Clonal hematopoiesis in breast cancer: moving beyond prevalence toward clinical relevance

Introduction

Clonal hematopoiesis (CH) has become increasingly relevant in oncology as genomic sequencing incidentally uncovers somatic mutations in hematopoietic stem cells among patients undergoing evaluation for drivers of their underlying malignancy (1-3). Based on large-scale sequencing studies, CH is associated with increased risks of myeloid malignancy and adverse cardiovascular events, and its prevalence rises substantially with age and cytotoxic therapy exposure (4-6). CH of indeterminate potential (CHIP) by definition requires a mutation in a gene associated with myeloid malignancies with a minimum variant allele frequency of 2% in absence of hematologic abnormalities (7). The expanding use of tumor sequencing, germline testing, and circulating tumor DNA (ctDNA) assays has made CH a frequent incidental finding in oncology, including breast cancer care. Given the long-term survivorship of most breast cancer patients and their exposure to chemotherapy and radiation, which are the same exposures known to promote clonal expansion, clarifying the clinical implications of CH is increasingly important. The review by Mayerhofer et al. addresses this emerging field by examining evidence regarding CH prevalence in women with breast cancer, highlighting its enrichment following chemotherapy, and noting the lack of demonstrated associations with breast cancer-specific outcomes (8). Here we will summarize and critically appraise this review and share our perspectives related to the intersection between breast cancer and CHIP, including our views on the implications for current practice and future research.

Overview of data presented in Mayerhofer et al.’s review

To emphasize the importance of understanding the interplay between CH and breast cancer, the authors explored the central role of inflammation in the pathophysiology of CH through extensive evidence (9,10). While CH does not appear more prevalent in patients with breast cancer compared to other malignancies, due to the high proportion of patients treated with curative intent, a clear understanding of any longitudinal health risks posed by CH would best inform survivorship care.

The authors’ central conclusion, that CH has not been shown to influence breast cancer–specific outcomes, is generally consistent with current evidence. Studies evaluating recurrence, progression, and mortality have not found statistically robust associations between CH and breast cancer prognosis (10). A future opportunity, should larger studies allow, would be to analyze on a mutation-specific level, as different mutations likely carry different risks. For example, high-variant allele frequency TP53 or PPM1D carry higher risk of therapy-related myeloid neoplasms (tMN) and may influence non-cancer outcomes such as anthracycline-induced cardiomyopathy (11).

Overall, the most clinically meaningful insight from this review is that CH in patients with breast cancer appears to function less as a determinant of breast cancer–specific prognosis and more as a marker of broader long-term health vulnerability, particularly through inflammatory mechanisms linked to cardiovascular disease and tMN. This distinction reinforces the importance of integrating CH into survivorship frameworks rather than oncologic decision-making alone, highlighting the need for longitudinal monitoring, mutation-specific risk stratification, and multidisciplinary management strategies to mitigate non-breast cancer morbidity in this growing survivor population.

Additional perspectives

Several important studies not included in the review provide additional insights into how CH evolves during cancer therapy and may affect long-term outcomes. Recent longitudinal sequencing investigations demonstrate that chemotherapy accelerates clonal expansion in a mutation-specific manner. Arends et al. demonstrated that patients with relapsed high-grade ovarian cancer receiving carboplatin, PARP inhibitors, and HSP90 inhibitors have significant expansion of TP53- and PPM1D-mutated clones as compared to DNMT3A- or TET2-mutated clones during treatment (12). The mechanistic basis for PPM1D expansion following platinum therapy is explained by Hsu et al., who demonstrated these mutations were present in one-fifth of patients with therapy-related AML/MDS and strongly correlated with cisplatin exposure (13). Additionally, mutant PPM1D hematopoietic cells outcompeted wild-type counterparts in vivo after exposure to cisplatin and doxorubicin through increased resistance to apoptosis (13). These data suggest that CH prevalence after therapy may be underestimated in studies relying on baseline-only sequencing, potentially influencing the interpretation of chemotherapy-associated risks.

