Background: Recent genomic studies have identified somatic mutations in leukemia genes in asymptomatic individuals without hematologic malignancy. A subset of patients (pts) with clonal hematopoiesis (CH) subsequently develops hematologic malignancies. However, the incidence of CH in pts with solid tumors has not been extensively studied. We sought to assess for CH and its associated clinical impact in pts with solid tumors who were profiled using paired tumor/blood sequencing.
Methods: This study included pts who were consented on protocol NCT01775072. All had tumor and blood genomic profiling using the MSK-IMPACT hybridization capture-based next-generation sequencing assay, encompassing all protein-coding exons of 410 cancer-associated genes. In matched blood, we investigated for hotspot mutations from COSMIC database (v71) and non-hotspot mutations in leukemia-associated genes and genes reported in prior CH studies. Mutations were scored as present if variant allele frequency (VAF) in blood was greater than 2% and at least twice the VAF seen in tumor. For cases where at least one mutation exceeded these thresholds, we reduced the VAF threshold in blood to 1% to detect subsequent events. Mutations with VAF >35% in both blood and tumor were excluded as likely germline events.
Results: We analyzed 2,146 pts, including 239 pts (11%) with CH. Most commonly identified mutations were in DNMT3A, TET2, and TP53, seen in 167, 52, and 18 pts, respectively. The mean age at time of testing was 62.6 years in pts with CH and 55.4 years in pts without CH (p< 0.001). When comparing baseline blood parameters, there were no statistically significant differences except for higher MCV in CH vs. non-CH pts (91 vs. 90, p = 0.047). 51% of pts with CH had previous radiation therapy compared to 45% of pts without clonal mutations in their blood (p = 0.057). There was no statistically significant difference in the proportion of pts who had received previous chemotherapy (71% of pts in each group). On prospective follow up of pts with CH, no pts have progressed to develop overt hematologic malignancy, with limited follow up (median 13.1 months). Overall survival (OS) was estimated for pts without CH (n = 1907; 1-yr OS: 0.70), CH with 1 mutation (n = 184; 1-yr OS: 0.64), and CH with >1 mutation (n = 55; 1-yr OS: 0.59). The univariate hazard ratios were 1.16 (p = 0.269) and 1.63 (p = 0.015) for 1 mutation and >1 mutation, respectively, when compared to pts without CH. After adjusting for age and sex, a marginal OS association persisted for >1 mutation compared to no CH (HR: 1.46, p = 0.060)
Conclusions: CH is common among solid tumor pts without known hematologic malignancy, occurring in 11% of pts, and appears to be associated with decreased OS. Analyses will be replicated in a larger cohort with longer follow up to determine the clinical impact of these mutations in cancer pts.
Citation Format: Catherine Coombs, Ahmet Zehir, Sean Devlin, Sumit Middha, Donavan Cheng, Ashwin Kishtagari, David Hyman, David Solit, Mark Robson, Jose Baselga, Maria Arcila, Martin Tallman, Ross Levine, Michael Berger. Clonal hematopoiesis identified by matched-normal blood sequencing of solid tumor patients without hematologic malignancy is common and is associated with decreased overall survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2640.