Breast Cancer

SS 21 - Breast 2 - Biology and SBRT

133 - Gene Expression Changes Predict Acute and Late Toxicity to Combined PARP1 Inhibition and Radiation (RT) in High Risk Breast Cancer Patients- Results of the Biomarker Analysis of TBCRC 024

Tuesday, October 23
7:55 AM - 8:05 AM
Location: Room 214 A/B

Gene Expression Changes Predict Acute and Late Toxicity to Combined PARP1 Inhibition and Radiation (RT) in High Risk Breast Cancer Patients- Results of the Biomarker Analysis of TBCRC 024
C. Speers1, B. Chandler1, E. Olsen1, L. Moubadder1, D. Thomas1, M. Liu1, K. Griffith2, J. R. Bellon3, W. A. Woodward4, J. K. Horton5, A. Y. Ho6, B. Overmoyer7, M. S. Sabel1, A. F. Schott1, F. Y. Feng8, L. J. Pierce9, and R. Jagsi1; 1University of Michigan, Ann Arbor, MI, 2Department of Biostatistics, University of Michigan, Ann Arbor, MI, 3Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, 4The University of Texas MD Anderson Cancer Center, Department of Radiation Oncology, Houston, TX, 5Duke University Medical Center, Durham, NC, 6Cedars Sinai, Los Angeles, CA, 7Dana Farber Cancer Institute, Boston, MA, 8Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 9Michigan Medicine, Ann Arbor, MI

Purpose/Objective(s): Sustained locoregional control of breast cancer is a significant issue in patients with high risk disease. We recently reported the results of a phase I clinical trial describing acute and late toxicity of PARP1 inhibition (PARPi) with concurrent veliparib and RT. The purpose of this study was to determine predictive biomarkers of acute (during treatment) and late (1, 2, and 3 year) toxicity in patients treated with PARPi and RT from that trial. We hypothesized that protein and gene expression changes in skin epithelial cells after concurrent PARPi and RT might be used as predictive biomarkers of toxicity.

Materials/Methods: Acute toxicity was any dose-limiting toxicity defined in the protocol; late toxicity was defined as any CTCAE v4 Grade 3 event, regardless of attribution. Skin punch biopsies from the irradiated field were taken from patients at baseline (pretreatment T=0) and 6 hrs after first fraction of RT alone (T=1). Veliparib was then started and a 3rd punch taken 6 hrs after the second fraction of RT (T=2). RNA was isolated from skin epithelial cells and gene expression assessed using Affymetrix Human Gene ST 2.1 arrays. GSEA and MSigDB software was used for analysis. Significant difference was predetermined as a log2 fold change of+/-1.5 and FDR adjusted p-value <0.05. Protein changes (pγH2AX, PAR, Ki67) were detected using IHC and quantitated using Aperio Digital Path software.

Results: Severe acute and late toxicity rates with combined therapy were 15% (5/33) and 21% (7/33), respectively. Acute toxicity was not a predictor of late toxicity. Indeed, the two were almost mutually exclusive. Gene expression analysis identified 31 genes whose expression was significantly different 6 hrs after RT and 54 genes differed after combined treatment, including genes associated with DNA damage repair (ATM, MDM2, XPC) and proliferation (Ki67, TP53TG1). 67 genes were associated with acute toxicity, including overrepresentation of miRNAs associated with gene repression. Additionally, 63 genes were associated with late toxicity and were associated with metabolism, inflammation, and DNA damage response. There was no overlap in biomarkers of acute and late toxicity. Both pγH2AX and PAR protein levels increased and Ki67 decreased significantly (more than 2 fold for all proteins) with RT and combined therapy (T1 and T2) but were not significantly associated with acute or late toxicity at any time point.

Conclusion: This demonstrates the feasibility of using skin punch biopsy in the irradiated field for biomarker analysis and identification of a number of putative biomarkers of early and late radiation toxicity following combined PARPi and RT treatment. Additionally, for the first time in patient skin punch samples we report (1) gene expression changes in acute responding genes shortly after RT and (2) decreased proliferation after combined treatment. Future trials will validate the utility of these biomarkers for predicting toxicity and will seek to identify biomarkers of treatment efficacy.

Author Disclosure: C. Speers: Stock; PFS Genomics. B. Chandler: None. E. Olsen: None. L. Moubadder: None. D. Thomas: None. M. Liu: None. J.R. Bellon: Paid author; UptoDate. Honoraria; EMMC Partridge Foundation Breast Cancer Symposium, ASTRO, speaker, ASTRO refresher course, Oncoclinicas. Travel Expenses; speaker, ASTRO refresher course. Breast Cancer Oral Boards Chair; ABR. clincial co-chair, ASTRO Spring educational sympos; ASTRO. W.A. Woodward: None. J.K. Horton: Research Grant; Gateway for Cancer Research. Stipend - Senior Editor; Int J of Radiation Oncology, Biology, Physics. Loan repayment; NIH Loan Repayment Program. Honoraria; The Oakstone Institute, Varian Medical Systems. Board Member; New Life After Cancer. A.Y. Ho: None. M.S. Sabel: None. F.Y. Feng: Research Grant; GenomeDx. Advisory Board; Sanofi, Dendreon, GenomeDx. Travel Expenses; GenomeDx. Stock; PFS Genomics. Liaison, GU Translational Research Program; Radiation Therapy Oncology Group. President and Founder; PFS Genomics. R. Jagsi: Research Grant; American Cancer Society, NCCN, Breast Cancer Research Foundation, Abbott and Abbvie Pharmaceuticals. Advisory Board; Eviti. Research Committee Chair; Radiation Oncology Institute. Board of Directors; ASCO.

Corey Speers, MD, PhD, BS

University of Michigan

University of Michigan Hospital: Assistant Professor: Employee; Veteran Affairs Hospital- Ann Arbor: Assistant Professor: Employee

PFS Genomics: Stock

Dr. Speers is an Assistant Professor at the University of Michigan Rogel Cancer Center in the Department of Radiation Oncology. He completed his medical and graduate degrees in the MSTP program at Baylor College of Medicine before completing his residency and Holman Pathway training at the University of Michigan in Ann Arbor. After joining the faculty at the University of Michigan as a physician scientist, he has continued his research exploring the biology of aggressive breast cancers, including inflammatory and triple-negative breast cancer. His laboratory is interested in “bench to bedside” research that includes basic mechanistic studies, translational pre-clinical studies, and clinical research. His interest in targeted therapies include PARP-inhibitors, CDK 4/6 inhibitors, and androgen receptor antagonists as agents for radiosensitization. His lab has also utilized kinome screens to identify novel targets for the treatment of aggressive breast cancers, including triple-negative breast cancer. In addition, his research group has a number of clinically oriented and bioinformatics based studies that focus on the nomination and validation of expression-based signatures to predict breast cancer patients that need treatment intensification and signatures to identify patient who will not need further adjuvant therapy for breast cancer. Finally, his translational work focuses on correlative studies looking at biospecimens from clinical trials to uncover ways to predict treatment efficacy and toxicity.


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133 - Gene Expression Changes Predict Acute and Late Toxicity to Combined PARP1 Inhibition and Radiation (RT) in High Risk Breast Cancer Patients- Results of the Biomarker Analysis of TBCRC 024

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