Emerging evidence also underscores substantial racial and ethnic variation in CH patterns and prevalence. Zhang & Cheng analyzed 245,388 participants in the All of Us Research Program and identified clear racial disparities in CH prevalence and mutational profiles. African Americans had higher odds of CH compared to White Americans and exhibited distinct mutation patterns (14). Furthermore, CH was more strongly linked to myeloproliferative neoplasms in African Americans compared with White Americans (14). Wen et al. compared 136,401 participants from the Mexico City Prospective Study (MCPS) to 416,118 individuals from the UK Biobank (UKB) and found that CH was significantly less common in MCPS compared to UKB (15). The study identified ancestry-specific variants in the TCL1B locus with opposing effects on DNMT3A-CH versus non-DNMT3A-CH, and meta-analysis identified five novel loci (15). Across large Chinese population-based cohorts, CH shows a distinct mutational spectrum when compared to European-ancestry populations (16,17). As compared to a Western cohort, the Chinese cohort had high incidence of common CH mutations including DNMT3A, TET2, and ASXL1, but with unique identification variants in 81 genes (16). In another Chinese-focused study, the risk for cardiovascular disease was linked to not only CH but also germline predisposition (17). These ancestry-linked differences suggest population-specific selective pressures and may partly explain variation in CH-associated hematologic malignancy and cardiovascular risk between East Asian and European groups.

These findings highlight that the intersection of CH biology with breast cancer disparities demands ancestry-informed research, as mutation-specific effects on breast cancer prognosis may differ across populations. More importantly, risk prediction models developed primarily in White populations may systematically misclassify risk in other ancestries, perpetuating existing inequities in precision oncology approaches.

Cardiovascular implications of CH are particularly relevant for breast cancer survivors who may receive cardiotoxic therapies such as anthracyclines or human epidermal growth factor receptor 2 (HER2)-directed agents. Mammadova et al. found that after adjusting for age, diabetes, dyslipidemia, and chest radiation, CH was independently associated with doxorubicin-induced cardiotoxicity in treated patients (18). Jensen et al. reviewed evidence that demonstrates CH mutations enhance anthracycline cardiac toxicity and discuss mechanistic pathways involving macrophage secretion of interleukin (IL)-1β and IL-6 (19). These findings suggest that CH may serve as a risk enhancer for treatment-related cardiotoxicity and could have major implications for survivorship care.

Finally, the growing use of cell-free DNA (cfDNA) and ctDNA assays in breast cancer introduces analytical challenges. CH-associated variants frequently appear in plasma sequencing and may be misinterpreted as tumor-derived mutations. Magee et al. analyzed 16,812 liquid biopsy profiles across 49 cancer types and found that 42.3% of patients had at least one CH variant among reportable clinical genes, with the median proportion of CH-classified variants ranging from 20% (ages 65–69 years) to 50% (ages 80+ years) (20). They also confirmed ongoing misclassification in clinical practice (20). As minimal residual disease testing becomes more widespread in early-stage breast cancer, failure to distinguish CH from tumor-derived alterations could lead to overtreatment or misinterpretation of recurrence risk. Sequencing cfDNA/ctDNA alongside paired normal DNA (genomic DNA) can help prevent misinterpretation of CH variants as tumor-derived alterations.

Emerging evidence linking CH and breast cancer risk, treatment exposure, and age-specific outcomes

Recent studies published after the original review further refine the relationship between CH and breast cancer across the disease continuum. A large population-based analysis in the UK Biobank identified complex associations between CH-predisposing variants and breast cancer risk, including signals involving DNA-damage-response pathways such as ATM, raising the possibility that shared germline susceptibility may contribute to both CH and breast cancer development in some individuals (21). Complementary work also suggests that mutation or genotype-specific effects may shape clinical associations between CH and breast cancer, although current datasets remain limited in size and require validation in larger cohorts (22).

Prospective and observational clinical studies provide additional context across age groups. In older patients receiving chemotherapy, CH is common at baseline and demonstrates dynamic clonal behavior during treatment, with expansion of DNA-damage-response gene mutations such as TP53 and PPM1D and associations with treatment-related cytopenias and dose modification, supporting potential clinical relevance in survivorship and treatment tolerance (23). Parallel investigations in younger women and broader contemporary cohorts of breast cancer patients likewise document measurable CH prevalence and clinical correlates, reinforcing that CH can be detected across the age spectrum (24). However, in young women treated for breast cancer with cytotoxic therapies, no association was found between the presence of CH and adverse breast cancer or non-breast cancer-related outcomes, with paired blood samples showing no evidence of mutant clonal expansion over 4 years (25). This highlights that the dynamic clonal behavior of CH and its influence on adverse clinical outcomes can differ based on the population being studied.

