272 results on '"Daniel G. Stover"'
Search Results
2. The survival benefit of adjuvant trastuzumab with or without chemotherapy in the management of small (T1mic, T1a, T1b, T1c), node negative HER2+ breast cancer
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Kai C. C. Johnson, Ai Ni, Dionisia Quiroga, Ashley C. Pariser, Preeti K. Sudheendra, Nicole O. Williams, Sagar D. Sardesai, Mathew Cherian, Daniel G. Stover, Margaret Gatti-Mays, Bhuvaneswari Ramaswamy, Maryam Lustberg, Sachin Jhawar, Roman Skoracki, and Robert Wesolowski
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract There is limited data regarding the added benefit of adjuvant systemic therapy in the management of small, node-negative, HER2+ breast cancer. In a multi-institutional retrospective analysis using the American Society of Clinical Oncology CancerLinQ database, we compared survival outcomes among T1a-c N0 HER2+ patients diagnosed between 2010 to 2021 who received locoregional therapy alone or in combination with adjuvant trastuzumab (+/− chemotherapy). Primary outcomes were invasive disease-free survival (iDFS) and overall survival (OS). Of the 1,184 patients, 436 received locoregional therapy alone. We found a statistically significant improvement in iDFS (HR 0.73, P = 0.003) and OS (HR 0.63, P = 0.023) on univariate analysis with adjuvant trastuzumab with or without chemotherapy which remained statistically significant on multivariate analysis. Three-arm univariate analysis found that iDFS was significantly improved with trastuzumab monotherapy (P = 0.003) and combination therapy (P = 0.027) compared to observation. Subgroup data suggests that T1b/c tumors derive the greatest benefit.
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- 2024
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3. A video intervention to improve patient understanding of tumor genomic testing in patients with cancer
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Deloris J. Veney, Lai Y. Wei, Amanda E. Toland, Carolyn J. Presley, Heather L. Hampel, Tasleem J. Padamsee, Clara N. Lee, William J. Irvin Jr, Michael J. Bishop, James J. Kim, Shelly R. Hovick, Leigha A. Senter, and Daniel G. Stover
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biomarkers ,cancer education ,cancer management ,genomics ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Introduction Tumor genomic testing (TGT) is standard‐of‐care for most patients with advanced/metastatic cancer. Despite established guidelines, patient education prior to TGT is frequently omitted. The purpose of this study was to evaluate the impact of a concise 4 min video for patient education prior to TGT. Methods Based on a quality improvement cycle, an animated video was created to be applicable to any cancer type, incorporating culturally diverse images, available in English and Spanish. Patients undergoing standard‐of‐care TGT were enrolled at a tertiary academic institution and completed survey instruments prior to video viewing (T1) and immediately post‐viewing (T2). Instruments included: (1) 10‐question objective genomic knowledge; (2) 10‐question video message‐specific knowledge; (3) 11‐question Trust in Provider; (4) attitudes regarding TGT. Results A total of 150 participants were enrolled. For the primary objective, there was a significant increase in video message‐specific knowledge (median 10 point increase; p
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- 2024
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4. FinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA
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Yaping Liu, Sarah C. Reed, Christopher Lo, Atish D. Choudhury, Heather A. Parsons, Daniel G. Stover, Gavin Ha, Gregory Gydush, Justin Rhoades, Denisse Rotem, Samuel Freeman, David W. Katz, Ravi Bandaru, Haizi Zheng, Hailu Fu, Viktor A. Adalsteinsson, and Manolis Kellis
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Science - Abstract
Abstract Analysis of DNA methylation in cell-free DNA reveals clinically relevant biomarkers but requires specialized protocols such as whole-genome bisulfite sequencing. Meanwhile, millions of cell-free DNA samples are being profiled by whole-genome sequencing. Here, we develop FinaleMe, a non-homogeneous Hidden Markov Model, to predict DNA methylation of cell-free DNA and, therefore, tissues-of-origin, directly from plasma whole-genome sequencing. We validate the performance with 80 pairs of deep and shallow-coverage whole-genome sequencing and whole-genome bisulfite sequencing data.
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- 2024
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5. Case report: Characterization of the immunologic and molecular landscape in a unique presentation of invasive lobular carcinoma with concurrent uterine carcinosarcoma treated with immunotherapy
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Courtney J. Riedinger, Caprice D. Eisele, Ashwini Esnakula, Daniel G. Stover, Aharon G. Freud, and Casey M. Cosgrove
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carcinosarcoma ,lobular breast cancer ,epithelial to mesenchymal (EMT) ,immunotherapy ,NK cell (NKC) ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Invasive lobular breast cancer (ILC) is characterized by a relatively high risk for late recurrence and a unique metastatic pattern with an increased risk for metastasis to gynecologic organs and peritoneum. We present a unique case of recurrent ILC with metastasis to the abdominal peritoneum as well as the uterine myometrium and cervix. Treatment was complicated by the discovery of concomitant uterine carcinosarcoma. This patient was effectively treated with a combination of hormonal therapy for her metastatic ILC and a combination of chemotherapy and immunotherapy for uterine carcinosarcoma. Molecular evaluation revealed a characteristic CDH1 mutation within the ILC and a PI3KCA mutation within the uterine carcinosarcoma, both of which have been linked to epithelial-to-mesenchymal transitions. Examination of the tumor immune microenvironment revealed proportionally more cytotoxic NK cells. This robust immune infiltration may be an indicator of the response to immunotherapy observed in this tumor or a result of the metastatic breast cancer within the uterus. This report provides a characterization of the molecular and immunologic landscape in this case with metastatic ILC and uterine carcinosarcoma.
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- 2024
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6. Real‐world treatment patterns of adjuvant endocrine therapy and ovarian suppression in premenopausal HR+/HER2+ breast cancer
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Jasmine S. Sukumar, Sagar Sardesai, Andy Ni, Nicole Williams, Kai Johnson, Dionisia Quiroga, Bhuvana Ramaswamy, Robert Wesolowski, Mathew Cherian, Daniel G. Stover, Margaret Gatti‐Mays, Ashley Pariser, Preeti Sudheendra, Mridula A. George, and Maryam Lustberg
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adjuvant therapy ,breast cancer ,endocrine therapy ,HER2‐positive ,hormone receptor positive ,premenopausal ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The optimal adjuvant endocrine therapy (ET) in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 positive (HER2+) premenopausal breast cancer (BC) remains unclear. Moreover, the benefit and clinical indications of ovarian suppression (OS) is poorly elucidated. We described real‐world patterns surrounding choice of ET and clinicopathologic features which predicted treatment with OS in a contemporary cohort of premenopausal women with HR+/HER2+ BC. Methods This retrospective analysis included premenopausal patients with nonmetastatic HR+/HER2+ BC from the CancerLinQ Discovery database from January 2010 to May 2020. Women were less than 50 years and received chemotherapy, anti‐HER2 therapy, and ET. They were categorized into 1 of 4 groups based on type of ET prescribed at initiation: aromatase inhibitor (AI) + OS, OS, tamoxifen + OS, or tamoxifen. Multivariable logistic regression assessed associations between clinicopathologic features and OS use. Results Out of 360,540 patients with BC, 937 were included. The majority (n = 818, 87%) were prescribed tamoxifen, whereas 4 (0.4%), 50 (5.3%), and 65 (6.9%) received OS, tamoxifen + OS and AI + OS, respectively. No clinicopathologic features predicted OS use apart from age; patients
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- 2024
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7. Survival outcomes seen with neoadjuvant chemotherapy in the management of locally advanced inflammatory breast cancer (IBC) versus matched controls
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Kai CC Johnson, Michael Grimm, Jasmine Sukumar, Patrick M. Schnell, Ko Un Park, Daniel G. Stover, Sachin R. Jhawar, Margaret Gatti-Mays, Robert Wesolowski, Nicole Williams, Sagar Sardesai, Ashley Pariser, Preeti Sudheendra, Gary Tozbikian, Bhuvaneswari Ramaswamy, Dureti Doto, and Mathew A. Cherian
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Inflammatory breast cancer ,Overall survival ,Disease-free survival ,Neoadjuvant chemotherapy ,Complete pathological response ,Stage 3 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Inflammatory breast cancer (IBC) poses an ongoing challenge as rates of disease recurrence and mortality remain high compared to stage-matched controls. However, frontline therapy has evolved through the years, including the widespread use of neoadjuvant chemotherapy (NAC) given the prognostic importance of pathologic complete response (pCR). Due to these sweeping changes, we need new data to assess current recurrence and survival outcomes for locally advanced IBC in the context of matched non-inflammatory controls. We conducted a retrospective analysis of institutional IBC data from 2010 to 2016 with the primary objective of comparing overall survival (OS), relapse-free survival (RFS), and distant relapse-free survival (DRFS). We matched IBC patients to non-inflammatory controls based on age, receptor status, tumor grade, clinical stage, and receipt of prior NAC. Secondary objectives included assessing pCR rates and identifying prognostic factors. Among NAC recipients, we observed similar pCR rates (47.6 % vs. 49.4 %, p = 0.88) between IBC (n = 84) and matched non-IBC (n = 81) cohorts. However, we noted a significant worsening of OS (p = 0.0001), RFS (p = 0.0001), and DRFS (p = 0.001) in the IBC group. Specifically, 5-year OS in the IBC cohort was 58.9 % vs. 86.7 % for matched controls (p = 0.0003). Older age was a weak negative predictor for OS (HR 1.03, p = 0.001) and RFS (HR 1.02, p = 0.01). For DRFS, older age was also a weak negative predictor (HR 1.02, p = 0.02), whereas the use of NAC was a positive predictor (HR 0.47, p = 0.02). Despite no clear difference in pCR, survival outcomes remain poor for IBC compared to matched non-inflammatory controls.
