No APHINITY between statin use and survival outcomes in early HER2-positive breast cancer

Statin use was not associated with improved survival outcomes in the phase III APHINITY trial investigating the addition of pertuzumab to trastuzumab and chemotherapy as adjuvant treatment for patients with early HER2-positive breast cancer (BC).

Preclinical work, including a BC model, suggests that statins may induce apoptosis and reduce tumour growth, angiogenesis, and metastasis. [Carcinogenesis 2004;25:1887-1898; Gynecol Oncol 129:417-424] However, observational studies have provided conflicting data regarding the possible impact of statins on BC outcomes, with some, including two meta-analyses, reporting a protective association between statin use and BC-specific death and/or overall survival (OS), while others have found no correlation. [BMC Cancer 2019;doi:10.1186/s12885-018-5263-z; PLoS ONE 2014;doi:10.1371/journal.pone.0110231; Br J Cancer 2016;115:592-598; Front Oncol 2022;doi:10.3389/fonc.2022.835320]

APHINITY was a prospective, randomized, double-blind phase III trial (n=4,804) that showed improved invasive disease-free survival (iDFS) with the addition of pertuzumab to trastuzumab and chemotherapy in patients with early HER2-positive BC who had node-positive disease. [J Clin Oncol 2021;doi:10.1200/JCO.20.01204] The primary objective of the present substudy, which included all patients in the intent-to-treat population, was to determine if there was any association between statin use and iDFS, distant relapse-free interval (DRFI), and OS. [Breast Cancer Res Treat 2025;212:57-69]

Overall, 8.8 percent of APHINITY patients were classified as statin users. The exact start and stop dates of statin treatment were missing for 54.4 percent of statin users, but 91.5 percent of statin users were on statin treatment at baseline and during study treatment. Compared with non-statin users, statin users were older (median age, 62 vs 50 years), more frequently postmenopausal (91.1 vs 47.6 percent), had a higher body–mass index (BMI; median, 27.3 vs 24.4 kg/m²), had smaller tumours (≤1.9 cm, 46.1 vs 39.5 percent), were treated more often with breast-conserving surgery than with mastectomy (54.1 vs 44.9 percent), were treated less frequently with anthracycline-containing regimens (71.4 vs 78.6 percent), and were more often diagnosed with diabetes (24.6 vs 3.9 percent), hypertension (64.1 vs 18.4 percent), coronary heart disease (4.0 vs 0.6 percent), and hyperlipidaemia (83.0 vs 3.4 percent).

The median follow-up for OS was 73.8 months for statin users and 74.1 months for non-statin users. During this time, iDFS events occurred in 12.8 percent of statin users and 10.4 percent of non-statin users, while 8.5 and 5.4 percent of patients in the respective subgroups died. Numerically, there were more non–BC-related deaths in statin users (41.7 percent) than in non-statin users (29.7 percent).

Multivariate analysis found no association between statin use and iDFS (hazard ratio [HR], 1.11; 95 percent CI, 0.80–1.52), DRFI (HR, 1.21; 95 percent CI, 0.81–1.81), or OS (HR, 1.16; 95 percent CI, 0.78–1.73). In univariate analysis, statin use was associated with a trend towards worse OS (HR, 1.62; 95 percent CI, 1.14–2.31; p=0.007), which did not reach statistical significance. There were no significant associations between statin use and iDFS, DRFI, and OS among any of the patient subgroups. “When stratified by treatment arm within the APHINITY trial, menopausal status, BMI, tumour size, nodal status, or hormone receptor status, treatment with statins in general, or with lipophilic or hydrophilic statins, was not associated with survival outcomes,” wrote the researchers.

“In conclusion, in our analysis within the APHINITY trial, statin use was not associated with improved outcomes in terms of iDFS, DRFI, and OS in patients with early HER2-positive BC,” they summarized. “So far, apart from the current known indications for statin use, adding statins [to treat] early HER2-positive BC is not recommended.”