Clinical implications

The review’s conclusions are broadly aligned with current clinical practice: CH testing is not routinely indicated, and CH should generally not guide decisions about chemotherapy or radiation. There is no evidence that CH predicts breast cancer recurrence or modifies the benefits of standard breast cancer therapy. However, although CH should not influence breast cancer-specific treatment decisions, certain mutation patterns, particularly high-VAF TP53 and PPM1D, may indicate increased susceptibility to tMN in patients undergoing anthracycline- or platinum-based regimens (12,13). While this should not prompt withholding curative therapy, it may justify enhanced hematologic monitoring or consultation with hematology in select cases. Importantly, CH is biologically heterogeneous and may emerge under distinct environmental or therapeutic stressors, with differing clinical implications across mutation types. For example, recent descriptions of emergent BAX-mutated CH following cellular stress further underscore that not all CH clones confer equivalent risk, in contrast to the particularly strong association between TP53-mutated CH and tMN (26).

Additionally, emerging research shows that CH prevalence, mutation patterns, and disease associations differ substantially across racial, ethnic, and age groups. Notably, African American and Mexican-ancestry populations demonstrate distinct mutational landscapes and risk profiles compared with White and UK Biobank cohorts. Furthermore, the presence of CH may have stronger clinical relevance regarding treatment response and resilience in older populations as compared to younger patients. These findings indicate that risk models based primarily on older, White populations may misclassify risk in other ancestries and age groups, underscoring the need for ancestry and age-informed CH research to avoid perpetuating inequities in precision oncology.

Third, the cardiovascular implications of CH in patients with breast cancer deserve greater emphasis. Given the strong association between CH and treatment-related cardiotoxicity, ongoing research may allow clinicians to incorporate CH status into survivorship cardiovascular risk assessments, particularly for patients with additional risk factors.

Furthermore, as ctDNA becomes integrated into clinical decision-making in early breast cancer, clinicians must be trained to interpret CH-associated variants appropriately. Failure to recognize CH as a potential confounder in interpretation of sequencing studies could result in erroneous assessments of minimal residual disease, leading to unnecessary escalation of therapy or inappropriate therapeutic selection as has been demonstrated in other studies.

Collectively, in combination with newer data, Mayerhofer et al.’s review helps highlight several emerging themes: (I) shared germline and somatic DNA-repair biology may underlie overlapping susceptibility to CH and breast cancer; (II) mutation-specific CH effects, particularly involving DNA-damage-response genes, may influence treatment tolerance and long-term health risks rather than breast cancer-specific prognosis; and (III) age and therapy exposure remain key modifiers of CH prevalence and clonal dynamics. These findings extend prior conclusions while highlighting the need for larger, mutation-resolved longitudinal studies to clarify how CH should inform breast cancer risk stratification, treatment planning, and survivorship care.

Future directions

Important gaps remain in our understanding of CH in breast cancer. Large longitudinal studies assessing CH dynamics before, during, and after chemotherapy are needed to clarify how specific regimens influence clonal evolution. Studies must be diverse in terms of race and age groups to capture ancestry and age-associated mutation patterns and ensure generalizability. Prospective trials that incorporate CH as a stratification factor could elucidate mutation-specific risks for tMN and cardiovascular toxicity. Additionally, survivorship studies evaluating whether CH predicts long-term cardiovascular outcomes in breast cancer survivors could answer an important clinically relevant question.

Conclusions

CH is increasingly encountered in breast cancer care, largely as an incidental finding resulting from widespread genomic testing. While current evidence does not demonstrate an association between CH and breast cancer-specific outcomes, CH remains highly relevant to the broader context of cancer survivorship, treatment toxicity, and cardiovascular risk. The review by Mayerhofer et al. correctly concludes that CH should not guide treatment decisions at present, though future studies may clarify the implication of CH as it relates to the risk/benefit profile of cytotoxic chemotherapy especially in the adjuvant setting. Clinicians should refrain from routine CH testing yet interpret incidentally discovered CH with awareness of its potential implications for therapy-related toxicity and cardiovascular health. Future research must prioritize longitudinal, mutation-specific, and racially diverse studies to determine whether CH can eventually serve as an actionable biomarker in breast cancer management.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0028/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0028/coif). C.C.C. received consulting fees from AbbVie, AstraZeneca, BeOne, BMS, Lilly, Genentech, Johnson and Johnson; payment or honoraria from AstraZeneca, BeOne, Lilly; and stock or stock options from Geron. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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