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- 2023
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8. Clinicopathologic and sociodemographic factors associated with late relapse triple negative breast cancer in a multivariable logistic model: A multi-institution cohort study
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Adith Abraham, Carlos H. Barcenas, Richard J. Bleicher, Adam L. Cohen, Sara H. Javid, Ellis G. Levine, Nancy U. Lin, Beverly Moy, Joyce C. Niland, Antonio C. Wolff, Michael J. Hassett, Sarah Asad, and Daniel G. Stover
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Triple-negative breast cancer ,Late relapse ,Body mass index ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Most metastatic recurrences of triple negative breast cancer (TNBC) occur within five years of diagnosis, yet late relapses of TNBC (lrTNBC) do occur. Our objective was to develop a risk prediction model of lrTNBC using readily available clinicopathologic and sociodemographic features. Methods: We included patients diagnosed with stage I–III TNBC between 1998 and 2012 at ten academic cancer centers. lrTNBC was defined as relapse or mortality greater than 5 years from diagnosis. Features associated with lrTNBC were included in a multivariable logistic model using backward elimination with a p
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- 2023
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9. A framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA
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Anna-Lisa Doebley, Minjeong Ko, Hanna Liao, A. Eden Cruikshank, Katheryn Santos, Caroline Kikawa, Joseph B. Hiatt, Robert D. Patton, Navonil De Sarkar, Katharine A. Collier, Anna C. H. Hoge, Katharine Chen, Anat Zimmer, Zachary T. Weber, Mohamed Adil, Jonathan B. Reichel, Paz Polak, Viktor A. Adalsteinsson, Peter S. Nelson, David MacPherson, Heather A. Parsons, Daniel G. Stover, and Gavin Ha
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Science - Abstract
Nucleosome profiling from cell-free DNA (cfDNA) represents a potential approach for cancer detection and classification. Here, the authors develop Griffin, a computational framework for tumour subtype classification based on cfDNA nucleosome profiling that can work with ultra-low pass sequencing data.
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- 2022
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10. Association of body mass index and inflammatory dietary pattern with breast cancer pathologic and genomic immunophenotype in the nurses’ health study
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Sarah Asad, Adrienne Damicis, Yujing J. Heng, Kathryn Kananen, Katharine A. Collier, Elizabeth J. Adams, Kevin H. Kensler, Gabrielle M. Baker, Robert Wesolowski, Sagar Sardesai, Margaret Gatti-Mays, Bhuvaneswari Ramaswamy, A. Heather Eliassen, Susan E. Hankinson, Fred K. Tabung, Rulla M. Tamimi, and Daniel G. Stover
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Breast cancer ,Tumor microenvironment ,Tumor infiltrating lymphocytes ,Gene expression signature ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Breast tumor immune infiltration is clearly associated with improved treatment response and outcomes in breast cancer. However, modifiable patient factors associated with breast cancer immune infiltrates are poorly understood. The Nurses’ Health Study (NHS) offers a unique cohort to study immune gene expression in tumor and adjacent normal breast tissue, immune cell-specific immunohistochemistry (IHC), and patient exposures. We evaluated the association of body mass index (BMI) change since age 18, physical activity, and the empirical dietary inflammatory pattern (EDIP) score, all implicated in systemic inflammation, with immune cell-specific expression scores. Methods This population-based, prospective observational study evaluated 882 NHS and NHSII participants diagnosed with invasive breast cancer with detailed exposure and gene expression data. Of these, 262 women (training cohort) had breast tumor IHC for four classic immune cell markers (CD8, CD4, CD20, and CD163). Four immune cell-specific scores were derived via lasso regression using 105 published immune expression signatures’ association with IHC. In the remaining 620 patient evaluation cohort, we evaluated association of each immune cell-specific score as outcomes, with BMI change since age 18, physical activity, and EDIP score as predictors, using multivariable-adjusted linear regression. Results Among women with paired expression/IHC data from breast tumor tissue, we identified robust correlation between novel immune cell-specific expression scores and IHC. BMI change since age 18 was positively associated with CD4+ (β = 0.16; p = 0.009), and CD163 novel immune scores (β = 0.14; p = 0.04) in multivariable analyses. In other words, for each 10 unit (kg/m2) increase in BMI, the percentage of cells positive for CD4 and CD163 increased 1.6% and 1.4%, respectively. Neither physical activity nor EDIP was significantly associated with any immune cell-specific expression score in multivariable analyses. Conclusions BMI change since age 18 was positively associated with novel CD4+ and CD163+ cell scores in breast cancer, supporting further study of the effect of modifiable factors like weight gain on the immune microenvironment.
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- 2022
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11. Matched cohort study of germline BRCA mutation carriers with triple negative breast cancer in brightness
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Otto Metzger-Filho, Katharine Collier, Sarah Asad, Peter J. Ansell, Mark Watson, Junu Bae, Mathew Cherian, Joyce O’Shaughnessy, Michael Untch, Hope S. Rugo, Jens B. Huober, Mehra Golshan, William M. Sikov, Gunter von Minckwitz, Priya Rastogi, Lang Li, Lijun Cheng, David Maag, Norman Wolmark, Carsten Denkert, W. Fraser Symmans, Charles E. Geyer, Sibylle Loibl, and Daniel G. Stover
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract In the BrighTNess trial, carboplatin added to neoadjuvant chemotherapy (NAC) was associated with increased pathologic complete response (pCR) rates in patients with stage II/III triple-negative breast cancer (TNBC). In this matched cohort study, cases with a germline BRCA1/2 mutation (gBRCA; n = 75) were matched 1:2 with non-gBRCA controls (n = 150) by treatment arm, lymph node status, and age to evaluate pCR rates and association of benefit from platinum/PARP inhibitors with validated RNA expression-based immune, proliferation, and genomic instability scores among gBRCA with the addition of carboplatin ± veliparib to NAC. Among the well-matched cohorts, odds of pCR were not higher in gBRCA cancers who received standard NAC with carboplatin (OR 0.24, 95% CI [0.04-1.24], p = 0.09) or with carboplatin/veliparib (OR 0.44, 95% CI [0.10-1.84], p = 0.26) compared to non-gBRCA cancers. Higher PAM50 proliferation, GeparSixto immune, and CIN70 genomic instability scores were each associated with higher pCR rate in the overall cohort, but not specifically in gBRCA cases. In this study, gBRCA carriers did not have higher odds of pCR than non-gBRCA controls when carboplatin ± veliparib was added to NAC, and showed no significant differences in molecular, immune, chromosomal instability, or proliferation gene expression metrics.
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- 2021
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12. Circulating tumor DNA is readily detectable among Ghanaian breast cancer patients supporting non-invasive cancer genomic studies in Africa
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Samuel Terkper Ahuno, Anna-Lisa Doebley, Thomas U. Ahearn, Joel Yarney, Nicholas Titiloye, Nancy Hamel, Ernest Adjei, Joe-Nat Clegg-Lamptey, Lawrence Edusei, Baffour Awuah, Xiaoyu Song, Verna Vanderpuye, Mustapha Abubakar, Maire Duggan, Daniel G. Stover, Kofi Nyarko, John M. S. Bartlett, Francis Aitpillah, Daniel Ansong, Kevin L. Gardner, Felix Andy Boateng, Anne M. Bowcock, Carlos Caldas, William D. Foulkes, Seth Wiafe, Beatrice Wiafe-Addai, Montserrat Garcia-Closas, Alexander Kwarteng, Gavin Ha, Jonine D. Figueroa, Paz Polak, and the Ghana Breast Health Study Team
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Circulating tumor DNA (ctDNA) sequencing studies could provide novel insights into the molecular pathology of cancer in sub-Saharan Africa. In 15 patient plasma samples collected at the time of diagnosis as part of the Ghana Breast Health Study and unselected for tumor grade and subtype, ctDNA was detected in a majority of patients based on whole- genome sequencing at high (30×) and low (0.1×) depths. Breast cancer driver copy number alterations were observed in the majority of patients.
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- 2021
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13. Exploring approaches for predictive cancer patient digital twins: Opportunities for collaboration and innovation
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Eric A. Stahlberg, Mohamed Abdel-Rahman, Boris Aguilar, Alireza Asadpoure, Robert A. Beckman, Lynn L. Borkon, Jeffrey N. Bryan, Colleen M. Cebulla, Young Hwan Chang, Ansu Chatterjee, Jun Deng, Sepideh Dolatshahi, Olivier Gevaert, Emily J. Greenspan, Wenrui Hao, Tina Hernandez-Boussard, Pamela R. Jackson, Marieke Kuijjer, Adrian Lee, Paul Macklin, Subha Madhavan, Matthew D. McCoy, Navid Mohammad Mirzaei, Talayeh Razzaghi, Heber L. Rocha, Leili Shahriyari, Ilya Shmulevich, Daniel G. Stover, Yi Sun, Tanveer Syeda-Mahmood, Jinhua Wang, Qi Wang, and Ioannis Zervantonakis
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digital twins ,oncology ,cancer patient ,predictive medicine ,artificial intelligence ,mathematical modeling ,Medicine ,Public aspects of medicine ,RA1-1270 ,Electronic computers. Computer science ,QA75.5-76.95 - Abstract
We are rapidly approaching a future in which cancer patient digital twins will reach their potential to predict cancer prevention, diagnosis, and treatment in individual patients. This will be realized based on advances in high performance computing, computational modeling, and an expanding repertoire of observational data across multiple scales and modalities. In 2020, the US National Cancer Institute, and the US Department of Energy, through a trans-disciplinary research community at the intersection of advanced computing and cancer research, initiated team science collaborative projects to explore the development and implementation of predictive Cancer Patient Digital Twins. Several diverse pilot projects were launched to provide key insights into important features of this emerging landscape and to determine the requirements for the development and adoption of cancer patient digital twins. Projects included exploring approaches to using a large cohort of digital twins to perform deep phenotyping and plan treatments at the individual level, prototyping self-learning digital twin platforms, using adaptive digital twin approaches to monitor treatment response and resistance, developing methods to integrate and fuse data and observations across multiple scales, and personalizing treatment based on cancer type. Collectively these efforts have yielded increased insights into the opportunities and challenges facing cancer patient digital twin approaches and helped define a path forward. Given the rapidly growing interest in patient digital twins, this manuscript provides a valuable early progress report of several CPDT pilot projects commenced in common, their overall aims, early progress, lessons learned and future directions that will increasingly involve the broader research community.
