Radiation and Cancer Biology

SS 39 - Biology 7 - Special Session: Innovative Biologic Approaches to Improve Risk Stratification and Treatment Outcomes

287 - Circulating microRNAs as Biomarkers of Radiation-Induced Cardiac Toxicity in Non-Small Cell Lung Cancer

Wednesday, October 24
2:10 PM - 2:20 PM
Location: Room 206

Circulating microRNAs as Biomarkers of Radiation-Induced Cardiac Toxicity in Non-Small Cell Lung Cancer
P. G. Hawkins1, Y. Sun2, R. T. Dess1, W. C. Jackson1, G. Sun1, N. Bi3, M. Tewari4, J. A. Hayman5, G. P. Kalemkerian6, T. S. Lawrence1, R. K. Ten Haken1, M. M. Matuszak1, F. M. Kong7, M. Schipper2, and S. Jolly1; 1Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 2Department of Biostatistics, University of Michigan, Ann Arbor, MI, 3National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, 4Departments of Internal Medicine and Biomedical Engineering, Biointerfaces Institute, and Center for Computation Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 5Michigan Medicine, Ann Arbor, MI, 6Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, 7Indiana University Radiation Oncology, Indianapolis, IN

Purpose/Objective(s): Circulating microRNAs (c-miRNAs) have shown promise as biomarkers in non-small cell lung cancer (NSCLC) and cardiac disease. We sought to identify a c-miRNA signature prognostic for radiation-induced cardiac toxicity (RICT) in patients undergoing definitive radiotherapy (RT) for NSCLC.

Materials/Methods: Data from 65 patients treated from 2004-2013 with definitive RT for stages II-III NSCLC on four consecutive prospective clinical trials were analyzed. The primary endpoint was time to first grade 3 or greater (G3+) cardiac event, as graded using Common Terminology Criteria for Adverse Events version 4.03. Pretreatment serum levels of 62 miRNA species were measured by quantitative reverse transcription polymerase chain reaction array. Prognostic models of G3+ RICT based on c-miRNA profile (“c-miRNA”), mean heart dose and baseline cardiac disease (“clinical”), and a combination of these (“c-miRNA + clinical”) were developed. Elastic net Cox regression was used for variable selection and parameter estimation. Model assessment and tuning parameter selection were performed through full cross validation. Area under the receiver operating curve (AUC) and C-index were used for comparison of model performance.

Results: The cumulative incidence of G3+ RICT was 16.9%. We identified 14 c-miRNA species prognostic for G3+ cardiac toxicity: miR-25, -34a, -100, -106b, -134, -145, -146a, -192, -195, -200b, -223, -574, -885, and let-7c. Two species previously shown to be associated with RICT in animal models, miR-15b and -21, were not significantly prognostic in this cohort and therefore not selected for the c-miRNA model. C-indices for the c-miRNA, clinical, and c-miRNA + clinical models were 0.701, 0.722, and 0.704, respectively. AUC values for these models were 0.643, 0.642, and 0.634, respectively. Hazard ratios for G3+ RICT in low- vs. high-risk patients, as defined using each model, were 0.25 (p=0.04, 95%CI 0.06-0.94) for the c-miRNA, 0.17 (p=0.02, 95%CI 0.04-0.76) for the clinical, and 0.29 (p=0.07, 95%CI 0.08-1.12) for the c-miRNA + clinical models.

Conclusion: We identified a pretreatment c-miRNA signature that was prognostic for G3+ RICT in NSCLC. This signature performed similarly to a model based on dosimetric and clinical factors. This finding suggests that these c-miRNAs may represent biomarkers of underlying cardiac disease, which is consistent with the published literature regarding most of the identified species. It is therefore possible that midtreatment changes in these c-miRNAs could serve as an indicator of RT-induced worsening of cardiac function, which in turn could guide adaptation of therapy. Additionally, further investigation of these miRNAs may elucidate mechanisms of cardiac damage and protection.

Author Disclosure: P.G. Hawkins: None. Y. Sun: None. R.T. Dess: None. N. Bi: None. M. Tewari: Consultant; Miroculus. J.A. Hayman: Research Grant; Blue Cross Blue Shield of Michigan. G.P. Kalemkerian: None. T.S. Lawrence: royalties; Lippincott, Williams and Wilkins. Honoraria; Massachusetts General Hospital, Pfizer Oncology Innovation Summit, Sidney Kimmel Foundation for Cancer Research. Consultant; Pfizer Oncology Innovation Summit. Advisory Board; ASTRO Radiation Oncology Institute, Dana Farber Cancer Institute, Massachusetts General Hospital, Sidney Kimmel Compreh Cancer Ctr at Johns Hopkins, Sidney Kimmel Foundation for Cancer Research, St. Jude Children's Research Hospital, University of Wisconsin Comprehensive Cancer Ctr. Travel Expenses; AACR, ASTRO Radiation Oncology Institute, Dana Farber Cancer Institute, Lippincott, Williams and Wilkins, Massachusetts General Hospital, Pfizer Oncology Innovation Summit, RSNA, Sidney Kimmel Compreh Cancer Ctr at Johns Hopkins, Sidney Kimmel Foundation for Cancer Research, St. Jude Children's Research Hospital, University of Wisconsin Comprehensive Cancer Ctr. Patent/License Fees/Copyright; Pi Squared Therapeutics. Editor, Cancer Discovery; AACR. Member, Editorial Advisory Board, Cancer Today; AACR. Senior Editor, Cancer Research; AACR. Member, External Advisory Board for Lung SPORE; Dana Farber Cancer Institute. Co-Editor of Principles and Practices of Oncology; Lippincott, Williams and Wilkins. Member, NCI Board of Scientific Advisors; NCI - BSA. President; ROI. Member, External Advisory Board for the Cancer Ctr; Sidney Kimmel CCC at Johns Hopkins University. Member of the Medical Advisory Board; Sidney Kimmel Foundation for Cancer Research. Vice-Chair, St. Jude Scientific Advisory Board; St. Jude Children's Research Hospital. Member, V Foundation Scientific Advisory Board; V Foundation for Cancer Research. R.K. Ten Haken: Research Grant; NIH-NCI. Honoraria; University of Copenhagen. Travel Expenses; Varian Medical Systems Inc, University of Copenhagen. M.M. Matuszak: Employee; William Beaumont Hospital. F.(. Kong: Research Grant; Varian, NCI/NIH. Founding President and Board of Director; Sino-American Network for Therapeutic Radiation On. President 2015; American Association of Women Radiologists (AAWR). President 2012-2013; Association for Chinese Professors. Founding Board Member; Sino-American Network for Therapeutic Radiology. M. Schipper: Consultant; Armune Bioscience, Hygieia Sciences. S. Jolly: None.

Peter Hawkins, MD, PhD

University of Michigan

Disclosure:
No relationships to disclose.

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