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Pöllinger B, Haiderali A, Huang M, Akyol Ersoy B, Abdelaziz AH, Kassem L, Elsisi GH. The cost-effectiveness of treatment for high-risk, early-stage, triple-negative breast cancer in Egypt: an analysis of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant single-agent pembrolizumab. J Med Econ 2025; 28:105-113. [PMID: 39665251 DOI: 10.1080/13696998.2024.2441073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 12/09/2024] [Accepted: 12/09/2024] [Indexed: 12/13/2024]
Abstract
OBJECTIVE The cost-effectiveness of neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab compared to neoadjuvant chemotherapy plus placebo followed by adjuvant placebo was assessed in high-risk, early-stage, triple-negative breast cancer patients from an Egyptian societal perspective over a lifetime horizon. METHODS A 4-state Markov cohort model was developed to compare the cost-effectiveness of pembrolizumab + chemotherapy/pembrolizumab vs chemotherapy alone for the treatment of high-risk, early-stage, triple-negative breast cancer. The model simulated the clinical course of high-risk, early-stage, triple-negative breast cancer across four health states: event-free survival, locoregional recurrence, distant metastasis, and death. Clinical inputs for the simulation were derived from modeling of efficacy and safety data collected in the KEYNOTE-522 trial. Direct medical costs and indirect costs were reported in 2022 Egyptian pounds (EGP) and converted to US dollars ($). Probabilistic and deterministic sensitivity analyses were conducted to assess the robustness of model results. RESULTS Compared with chemotherapy alone, pembrolizumab + chemotherapy/pembrolizumab led to expected gains of 2.92 life years and 2.25 quality-adjusted life years, respectively, while increasing overall treatment costs by EGP 491,695 ($102,436). Incremental costs per year gained were EGP 218,285 ($45,476) per quality-adjusted life year and EGP 168,223 ($35,046) per life year, both of which were lower than the 2022 Egyptian cost-effectiveness threshold of EGP 398,439 ($83,008). The findings of sensitivity analyses indicated that the model was robust across a range of inputs and assumptions. CONCLUSIONS In Egypt, pembrolizumab + chemotherapy/pembrolizumab is a cost-effective treatment for high-risk, early-stage, triple-negative breast cancer when considering health-related quality-of-life and years of life gained.
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Affiliation(s)
- Bernadette Pöllinger
- Center for Outcomes Research and Health Economy, MSD Sharp & Dohme GmbH, Munich, Germany
| | - Amin Haiderali
- Center for Outcomes Research and Health Economy, Merck & Co., Inc, Rahway, NJ, USA
| | - Min Huang
- Center for Outcomes Research and Health Economy, Merck & Co., Inc, Rahway, NJ, USA
| | | | | | - Loay Kassem
- Faculty of Medicine, Cairo University, Giza, Egypt
| | - Gihan Hamdy Elsisi
- HTA Office, Cairo, Egypt
- Faculty of Economics, American University, Cairo, Egypt
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Chisaki Y, Nakamura N, Komuro T, Nyuji H, Harano M, Kitada N. Cost-Effectiveness Analysis of Pembrolizumab Plus Chemotherapy Compared with Chemotherapy as First-Line Treatment for Advanced PD-L1-Positive Triple-Negative Breast Cancer from a Japanese Healthcare Perspective. Clin Drug Investig 2025:10.1007/s40261-025-01445-8. [PMID: 40317386 DOI: 10.1007/s40261-025-01445-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND AND OBJECTIVES Pembrolizumab has been approved for the immunotherapy of programmed death ligand 1 (PD-L1)-positive triple-negative breast cancer (TNBC) based on the KEYNOTE-355 trial. However, cost-effectiveness evidence is limited. The purpose of this study was to evaluate the cost-effectiveness of pembrolizumab plus chemotherapy compared with chemotherapy alone for patients with PD-L1-positive inoperable or metastatic