Clonal hematopoiesis in older patients with breast cancer receiving chemotherapy

Abstract

Background The expansion of hematopoietic stem cells carrying recurrent somatic mutations, termed clonal hematopoiesis (CH), is common in elderly individuals and associated with increased risk of myeloid malignancy and all-cause mortality. Though chemotherapy is a known risk factor for developing CH, how myelosuppressive therapies affect the short-term dynamics of CH remains incompletely understood. Most studies have been limited by retrospective design, heterogeneous patient populations, varied techniques to identifying CH, and analysis of single time points. Methods We examined serial samples from 40 older females with triple-negative or hormone receptor-positive breast cancer treated on the prospective ADjuVANt Chemotherapy in the Elderly (ADVANCE) trial to evaluate the prevalence and dynamics of CH at baseline and throughout chemotherapy (6 and 12 weeks). Results CH was detected in 44% of patients at baseline and in 53% at any timepoint. Baseline patient characteristics were not associated with CH. Over the course of treatment, mutations exhibited a variety of dynamics, including emergence, expansion, contraction, and disappearance. All mutations in TP53 (n = 3) and PPM1D (n = 4), genes that regulate the DNA damage response, either became detectable or expanded over the course of treatment. Neutropenia was more common in patients with CH, particularly when the mutations became detectable during treatment, and CH was significantly associated with cyclophosphamide dose reductions and holds (p = .02). Conclusions Our study shows that CH is common, dynamic, and of potential clinical significance in this population. Our results should stimulate larger efforts to understand the biological and clinical importance of CH in solid tumor malignancies. Trial Registration ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03858322). Clinical trial registration number: NCT03858322

Convergent somatic evolution commences in utero in a germline ribosomopathy

“…In this study, we have shown that the strong selective pressure to overcome impaired ribosome biogenesis and avoid p53-mediated cell death in SDS results in convergent somatic mutations in a unique set of target genes, not observed in the context of ageing 45 – 47 or haematological perturbations such as autoimmunity 48 or chemotherapy 49 . The survival advantage conferred by such mutations results in HSC clonal expansions, often commencing very early in life, even in utero, in individuals with SDS.…”

Circulating tumour DNA testing in metastatic breast cancer: Integration with tissue testing

“…Interpretation of ctDNA results requires careful consideration especially regarding non‐tumour mutations that may occur in CHIP. These mutations can overlap with common somatic alterations, 100 thus filtering out CHIP‐associated genes is important, particularly for genes such as ATM , BRCA1/2 , TP53 , and PTEN 101 . In terms of gene fusion analyses, ctDNA‐based assays have proven essential in complementing tissue testing 102 .…”