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Statin Use Is Not Associated With Improved Outcomes in Early HER2+ Breast Cancer

A post hoc analysis from the APHINITY trial showed statin use did not improve survival in early-stage HER2-positive breast cancer.

Image Credit: ©  Sebastian Kaulitzki – stock.adobe.com

Image Credit: ©
Sebastian Kaulitzki – stock.adobe.com

Statin use was not associated with improved long-term outcomes in patients with early-stage HER2-positive breast cancer, according to post hoc findings from the phase 3 APHINITY trial (NCT01358877), which evaluated the addition of pertuzumab (Perjeta) to trastuzumab (Herceptin) and chemotherapy as adjuvant therapy.1

Findings published in Breast Cancer Research and Treatment showed that at a median follow-up of 73.8 months (interquartile range [IQR], 69.3-75.5) for statin users and 74.1 months (IQR, 69.3-75.5) for non-users, invasive disease-free survival (IDFS) events occurred in 12.8% of statin users (n = 423) and 10.4% of non-users (n = 4381). Distant relapse-free interval (DRFI) events were reported in 7.8% of statin users and 7.1% of non-users. Additionally, 8.5% of patients in the statin group had dies compared with 5.4% of the non-statin group.

Using a Bonferroni correction (adjusted P < .00167), statin use was not significantly associated with improved IDFS (HR, 1.27; 95% CI, 0.95-1.68; P = .10) or DRFI (HR, 1.13; 95% CI, 0.79-1.61; P = .52) in univariate analyses. A trend toward worse OS outcomes was observed in statin users (HR, 1.62; 95% CI, 1.14-2.31; P = .007), although this did not reach statistical significance under the corrected threshold.

“In our analysis, the use of statins within the APHINITY trial was not associated with improved outcomes in terms of IDFS, DRFI, and overall survival [OS] in patients with early HER2-positive breast cancer. Only a prospective, randomized study would be able to clarify whether the prognosis of patients with early breast cancer could be improved by statins,” lead study author Christian Maurer, MD of University of Cologne, and colleagues wrote in a publication of the data.

APHINITY Trial Breakdown

APHINITY was a prospective, randomized, double-blind, phase 3 trial evaluating the addition of pertuzumab to trastuzumab and chemotherapy as adjuvant therapy in patients with early-stage HER2-positive breast cancer. Prior findings from the study supported the December 2017 FDA approval of pertuzumab in combination with trastuzumab and chemotherapy as adjuvant treatment for patients with HER2-positive early breast cancer at high risk of recurrence.2

A total of 4805 patients were randomly assigned to receive standard chemotherapy and trastuzumab in combination with pertuzumab or placebo.1

The post hoc analysis was conducted to assess the association between statin use and clinical outcomes. The analysis included all patients in the intention-to-treat (ITT) population (n = 4804), and they were divided into subgroups. Statin users were defined as those who were taking statins at baseline or who initiated statin therapy within 1 year of randomization. Those who began statin use more than 1 year after randomization were considered non-users to minimize lead-time bias. Statin use and other co-medications were captured through case report forms and ongoing documentation throughout the trial.

The primary objectives of the post hoc analysis were to evaluate the association between statin use and outcomes in terms of IDFS, DRFI, and OS, using the same definitions employed in the main trial protocol.

Baseline Patient Demographics

From the ITT population of the APHINITY trial, 8.8% of patients (n = 423) were classified as statin users, and the remainder (n = 4381) were non-users. Among statin users, 302 patients received only lipophilic statins, 116 patients received only hydrophilic statins, and 5 patients received both. In the statin group, 47.5% of patients were randomly assigned to the pertuzumab arm, and 52.5% were assigned to the placebo arm. These rates were 50.2% and 49.8%, respectively, in the non-user group.

The median age among statin users was 62 years (IQR, 57-68) compared with 50 years (IQR, 43-58) in non-users. Notably, 60.5% of patients in the statin group were under 65 years of age compared with 89.9% of patients in the non-statin group. Postmenopausal status was reported in 91.1% of statin users vs 47.6% of non-users. The median body mass index was 27.3 kg/m² in statin users compared with 24.4 kg/m² in non-users. Tumor size at diagnosis was less than 1.9 cm in 46.1% of statin users vs 39.5% of non-users.

With respect to surgical management, breast-conserving surgery was performed in 54.1% of statin users and 44.9% of non-users; mastectomy was less common in the statin group at 45.9% vs 55.1% for the non-statin group. Anthracycline-containing chemotherapy was administered in 71.4% of statin users compared with 78.6% of non-users.

Diabetes was reported in 24.6% of statin users vs 3.9% of non-users; the respective rates of hypertension were 64.1% vs 18.4%;the rates of coronary heart disease were 4.0% vs 0.6%, respectively; and the rates of hyperlipidemia were 83.0% vs 3.4%, respectively.

Regarding statin use patterns, 91.5% of users were receiving a statin at baseline and during trial treatment. A total of 5.9% initiated statin therapy after randomization at a median time from randomization to initiation of 2.3 months (range, 2 days to 6.6 months). Complete treatment duration data were available in 9.9% of users, who had a median statin exposure of 5 months (IQR, 2-34). Partial timing data were reported in 35.7% of users, including missing statin start dates in 7.6% and missing end dates in 28.1%.

Breast cancer recurrence remained the leading cause of death in both groups, accounting for 58.3% of deaths in statin users and 70.3% in non-users. Non–breast cancer–related mortality was numerically higher among statin users (41.7%) compared with non-users (29.7%).

“Statin use overall was associated with a trend to worse OS in univariate analysis, [however] the results were not statistically significant and may be subject to residual confounding,” study authors concluded. “It should come as no surprise that patients who take statins under the assumption of a concomitant disease could have a higher risk of death during the course of a clinical trial follow-up.”

References

  1. Maurer C, Agostinetto E, Lieveke A, 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(1):57-69. doi:10.1007/s10549-025-07699-2
  2. FDA grants regular approval to pertuzumab for adjuvant treatment of HER2-positive breast cancer. FDA. Updated December 21, 2017. Accessed May 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-pertuzumab-adjuvant-treatment-her2-positive-breast-cancer

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