TNBC from a Japanese healthcare perspective. METHODS The cost-effectiveness analysis was performed for pembrolizumab, of which the drug price was determined at 214,498 Japanese yen (JPY), or 1631 US dollars (USD) (1 USD = 131.5 JPY) for KEYTRUDA® (100 mg), using a partition survival model based on the KEYNOTE-355 trial subgroup analysis in Japan. The comparison was made using quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER). One-way deterministic and probabilistic sensitivity analyses (PSA), which evaluate the impact of parameter uncertainty, were performed to assess the robustness and calculate the acceptable probability, defined as the probability of the ICER being below the willingness-to-pay (WTP). RESULTS Pembrolizumab plus chemotherapy provided an additional 0.676 QALYs at an incremental cost of 8,503,072 JPY. The ICER for pembrolizumab plus chemotherapy compared with conventional chemotherapy was 12,577,178 JPY (95,644 USD) per QALY. The ICER per QALY was below the willingness-to-pay threshold of 15,000,000 JPY. PSAs revealed that the acceptable probability was 83.9% at 15,000,000 JPY. CONCLUSIONS The pembrolizumab plus chemotherapy is likely to be a cost-effective option compared with conventional chemotherapy for patients with PD-L1-positive inoperable or metastatic TNBC in a Japanese medical environment from a healthcare system.
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Affiliation(s)
- Yugo Chisaki
- Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, 5-Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan.
| | - Nobuhiko Nakamura
- Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, 5-Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan
| | - Takako Komuro
- Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, 5-Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan
| | - Hirokatsu Nyuji
- Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, 5-Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan
| | - Mai Harano
- Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, 5-Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan
| | - Noriaki Kitada
- Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, 5-Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan
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Monberg MJ, Keefe S, Karantza V, Tryfonidis K, Toker S, Mejia J, Orlowski R, Haiderali A, Prabhu VS, Aktan G. A Narrative Review of the Clinical, Humanistic, and Economic Value of Pembrolizumab-Based Immunotherapy for the Treatment of Breast and Gynecologic Cancers. Oncol Ther 2024; 12:701-734. [PMID: 39453600 PMCID: PMC11573950 DOI: 10.1007/s40487-024-00308-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 09/04/2024] [Indexed: 10/26/2024] Open
Abstract
Breast and gynecologic cancers are common across the world and are associated with substantial societal and economic burden. Pembrolizumab was among the first immune checkpoint inhibitors targeting programmed cell death protein 1 to be approved for the treatment of patients with triple-negative breast cancer, cervical cancer, and endometrial cancer. Recent clinical trials have established pembrolizumab regimens as a standard of care treatment for these tumor types. Clinical data are further supported by patient-reported outcome, cost-effectiveness, and real-world evidence. Pembrolizumab monotherapy and combination regimens do not negatively influence health-related quality of life and are cost-effective relative to comparators. Ongoing phase 3 studies with pembrolizumab will expand the current understanding of its use in breast and gynecologic cancers. Several of these studies are in patients with early-stage disease with the hope of curing patients. The main objective of this review is to summarize the clinical, humanistic, and economic value of pembrolizumab in these settings and to describe the future challenges for patients, caregivers, clinicians, and payers.
