123 - Clonal Hematopoiesis Following Radiation Therapy as a Novel Predictor of Cancer Control and Survival: Analyses from Prospective Trials
Presenter(s)
K. T. Nead1,2, T. Kim3, A. D. Sherry3,4, T. McDowell3, K. E. Johnson3, S. Su5, S. Vijayan3, J. Yang5, S. G. Chun6, P. Msaouel7, N. Tannir7, E. Jonasch7, P. G. Corn7, D. Ramirez8, B. Smaglo9, D. Zhao9, E. B. Ludmir10, P. T. Tran11, P. Scheet3, and C. Tang11,12; 1Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 2Department of Breast Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 3The University of Texas MD Anderson Cancer Center, Houston, TX, 4Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 5Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 6Department of Thoracic Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 7Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 8Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 9Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 10Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 11Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 12Department of Genitourinary Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Purpose/Objective(s):
Clonal hematopoiesis of indeterminate potential (CHIP) is a hematologic condition where acquired mutations that enhance cell fitness lead to clonal expansion. CHIP is associated with numerous adverse health outcomes, including reduced survival in general populations, and is common in patients with solid cancer (~20–50%). Radiation therapy (RT) confers a 50% increased risk of CHIP (RT-CHIP). Impaired tumor surveillance may permit both RT-CHIP and cancer progression while CHIP itself contributes to immune dysfunction. However, the clinical significance of RT-CHIP is incompletely defined. Our prior registry-based analysis of 29 individuals undergoing chemoradiation found a novel association between RT-CHIP in DNA damage repair (DDR) genes and overall survival (OS). Here we test the hypothesis that RT-CHIP predicts worse OS in prospective trials.Materials/Methods:
We analyzed two phase 2 studies: a single-arm trial of patients with oligometastatic renal cell carcinoma (RCC; NCT03575611) treated with metastasis-directed therapy (MDT) without systemic therapy and EXTEND (NCT03599765), which randomized patients with various oligometastatic solid tumor types to standard-of-care systemic therapy (SOC) with or without MDT. Patients with enrollment and first follow-up blood samples underwent targeted DNA sequencing to identify CHIP (=0.5% variant allele fraction) categorized by clone size and presence in DDR genes. We defined RT-CHIP as the expansion (clone size) or acquisition (count) of CHIP based on blood draw at, and 3 months following, enrollment. Associations of CHIP with progression-free survival (PFS) and OS were assessed using multivariable adjusted Cox regression models.Results:
We identified 298 eligible patients (98 RCC; 200 EXTEND [MDT=115, SOC=85]): mean age 66 years; 27% female; 88% white. The most common cancers were kidney (43%) and prostate (35%). Median follow-up was 3.1 years (IQR 2.7–3.7). Baseline CHIP was present in 149 (50%) individuals, including 55 (18%) with DDR CHIP. Following RT individuals assigned to MDT had increased DDR CHIP clone size (b=0.48; 95% CI 0.14–0.79, p=0.010) and numerically increased DDR CHIP count (b=0.41; 95% CI -0.06–0.88, p=0.088). Among patients assigned to MDT there were 79 (27%) individuals with RT-CHIP in DDR genes: TP53, PPM1D, CHEK2. RT-CHIP in DDR genes was associated with worse PFS as a function of greater clone size (HR=1.33; 95% CI 1.09–1.62; p=0.004) and increased count (HR=1.71; 95% CI 1.21–2.44; p=0.003). Increased DDR RT-CHIP count was associated with worse OS (HR=2.23; 95% CI 1.17–4.26; p=0.015). Enrollment CHIP characteristics were not associated with outcomes.Conclusion:
Across two prospective trials, RT-CHIP in DDR genes was common and associated with worse PFS and OS. Our findings suggest that RT-CHIP is a common but poorly described predictor of worse cancer outcomes. Future work will identify actionable dosimetric predictors of RT-CHIP and validate the prognostic utility of this novel biomarker.