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- 2022
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14. Modeling clonal structure over narrow time frames via circulating tumor DNA in metastatic breast cancer
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Zachary T. Weber, Katharine A. Collier, David Tallman, Juliet Forman, Sachet Shukla, Sarah Asad, Justin Rhoades, Samuel Freeman, Heather A. Parsons, Nicole O. Williams, Romualdo Barroso-Sousa, Elizabeth H. Stover, Haider Mahdi, Carrie Cibulskis, Niall J. Lennon, Gavin Ha, Viktor A. Adalsteinsson, Sara M. Tolaney, and Daniel G. Stover
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ctDNA ,Circulating tumor DNA ,Tumor evolution ,Neoantigens ,Serial sequencing ,Ultra-low pass whole genome sequencing ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Circulating tumor DNA (ctDNA) offers minimally invasive means to repeatedly interrogate tumor genomes, providing opportunities to monitor clonal dynamics induced by metastasis and therapeutic selective pressures. In metastatic cancers, ctDNA profiling allows for simultaneous analysis of both local and distant sites of recurrence. Despite the promise of ctDNA sampling, its utility in real-time genetic monitoring remains largely unexplored. Methods In this exploratory analysis, we characterize high-frequency ctDNA sample series collected over narrow time frames from seven patients with metastatic triple-negative breast cancer, each undergoing treatment with Cabozantinib, a multi-tyrosine kinase inhibitor (NCT01738438, https://clinicaltrials.gov/ct2/show/NCT01738438 ). Applying orthogonal whole exome sequencing, ultra-low pass whole genome sequencing, and 396-gene targeted panel sequencing, we analyzed 42 plasma-derived ctDNA libraries, representing 4–8 samples per patient with 6–42 days between samples. Integrating tumor fraction, copy number, and somatic variant information, we model tumor clonal dynamics, predict neoantigens, and evaluate consistency of genomic information from orthogonal assays. Results We measured considerable variation in ctDNA tumor faction in each patient, often conflicting with RECIST imaging response metrics. In orthogonal sequencing, we found high concordance between targeted panel and whole exome sequencing in both variant detection and variant allele frequency estimation (specificity = 95.5%, VAF correlation, r = 0.949), Copy number remained generally stable, despite resolution limitations posed by low tumor fraction. Through modeling, we inferred and tracked distinct clonal populations specific to each patient and built phylogenetic trees revealing alterations in hallmark breast cancer drivers, including TP53, PIK3CA, CDK4, and PTEN. Our modeling revealed varied responses to therapy, with some individuals displaying stable clonal profiles, while others showed signs of substantial expansion or reduction in prevalence, with characteristic alterations of varied literature annotation in relation to the study drug. Finally, we predicted and tracked neoantigen-producing alterations across time, exposing translationally relevant detection patterns. Conclusions Despite technical challenges arising from low tumor content, metastatic ctDNA monitoring can aid our understanding of response and progression, while minimizing patient risk and discomfort. In this study, we demonstrate the potential for high-frequency monitoring of evolving genomic features, providing an important step toward scalable, translational genomics for clinical decision making.
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- 2021
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15. Genomic features of rapid versus late relapse in triple negative breast cancer
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Yiqing Zhang, Sarah Asad, Zachary Weber, David Tallman, William Nock, Meghan Wyse, Jerome F. Bey, Kristin L. Dean, Elizabeth J. Adams, Sinclair Stockard, Jasneet Singh, Eric P. Winer, Nancy U. Lin, Yi-Zhou Jiang, Ding Ma, Peng Wang, Leming Shi, Wei Huang, Zhi-Ming Shao, Mathew Cherian, Maryam B. Lustberg, Bhuvaneswari Ramaswamy, Sagar Sardesai, Jeffrey VanDeusen, Nicole Williams, Robert Wesolowski, Samilia Obeng-Gyasi, Gina M. Sizemore, Steven T. Sizemore, Claire Verschraegen, and Daniel G. Stover
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Breast Cancer ,Triple-negative breast cancer ,Machine learning ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previously shown that rapid relapse of TNBC is associated with distinct sociodemographic features. We hypothesized that rapid versus late relapse in TNBC is also defined by distinct clinical and genomic features of primary tumors. Methods Using three publicly-available datasets, we identified 453 patients diagnosed with primary TNBC with adequate follow-up to be characterized as ‘rapid relapse’ (rrTNBC; distant relapse or death ≤2 years of diagnosis), ‘late relapse’ (lrTNBC; > 2 years) or ‘no relapse’ (nrTNBC: > 5 years no relapse/death). We explored basic clinical and primary tumor multi-omic data, including whole transcriptome (n = 453), and whole genome copy number and mutation data for 171 cancer-related genes (n = 317). Association of rapid relapse with clinical and genomic features were assessed using Pearson chi-squared tests, t-tests, ANOVA, and Fisher exact tests. We evaluated logistic regression models of clinical features with subtype versus two models that integrated significant genomic features. Results Relative to nrTNBC, both rrTNBC and lrTNBC had significantly lower immune signatures and immune signatures were highly correlated to anti-tumor CD8 T-cell, M1 macrophage, and gamma-delta T-cell CIBERSORT inferred immune subsets. Intriguingly, lrTNBCs were enriched for luminal signatures. There was no difference in tumor mutation burden or percent genome altered across groups. Logistic regression mModels that incorporate genomic features significantly outperformed standard clinical/subtype models in training (n = 63 patients), testing (n = 63) and independent validation (n = 34) cohorts, although performance of all models were overall modest. Conclusions We identify clinical and genomic features associated with rapid relapse TNBC for further study of this aggressive TNBC subset.
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- 2021
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16. Clinical impact of interruption in adjuvant Trastuzumab therapy in patients with operable HER-2 positive breast cancer
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Sagar Sardesai, Jasmine Sukumar, Mahmoud Kassem, Marilly Palettas, Julie Stephens, Evan Morgan, Daniel Addison, Ragavendra Baliga, Daniel G. Stover, Jeffrey VanDeusen, Nicole Williams, Mathew Cherian, Maryam Lustberg, Robert Wesolowski, and Bhuvaneswari Ramaswamy
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HER2 ,Breast cancer ,Trastuzumab ,Cardio-oncology ,Chemotherapy ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Trastuzumab-induced cardiotoxicity (TIC) can lead to early discontinuation of adjuvant therapy, however there is limited evidence on long-term survival outcomes in patients with operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) experiencing treatment interruption or discontinuation. Methods The primary objective of the study was to evaluate disease-free survival (DFS) in non-metastatic, HER2-positive, female BC patients who experienced treatment interruption or early discontinuation of trastuzumab therapy. Clinical and histopathological data were collected on 400 patients at The Ohio State University, an NCI-designated comprehensive cancer center between January 2005 and December 2015. Treatment interruption was defined as any delay of ≥2 weeks during trastuzumab therapy, including permanent cessation prior to completing planned therapy. TIC was defined as LVEF 15 points decline from baseline as evaluated by 2D echocardiogram after initiation of (neo) adjuvant therapy. DFS was defined as the time from diagnosis to first recurrence (loco-regional or distant recurrence) including second primary BC or death. Overall survival (OS) was defined as the time from diagnosis to death or last known follow up. OS/DFS estimates were generated using Kaplan-Meier methods and compared using Log-rank tests. Cox proportional hazard models were used to calculate adjusted hazard ratios (aHR) for OS/DFS. Results A total of 369 patients received trastuzumab therapy; 106 (29%) patients experienced treatment interruption at least once and 42 (11%) permanently discontinued trastuzumab prior to completing planned therapy. TIC was the most common reason for interruption (66 patients, 62%). The median duration of trastuzumab in patients with treatment interruption was 11.3 months (range: 0.5–16.9) with 24 (23%) patients receiving ≤6 months of therapy. This duration includes the time delay related to treatment interruption. Patients with any treatment interruption had worse DFS (aHR: 4.4, p = 0.001) and OS (aHR: 4.8, p
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- 2020
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17. Activity of Estrogen Receptor β Agonists in Therapy-Resistant Estrogen Receptor-Positive Breast Cancer
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Jharna Datta, Natalie Willingham, Jasmine M. Manouchehri, Patrick Schnell, Mirisha Sheth, Joel J. David, Mahmoud Kassem, Tyler A. Wilson, Hanna S. Radomska, Christopher C. Coss, Chad E. Bennett, Ramesh K. Ganju, Sagar D. Sardesai, Maryam Lustberg, Bhuvaneswari Ramaswamy, Daniel G. Stover, and Mathew A. Cherian
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ERα ,ERβ ,ER+ breast cancer ,OSU-ERb-12 ,LY500307 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
BackgroundAmong women, breast cancer is the leading cause of cancer-related death worldwide. Estrogen receptor α-positive (ERα+) breast cancer accounts for 70% of all breast cancer subtypes. Although ERα+ breast cancer initially responds to estrogen deprivation or blockade, the emergence of resistance compels the use of more aggressive therapies. While ERα is a driver in ERα+ breast cancer, ERβ plays an inhibitory role in several different cancer types. To date, the lack of highly selective ERβ agonists without ERα activity has limited the exploration of ERβ activation as a strategy for ERα+ breast cancer.MethodsWe measured the expression levels of ESR1 and ESR2 genes in immortalized mammary epithelial cells and different breast cancer cell lines. The viability of ERα+ breast cancer cell lines upon treatments with specific ERβ agonists, including OSU-ERb-12 and LY500307, was assessed. The specificity of the ERβ agonists, OSU-ERb-12 and LY500307, was confirmed by reporter assays. The effects of ERβ agonists on cell proliferation, cell cycle, apoptosis, colony formation, cell migration, and expression of tumor suppressor proteins were analyzed. The expression of ESR2 and genes containing ERE-AP1 composite response elements was examined in ERα+ human breast cancer samples to determine the correlation between ESR2 expression and overall survival and that of putative ESR2-regulated genes.ResultsIn this study, we demonstrate the efficacy of highly selective ERβ agonists in ERα+ breast cancer cell lines and drug-resistant derivatives. ERβ agonists blocked cell proliferation, migration, and colony formation and induced apoptosis and S and/or G2/M cell-cycle arrest of ERα+ breast cancer cell lines. Also, increases in the expression of the key tumor suppressors FOXO1 and FOXO3a were noted. Importantly, the strong synergy between ERβ agonists and ERα antagonists suggested that the efficacy of ERβ agonists is maximized by combination with ERα blockade. Lastly, ESR2 (ERβ gene) expression was negatively correlated with ESR1 (ERα gene) and CCND1 RNA expression in human metastatic ERα+/HER2- breast cancer samples.ConclusionOur results demonstrate that highly selective ERβ agonists attenuate the viability of ERα+ breast cancer cell lines in vitro and suggest that this therapeutic strategy merits further evaluation for ERα+ breast cancer.