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Affiliation(s)
| | - Steve Keefe
- Merck & Co., Inc., 2025 E Scott Ave, Rahway, NJ, 07065, USA
| | | | | | - Sarper Toker
- Merck & Co., Inc., 2025 E Scott Ave, Rahway, NJ, 07065, USA
| | - Jaime Mejia
- Merck & Co., Inc., 2025 E Scott Ave, Rahway, NJ, 07065, USA
| | | | - Amin Haiderali
- Merck & Co., Inc., 2025 E Scott Ave, Rahway, NJ, 07065, USA
| | | | - Gursel Aktan
- Merck & Co., Inc., 2025 E Scott Ave, Rahway, NJ, 07065, USA
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Favre-Bulle A, Huang M, Haiderali A, Bhadhuri A. Cost-Effectiveness of Neoadjuvant Pembrolizumab plus Chemotherapy Followed by Adjuvant Pembrolizumab in Patients with High-Risk, Early-Stage, Triple-Negative Breast Cancer in Switzerland. PHARMACOECONOMICS - OPEN 2024; 8:91-101. [PMID: 37999854 PMCID: PMC10781656 DOI: 10.1007/s41669-023-00445-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/14/2023] [Indexed: 11/25/2023]
Abstract
AIM This study assessed the cost-effectiveness of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab versus neoadjuvant chemotherapy plus placebo followed by adjuvant placebo for patients with high-risk, early-stage, triple-negative breast cancer (TNBC) from a Swiss third-party payer perspective over a lifetime horizon (51 years). MATERIALS AND METHODS A transition model with four health states (event-free, locoregional recurrence, distant metastasis, and death) was developed to assess the cost-effectiveness of pembrolizumab plus chemotherapy versus chemotherapy alone for the treatment of high-risk, early-stage TNBC. Data were utilized from the KEYNOTE-522 randomized controlled trial (ClinicalTrials.gov, NCT03036488). The incremental cost-effectiveness ratio (ICER) was calculated, which was reported as cost per life year or quality-adjusted life year (QALY) gained. A one-way deterministic sensitivity analysis, a probabilistic sensitivity analysis (PSA) and scenario analyses were conducted to assess the robustness of the model results. RESULTS Base-case results estimated an ICER of 14,114 Swiss francs (CHF)/QALY for pembrolizumab plus chemotherapy versus chemotherapy alone. Results were most sensitive to changes in the extrapolation of event-free survival (EFS). All sensitivity and scenario analyses generated ICERs below the willingness-to-pay threshold of CHF100,000/QALY, and the PSA showed a 98.8% probability that the ICER would be below this threshold. LIMITATIONS Due to the limited follow-up period in the KEYNOTE-522 trial, EFS data were extrapolated over the lifetime horizon to inform transition probabilities. Extensive validation and scenario analyses ensured the results were robust. CONCLUSION The model demonstrated that neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab was cost-effective versus chemotherapy alone in patients with high-risk, early-stage TNBC in Switzerland.
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Affiliation(s)
| | | | | | - Arjun Bhadhuri
- Department of Public Health, Health Economics Facility, Institute of Pharmaceutical Medicine (ECPM), University of Basel, Basel, Switzerland
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Araghi M, Gharebakhshi F, Faramarzi F, Mafi A, Mousavi T, Alimohammadi M, Soleimantabar H. Efficacy and Safety of Pembrolizumab Monotherapy or Combined Therapy in Patients with Metastatic Triple-negative Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Curr Gene Ther 2024; 25:72-88. [PMID: 39468438 DOI: 10.2174/0115665232283880240301035621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 02/17/2024] [Accepted: 02/19/2024] [Indexed: 10/30/2024]
Abstract
BACKGROUND Metastatic Triple-negative Breast Cancer (mTNBC) is the most aggressive form of breast cancer, with a greater risk of metastasis and recurrence. Research studies have published in-depth analyses of the advantages and disadvantages of pembrolizumab, and early data from numerous trials suggests that patients with mTNBC have had remarkable outcomes. This meta-analysis compares the data from numerous relevant studies in order to evaluate the safety and efficacy of pembrolizumab monotherapy or combination therapies for mTNBC. METHODS To identify eligible RCTs, a thorough literature search was carried out using electronic databases. CMA software was utilized to perform heterogeneity tests using fixed and random-effects models. RESULTS According to our pooled data, the median Progression-free Survival (PFS) was 2.66 months, and the median overall survival (OS) was 12.26 months. Furthermore, by comparing efficacy indicators between PD-L1-positive and PD-L1-negative groups, a correlation was found between the overexpression of PD-L1 with OS, PFS, and ORR. Patients with PD-L1-positive tumors had a higher response rate, with an ORR of 21.1%, compared to the patients with PD-L1-negative tumors. The ORR for first-line immunotherapy was higher than that of ≥second-line immunotherapy. In addition, pembrolizumab plus combination treatment resulted in a pooled incidence of immune- related adverse events of 22.7%. CONCLUSION A modest response to pembrolizumab monotherapy was detected in the mTNBC patients. Furthermore, a better outcome from pembrolizumab treatment may be predicted by PD-L1-- positive status, non-liver/lung metastases, combination therapy, and first-line immunotherapy. Pembrolizumab, in combination with chemotherapy, may be more beneficial for patients whose tumors are PD-L1 positive.
