Oncologic Therapy for Solid Tumors Alters the Risk of Clonal Hematopoiesis
Authors: Bolton Kelly , Ptashkin Ryan , Braunstein Lior , Kelly Daniel , Devlin Sean M , Coombs Catherine C. , Moarii Matahi , Patel Minal , Bernard Elsa , Berthon Antonin , Glodzik Dominik , Walsh Michael Francis , Mandelker Diana , Patel Akshar , Schulman Jessica , Gundem Gunes , Lee Choonsik , García-Closas Montserrat , Gardos Stuart , Baselga Jose , Hyman David M. , Tallman Martin S. , Scher Howard , Bajorin Dean , Yabe Mariko , Klimek Virginia M. , Diaz Luis Alberto , Chatterjee Nilanjan , Berger Michael F. , Morton Lindsay M. , Levine Ross L. , Zehir Ahmet , Papaemmanuil Elli 
Published: October 2019

Abstract
Background: Solid tumor patients are at a heightened risk for developing therapy-related myeloid neoplasms (tMN). Recent studies show evidence of somatic mutations in leukemia-associated genes in normal healthy individuals, referred to as clonal hematopoiesis (CH). We and others have shown that clonal hematopoiesis (CH) is also frequent in cancer patients. A detailed characterization of the relationship between exposure to specific oncologic regimens, the molecular features of CH presentation and how these relate to tMN risk is warranted to inform treatment decisions, early detection and prevention strategies.
Methods: To determine the relationship between CH and oncologic therapy, we performed a systematic interrogation of CH in a cohort of 17,478 solid tumor patients with clinical, outcome and molecular profiling by MSK-IMPACT. MSK-IMPACT is 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 (median coverage at 600x) using the matched tumor as a comparator and accounted for background sequencing error rates.
Results: Overall, 40% of the 17,478 patients were treatment naïve prior to IMPACT testing, 37% had received chemotherapy alone, 17% had received radiation therapy and 18% had received both. CH was identified in 4013 (23%) of patients, median VAF was 4% (range=1-80%). The vast majority (76%) had a single mutation whereas 9% had two and 5% had three or more. The number of mutations correlated with clone size (p-value=<0.001). The proportion of patients with CH greatly increased with each decade of life (p<0.001). In multivariate regression analyses adjusted by age, CH was more often found in former or current smokers (p=0.03) than in non-smokers and in Whites compared to Asians (p=0.005) and Hispanics (p=0.005). There were no significant differences by gender. Rates of CH varied greatly by solid tumor type but when limited to treatment naïve patients, no significant differences remained, suggesting that this was driven by different treatment exposures. As previously reported in healthy patient cohorts, CH in the DNA hydroxymethylation pathway predominated (52% of total CH mutations). There was a higher proportion of patients with mutations in the DNA repair/cell cycle pathway (including TP53, PPM1D and CHEK2) and among patients who received chemotherapy and radiation therapy prior to IMPACT testing compared to those who were treatment naïve (p<0.001). Exposure to prior cytotoxic chemotherapy (OR=1.2, 95%CI=1.0-1.3; p=0.03) and radiation therapy (OR=1.6, 95%CI=1.4-1.9, p<0.002) was associated with having CH while exposure to immunotherapy and targeted therapy was not. There was evidence of specific gene, treatment and dosage effects. To further examine the relationship between oncologic therapy and clonal evolution of CH mutations, we have collected 375 sequential samples collected at least 18 months apart. A subset of patients with CH were consented to germline testing for cancer predisposition genes (N=1835). We observe a lower rate of CH among patients with a germline mutation in the homologous recombination deficiency pathway (ie BRCA1, BRCA2) (OR=0.66, 95% CI: 0.43-0.99, p-value=0.05) and a higher rate of CH among patients with a germline mutation in the cell cycle/DNA repair pathway (i.e. CHEK2, TP53) when compared to patients without germline mutations (OR=1.6, 95% CI: 1.0-2.6, p-value=0.05). In analyses stratified by prior treatment, patients with germline mutations in the cell cycle/DNA repair pathway (i.e. CHEK2, TP53) with prior radiation therapy exposure were more likely to have CH compared to patients with no germline mutations who were exposed to radiation therapy (OR=4.1,95%CI=1.1-17.0, p-value for interaction=0.04).
Conclusions: 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. Taken together, we show that screening of CH in cancer cohorts is critical to the development of future clinical guidelines, the development of risk-adapted treatment decisions, surveillance programs and definition of patient subsets at highest risk for tMN.

Disclosures
Coombs: Incyte: Other: Travel fees; DAVA Oncology: Honoraria; Abbvie: Consultancy; H3 Biomedicine: Honoraria; AROG: Other: Travel fees. Tallman:Daiichi-Sankyo: Other: Advisory board; Cellerant: Research Funding; BioSight: Other: Advisory board; AROG: Research Funding; Orsenix: Other: Advisory board; AbbVie: Research Funding; ADC Therapeutics: Research Funding. Yabe:Y-mAbs Therapeutics: Consultancy. Levine:Celgene: Consultancy, Research Funding; Novartis: Consultancy; Gilead: Honoraria; Isoplexis: Equity Ownership; Epizyme: Patents & Royalties; Prelude: Research Funding; C4 Therapeutics: Equity Ownership; Janssen: Consultancy, Honoraria; Imago: Equity Ownership; Qiagen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Research Funding; Loxo: Consultancy, Equity Ownership.