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- 2022
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18. Features, Outcomes, and Management Strategies of Male Breast Cancer: A Single Institution Comparison to Well-Matched Female Controls
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Joseph Liu, Anupama Suresh, Marilly Palettas, Julie Stephens, Akaansha Ganju, Evan Morgan, Mahmoud Kassem, Yanjun Hou, Anil Parwani, Anne Noonan, Raquel Reinbolt, Jeffrey VanDeusen, Sagar Sardesai, Nicole Williams, Mathew Cherian, Gary Tozbikian, Daniel G. Stover, Maryam Lustberg, Zaibo Li, Bhuvaneswari Ramaswamy, and Robert Wesolowski
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male breast cancer ,matched-pair analysis ,rare disease ,recurrence score ,survival analysis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Medicine - Abstract
Objective: The primary objective of this study was to delineate differences in management, overall and distant disease-free survival in males diagnosed with breast cancer and treated at The Ohio State University Comprehensive Cancer Center as compared to comprehensively matched female subjects. Secondary objectives included assessment of clinical and histopathologic features and recurrence score, as measured by Oncotype DX and the modified Magee equation #2.Materials and Methods: This single institution retrospective study compared male and comprehensively matched female patients (1:2) with stage I-III breast cancer between 1994 and 2014. Recurrence risk was estimated using a modified Magee equation. Overall survival and distant disease-free survival were estimated and compared using Kaplan-Meier and Log-rank methods.Results: Forty-five male breast cancer patients were included (stage I: 26.7%; stage II: 53.3%; stage III: 20.0%; hormone receptor positive: 97.8%; human epidermal growth factor receptor 2 negative: 84.4%) with a median age of 63.8 (43.0-79.4) years at diagnosis. Intermediate and low recurrence scores were most common in male and female patients respectively; mean score was similar between groups (20.3 vs. 19.8). The proportion of male breast cancer patients treated with adjuvant chemotherapy and post-mastectomy radiation was lower compared to female patients (42.2% vs. 65.3%, p=0.013; 22.7% vs. 44.4%, p=0.030, respectively). Overall survival and distant disease-free survival between male and female patients were similar.Conclusion: Male breast cancer patient outcomes were similar compared to well-matched female patients suggesting that breast cancer specific factors are more prognostic than gender.
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- 2020
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19. Erythrocyte membrane fatty acids and breast cancer risk by tumor tissue expression of immuno-inflammatory markers and fatty acid synthase: a nested case-control study
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Emma E. McGee, Claire H. Kim, Molin Wang, Donna Spiegelman, Daniel G. Stover, Yujing J. Heng, Laura C. Collins, Gabrielle M. Baker, Maryam S. Farvid, Pepper Schedin, Sonali Jindal, Rulla M. Tamimi, and A. Heather Eliassen
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Breast cancer ,Erythrocyte membrane ,Fatty acid ,Immune marker ,Inflammation ,Tumor-infiltrating lymphocytes ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Previous studies of fatty acids and breast cancer risk have shown mixed results, which may be due in part to tumor heterogeneity. Prior research has also illustrated an important role of specific fatty acids in immune regulation, T cell function, and inflammation, indicating that the effects of specific fatty acids on breast cancer risk may vary by tumor expression of immuno-inflammatory markers. We therefore aimed to evaluate the relationships between prediagnostic erythrocyte membrane fatty acids and breast cancer risk by tumor tissue expression of immuno-inflammatory markers (CD4, CD8, CD20, CD163, COX-2) and fatty acid synthase (FAS). Methods We conducted a matched case-control study nested within the Nurses’ Health Study II (n = 235 cases and 235 controls). Blood samples were collected from 1996 to 1999. Tumor tissue blocks were collected for cases diagnosed after blood collection and through 2006. Unconditional nominal polytomous logistic regression adjusted for matching factors and potential confounders was used to assess whether associations between fatty acids and breast cancer risk varied by tumor expression subtype, ascertained via immunohistochemistry. Odds ratios (OR) and 95% confidence intervals (CI) were estimated separately by tumor expression subtype using unconditional logistic regression. Results Associations between fatty acids and breast cancer risk did not vary substantially by tumor CD4, CD20, CD163, or COX-2. However, n-3 polyunsaturated fatty acids (PUFAs) were inversely associated with CD8low but not CD8high cancers (CD8low ORT3 vs T1 = 0.45, 95% CI 0.23–0.87, P trend = 0.02; CD8high ORT3 vs T1 = 1.19, 95% CI 0.62–2.26, P trend = 0.62; P het = 0.04). n-6 PUFAs were suggestively inversely associated with CD8high but not CD8low cancers (CD8high ORT3 vs T1 = 0.61, 95% CI 0.32–1.14, P trend = 0.11; CD8low ORT3 vs T1 = 1.63, 95% CI 0.87–3.04, P trend = 0.12; P het = 0.02). Trans fatty acids were positively associated with FAShigh but not FASlow tumors (FAShigh ORT3 vs T1 = 2.94, 95% CI 1.46–5.91, P trend = 0.002; FASlow ORT3 vs T1 = 0.99, 95% CI 0.52–1.92, P trend = 0.97; P het = 0.01). Conclusion Results indicate that the effects of n-3 PUFAs, n-6 PUFAs, and trans fatty acids on breast cancer risk may vary by tumor tissue expression subtypes. Findings suggest potential immuno-modulatory and FAS-mediated mechanisms.
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- 2020
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20. Metastatic breast cancer patient perceptions of somatic tumor genomic testing
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Elizabeth J. Adams, Sarah Asad, Raquel Reinbolt, Katharine A. Collier, Mahmoud Abdel-Rasoul, Susan Gillespie, James L. Chen, Mathew A. Cherian, Anne M. Noonan, Sagar Sardesai, Jeffrey VanDeusen, Robert Wesolowski, Nicole Williams, Charles L. Shapiro, Erin R. Macrae, Robert Pilarski, Amanda E. Toland, Leigha Senter, Bhuvaneswari Ramaswamy, Clara N. Lee, Maryam B. Lustberg, and Daniel G. Stover
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Metastatic breast cancer ,Genomics ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background To assess metastatic breast cancer (MBC) patient psychological factors, perceptions, and comprehension of tumor genomic testing. Methods In a prospective, single institution, single-arm trial, patients with MBC underwent next-generation sequencing at study entry with sequencing results released at progression. Patients who completed surveys before undergoing sequencing were included in the present secondary analysis (n = 58). We administered four validated psychosocial measures: Center for Epidemiologic Studies Depression Scale, Beck Anxiety Inventory, Trust in Physician Scale, and Communication and Attitudinal Self-Efficacy scale for Cancer. Genetic comprehension was assessed using 7-question objective and 6-question subjective measures. Longitudinal data were assessed (n = 40) using paired Wilcoxon signed rank and McNemar’s test of agreement. Results There were no significant differences between the beginning and end of study in depression, anxiety, physician trust, or self-efficacy (median time on study: 7.6 months). Depression and anxiety were positively associated with each other and both negatively associated with self-efficacy. Self-efficacy decreased from pre- to post-genomic testing (p = 0.05). Objective genetics comprehension did not significantly change from pre- to post-genomic testing, but patients expressed increased confidence in their ability to teach others about genetics (p = 0.04). Objective comprehension was significantly lower in non-white patients (p = 0.02) and patients with lower income (p = 0.04). Conclusions This is the only study, to our knowledge, to longitudinally evaluate multiple psychological metrics in MBC as patients undergo tumor genomic testing. Overall, psychological dimensions remained stable over the duration of tumor genomic testing. Among patients with MBC, depression and anxiety metrics were negatively correlated with patient self-efficacy. Patients undergoing somatic genomic testing had limited genomic knowledge, which varied by demographic groups and may warrant additional educational intervention. Clinical trial information NCT01987726 , registered November 13, 2013.
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- 2020
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21. Assessment of outcomes and novel immune biomarkers in metaplastic breast cancer: a single institution retrospective study
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Evan Morgan, Anupama Suresh, Akaansha Ganju, Daniel G. Stover, Robert Wesolowski, Sagar Sardesai, Anne Noonan, Raquel Reinbolt, Jeffrey VanDeusen, Nicole Williams, Mathew A. Cherian, Zaibo Li, Gregory Young, Marilly Palettas, Julie Stephens, Joseph Liu, Amanda Luff, Bhuvaneswari Ramaswamy, and Maryam Lustberg
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Metaplastic breast cancer ,Clinical outcomes ,Distant disease-free survival ,Overall survival ,Triple-negative breast cancer ,Immune markers ,Surgery ,RD1-811 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Metaplastic breast cancer remains poorly characterized given its rarity and heterogeneity. The majority of metaplastic breast cancers demonstrate a phenotype of triple-negative breast cancer; however, differences in clinical outcomes between metaplastic breast cancer and triple-negative breast cancer in the era of third-generation chemotherapy remain unclear. Methods We compared the clinical outcomes between women with metaplastic breast cancer and women with triple-negative breast cancer diagnosed between 1994 and 2014. Metaplastic breast cancer patients were matched 1:3 to triple-negative breast cancer patients by stage and age at diagnosis. Distant disease-free survival (DDFS) and overall survival (OS) were estimated using Kaplan Meier methods and Cox proportional hazard regression models. Immune checkpoint markers were characterized by immunohistochemistry in a subset of samples. Results Forty-four metaplastic breast cancer patients (stage I 14%; stage II 73%; stage III 11%; stage IV 2%) with an average age of 55.4 (± 13.9) years at diagnosis. Median follow-up for the included metaplastic breast cancer and triple-negative breast cancer patients (n = 174) was 2.8 (0.1–19.0) years. The DDFS and OS between matched metaplastic breast cancer and triple-negative breast cancer patients were similar, even when adjusting for clinical covariates (DDFS: HR = 1.64, p = 0.22; OS: HR = 1.64, p = 0.26). Metaplastic breast cancer samples (n = 27) demonstrated greater amount of CD163 in the stroma (p = 0.05) and PD-L1 in the tumor (p = 0.01) than triple-negative breast cancer samples (n = 119), although more triple-negative breast cancer samples were positive for CD8 in the tumor than metaplastic breast cancer samples (p = 0.02). Conclusions Patients with metaplastic breast cancer had similar outcomes to those with triple-negative breast cancer based on DDFS and OS. The immune checkpoint marker profile of metaplastic breast cancers in this study may prove useful in future studies attempting to demonstrate an association between immune profile and survival.