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Affiliation(s)
- Mahmood Araghi
- Department of Pathology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Farshad Gharebakhshi
- Department of Radiology, School of Medicine, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Faramarzi
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Tahoora Mousavi
- Molecular and Cell Biology Research Center (MCBRC), Hemoglobinopathy Institute, Mazandaran University of Medical Sciences, Sari, Iran
- Medical Sciences Technologies, Molecular and Cell Biology Research Center (MCBRC), Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mina Alimohammadi
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hussein Soleimantabar
- Department of Radiology, School of Medicine, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Kim SL, Choi HS, Lee DS. BRD4/nuclear PD-L1/RelB circuit is involved in the stemness of breast cancer cells. Cell Commun Signal 2023; 21:315. [PMID: 37924094 PMCID: PMC10623882 DOI: 10.1186/s12964-023-01319-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 09/14/2023] [Indexed: 11/06/2023] Open
Abstract
BACKGROUND Breast cancer (BC) is the most common cancer diagnosed in women worldwide. BC stem cells (BCSCs) have been known to be involved in the carcinogenesis of the breast and contribute to therapeutic resistance. The programmed death-ligand 1 (PD-L1) expression of BC correlated with a poor prognosis. Immunotherapies that target PD-L1 have great potential and have been successful when applied to cancer treatment. However, whether PD-L1 regulates BCSC formation is unknown. METHODS BCSCs were enriched by serum-free suspension culture. The properties of BCSCs were examined by mammosphere formation assay, CD44+/Cd24-, aldehyde dehydrogenase (ALDH) assay, CSC marker analysis, and mammosphere growth assay. To elucidate the functions of bromodomain-containing protein 4 (BRD4), nuclear PD-L1, and RelB proteins in the stemness of BCSCs, mammosphere formation was examined using BRD4 inhibitor and degrader, PD-L1 degrader, and RelB inhibitor. The antitumor function of 3',4',7,8-tetrahydroxyflavone (THF), a specific BRD4 inhibitor, was studied through in vivo tumor model and mouse studies, and the protein levels of c-Myc, PD-L1, and RelB were examined in tumor model under THF treatment. RESULTS BRD4 was upregulated in breast CSCs and regulates the stemness of BCs. The downregulation of BRD4 using BRD4 PROTAC, ARV-825, and BRD4 inhibitor, (+)-JQ1, inhibits mammosphere formation and reduces the levels of breast CSC markers (CD44+/CD24- and ALDH1), stem cell marker genes, and mammosphere growth. BRD4 inhibitor (JQ1) and degrader (ARV825) downregulate membrane and nuclear fractions of PD-L1 through the inhibition of PD-L1 transcript levels. The knockdown of PD-L1 inhibits mammosphere formation. Verteporfin, a PD-L1 degrader, inhibits the transcripts and protein levels of PD-L1 and downregulates the transcript and protein levels of RelB. Calcitriol, a RelB inhibitor, and the knockdown of RelB using si-RelB regulate mammosphere formation through interleukin-6 (IL-6) expression. THF is a natural product and a potent selective BRD4 inhibitor, inhibits mammosphere formation, and reduces the levels of CD44+/CD24- and mammosphere growth by downregulating c-Myc, PD-L1, and RelB. 3',4',7,8-THF shows tumoricidal activity and increased levels of CD3+CD4+ and CD3+CD8+ T-cells in the tumor and tumor-draining lymph nodes (TDLNs) in the murine tumor model using 4T1 and MC38 cells. CONCLUSIONS The results show the first evidence of the essential role of the BRD4/nuclear PD-L1/RelB axis in breast CSC formation. The nuclear PD-L1 regulates RelB, and the RelB/p65 complex induces IL6 and breast CSC formation. Targeting nuclear PD-L1 represents a potential and novel tool for immunotherapies of intractable BC. Video Abstract.
