Clonal hematopoiesis and clinical outcomes in metastatic castration-resistant prostate cancer patients given androgen receptor pathway inhibitors (Alliance A031201) Journal Article

   


Authors: Jensen, J. L.; Bobek, O.; Chan, I. C. C.; Miller, B. C.; Hillman, D. W.; Heller, G.; Druley, T.; Armstrong, A. J.; Morris, M. J.; Milowsky, M. I.; Beltran, H.; Bolton, K. L.; Coombs, C. C.
Article Title: Clonal hematopoiesis and clinical outcomes in metastatic castration-resistant prostate cancer patients given androgen receptor pathway inhibitors (Alliance A031201)
Abstract: Purpose: Mutations in hematopoietic progenitor cells accumulate with age leading to clonal expansion, termed clonal hematopoiesis (CH). CH in the general population is associated with hematopoietic neoplasms and reduced overall survival (OS), predominantly through cardiovascular adverse events (CVAE). Because androgen receptor pathway inhibitors (ARPI) used in metastatic castration-resistant prostate cancer (mCRPC) are also associated with CVAEs and because CH negatively impacted survival in an advanced solid tumor cohort, we hypothesized that CH in mCRPC may be associated with increased CVAEs and inferior survival. Experimental Design: A targeted DNA sequencing panel captured common CH mutations in pretreatment blood samples from 957 patients enrolled in Alliance A031201: a randomized trial of enzalutamide ± abiraterone/prednisone in the first-line mCRPC setting. The primary outcome was the impact of CH on OS; the secondary outcomes were progression-free survival (PFS) and CVAEs. Results: Baseline comorbidities were similar by CH status. No differences in OS/progression-free survival were detected regardless of treatment arm or the variant allele frequency threshold used to define CH [primary: 2% (normal-CH, N-CH); exploratory: 0.5% (low-CH) and 10% (high-CH, H-CH)]. Patients with H-CH (7.2%) and TET2-mutated N-CH (6.0%) had greater odds of any CVAE (14.5% vs. 4.0%; P = 0.0004 and 12.3% vs. 4.2%; P = 0.010, respectively). More major CVAEs were observed in patients with H-CH (5.8% vs. 1.9%; P = 0.042) and N-CH (3.4% vs. 1.8%; P = 0.147). Conclusions: CH did not affect survival in patients with mCRPC treated with ARPIs in A031201. H-CH and TET2-mutated CH were associated with more CVAEs. These findings inform the risk/benefit discussion about ARPIs in mCRPC. © 2024 American Association for Cancer Research.
Keywords: survival; adult; controlled study; treatment outcome; aged; aged, 80 and over; middle aged; dna binding protein; tet2 protein, human; gene mutation; major clinical study; overall survival; genetics; mutation; dna-binding proteins; proto-oncogene proteins; prednisone; clinical trial; mortality; hypertension; antineoplastic agent; allele; gene; metastasis; progression free survival; randomized controlled trial; antineoplastic combined chemotherapy protocols; genetic variability; pathology; retrospective study; prostate cancer; coronary artery bypass graft; heart infarction; diabetes mellitus; comorbidity; neoplasm metastasis; hematopoiesis; androgen receptor; phase 3 clinical trial; pathogenicity; receptors, androgen; drug therapy; dna extraction; nitriles; nitrile; heart arrest; castration resistant prostate cancer; phenylthiohydantoin; ar protein, human; dna methyltransferase 3a; progression-free survival; adverse event; benzamide derivative; benzamides; abiraterone; androgen receptor antagonist; clinical outcome; angina pectoris; tet2; acute coronary syndrome; clonal hematopoiesis; androgen receptor antagonists; dioxygenase; enzalutamide; very elderly; dna sequencing; humans; human; male; article; prostatic neoplasms, castration-resistant; metastatic castration resistant prostate cancer; androstane derivative; ecog performance status; major adverse cardiac event; coronary atherosclerosis; canakinumab; proto oncogene protein; dioxygenases; androstenes
Journal Title: Clinical Cancer Research
Volume: 30
Issue: 21
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2024-11-01
Start Page: 4910
End Page: 4919
Language: English
DOI: 10.1158/1078-0432.Ccr-24-0803
PUBMED: 39287426
PROVIDER: scopus
PMCID: PMC11539927
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85208253417&doi=10.1158%2f1078-0432.CCR-24-0803&partnerID=40&md5=2ffda8fb191e47c8e9b7b11d887717f5
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Scopus
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MSK Authors
  1. Glenn Heller
    399 Heller
  2. Michael Morris
    578 Morris
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