Does BMI Matter in mBC Outcomes? 

As CDK4/6 inhibitors have reshaped outcomes for patients with HR+/HER2− metastatic breast cancer (mBC), attention has turned toward factors that might refine prognostication beyond tumor biology alone. Body mass index (BMI) has emerged as one such candidate, driven by the metabolic roles of adipose tissue and the expanding recognition that CDK4/6 signaling intersects with energy balance, adipogenesis, and muscle metabolism.

This systematic review brings together a decade of real-world and clinical trial evidence to ask the following question: does BMI meaningfully influence outcomes in patients receiving CDK4/6 inhibitors?

Study Design

The authors conducted a PRISMA-compliant systematic literature review of PubMed and Scopus between 2015 and 2025, identifying 14 eligible studies published. These included retrospective and prospective cohorts, ambispective studies, and post-hoc analyses of randomized trials. Collectively, the studies evaluated thousands of patients with HR+/HER2− mBC treated with palbociclib, ribociclib, or abemaciclib in combination with endocrine therapy.

Key outcomes included progression-free survival (PFS), overall survival (OS), and response rate metrics. BMI was typically analyzed using standard WHO categories, while select studies incorporated computed tomography–based assessments of visceral adipose tissue (VAT) and skeletal muscle area (SMA).

What BMI Reveals—and Doesn’t

Across the included studies, BMI showed an inconsistent relationship with clinical outcomes. Four studies suggested a prognostic advantage for patients with higher BMI. In one prospective cohort, patients with BMI <25 experienced significantly shorter PFS than those with BMI ≥25 (hazard ratio [HR] 2.32; p=0.033). Other cohorts reported reduced risk of progression with increasing BMI (HR 0.943; p=0.003) or longer PFS among overweight patients compared with normal-weight counterparts (p=0.02).

However, the majority of studies, including large real-world datasets and subgroup analyses from randomized trials, found no significant association between BMI and PFS or OS. In pooled analyses of pivotal abemaciclib trials, BMI did not influence PFS (HR 1.03; p=0.81), although higher BMI was associated with lower objective response rates (odds ratio 0.73; p=0.04). Importantly, early-stage disease analyses similarly showed no impact of BMI on invasive disease-free survival or biological response.

Body Composition Over Body Weight

A recurring insight from this review is that BMI may be too blunt an instrument to capture clinically relevant metabolic differences. Two studies using CT-based body composition analysis found that sarcopenia, defined as low skeletal muscle mass, was significantly associated with shorter PFS. Conversely, higher visceral adiposity was paradoxically linked to improved PFS.

These findings are biologically plausible. CDK4 and CDK6 regulate only cell-cycle progression, adipocyte differentiation, lipid synthesis, and muscle metabolism. Low muscle mass and depleted adipose reserves may alter drug pharmacokinetics, increase hematologic toxicity, and compromise treatment adherence. Indeed, lower BMI has been associated with higher drug exposure and increased dose-limiting toxicities, potentially shortening effective treatment duration.

Clinical Takeaways

This review reinforces that BMI alone does not consistently predict outcomes for patients with HR+/HER2− mBC treated with CDK4/6 inhibitors. While select studies suggest an “obesity paradox,” the signal is neither uniform nor robust. In contrast, more granular assessments of body composition, such as sarcopenia and visceral fat, appear to carry clearer prognostic relevance.

For clinicians, these findings argue against using BMI in isolation to guide expectations or treatment decisions. For researchers, they underscore the need for prospective studies incorporating standardized, imaging-based body composition metrics.

Reference:
Badau LM, Oprean CM, Ciocoiu AD, Epure P, Vlaicu B. The Prognostic and Predictive Value of Body Mass Index in Patients with HR+/HER2- Breast Cancer Treated with CDK4/6 Inhibitors: A Systematic Literature Review. Cancers (Basel). 2025;18(1):81. doi:10.3390/cancers18010081