Letter to the editor - Letter to the editor regarding The impact of body mass index on the efficacy of CDK4/6 inhibitors in patients with metastatic breast cancer

Sep 30, 2026

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Letter to the editor evaluating an article on the association between body mass index (BMI) and outcomes in metastatic hormone receptor-positive breast cancer treated with CDK4/6 inhibitors. The letter argues that BMI dichotomization at a single cutoff may obscure known U- or J-shaped relationships with mortality, and that key prognostic variables were not adjusted, including performance status and muscle mass, producing residual confounding. It also notes missing relative dose intensity data and internal inconsistency between overall survival and progression-free survival, questioning an “obesity paradox” interpretation.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages2

Reading Time5 min

AccessFree to download

Letter to the editor

Key methodological concerns

Residual confounding and treatment exposure

Internal consistency and interpretation

Summary and future directions

Acknowledgments and author contributions

Disclosure statement and funding

References

AnnAls of Medicine 2026, Vol. 58, no. 1, 2609409 [https://doi.org/10.1080/07853890.2025.2609409](https://doi.org/10.1080/07853890.2025.2609409) LETTER TO THE EDITOR Letter to the editor regarding: ‘The impact of body mass index on the efficacy of CDK4/6 inhibitors in patients with metastatic breast cancer’ We read with great interest the article by Ma et al. [1] titled ‘The impact of body mass index on the efficacy of CDK4/6 inhibitors in patients with metastatic breast cancer’. The authors investigated the association between body mass index (BMI) and outcomes in patients with metastatic hormone receptor-positive breast cancer treated with CDK4/6 inhibitors. While the observation of longer overall survival (OS) in patients with higher BMI (≥24 kg/m2 ) is intriguing, we wish to highlight methodological considerations that may affect the interpretation of these findings. First, dichotomizing BMI at a single cut-off (24 kg/m2 ) may oversimplify its relationship with survival. Extensive epidemiological evidence suggests a U- or J-shaped association between BMI and mortality, where both low and very high BMI are linked to increased risk [2] . In oncology, some studies suggest a potential survival benefit only for overweight, but not obese, patients [3] . Using a binary classification may mask such non-linear effects and lead to misinterpretation. Second, although the authors acknowledge certain limitations, we believe their impact is understated. Crucially, the study did not adjust for performance status or muscle mass – established strong prognostic factors. Their absence likely introduces residual confounding, meaning the estimated BMI effect may partly reflect the influence of these unmeasured variables. Furthermore, the study did not capture relative dose intensity (RDI) of CDK4/6 inhibitors – a key mediator linking patient characteristics to outcomes. If higher BMI is associated with better tolerance and thus higher treatment exposure, the survival difference may reflect treatment quality rather than a direct biological effect of BMI. Without accounting for these factors, causal inference remains fragile. Finally, internal inconsistencies challenge the ‘obesity paradox’ interpretation [4] . While OS differed in the first-line setting, progression-free survival – a more direct measure of drug activity – did not reach statistical significance (p = 0.488) . Moreover, the BMI ‘effect’ was absent in later lines of therapy. This pattern may better align with the notion that BMI might merely serve as a proxy for initial physiological reserve and treatment tolerance potential – an advantage that diminishes with disease progression and cumulative toxicity, rather than representing a stable biological protective factor. In summary, while Ma et al. highlight an important clinical association, labeling it an ‘obesity paradox’ maybe premature. Future studies should incorporate detailed body composition analysis, performance status, treatment exposure metrics, and consider non-linear BMI effects to better elucidate the relationship between patient factors and treatment outcomes. Thereby establishing a solid foundation for personalized clinical therapy. Acknowledgments Luxin Zhang: Formal analysis, Resources, Visualization, Writing – original draft, Writing – review and editing; Jiyuan Ding: Supervision, Visualization, Writing – original draft, Writing – review and editing. All authors have read and approved the final manuscript. Authors contributions CRediT: Luxin Zhang: Writing – original draft, Writing – review & editing; Jiyuan Ding: Investigation. Disclosure statement No potential conflict of interest was reported by the author(s) . Funding The author(s) reported there is no funding associated with the work featured in this article. 2 L. ZHANG AND J. DING References [1] Ma Y, Wu S, Li X, et al. The impact of body mass index on the efficacy of CDK4/6 inhibitors in patients with metastatic brea

FAQs

Why does the letter question using BMI dichotomized at a single cutoff?

The letter states that using one cutoff (24 kg/m2) may oversimplify BMI’s relationship with survival. Epidemiological evidence suggests U- or J-shaped associations where both low and very high BMI relate to higher risk.

What major confounders does the letter say were not adjusted for?

The letter argues the study did not adjust for performance status or muscle mass, which are established strong prognostic factors. It also highlights the lack of relative dose intensity (RDI), which may affect outcomes through treatment exposure.

How does the letter evaluate the “obesity paradox” interpretation?

The letter points to internal inconsistencies: overall survival differed in the first-line setting, but progression-free survival did not reach statistical significance. It further notes the BMI “effect” was absent in later therapy lines, suggesting BMI may reflect physiological reserve and tolerance rather than stable biological protection.

Sep 30, 2026

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