Further considerations regarding the APHINITY statin analysis

Maurer et al. (1) have recently published their study examining the association between statin use and survival outcomes in patients with early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer enrolled in the APHINITY trial. While we acknowledge the value of exploratory analyses in generating hypotheses from well-conducted randomized trials, and the authors commendably acknowledge several limitations, we believe additional methodological considerations merit discussion to better contextualize and interpret their findings.

First, the study does not cite the recent and comprehensive meta-analysis by de Moraes et al. (2), which included 31 studies in meta-analysis and 344,936 patients. That analysis demonstrated a significant association between statin use and improved overall and breast cancer-specific survival. It should be noted that this meta-analysis, like most existing evidence, was heavily weighted toward hormone receptor-positive disease, and extrapolation of these findings to HER2-positive populations remains uncertain. Nevertheless, its exclusion represents a missed opportunity to position the APHINITY data within the broader literature and to explain how these findings might differ from those observed in predominantly hormone receptor-positive populations.

Beyond the literature gap, several methodological considerations warrant attention. Although the authors note missing data on statin adherence and lipid profiles, the analysis did not stratify by statin type or lipophilicity, despite preclinical data suggesting differential anticancer effects. While we recognize that detailed statin information may not have been prospectively collected in the APHINITY dataset, limiting the feasibility of such stratified analyses, lipophilic statins, such as simvastatin and atorvastatin, may exert more potent anticancer activity than hydrophilic counterparts. Dose, duration, and timing relative to systemic therapy were also not explored, limiting the granularity of interpretation.

Third, potential confounding from other cardiometabolic medications—such as metformin, aspirin, or beta-blockers—was not addressed. These are commonly co-prescribed with statins and may independently influence breast cancer outcomes, particularly in older patients with comorbidities (3).

Fourth, the relatively small statin-user subgroup (8.8%) raises concerns about residual confounding and limited statistical power. While we acknowledge that the small statin-user subgroup may limit the power of such techniques, more robust causal inference methods, such as propensity score matching or inverse probability of treatment weighting, would enhance the reliability of these exploratory results.

Fifth, at a mechanistic level, statins appear to inhibit membrane localization of Rac1, a target protein of geranylgeranylation, and suppress the activation of HER2 downstream AKT and ERK pathways. Rac1 expression could therefore be used as a biomarker to stratify HER2-positive breast cancer patients who might benefit from dual blockade—targeting HER2 and inhibiting Rac1 geranylgeranylation with statins—thereby opening avenues for precision medicine in a new subset of Rac1-high/HER2-positive breast cancer (4).

Looking forward, we commend ongoing efforts to address these questions in randomized clinical trials. Notably, the MASTER trial (MAmmary cancer STatins in ER-positive breast cancer) (5) is a large, double-blind, phase III randomised controlled trial (RCT) evaluating the effect of high-dose atorvastatin versus placebo in women with early-stage estrogen receptor (ER)-positive breast cancer receiving systemic (neo)adjuvant therapy. With a target enrollment of 3,360 patients and invasive disease-free survival as the primary endpoint, MASTER is poised to provide definitive evidence regarding the role of statins in modifying breast cancer outcomes. While MASTER focuses on ER-positive disease, similar dedicated trials in HER2-positive breast cancer are urgently needed to definitively establish the role of statins in this molecular subtype.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-20/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-20/coif). K.M. serves as an unpaid editorial board member of Translational Breast Cancer Research from May 2025 to June 2027. K.M. reports receiving honoraria for offering academic and clinical advice to Merit Medical and Q Medical corporations and owns shares in HCA Healthcare UK. The other authors have 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.

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References

1. Maurer C, Agostinetto E, Ameye L, et al. Association of statin use on survival outcomes of patients with early-stage HER2-positive breast cancer in the APHINITY trial. Breast Cancer Res Treat 2025;212:57-69. [Crossref] [PubMed]
2. de Moraes FCA, de Souza Wagner PH, de Lara ICA, et al. Statins and prognosis of female breast cancer: a meta-analysis. Clin Transl Oncol 2025;27:3886-901. [Crossref] [PubMed]
3. Löfling LL, Støer NC, Andreassen BK, et al. Low-dose aspirin, statins, and metformin and survival in patients with breast cancers: a Norwegian population-based cohort study. Breast Cancer Res 2023;25:101. [Crossref] [PubMed]
4. Kato C, Iizuka-Ohashi M, Honda M, et al. Additional statin treatment enhances the efficacy of HER2 blockade and improves prognosis in Rac1-high/HER2-positive breast cancer. Biochim Biophys Acta Mol Basis Dis 2024;1870:167458. [Crossref] [PubMed]
5. Borgquist S, Jensen MB, Bendorff CL, et al. Statin Therapy in Early Breast Cancer: The MASTER Trial; A Randomized Phase III, Placebo-Controlled Comparison of Standard (Neo)Adjuvant Therapy Plus Atorvastatin versus Standard (Neo)Adjuvant Therapy Plus Placebo. Clin Epidemiol 2025;17:409-19. [Crossref] [PubMed]