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- 2020
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22. Author Correction: A framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA
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Anna-Lisa Doebley, Minjeong Ko, Hanna Liao, A. Eden Cruikshank, Katheryn Santos, Caroline Kikawa, Joseph B. Hiatt, Robert D. Patton, Navonil De Sarkar, Katharine A. Collier, Anna C. H. Hoge, Katharine Chen, Anat Zimmer, Zachary T. Weber, Mohamed Adil, Jonathan B. Reichel, Paz Polak, Viktor A. Adalsteinsson, Peter S. Nelson, David MacPherson, Heather A. Parsons, Daniel G. Stover, and Gavin Ha
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Science - Published
- 2023
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23. Replicative Instability Drives Cancer Progression
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Benjamin B. Morris, Jason P. Smith, Qi Zhang, Zhijie Jiang, Oliver A. Hampton, Michelle L. Churchman, Susanne M. Arnold, Dwight H. Owen, Jhanelle E. Gray, Patrick M. Dillon, Hatem H. Soliman, Daniel G. Stover, Howard Colman, Arnab Chakravarti, Kenneth H. Shain, Ariosto S. Silva, John L. Villano, Michael A. Vogelbaum, Virginia F. Borges, Wallace L. Akerley, Ryan D. Gentzler, Richard D. Hall, Cindy B. Matsen, C. M. Ulrich, Andrew R. Post, David A. Nix, Eric A. Singer, James M. Larner, Peter Todd Stukenberg, David R. Jones, and Marty W. Mayo
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replicative instability (RIN) ,cancer progression ,metastasis ,MYBL2 ,single-strand break repair ,translesion synthesis ,Microbiology ,QR1-502 - Abstract
In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.
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- 2022
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24. Anthracycline-free or short-term regimen as adjuvant chemotherapy for operable breast cancer: A phase III randomized non-inferiority trial
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Ke-Da Yu, Xi-Yu Liu, Li Chen, Miao Mo, Jiong Wu, Guang-Yu Liu, Gen-Hong Di, Claire Verschraegen, Daniel G. Stover, Zhi-Gang Zhuang, François Bertucci, Armando Orlandi, Jie Wang, Giuseppe Lippi, Ke-Jin Wu, Mohammed A. Osman, Lei Fan, and Zhi-Ming Shao
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Public aspects of medicine ,RA1-1270 - Abstract
Background: De-escalating anthracycline is gaining popularity for breast cancer patients. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracycline-based regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Methods: It is a prospective, open-label, phase 3, randomized non-inferiority trial from June 1, 2010 to June 1, 2017. Follow-up had been kept until July 2019. This trial was conducted at Fudan University Shanghai Cancer Center. Patients with pT1–3N+ or pT2–3N0 but high-risk (grade II/III, lymphovascular invasion, ≤35 years of age or hormone-receptor negative) HER2-negative operable breast cancer were eligible and stratified by age, pathological tumour stage, pathological node status and hormone-receptor status. Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC, n = 524), 3 cycles of cyclophosphamide/epirubicin/fluorouracil followed by 3 cycles of docetaxel (CEF-T, n = 523) or epirubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 12 weeks (EC-P, n = 524) as the intention-to-treat population. Of these patients, 94% completed allocated therapy. Difference in disease-free survival (DFS) compared to EC-P. The prespecified non-inferiority margin was 4.5%, corresponding to the hazard ratio (HR) of 1.44 (one-sided α = 0.05), with an assumed 5-year DFS of 89% for EC-P. Findings: Included in the intention-to-treat population were 1571 patients (median [IQR] age, 50 [45–57] years; 92% estrogen receptor [ER]-positive; 59% pN+). Through a median follow-up of 5.5 years, HR for TC versus EC-P was 1.05 (5-year DFS: 85.0% vs. 85.9%; 90% confidence interval [CI]: 0.79–1.39, non-inferior P = 0.048) and for CEF-T versus EC-P, 0.99 (5-year DFS: 85.1% vs. 85.9%; 90% CI: 0.75–1.30, non-inferior P = 0.045). Grade 3 or 4 adverse events for TC included rash (3.9%) and peripheral neuropathy (2.8%) and for CEF-T and EC-P diarrhea and nausea/vomiting were predominant. Results of per-protocol analyses were similar. Interpretation: Both TC and CEF-T are non-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer. TC is a safe regimen that avoids anthracycline-related side effects. Funding: This work was supported by grants from the National Natural Science Foundation of China (Grants 81672600, 81722032, 82072916, and 91959207), the 2018 Shanghai Youth Excellent Academic Leader, the Fudan ZHUOSHI Project, the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (grant SHDC12010116), the Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System (grant 2013ZYJB0302), the Innovation Team of the Ministry of Education (grant IRT1223), and the Shanghai Key Laboratory of Breast Cancer (grant 12DZ2260100) and the National Cancer Institute (grant P30 CA16058).
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- 2021
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25. Abrupt involution induces inflammation, estrogenic signaling, and hyperplasia linking lack of breastfeeding with increased risk of breast cancer
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Mustafa M. Basree, Neelam Shinde, Christopher Koivisto, Maria Cuitino, Raleigh Kladney, Jianying Zhang, Julie Stephens, Marilly Palettas, Allen Zhang, Hee Kyung Kim, Santiago Acero-Bedoya, Anthony Trimboli, Daniel G. Stover, Thomas Ludwig, Ramesh Ganju, Daniel Weng, Peter Shields, Jo Freudenheim, Gustavo W. Leone, Gina M. Sizemore, Sarmila Majumder, and Bhuvaneswari Ramaswamy
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Breastfeeding ,Breast cancer ,Abrupt involution ,Luminal progenitor cells ,Collagen ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background A large collaborative analysis of data from 47 epidemiological studies concluded that longer duration of breastfeeding reduces the risk of developing breast cancer. Despite the strong epidemiological evidence, the molecular mechanisms linking prolonged breastfeeding to decreased risk of breast cancer remain poorly understood. Methods We modeled two types of breastfeeding behaviors in wild type FVB/N mice: (1) normal or gradual involution of breast tissue following prolonged breastfeeding and (2) forced or abrupt involution following short-term breastfeeding. To accomplish this, pups were gradually weaned between 28 and 31 days (gradual involution) or abruptly at 7 days postpartum (abrupt involution). Mammary glands were examined for histological changes, proliferation, and inflammatory markers by immunohistochemistry. Fluorescence-activated cell sorting was used to quantify mammary epithelial subpopulations. Gene set enrichment analysis was used to analyze gene expression data from mouse mammary luminal progenitor cells. Similar analysis was done using gene expression data generated from human breast samples obtained from parous women enrolled on a tissue collection study, OSU-2011C0094, and were undergoing reduction mammoplasty without history of breast cancer. Results Mammary glands from mice that underwent abrupt involution exhibited denser stroma, altered collagen composition, higher inflammation and proliferation, increased estrogen receptor α and progesterone receptor expression compared to those that underwent gradual involution. Importantly, when aged to 4 months postpartum, mice that were in the abrupt involution cohort developed ductal hyperplasia and squamous metaplasia. Abrupt involution also resulted in a significant expansion of the luminal progenitor cell compartment associated with enrichment of Notch and estrogen signaling pathway genes. Breast tissues obtained from healthy women who breastfed for
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- 2019
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26. The COVID-19 & Cancer Consortium (CCC19) and Opportunities for Radiation Oncology
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Sachin R. Jhawar, MD, MSCI, Joshua D. Palmer, MD, Shang-Jui Wang, MD, Danielle Bitterman, MD, Brett Klamer, PhD, Minh Huynh-Le, MD, Caroline Chung, MD, MSc, FRCPC, CIP, Nitin Ohri, MD, Daniel G. Stover, MD, Maryam B. Lustberg, MD, MPH, Sanjay Mishra, PhD, Jeremy Warner, MD, MS, Salma Jabbour, MD, and Sharad Goyal, MD
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Medical physics. Medical radiology. Nuclear medicine ,R895-920 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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27. TTF-1 Positive Primary Small Cell Carcinoma of the Breast: A Case Report and Review of the Literature
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Hinda Boutrid, Mahmoud Kassem, Gary Tozbikian, Evan Morgan, Julia White, Manisha Shah, Jeffrey Vandeusen, Sagar Sardesai, Nicole Williams, Daniel G. Stover, Maryam Lustberg, Robert Wesolowski, Vinay Pudavalli, Terence M. Williams, Bhavana Konda, Stephanie Fortier, David Carbone, Bhuvaneswari Ramaswamy, and Mathew A. Cherian
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TTF-1 ,small cell cancer ,breast cancer ,PDL-1 ,neuroendocrine cancer ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Primary small cell carcinoma of the breast (SCCB) is a rare tumor subtype comprising
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- 2020
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28. Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors
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Viktor A. Adalsteinsson, Gavin Ha, Samuel S. Freeman, Atish D. Choudhury, Daniel G. Stover, Heather A. Parsons, Gregory Gydush, Sarah C. Reed, Denisse Rotem, Justin Rhoades, Denis Loginov, Dimitri Livitz, Daniel Rosebrock, Ignaty Leshchiner, Jaegil Kim, Chip Stewart, Mara Rosenberg, Joshua M. Francis, Cheng-Zhong Zhang, Ofir Cohen, Coyin Oh, Huiming Ding, Paz Polak, Max Lloyd, Sairah Mahmud, Karla Helvie, Margaret S. Merrill, Rebecca A. Santiago, Edward P. O’Connor, Seong H. Jeong, Rachel Leeson, Rachel M. Barry, Joseph F. Kramkowski, Zhenwei Zhang, Laura Polacek, Jens G. Lohr, Molly Schleicher, Emily Lipscomb, Andrea Saltzman, Nelly M. Oliver, Lori Marini, Adrienne G. Waks, Lauren C. Harshman, Sara M. Tolaney, Eliezer M. Van Allen, Eric P. Winer, Nancy U. Lin, Mari Nakabayashi, Mary-Ellen Taplin, Cory M. Johannessen, Levi A. Garraway, Todd R. Golub, Jesse S. Boehm, Nikhil Wagle, Gad Getz, J. Christopher Love, and Matthew Meyerson
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Science - Abstract
Identifying the mutational landscape of tumours from cell-free DNA in the blood could help diagnostics in cancer. Here, the authors present ichorCNA, software that quantifies tumour content in cell free DNA, and they demonstrate that cell-free DNA whole-exome sequencing is concordant with metastatic tumour whole-exome sequencing.
