Abstract 5703: Oncologic therapy shapes the fitness landscape of clonal hematopoiesis
Authors: Bolton Kelly L. , Ptashkin Ryan N. , Gao Teng , Braunstein Lior , Devlin Sean M. , Patel Minal , Berthon Antonin , Syed Aijazuddin , Yabe Mariko , Coombs Catherine , Caltabellotta Nicole M. , Walsh Mike , Offit Ken , Stadler Zsofia , Lee Choonsik , Pharoah Paul , Stopsack Konrad H. , Spitzer Barbara , Mantha Simon , Fagin James , Boucai Laura , Gibson Christopher J. , Ebert Benjamin , Young Andrew L. , Druley Todd , Takahashi Koichi , Gillis Nancy , Ball Markus , Padron Eric , Hyman David , Baselga Jose , Norton Larry , Gardos Stuart , Klimek Virginia , Scher Howard , Bajorin Dean , Paraiso Eder , Benayed Ryma , Arcilla Maria , Ladanyi Marc , Solit David , Berger Michael , Tallman Martin , Garcia-Closas Montserrat , Chatterjee Nilanjan , Diaz Luis , Levine Ross , Morton Lindsay , Zehir Ahmet , Papaemmanuil Elli 
Published: September 2020

Abstract
Recent studies among healthy individuals show evidence of somatic mutations in leukemia-associated genes, referred to as clonal hematopoiesis (CH). To determine the relationship between CH and oncologic therapy we collected sequential blood samples from 525 cancer patients (median sampling interval time = 23 months, range: 6-53 months) of whom 61% received cytotoxic therapy or external beam radiation therapy and 39% received either targeted/immunotherapy or were untreated. Samples were sequenced using deep targeted capture-based platforms. To determine whether CH mutational features were associated with tMN risk, we performed Cox proportional hazards regression on 9,549 cancer patients exposed to oncologic therapy of whom 75 cases developed tMN (median time to transformation=26 months). To further compare the genetic and clonal relationships between tMN and the proceeding CH, we analyzed 35 cases for which paired samples were available. We compared the growth rate of the variant allele fraction (VAF) of CH clones across treatment modalities and in untreated patients. A significant increase in the growth rate of CH mutations was seen in DDR genes among those receiving cytotoxic (p=0.03) or radiation therapy (p=0.02) during the follow-up period compared to patients who did not receive therapy. Similar growth rates among treated and untreated patients were seen for non-DDR CH genes such as DNMT3A. Increasing cumulative exposure to cytotoxic therapy (p=0.01) and external beam radiation therapy (2x10-8) resulted in higher growth rates for DDR CH mutations. Among 34 subjects with at least two CH mutations in which one mutation was in a DDR gene and one in a non-DDR gene, we studied competing clonal dynamics for multiple gene mutations within the same patient. The risk of tMN was positively associated with CH in a known myeloid neoplasm driver mutation (HR=6.9, p&lt;10-6), and increased with the total number of mutations and clone size. The strongest associations were observed for mutations in TP53 and for CH with mutations in spliceosome genes (SRSF2, U2AF1 and SF3B1). Lower hemoglobin, lower platelet counts, lower neutrophil counts, higher red cell distribution width and higher mean corpuscular volume were all positively associated with increased tMN risk. Among 35 cases for which paired samples were available, in 19 patients (59%), we found evidence of at least one of these mutations at the time of pre-tMN sequencing and in 13 (41%), we identified two or more in the pre-tMN sample. In all cases the dominant clone at tMN transformation was defined by a mutation seen at CH Our serial sampling data provide clear evidence that oncologic therapy strongly selects for clones with mutations in the DDR genes and that these clones have limited competitive fitness, in the absence of cytotoxic or radiation therapy. We further validate the relevance of CH as a predictor and precursor of tMN in cancer patients. We show that CH mutations detected prior to tMN diagnosis were consistently part of the dominant clone at tMN diagnosis and demonstrate that oncologic therapy directly promotes clones with mutations in genes associated with chemo-resistant disease such as TP53.
Citation Format: Kelly L. Bolton, Ryan N. Ptashkin, Teng Gao, Lior Braunstein, Sean M. Devlin, Minal Patel, Antonin Berthon, Aijazuddin Syed, Mariko Yabe, Catherine Coombs, Nicole M. Caltabellotta, Mike Walsh, Ken Offit, Zsofia Stadler, Choonsik Lee, Paul Pharoah, Konrad H. Stopsack, Barbara Spitzer, Simon Mantha, James Fagin, Laura Boucai, Christopher J. Gibson, Benjamin Ebert, Andrew L. Young, Todd Druley, Koichi Takahashi, Nancy Gillis, Markus Ball, Eric Padron, David Hyman, Jose Baselga, Larry Norton, Stuart Gardos, Virginia Klimek, Howard Scher, Dean Bajorin, Eder Paraiso, Ryma Benayed, Maria Arcilla, Marc Ladanyi, David Solit, Michael Berger, Martin Tallman, Montserrat Garcia-Closas, Nilanjan Chatterjee, Luis Diaz, Ross Levine, Lindsay Morton, Ahmet Zehir, Elli Papaemmanuil. Oncologic therapy shapes the fitness landscape of clonal hematopoiesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5703.