Reduced duration adjuvant trastuzumab in the treatment of patients with HER2-positive breast cancer: a meta-analysis of randomised controlled non-inferiority trials including IPD data

Helena M Earl; Louise Hiller; Janet A Dunn; Mubarak Patel; PierFranco Conte; Roberto D'Amico; Valentina Guarneri; Heikki Joensuu; Teppo Huttunen; Dora Hatzidaki; Vassilis Georgoulias; Jean E Abraham; David Miles; David A Cameron; Andrew M Wardley; Xavier Pivot

doi:10.1136/bmjonc-2025-000810

Reduced duration adjuvant trastuzumab in the treatment of patients with HER2-positive breast cancer: a meta-analysis of randomised controlled non-inferiority trials including IPD data

BMJ Oncol. 2025 Jun 20;4(1):e000810. doi: 10.1136/bmjonc-2025-000810. eCollection 2025.

Authors

Helena M Earl^{1

2}, Louise Hiller³, Janet A Dunn³, Mubarak Patel³, PierFranco Conte⁴, Roberto D'Amico⁵, Valentina Guarneri⁴, Heikki Joensuu⁶, Teppo Huttunen⁷, Dora Hatzidaki⁸, Vassilis Georgoulias⁸, Jean E Abraham^{1

2

9}, David Miles¹⁰, David A Cameron¹¹, Andrew M Wardley¹², Xavier Pivot¹³

Affiliations

¹ Department of Oncology, Cambridge University, Cambridge, UK.
² NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
³ Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.
⁴ Istituto Oncologico Veneto IRCCS, Padua, Italy.
⁵ Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
⁶ HUS Helsinki University Hospital, Helsinki, Finland.
⁷ EstiMates, Turku, Finland.
⁸ Laboratory of Translational Oncology, Hellenic Oncology Research Group, University of Crete School of Medicine, Heraklion, Greece.
⁹ Precision Breast Cancer Institute, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁰ Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK.
¹¹ Edinburgh Cancer Research Centre, Edinburgh, UK.
¹² Cancer Services, Manchester, UK.
¹³ Institut de Cancerologie Strasbourg Europe, Strasbourg, France.

Abstract

Objectives: Adjuvant trastuzumab in combination with chemotherapy has significantly improved survival in patients with HER2-positive early breast cancer but, since introduction in 2005, the 12 months duration has been questioned and trials have tested shorter durations.

Methods and analysis: A systematic review and meta-analysis using individual patient data (IPD) (when available) from non-inferiority trials of reduced duration trastuzumab was carried out according to PRISMA-IPD guidelines. Primary outcome was invasive disease-free survival (IDFS); secondary outcomes were distant relapse-free survival (DRFS) and overall survival (OS). Estimated survival was calculated using random-effects and fixed-effects modelling, reported by 5 year rates and analysed using non-inferiority methods. Illustrative comparative risks were also tabled as in Cochrane Systematic Reviews.

Results: Five trials were identified: PERSEPHONE, PHARE and HORG compared 12 months (m) with 6 m; SOLD and Short-HER compared 12 m with 9 weeks. In the 5-trial analysis (11 389 patients), and in the SOLD and Short-HER (3428 patients) analysis, non-inferiority of the shorter duration was not confirmed. In contrast, for the comparison of 12 m versus 6 m (7961 patients), non-inferiority was confirmed with a 2.5% critical margin, for IDFS, DRFS and OS. The Kaplan-Meier curves demonstrated overlap of credibility intervals throughout follow-up. For every 1000 patients given 6 m trastuzumab, by 5 years, there might be 11 extra IDFS events (in addition to 141 expected for 12 m), 12 more DRFS events (in addition to 106) and nine more deaths (in addition to 73).

Conclusions: We have demonstrated that 6 m trastuzumab in early HER2-positive breast cancer is not inferior to 12 m and is an option for patients.

Prospero registration number: CRD42020172267.

Keywords: Adjuvant therapy; Breast cancer (female); Health economics.