that targeting OPN with aptamers that have high affinity and specificity could be a promising therapeutic strategy. Bi-specific aptamers targeting ligands for cellular internalization were conjugated to siRNAs to suppress OPN were created, and therapeutic leads were selected based on target engagement and

Increasing Referral Of At-Risk Women For Genetic Counseling And Brca Testing Using A Screening Tool In A Community Breast Imaging Center, Banu K Arun, Susan K Peterson, Lilian E Sweeney, Rachel D Bluebond, Rebecca S S Tidwell, Sukh Makhnoon, Anne C Kushwaha

Faculty, Staff and Student Publications

BACKGROUND: Genetic evaluation and testing for hereditary breast and ovarian cancer (HBOC) remain suboptimal. The authors evaluated the feasibility of using a screening tool at a breast imaging center to increase HBOC assessment referrals.

METHODS: A brief questionnaire based on the National Comprehensive Cancer Network HBOC genetic counseling referral guidelines was developed and added to the standard intake forms of patients undergoing mammography at a community breast imaging center from 2012 through 2015. Patients who met the criteria in the guidelines were referred for genetic counseling.

RESULTS: A total of 34,851 patients were screened during the study period, and 1246 …

A Novel Group Of Genes That Cause Endocrine Resistance In Breast Cancer Identified By Dynamic Gene Expression Analysis, Arvand Asghari, Katherine Wall, Michael Gill, Natascha Del Vecchio, Farnaz Allahbakhsh, Jacky Wu, Nan Deng, W Jim Zheng, Hulin Wu, Michihisa Umetani, Vahed Maroufy

Faculty, Staff and Student Publications

Breast cancer (BC) is the most common type of cancer diagnosed in women. Among female cancer deaths, BC is the second leading cause of death worldwide. For estrogen receptor-positive (ER-positive) breast cancers, endocrine therapy is an effective therapeutic approach. However, in many cases, an ER-positive tumor becomes unresponsive to endocrine therapy, and tumor regrowth occurs after treatment. While some genetic mutations contribute to resistance in some patients, the underlying causes of resistance to endocrine therapy are mostly undetermined. In this study, we utilized a recently developed statistical approach to investigate the dynamic behavior of gene expression during the development of …

Residual Cancer Burden After Neoadjuvant Chemotherapy And Long-Term Survival Outcomes In Breast Cancer: A Multicentre Pooled Analysis Of 5161 Patients, Christina Yau, Marie Osdoit, Marieke Van Der Noordaa, Sonal Shad, Jane Wei, Diane De Croze, Anne-Sophie Hamy, Marick Laé, Fabien Reyal, Gabe S Sonke, Tessa G Steenbruggen, Maartje Van Seijen, Jelle Wesseling, Miguel Martín, Maria Del Monte-Millán, Sara López-Tarruella, Judy C Boughey, Matthew P Goetz, Tanya Hoskin, Rebekah Gould, Vicente Valero, Stephen B Edge, Jean E Abraham, John M S Bartlett, Carlos Caldas, Janet Dunn, Helena Earl, Larry Hayward, Louise Hiller, Elena Provenzano, Stephen-John Sammut, Jeremy S Thomas, David Cameron, Ashley Graham, Peter Hall, Lorna Mackintosh, Fang Fan, Andrew K Godwin, Kelsey Schwensen, Priyanka Sharma, Angela M Demichele, Kimberly Cole, Lajos Pusztai, Mi-Ok Kim, Laura J Van 'T Veer, Laura J Esserman, W Fraser Symmans

Faculty, Staff and Student Publications

Background: Previous studies have independently validated the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. We used results from several independent cohorts in a pooled patient-level analysis to evaluate the relationship of RCB with long-term prognosis across different phenotypic subtypes of breast cancer, to assess generalisability in a broad range of practice settings.

Methods: In this pooled analysis, 12 institutes and trials in Europe and the USA were identified by personal communications with site investigators. We obtained participant-level RCB results, and data on clinical and pathological stage, tumour subtype and grade, and treatment and follow-up in November, 2019, …

Evaluating A Pilot Culturally Sensitive Psychosocial Intervention On Posttraumatic Growth For Chinese American Breast Cancer Survivors, Qiao Chu, Moni Tang, Lingjun Chen, Lucy Young, Alice Loh, Carol Wang, Qian Lu

Faculty, Staff and Student Publications

This study investigated the potential benefit of a pilot culturally sensitive group support intervention, named Joy Luck Academy (JLA), in fostering posttraumatic growth among Chinese American breast cancer survivors. Eighty-six Chinese American breast cancer survivors participated in an eight-week single-arm pre-/post-test trial of an intervention program, which included educational lectures and peer mentor support. The JLA participants were compared with an independent sample of 109 Chinese American breast cancer survivors who went through routine care. Both groups completed baseline and eight-week follow-up assessments of the five facets of posttraumatic growth (meaningful interpersonal relationships, finding new possibilities in life, personal strength, …

Accuracy And Self Correction Of Information Received From An Internet Breast Cancer List: Content Analysis, Adol Esquivel, Funda Meric-Bernstam, Elmer V Bernstam

Faculty, Staff and Student Publications

OBJECTIVES: To determine the prevalence of false or misleading statements in messages posted by internet cancer support groups and whether these statements were identified as false or misleading and corrected by other participants in subsequent postings. DESIGN: Analysis of content of postings. SETTING: Internet cancer support group Breast Cancer Mailing List. MAIN OUTCOME MEASURES: Number of false or misleading statements posted from 1 January to 23 April 2005 and whether these were identified and corrected by participants in subsequent postings. RESULTS: 10 of 4600 postings (0.22%) were found to be false or misleading. Of these, seven were identified as false …