Pre-operative chemotherapy versus surgery first with peri-operative interventions in early triple-negative and HER2-positive breast cancer: An open-label, phase 3, randomized controlled trial (PRaCTiSE).

Abstract

TPS659 Background: Surgery is a mainstay of treatment of breast cancer. Neoadjuvant chemotherapy (NACT) has not proven to be more effective in improving long-term outcomes when compared with adjuvant (EBCTCG, Lancet Oncol, 2018). Although pathological complete response (pCR) is surrogate at the individual patient level, it has not translated into improved outcomes across trials (BMJ, 2021).Triple-negative (TN) and HER2-positive breast cancer patients with non-pCR are treated with risk-adapted maintenance regimens (NEJM, 2025; NEJM, 2017). We previously proved efficacy of pre-operative progesterone and intra-operative peri-tumoural lignocaine in improving disease-free and overall survival (JCO, 2011; JCO, 2023). We are currently testing the effectiveness of a “Surgery first” versus “PRe-operative ChemoTherapy” approach in patients with early TN and HER2-positive tumours. Methods: This is a prospective, open-label randomized trial. Patients with cT1c/2,cN0/1, histologically proven, TN or HER2-positive breast cancer are screened. The study is approved by Institutional Ethics and has been registered on CTRI (CTRI/2024/02/063118). Eligible patients fit for surgery and NACT are randomized after consenting. Stratification criteria are menopausal status (pre-peri/post), cN stage (N0/N1), and TN/HER2+. “Surgery first” arm receives intramuscular progesterone injection 4-14 days before surgery and peri-tumoral 0.5% lignocaine infiltration intra-operatively. All patients are treated with standard adjuvant chemotherapy and targeted therapy and radiotherapy protocols. “PRe-operative ChemoTherapy” arm receives standard NACT. Chemotherapy backbone is anthracycline, cyclophosphamide, and paclitaxel in all patients, with addition of carboplatin and pembrolizumab in NACT for TN and anti-HER2 targeted therapy (dual if node positive) in HER2+ setting. Response assessment is done clinically after each cycle and with imaging after every 3-4 cycles. Maintenance pembrolizumab/capecitabine for TN and anti-HER2 targeted therapy/t-DM1 for HER2+ tumours as per response is offered for standard duration. Surgery in both arms is breast conservation surgery with or without oncoplasty or mastectomy with or without reconstruction, depending on imaging findings, response, and patient choice. All primary tumors are clipped in NACT arm. Axillary staging procedure is carried out and, if positive macro-metastatic nodes on frozen section, level I-III axillary dissection is done. A total sample size of 1350 (1500 accounting for loss-to-follow-up) split equally between two groups, or 257 events, achieves 80% power to detect hazard rate of 0.70173 when the proportions surviving in each group are 0.78 and 0.84 at a significance level (alpha) of 0.05 using a two-sided log rank test. An interim is planned at 50% DFS events. Clinical trial information: CTRI/2024/02/063118 .