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- 2017
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29. Stress-Inducible Gene Atf3 Dictates a Dichotomous Macrophage Activity in Chemotherapy-Enhanced Lung Colonization
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Justin D. Middleton, Jared Fehlman, Subhakeertana Sivakumar, Daniel G. Stover, and Tsonwin Hai
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chemotherapy ,breast cancer metastasis ,lung colonization ,macrophage dichotomy ,stress response ,Atf3 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Previously, we showed that chemotherapy paradoxically exacerbated cancer cell colonization at the secondary site in a manner dependent on Atf3, a stress-inducible gene, in the non-cancer host cells. Here, we present evidence that this phenotype is established at an early stage of colonization within days of cancer cell arrival. Using mouse breast cancer models, we showed that, in the wild-type (WT) lung, cyclophosphamide (CTX) increased the ability of the lung to retain cancer cells in the vascular bed. Although CTX did not change the WT lung to affect cancer cell extravasation or proliferation, it changed the lung macrophage to be pro-cancer, protecting cancer cells from death. This, combined with the initial increase in cell retention, resulted in higher lung colonization in CTX-treated than control-treated mice. In the Atf3 knockout (KO) lung, CTX also increased the ability of lung to retain cancer cells. However, the CTX-treated KO macrophage was highly cytotoxic to cancer cells, resulting in no increase in lung colonization—despite the initial increase in cell retention. In summary, the status of Atf3 dictates the dichotomous activity of macrophage: pro-cancer for CTX-treated WT macrophage but anti-cancer for the KO counterpart. This dichotomy provides a mechanistic explanation for CTX to exacerbate lung colonization in the WT but not Atf3 KO lung.
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- 2021
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30. Chemotherapy-Exacerbated Breast Cancer Metastasis: A Paradox Explainable by Dysregulated Adaptive-Response
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Justin D. Middleton, Daniel G. Stover, and Tsonwin Hai
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chemotherapy ,breast cancer metastasis ,stress response ,adaptive-response network ,ATF3 ,seed and soil theory ,cancer-host interaction ,tumor microenvironment ,immune modulation ,tumor immune environment ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
An emerging picture in cancer biology is that, paradoxically, chemotherapy can actively induce changes that favor cancer progression. These pro-cancer changes can be either inside (intrinsic) or outside (extrinsic) the cancer cells. In this review, we will discuss the extrinsic pro-cancer effect of chemotherapy; that is, the effect of chemotherapy on the non-cancer host cells to promote cancer progression. We will focus on metastasis, and will first discuss recent data from mouse models of breast cancer. Despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, resulting in an increased escape of cancer cells into the blood stream. Furthermore, chemotherapry changes the tissue microenvironment at the distant sites, making it more hospitable to cancer cells upon their arrival. We will then discuss the idea and evidence that these devastating pro-metastatic effects of chemotherapy can be explained in the context of adaptive-response. At the end, we will discuss the potential relevance of these mouse data to human breast cancer and their implication on chemotherapy in the clinic.
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- 2018
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31. Typhoid vaccine does not impact feelings of social connection or social behavior in a randomized crossover trial among middle-aged female breast cancer survivors
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Annelise A. Madison, Baldwin Way, Kyle G. Ratner, Megan Renna, Rebecca Andridge, Juan Peng, M. Rosie Shrout, John Sheridan, Maryam Lustberg, Bhuvaneswari Ramaswamy, Robert Wesolowski, Jeffrey B. VanDeusen, Nicole O. Williams, Sagar D. Sardesai, Anne M. Noonan, Raquel E. Reinbolt, Daniel G. Stover, Mathew A. Cherian, William B. Malarkey, and Janice K. Kiecolt-Glaser
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Behavioral Neuroscience ,Cancer Survivors ,Endocrine and Autonomic Systems ,Typhoid-Paratyphoid Vaccines ,Immunology ,Humans ,Female ,Breast Neoplasms ,Middle Aged ,Social Behavior - Abstract
Inflammation can have social consequences, which may be relevant to inflammation's link with depression. The current study tests whether a typhoid vaccine increases feelings of social disconnection and avoidance behavior.In two full-day visits at least three weeks apart, 172 postmenopausal breast cancer survivors (Stage I-IIIA) each received a typhoid capsular polysaccharide vaccination and a saline placebo injection in a random sequence. Blood was drawn prior to the injection, as well as every 90 min thereafter for 8 h to assess the inflammatory response (interleukin-6, IL-6; interleukin-1 receptor antagonist, IL-1Ra). At both visits, women completed the Social Connection Scale at 0 and 8.5 h post-vaccination as well as implicit and explicit social avoidance tasks at 7 h post-vaccination.The typhoid vaccine triggered rises in both inflammatory markers (ps 0.01), but it did not impact feelings of social connection (p = .32), or performance on the implicit (p = .34) or explicit tasks (p = .37). Inflammatory rises did not predict feelings of social connection (ps 0.64) or performance on explicit (ps 0.73) or implicit (ps 0.88) social avoidance tasks.Milder inflammatory stimuli may not affect social processes. Higher levels of inflammation or, relatedly, more sickness symptoms may be necessary to recapitulate prior findings of social avoidance.
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- 2023
32. Patient Understanding of Tumor Genomic Testing: A Quality Improvement Effort
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Leigha Senter, Deloris Veney, Taylor Surplus, Marcy Haynam, Elizabeth J. Adams, Heather Hampel, Amanda E. Toland, Carolyn J. Presley, Tasleem J. Padamsee, Clara N. Lee, Shelly R. Hovick, and Daniel G. Stover
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Oncology ,Oncology (nursing) ,Health Policy - Abstract
PURPOSE: Tumor genomic testing (TGT) has become increasingly adopted as part of standard cancer care for many cancers. Despite national guidelines around patient education before TGT, available evidence suggests that most patients' understanding of genomics remains limited, particularly lower-income and minority patients, and most patients are not informed regarding potential incidental germline findings. METHODS: To investigate and address limitations in patient understanding of TGT results, a Plan-Do-Study-Act (PDSA) approach is being used to assess needs, identify opportunities for improvement, and implement approaches to optimize patient education. We reviewed published guidelines related to pre-TGT provider-patient education and to identify key points (Plan). A provider quality improvement survey was completed (Do), which highlighted inconsistency in pre-TGT discussion practice across providers and minimal discussion with patients regarding the possibility of incidental germline findings. RESULTS: Patient focus groups and interviews (N = 12 patients) were completed with coding of each transcript (Study), which revealed themes including trouble differentiating TGT from other forms of testing, yet understanding that results could tailor therapy. The integration of data across this initial PDSA cycle identified consistent themes and opportunities, which were incorporated into a patient-directed, concise animated video for pre-TGT education (Act), which will form the foundation of a subsequent PDSA cycle. The video addresses how TGT may/may not inform treatment, the process for TGT using existing tissue or liquid biopsy, insurance coverage, and the potential need for germline genetics follow-up because of incidental findings. CONCLUSION: This PDSA cycle reveals key gaps and opportunities for improvement in patient education before TGT.
