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

Dear Editor
The authors are to be commended for addressing the clinically relevant question of whether BMI modifies outcomes in HR-positive metastatic breast cancer treated with CDK4/6 inhibitors [1]. However, several issues merit consideration.
First, using a binary BMI cut-off at 24 kg/m2, although aligned with Chinese criteria for overweight, oversimplifies a biologically complex exposure. BMI is treated as both a dichotomous and a continuous variable in different parts of the analysis, yet the rationale for the chosen threshold, and whether non-linear associations (e.g. U-shaped ‘obesity paradox’) were explored, is not provided. Prior work in metastatic breast cancer suggests that the obesity paradox, when observed, is often attenuated after appropriate adjustment for confounders and competing risks [2]. A more granular categorization (e.g. underweight, normal, overweight, obese) and evaluation of non-linear effects would be necessary before concluding that ‘low BMI’ per se is a negative prognostic factor in the CDK4/6 era.
Second, although the authors adjust for some clinicopathologic variables, the possibility of residual confounding by disease burden and timing of CDK4/6 inhibitor initiation remains substantial. Patients with lower BMI may disproportionately represent those with more aggressive biology, higher tumour burden, cancer-related cachexia, or more advanced lines of therapy-factors known to worsen survival independent of BMI [3]. The fact that the observed BMI effect is restricted to the first-line CDK4/6 cohort, and not reproduced in later lines, may simply reflect differences in case mix rather than a true effect modification by treatment line.
Third, in the first-line setting, higher BMI is associated with longer OS but not with a statistically significant improvement in PFS. This OS-PFS discordance is difficult to reconcile with a direct pharmacologic effect of BMI on CDK4/6 inhibitor efficacy. CDK4/6 inhibitors have shown consistent PFS benefit across BMI strata in large randomized trials and pooled analyses, without a clear signal that overweight patients derive superior benefit [4]. Improved OS in the absence of PFS gain more plausibly reflects downstream factors: better tolerance of subsequent therapies, fewer treatment interruptions, or differential access to later-line regimens in higher-BMI patients. These explanations should be considered preferentially over a mechanistic ‘protective’ role of adiposity.
Finally, the discussion leans towards supporting an ‘obesity paradox’ narrative in HR-positive metastatic breast cancer on CDK4/6 inhibitors. This conclusion appears stronger than warranted by the data and is not consistent with the broader literature in early-stage and advanced disease, where higher adiposity generally portends worse outcomes, particularly in endocrine-sensitive tumours [5]. Given the modest sample size and multiple subgroup and interaction analyses, the risk of chance findings and type I error is considerable.
In summary, while this study raises an important question about body size and outcomes with CDK4/6 inhibitors, the limitations in exposure definition, potential confounding by disease burden and treatment course and the OS-PFS discordance suggest that the observed association between lower BMI and poorer survival should be interpreted with considerable caution.