Clonal Hematopoiesis of Indeterminate Potential and its Association with Treatment Outcomes and Adverse Events in Patients with Solid Tumors
Tharani Krishnan, João Paulo Solar Vasconcelos, Emma Titmuss, Robert J. Vanner, David F. Schaeffer, Aly Karsan, Howard J. Lim, Cheryl Ho, Sharlene Gill, Stephen Yip, Stephen Chia, Hagen F. Kennecke, Derek J. Jonker, Eric X. Chen, Daniel J. Renouf, Chris J. O’Callaghan, Jonathan M. Loree
Abstract
ABSTRACT: Clonal hematopoiesis of indeterminate potential (CHIP) is the clonal expansion of hematopoietic stem cells from somatic mutations. It is a common incidental finding in cell-free DNA (cfDNA). We investigated the incidence of CHIP in cfDNA from patients with solid tumors and explored its association with treatment outcomes and adverse events. We reviewed cfDNA results from a local prospective solid tumor cohort (PREDiCT-l) and two randomized trials: Canadian Cancer Trials Group CO.26 [durvalumab + tremelimumab (D + T) or best supportive care in metastatic colorectal cancer] and Canadian Cancer Trials Group PA.7 (gemcitabine and nab-paclitaxel ± D + T in metastatic pancreatic adenocarcinoma). CHIP+ was defined as any mutation in DNMT3A, TET2, or ASXL1 with a variant allele frequency ≥2%. Presumed germline variants (variant allele frequency >40%) were removed. The first line of treatment after cfDNA was reviewed for grade ≥3 and dose-limiting toxicities. The prevalence of CHIP in the 465 included patients was 10% to 30%, and it was more common as age increased (P = 0.003). DNMT3A was the gene most frequently mutated in all cohorts. Patients with CHIP in PA.7 treated with immunotherapy showed an improved progression-free survival versus CHIP− [HR = 0.55 (0.28–1.07); P = 0.079, P-interaction = 0.098 (multivariable)]. However, patients with CHIP treated with chemotherapy in PREDiCT-l showed a trend toward worse progression-free survival [HR = 1.82 (0.98–3.38); P = 0.059]. There was no difference in adverse event rates between CHIP ± groups for those treated with chemotherapy or immunotherapy. CHIP is common in patients with solid tumors. Although not appearing to affect rates of adverse events, CHIP may affect outcomes from immunotherapy or chemotherapy. SIGNIFICANCE: Liquid biopsy is increasingly being used in oncology for tumor molecular characterization. CHIP is a common incidental finding in cfDNA, and its prevalence increases with age. This study builds on growing evidence of common CHIP variants in patients with solid tumors. The results suggest a possible clinical impact of CHIP on treatment outcomes from immunotherapy or chemotherapy. This may have implications for treatment selection for patients with solid tumors.