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- 2023
33. Breast cancer survivors’ typhoid vaccine responses: Chemotherapy, obesity, and fitness make a difference
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Janice K. Kiecolt-Glaser, Megan Renna, Juan Peng, John Sheridan, Maryam Lustberg, Bhuvaneswari Ramaswamy, Robert Wesolowski, Jeffrey B. VanDeusen, Nicole O. Williams, Sagar D. Sardesai, Anne M. Noonan, Raquel E. Reinbolt, Daniel G. Stover, Mathew A. Cherian, William B. Malarkey, and Rebecca Andridge
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Interleukin 1 Receptor Antagonist Protein ,Behavioral Neuroscience ,Cancer Survivors ,Interleukin-6 ,Endocrine and Autonomic Systems ,Obesity, Abdominal ,Typhoid-Paratyphoid Vaccines ,Immunology ,Humans ,Breast Neoplasms ,Female ,Obesity ,Article - Abstract
PURPOSE: To investigate breast cancer survivors’ inflammatory responses to typhoid vaccine as a window into their innate immune response to novel pathogens. METHODS: This double-blind crossover trial randomized 158 breast cancer survivors to either the vaccine/saline placebo or the placebo/vaccine sequence. The relative contributions of age, cardiorespiratory fitness (VO(2peak)), type of cancer treatment, central obesity, and depression to interleukin (IL)-6, IL-1 receptor antagonist (IL-1Ra), and WBC vaccine responses were assessed pre-injection and 1.5, 3, 4.5, 6, and 7.5 hours post-injection. RESULTS: The vaccine produced larger IL-6, IL-1Ra, and WBC responses than placebo, ps
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- 2022
34. Figure S3 from Interferon Signaling Is Diminished with Age and Is Associated with Immune Checkpoint Blockade Efficacy in Triple-Negative Breast Cancer
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Sandra S. McAllister, Elizabeth A. Mittendorf, Rachel A. Freedman, John N. Hutchinson, Victor Barrera, Daniel G. Stover, Tyler Laszewski, Yuanbo Qin, Jessalyn M. Ubellacker, Molly J. DeCristo, Sara Morrow, Kristin Wilson, Gregory J. Goreczny, and Jaclyn Sceneay
- Abstract
Supplementary Figure 3 shows the gating strategy and absolute numbers of CD8 cell subsets in the blood, spleen, and tumor to generate the heatmaps in figure 3
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- 2023
35. Table S1 from Interferon Signaling Is Diminished with Age and Is Associated with Immune Checkpoint Blockade Efficacy in Triple-Negative Breast Cancer
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Sandra S. McAllister, Elizabeth A. Mittendorf, Rachel A. Freedman, John N. Hutchinson, Victor Barrera, Daniel G. Stover, Tyler Laszewski, Yuanbo Qin, Jessalyn M. Ubellacker, Molly J. DeCristo, Sara Morrow, Kristin Wilson, Gregory J. Goreczny, and Jaclyn Sceneay
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Supplementary Table 1 provides a list of the antibodies used in this study
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- 2023
36. Supplementary File 1 from Interferon Signaling Is Diminished with Age and Is Associated with Immune Checkpoint Blockade Efficacy in Triple-Negative Breast Cancer
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Sandra S. McAllister, Elizabeth A. Mittendorf, Rachel A. Freedman, John N. Hutchinson, Victor Barrera, Daniel G. Stover, Tyler Laszewski, Yuanbo Qin, Jessalyn M. Ubellacker, Molly J. DeCristo, Sara Morrow, Kristin Wilson, Gregory J. Goreczny, and Jaclyn Sceneay
- Abstract
Supplementary File 1 lists the most differentially expressed genes from the RNAseq analysis
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- 2023
37. Data from Interferon Signaling Is Diminished with Age and Is Associated with Immune Checkpoint Blockade Efficacy in Triple-Negative Breast Cancer
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Sandra S. McAllister, Elizabeth A. Mittendorf, Rachel A. Freedman, John N. Hutchinson, Victor Barrera, Daniel G. Stover, Tyler Laszewski, Yuanbo Qin, Jessalyn M. Ubellacker, Molly J. DeCristo, Sara Morrow, Kristin Wilson, Gregory J. Goreczny, and Jaclyn Sceneay
- Abstract
Immune checkpoint blockade (ICB) therapy, which targets T cell–inhibitory receptors, has revolutionized cancer treatment. Among the breast cancer subtypes, evaluation of ICB has been of greatest interest in triple-negative breast cancer (TNBC) due to its immunogenicity, as evidenced by the presence of tumor-infiltrating lymphocytes and elevated PD-L1 expression relative to other subtypes. TNBC incidence is equally distributed across the age spectrum, affecting 10% to 15% of women in all age groups. Here we report that increased immune dysfunction with age limits ICB efficacy in aged TNBC-bearing mice. The tumor microenvironment in both aged mice and patients with TNBC shows decreased IFN signaling and antigen presentation, suggesting failed innate immune activation with age. Triggering innate immune priming with a STING agonist restored response to ICB in aged mice. Our data implicate age-related immune dysfunction as a mechanism of ICB resistance in mice and suggest potential prognostic utility of assessing IFN-related genes in patients with TNBC receiving ICB therapy.Significance:These data demonstrate for the first time that age determines the T cell–inflamed phenotype in TNBC and affects response to ICB in mice. Evaluating IFN-related genes from tumor genomic data may aid identification of patients for whom combination therapy including an IFN pathway activator with ICB may be required.This article is highlighted in the In This Issue feature, p. 1143
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- 2023
38. Supplementary Figure 5 from Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer
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Viktor A. Adalsteinsson, Todd R. Golub, Erica L. Mayer, Ann H. Partridge, G. Mike Makrigiorgos, J. Christopher Love, Ian Krop, Nancy U. Lin, Matthew Meyerson, Eric P. Winer, Gad Getz, Atish D. Choudhury, Daniel G. Stover, Gavin Ha, Nikhil Wagle, Niall J. Lennon, Samuel S. Freeman, Matthew DeFelice, Donna S. Neuberg, Carrie Cibulskis, Lorenzo Trippa, Brendan Blumenstiel, Kathy D. Miller, Laura C. Collins, Shoshana M. Rosenberg, Melissa E. Hughes, Ka Wai Leong, Mariana Fitarelli-Kiehl, Fangyan Yu, Ofir Cohen, Denisse Rotem, Gregory J. Kirkner, Mark Fleharty, Tianyu Li, Christopher C. Lo, Kan Xiong, Pedro Exman, Priyanka Ram, Gregory Gydush, Sarah C. Reed, Justin Rhoades, and Heather A. Parsons
- Abstract
Verification of detection power calculation. Comparison between the predicted detection power of 18 replicates and the actual fraction of those replicates that were called MRD+. 18 independent samples from a 1:100k dilution were probed with a 488 SNV panel (see methods). Replicates had their duplex consensus reads downsampled in increments of 10% and detection power was recalculated. Reported are the median and range of predicted detection powers for all replicates at each downsampling.
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- 2023
39. Supplemental Figure S1. from The Role of Proliferation in Determining Response to Neoadjuvant Chemotherapy in Breast Cancer: A Gene Expression–Based Meta-Analysis
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Laura M. Selfors, Eric P. Winer, Joan S. Brugge, William T. Barry, Jonathan L. Coloff, and Daniel G. Stover
- Abstract
Individual proliferation genes versus proliferation gene expression signatures.
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- 2023
40. Supplementary Figure 2 from Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer
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Viktor A. Adalsteinsson, Todd R. Golub, Erica L. Mayer, Ann H. Partridge, G. Mike Makrigiorgos, J. Christopher Love, Ian Krop, Nancy U. Lin, Matthew Meyerson, Eric P. Winer, Gad Getz, Atish D. Choudhury, Daniel G. Stover, Gavin Ha, Nikhil Wagle, Niall J. Lennon, Samuel S. Freeman, Matthew DeFelice, Donna S. Neuberg, Carrie Cibulskis, Lorenzo Trippa, Brendan Blumenstiel, Kathy D. Miller, Laura C. Collins, Shoshana M. Rosenberg, Melissa E. Hughes, Ka Wai Leong, Mariana Fitarelli-Kiehl, Fangyan Yu, Ofir Cohen, Denisse Rotem, Gregory J. Kirkner, Mark Fleharty, Tianyu Li, Christopher C. Lo, Kan Xiong, Pedro Exman, Priyanka Ram, Gregory Gydush, Sarah C. Reed, Justin Rhoades, and Heather A. Parsons
- Abstract
Early stage breast cancer cohort. (A) Overview of subtype distribution of cohort as well as the timing of blood draws relative to surgery and treatment. (B) REMARK diagram of the early stage breast cancer cohort. (C) Distribution of the number of mutations tracked for each patient.
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- 2023
41. Data from Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer
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Viktor A. Adalsteinsson, Todd R. Golub, Erica L. Mayer, Ann H. Partridge, G. Mike Makrigiorgos, J. Christopher Love, Ian Krop, Nancy U. Lin, Matthew Meyerson, Eric P. Winer, Gad Getz, Atish D. Choudhury, Daniel G. Stover, Gavin Ha, Nikhil Wagle, Niall J. Lennon, Samuel S. Freeman, Matthew DeFelice, Donna S. Neuberg, Carrie Cibulskis, Lorenzo Trippa, Brendan Blumenstiel, Kathy D. Miller, Laura C. Collins, Shoshana M. Rosenberg, Melissa E. Hughes, Ka Wai Leong, Mariana Fitarelli-Kiehl, Fangyan Yu, Ofir Cohen, Denisse Rotem, Gregory J. Kirkner, Mark Fleharty, Tianyu Li, Christopher C. Lo, Kan Xiong, Pedro Exman, Priyanka Ram, Gregory Gydush, Sarah C. Reed, Justin Rhoades, and Heather A. Parsons
- Abstract
Purpose:Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing.Experimental Design:We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2− metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples.Results:Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2–346). Clinical sensitivity was 81% (n = 13/16) in newly diagnosed MBC, 23% (n = 7/30) at postoperative and 19% (n = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3–58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4–39.2 months).Conclusions:Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.
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- 2023
42. Figure S4 from ER+ Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors
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Carlos L. Arteaga, Amparo Ruiz-Simon, Vicente Guillem, Mónica Arnedos, Fabrice André, Stefan Michiels, Mohamed Amine Bayar, Antonio Llombart-Cussac, Ana Lluch, J. Alejandro Perez-Fidalgo, Joaquín Gavilá, Alberto Servetto, Valerie M. Jansen, Monica V. Estrada, Jennifer M. Giltnane, Luis J. Schwarz, Kyung-Min Lee, Daniel G. Stover, Katherine E. Hutchinson, Luigi Formisano, Thomas P. Stricker, and Angel L. Guerrero-Zotano
- Abstract
E2F4 gene signature modulation and association with overall survival in ER+/HER2- breast cancer treated with endocrine therapy. a) E2F4 gene signature expression at baseline (pre) and after 2-weeks of aromatase inhibitor treatment (post), data from ACOSOGZ1031b study. Tumors were divided according to the E2F4 score at baseline in high, medium or low tertiles. After two-weeks of aromatase inhibitor treatment, there was a decrease in the E2F4 score in all groups. However, the proportion of tumors still expressing a high post-treatment E2F4 score was greater in patients with a high E2F4 score at baseline (60%) than the other groups. b) Overall survival in patients with ER+ breast cancer treated with adjuvant endocrine therapy in the METABRIC database (n=1498) according to E2F4 signature score tertiles. c) Overall survival in patients with ER+ tumors from METABRIC according to E2F4 score tertiles in Luminal A and d) Luminal B tumors.
