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 is 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 timepoints.

Methods: We examined serial samples from 40 older women with triple-negative or hormone receptor-positive breast cancer treated on the prospective ADjuVANt Chemotherapy in the Elderly 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.

Figure 1.

Study flow. Forty patients age 70 years and older from 2 biological different entities were recruited and targeted sequencing of 88 genes recurrently mutated in hematologic neoplasms was performed to assess clonal hematopoiesis (CH) at 3 different timepoints (Table 1). Feasibility, toxicity, and growth factor use were compared among chemotherapy groups and patients with and without CH (Table 2).

Figure 2.

Clonal hematopoiesis (CH) is shown at baseline and expanding during chemotherapy. These charts indicate comutations present in patients at baseline (A); the incidence of CH at baseline and at any timepoint in the study (B); the age of patients with or without CH at baseline (C); the variant allele fraction (VAF) of the largest clone in patients aged 69-75 years and aged 76 years and older, at baseline (D); mutations detected at later timepoints (6 or 12 weeks), baseline timepoint only, and at multiple timepoints (E); mutations acquired at later timepoints (F); and the variant allele fraction of mutations at baseline and following chemotherapy at later timepoints (G).

Figure 3.

Comutations and dynamics of patients with clonal hematopoiesis (CH) undergoing chemotherapy. These charts indicate somatic mutations (A) and comutations (B) present at any timepoint, along with the dynamics of variant allele fraction (VAF) in patients with CH at baseline, specifically patient 25 (C), patient 30 (D), and patient 39 (E).