Background The presence or absence of residual disease following neoadjuvant systemic anti-cancer therapy (neoSACT) for HER2-positive early breast cancer (HER2+ EBC) provides powerful prognostic information that may guide subsequent adjuvant treatment for the individual patient. Pathological complete response (pCR) following neoSACT identifies a population with excellent outcomes in whom the balance of toxicity associated with the current treatment pathway may be disproportionate to the absolute clinical benefit. Aims HER2-RADiCAL seeks to reduce the burden of toxicity and healthcare costs of treating HER2+ EBC by testing the hypothesis that pCR can be used as a functional response biomarker to select patients who can safely receive less intensive therapy, including avoiding anthracyclines, with minimal or no loss of efficacy in the population. Trial design and eligibility criteria HER2-RADiCAL is a response-directed interventional cohort (single-arm) study embedded within a real-world data driven clinical pathway model. Participants will be registered within 6 weeks of completion of breast cancer surgery. The main eligibility criteria include clinical stage T1N1 or T2N0-1 at diagnosis and locally-determined pCR (ypT0/Tis ypN0) after standard of care taxane-based (non-anthracycline) neoadjuvant chemotherapy, trastuzumab and pertuzumab. After registration participants will continue to receive trastuzumab to complete a total of 9 cycles including those (neo-)adjuvant cycles administered prior to study entry. Participants will receive no further pertuzumab nor any adjuvant chemotherapy. Statistical methods The primary clinical endpoint is relapse free interval. Recruitment of 720 participants over 3 years will provide 90% power to exclude an event rate >6.5% at 3 years. Secondary endpoints include relapse-free survival, invasive breast cancer-free survival, invasive disease-free survival, distant recurrence-free interval, breast cancer-free interval, treatment pathway adherence and cost-effectiveness. Real-world data driven clinical pathway model Health economic modelling will compare the protocol-driven study cohort with two comparator pathways: a non-response adapted maximum therapy pathway (the standard clinical pathway prior to the study) and a real-world representative pathway taken from 4-nation UK National Health Service data at the beginning and end of the study. Patient and public involvement Patient advocates have shaped the research by confirming that the main outcomes being evaluated are important to patients and that the interventional cohort design, with power to exclude an absolute risk of recurrence outwith a 2-3% margin of historical control data, is acceptable and preferable to a randomised controlled trial, which would take longer to get answers and need many more patients to be included. They have been involved in protocol design, including methodology, sample collection and patient follow-up, and their input has shaped the patient information materials and consent forms. Patient advocates will have an ongoing key role in overseeing the progress of the study as members of the Trial Management Group, and they will also have an important role in communicating the study results to patients and the public. Current status HER2-RADiCAL is planned to open at ~40 UK sites commencing in September 2021.

Citation Format: Iain Macpherson, Stuart McIntosh, Lucy Kilburn, Holly Tovey, Sarah Kernaghan, Katie Goddard, Indrani Bhattacharya, Clinton Boyd, Charlotte Coles, Cliona Kirwan, Mairead Mackenzie, Ciara O’Brien, Alistair Ring, Claire Snowdon, Hilary Stobart, Duncan Wheatley, Andrew Wardley, Abeer Shaaban, Peter Hall, David Cameron, Judith Bliss. The HER2-RADiCAL study (Response ADaptive CAre pLan) - Tailoring treatment for HER2 positive early breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-05-01.