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Affiliation(s)
- Su-Lim Kim
- Bio-Health Materials Core-Facility Center, Jeju National University, Jeju, 63243, Republic of Korea
- Graduate Program for Bio-health/Innovative Drug Development using Subtropical Bio-Resources, Jeju National University, Jeju, 63243, Republic of Korea
| | - Hack Sun Choi
- Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju, 63243, Republic of Korea.
- Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, SARI, Jeju, 63243, Republic of Korea.
| | - Dong-Sun Lee
- Bio-Health Materials Core-Facility Center, Jeju National University, Jeju, 63243, Republic of Korea.
- Graduate Program for Bio-health/Innovative Drug Development using Subtropical Bio-Resources, Jeju National University, Jeju, 63243, Republic of Korea.
- Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju, 63243, Republic of Korea.
- Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, SARI, Jeju, 63243, Republic of Korea.
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Jungles KM, Holcomb EA, Pearson AN, Jungles KR, Bishop CR, Pierce LJ, Green MD, Speers CW. Updates in combined approaches of radiotherapy and immune checkpoint inhibitors for the treatment of breast cancer. Front Oncol 2022; 12:1022542. [PMID: 36387071 PMCID: PMC9643771 DOI: 10.3389/fonc.2022.1022542] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 09/27/2022] [Indexed: 12/05/2022] Open
Abstract
Breast cancer is the most prevalent non-skin cancer diagnosed in females and developing novel therapeutic strategies to improve patient outcomes is crucial. The immune system plays an integral role in the body’s response to breast cancer and modulating this immune response through immunotherapy is a promising therapeutic option. Although immune checkpoint inhibitors were recently approved for the treatment of breast cancer patients, not all patients respond to immune checkpoint inhibitors as a monotherapy, highlighting the need to better understand the biology underlying patient response. Additionally, as radiotherapy is a critical component of breast cancer treatment, understanding the interplay of radiation and immune checkpoint inhibitors will be vital as recent studies suggest that combined therapies may induce synergistic effects in preclinical models of breast cancer. This review will discuss the mechanisms supporting combined approaches with radiotherapy and immune checkpoint inhibitors for the treatment of breast cancer. Moreover, this review will analyze the current clinical trials examining combined approaches of radiotherapy, immunotherapy, chemotherapy, and targeted therapy. Finally, this review will evaluate data regarding treatment tolerance and potential biomarkers for these emerging therapies aimed at improving breast cancer outcomes.
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Affiliation(s)
- Kassidy M. Jungles
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
- Department of Pharmacology, University of Michigan, Ann Arbor, MI, United States
| | - Erin A. Holcomb
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Ashley N. Pearson
- Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Kalli R. Jungles
- Department of Biology, Saint Mary’s College, Notre Dame, IN, United States
| | - Caroline R. Bishop
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
| | - Lori J. Pierce
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
| | - Michael D. Green
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, United States
- Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, United States
- *Correspondence: Michael D. Green, ; Corey W. Speers,
| | - Corey W. Speers
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
- Department of Radiation Oncology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Case Comprehensive Cancer Center, Cleveland, OH, United States
- *Correspondence: Michael D. Green, ; Corey W. Speers,
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