Abstract LB-304: Oncologic therapy for solid tumors alters the risk of clonal hematopoiesis
Authors: Bolton Kelly , Ptashkin Ryan , Braunstein Lior , Gao Teng , Devlin Sean M. , Kelly Daniel , Coombs Catherine , Patel Minal , Moarii Matahi , Bernard Elsa , Berthon Antonin , Boucai Laura , Glodzik Dominik , Martin Axel , Stadler Zsofia , Walsh Michael , Mandelker Diana , Patel Akshar , Schulman Jessica , Gundem Gunes , Syed Aijazuddin , Arcila Maria , Solit David B. , Robson Mark E. , Ladanyi Marc , Lee Choonsik , Philip John , Bajorin Dean , Garcia-Closas Montserrat , Gardos Stuart , Hyman David , Tallman Martin , Yabe Mariko , Offit Kenneth , Scher Howard , Klimek Virginia , Diaz Luis , Chatterjee Nilanjan , Berger Michael F. , Morton Lindsay , Levine Ross , Zehir Ahmet , Papaemmanuil Elli 
Published: August 2019

Abstract
Solid tumor patients often suffer from cytopenias and are at risk for therapy-related myeloid neoplasms (tMN). Somatic mutations in leukemia-associated genes can occur in normal healthy individuals, referred to as clonal hematopoiesis (CH). CH is associated with cytopenias, risk of leukemia and cardiovascular disease. We and others have shown that CH is frequent in cancer patients. Characterization of the relationship between exposure to specific oncologic regimens and CH and how these relate to cytopenias and tMN risk would inform treatment decisions and tMN prevention strategies.
To determine the relationship between CH and oncologic therapy we interrogated CH in a cohort of 9045 solid tumor patients. Subjects were sequenced using a targeted panel of cancer-associated mutations used to screen tumor samples against a blood control sample. Mutation detection was performed on blood-derived sequencing data using the matched tumor as a comparator and accounted for background sequencing error rates.
CH was identified in 23% of patients. In multivariate regression analyses adjusted by age, CH was more often found in current smokers (OR=1.20, 95%CI=1.07-1.35, p&lt;0.001) and less often found in Asians compared to Whites (OR=0.72, 95%CI=0.56-0.89, p&lt;0.001). Smoking was associated with CH mutations in ASXL1 (OR=3.75, 95%CI=2.73-5.17, p&lt;0.001). There was a higher proportion of patients with CH among those who had received chemotherapy (OR=1.14, 95%CI=1.02-1.26, p=0.02) and those who had received external beam radiation therapy (OR=1.45, 95%CI=1.28-1.63, p&lt;0.001) prior to blood collection. Mutations in the DNA repair/cell cycle pathway (including TP53, PPM1D and CHEK2) were more common among patients who received chemotherapy and radiation therapy prior to IMPACT testing compared to those who were treatment naïve (p&lt;0.001). Exposure to prior cytotoxic chemotherapy (OR=1.20, 95%CI=1.02-1.30; p=0.007) and radiation therapy (OR=1.6, 95%CI=1.4-1.9, p&lt;0.001) was associated with having CH while exposure to immunotherapy and targeted therapy was not. Increasing cumulative dose of chemotherapy overall and cytotoxic therapy was associated with a higher likelihood of CH (p=0.015 and p=0.007 respectively). There was evidence of specific gene, treatment and dosage effects. To further examine the relationship between oncologic therapy and clonal evolution of CH, we collected 375 sequential samples at least 18 months apart. T mean change in VAF of CH mutations per year was found to increase by 0.17% in patients who did not receive further therapy during the follow-up time and 0.49% in those who were exposed to cytotoxic chemotherapy. A subset of patients with CH were consented to germline testing for cancer predisposition genes (N=6368). We observe a higher rate of CH among patients with a germline mutation in the cell cycle/DNA repair pathway (i.e. TP53) when compared to patients without germline mutations (OR=3.7, 95% CI: 1.35-9.35, p-value=0.01).
CH is frequent in solid tumor patients and can be reliably detected when a matched tumor normal targeted gene sequencing approach is performed. Beyond age, CH is strongly associated with race, smoking and importantly prior exposure to oncologic therapy with evidence of specific treatment effects. Screening of CH in cancer cohorts is critical to the development of future clinical guidelines and risk-adapted prevention strategies for tMN.
Note: This abstract was not presented at the meeting.
Citation Format: Kelly Bolton, Ryan Ptashkin, Lior Braunstein, Teng Gao, Sean M. Devlin, Daniel Kelly, Catherine Coombs, Minal Patel, Matahi Moarii, Elsa Bernard, Antonin Berthon, Laura Boucai, Dominik Glodzik, Axel Martin, Zsofia Stadler, Michael Walsh, Diana Mandelker, Akshar Patel, Jessica Schulman, Gunes Gundem, Aijazuddin Syed, Maria Arcila, David B. Solit, Mark E. Robson, Marc Ladanyi, Choonsik Lee, John Philip, Dean Bajorin, Montserrat Garcia-Closas, Stuart Gardos, David Hyman, Martin Tallman, Mariko Yabe, Kenneth Offit, Howard Scher, Virginia Klimek, Luis Diaz, Nilanjan Chatterjee, Michael F. Berger, Lindsay Morton, Ross Levine, Ahmet Zehir, Elli Papaemmanuil. Oncologic therapy for solid tumors alters the risk of clonal hematopoiesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-304.