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- 2023
43. Supplementary Figure 3 from Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer
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Viktor A. Adalsteinsson, Todd R. Golub, Erica L. Mayer, Ann H. Partridge, G. Mike Makrigiorgos, J. Christopher Love, Ian Krop, Nancy U. Lin, Matthew Meyerson, Eric P. Winer, Gad Getz, Atish D. Choudhury, Daniel G. Stover, Gavin Ha, Nikhil Wagle, Niall J. Lennon, Samuel S. Freeman, Matthew DeFelice, Donna S. Neuberg, Carrie Cibulskis, Lorenzo Trippa, Brendan Blumenstiel, Kathy D. Miller, Laura C. Collins, Shoshana M. Rosenberg, Melissa E. Hughes, Ka Wai Leong, Mariana Fitarelli-Kiehl, Fangyan Yu, Ofir Cohen, Denisse Rotem, Gregory J. Kirkner, Mark Fleharty, Tianyu Li, Christopher C. Lo, Kan Xiong, Pedro Exman, Priyanka Ram, Gregory Gydush, Sarah C. Reed, Justin Rhoades, and Heather A. Parsons
- Abstract
Overview schematic of MRD assay. MRD assay workflow from characterizing a primary tumor to determining if a blood draw contains evidence of residual disease.
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- 2023
44. Supplementary Tables from ER+ Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors
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Carlos L. Arteaga, Amparo Ruiz-Simon, Vicente Guillem, Mónica Arnedos, Fabrice André, Stefan Michiels, Mohamed Amine Bayar, Antonio Llombart-Cussac, Ana Lluch, J. Alejandro Perez-Fidalgo, Joaquín Gavilá, Alberto Servetto, Valerie M. Jansen, Monica V. Estrada, Jennifer M. Giltnane, Luis J. Schwarz, Kyung-Min Lee, Daniel G. Stover, Katherine E. Hutchinson, Luigi Formisano, Thomas P. Stricker, and Angel L. Guerrero-Zotano
- Abstract
Supplemental Table S1: The Preoperative Endocrine Prognostic Index (PEPI score) Supplemental Table S2:* Baseline Ki67: 7 patients had missing values Supplemental Table S3a: Driver Mutations Supplemental Table S3b: Driver Copy Number Alterations Supplemental Table S3c: Mutations clinically actionable. Drug prescription Supplemental Table S4: Actionable CNAs. Drug prescription Supplemental Table S5: Overlap between genes upregulated in resistant tumors and transcription factor targets genes Suplemental Table S6: Change from baseline to surgery in gene expressions of the 47 most upregulated genes in the tumors resistant to prolonged neoadjuvant letrozole from 60 HR-positive/HER2-negative breast cancers in POP trial. A decreased gene expression translates into a geometric mean change < 1 . An increased or stable gene expression translates into a geometric mean change {greater than or equal to} 1. Supplemental Table S7: Mutations detected in this study(post-filtering) Supplemental Table S8: Gene expression values (FPKM)
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- 2023
45. Supplemental Table S2. from The Role of Proliferation in Determining Response to Neoadjuvant Chemotherapy in Breast Cancer: A Gene Expression–Based Meta-Analysis
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Laura M. Selfors, Eric P. Winer, Joan S. Brugge, William T. Barry, Jonathan L. Coloff, and Daniel G. Stover
- Abstract
Gene Expression Signatures
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- 2023
46. Supplementary Data from ER+ Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors
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Carlos L. Arteaga, Amparo Ruiz-Simon, Vicente Guillem, Mónica Arnedos, Fabrice André, Stefan Michiels, Mohamed Amine Bayar, Antonio Llombart-Cussac, Ana Lluch, J. Alejandro Perez-Fidalgo, Joaquín Gavilá, Alberto Servetto, Valerie M. Jansen, Monica V. Estrada, Jennifer M. Giltnane, Luis J. Schwarz, Kyung-Min Lee, Daniel G. Stover, Katherine E. Hutchinson, Luigi Formisano, Thomas P. Stricker, and Angel L. Guerrero-Zotano
- Abstract
Supplementary data information
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- 2023
47. Supplementary Figure 6 from Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer
- Author
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Viktor A. Adalsteinsson, Todd R. Golub, Erica L. Mayer, Ann H. Partridge, G. Mike Makrigiorgos, J. Christopher Love, Ian Krop, Nancy U. Lin, Matthew Meyerson, Eric P. Winer, Gad Getz, Atish D. Choudhury, Daniel G. Stover, Gavin Ha, Nikhil Wagle, Niall J. Lennon, Samuel S. Freeman, Matthew DeFelice, Donna S. Neuberg, Carrie Cibulskis, Lorenzo Trippa, Brendan Blumenstiel, Kathy D. Miller, Laura C. Collins, Shoshana M. Rosenberg, Melissa E. Hughes, Ka Wai Leong, Mariana Fitarelli-Kiehl, Fangyan Yu, Ofir Cohen, Denisse Rotem, Gregory J. Kirkner, Mark Fleharty, Tianyu Li, Christopher C. Lo, Kan Xiong, Pedro Exman, Priyanka Ram, Gregory Gydush, Sarah C. Reed, Justin Rhoades, and Heather A. Parsons
- Abstract
Validation of tumor fraction confidence interval and effects of biological variability on tumor fraction inference. (A) Confidence intervals inferred from simulated data were aggregated into coverage probability for each condition and compared against theoretical coverage probability of 95% (see Methods). (B) Biological variability of clonal evolution loss was simulated by removing tumor evidence from a fraction of the fingerprint panel. Tumor fraction was calculated for simulated and original samples for comparison.
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- 2023
48. Supplementary Figure 14 from Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer
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Viktor A. Adalsteinsson, Todd R. Golub, Erica L. Mayer, Ann H. Partridge, G. Mike Makrigiorgos, J. Christopher Love, Ian Krop, Nancy U. Lin, Matthew Meyerson, Eric P. Winer, Gad Getz, Atish D. Choudhury, Daniel G. Stover, Gavin Ha, Nikhil Wagle, Niall J. Lennon, Samuel S. Freeman, Matthew DeFelice, Donna S. Neuberg, Carrie Cibulskis, Lorenzo Trippa, Brendan Blumenstiel, Kathy D. Miller, Laura C. Collins, Shoshana M. Rosenberg, Melissa E. Hughes, Ka Wai Leong, Mariana Fitarelli-Kiehl, Fangyan Yu, Ofir Cohen, Denisse Rotem, Gregory J. Kirkner, Mark Fleharty, Tianyu Li, Christopher C. Lo, Kan Xiong, Pedro Exman, Priyanka Ram, Gregory Gydush, Sarah C. Reed, Justin Rhoades, and Heather A. Parsons
- Abstract
Patients who experienced local recurrence only after treatment for early stage breast cancer. cfDNA time points for all patients who experienced local recurrence only. End points represent time of last follow up or death.
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- 2023
49. Supplementary Data from Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer
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Viktor A. Adalsteinsson, Todd R. Golub, Erica L. Mayer, Ann H. Partridge, G. Mike Makrigiorgos, J. Christopher Love, Ian Krop, Nancy U. Lin, Matthew Meyerson, Eric P. Winer, Gad Getz, Atish D. Choudhury, Daniel G. Stover, Gavin Ha, Nikhil Wagle, Niall J. Lennon, Samuel S. Freeman, Matthew DeFelice, Donna S. Neuberg, Carrie Cibulskis, Lorenzo Trippa, Brendan Blumenstiel, Kathy D. Miller, Laura C. Collins, Shoshana M. Rosenberg, Melissa E. Hughes, Ka Wai Leong, Mariana Fitarelli-Kiehl, Fangyan Yu, Ofir Cohen, Denisse Rotem, Gregory J. Kirkner, Mark Fleharty, Tianyu Li, Christopher C. Lo, Kan Xiong, Pedro Exman, Priyanka Ram, Gregory Gydush, Sarah C. Reed, Justin Rhoades, and Heather A. Parsons
- Abstract
Supplementary Methods
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- 2023
50. Data from The Role of Proliferation in Determining Response to Neoadjuvant Chemotherapy in Breast Cancer: A Gene Expression–Based Meta-Analysis
- Author
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Laura M. Selfors, Eric P. Winer, Joan S. Brugge, William T. Barry, Jonathan L. Coloff, and Daniel G. Stover
- Abstract
Purpose: To provide further insight into the role of proliferation and other cellular processes in chemosensitivity and resistance, we evaluated the association of a diverse set of gene expression signatures with response to neoadjuvant chemotherapy (NAC) in breast cancer.Experimental Design: Expression data from primary breast cancer biopsies for 1,419 patients in 17 studies prior to NAC were identified and aggregated using common normalization procedures. Clinicopathologic characteristics, including response to NAC, were collected. Scores for 125 previously published breast cancer–related gene expression signatures were calculated for each tumor.Results: Within each receptor-based subgroup or PAM50 subtype, breast tumors with high proliferation signature scores were significantly more likely to achieve pathologic complete response to NAC. To distinguish “proliferation-associated” from “proliferation-independent” signatures, we used correlation and linear modeling approaches. Most signatures associated with response to NAC were proliferation associated: 90.5% (38/42) in ER+/HER2− and 63.3% (38/60) in triple-negative breast cancer (TNBC). Proliferation-independent signatures predictive of response to NAC in ER+/HER2− breast cancer were related to immune activity, while those in TNBC comprised a diverse set of signatures, including immune, DNA damage, signaling pathways (PI3K, AKT, Ras, and EGFR), and “stemness” phenotypes.Conclusions: Proliferation differences account for the vast majority of predictive capacity of gene expression signatures in neoadjuvant chemosensitivity for ER+/HER2− breast cancers and, to a lesser extent, TNBCs. Immune activation signatures are proliferation-independent predictors of pathologic complete response in ER+/HER2− breast cancers. In TNBCs, significant proliferation-independent signatures include gene sets that represent a diverse set of cellular processes. Clin Cancer Res; 22(24); 6039–50. ©2016 AACR.
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- 2023
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