Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate and high-risk early stage triple negative breast cancer

Turner, N. C. et al. (2023) Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate and high-risk early stage triple negative breast cancer. Annals of Oncology, 34(2), pp. 200-211. (doi: 10.1016/j.annonc.2022.11.005) (PMID:36423745)

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Abstract

Background: Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK-TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected (ctDNA+). Patients and methods: c-TRAK-TN, a multi-centre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or, stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three monthly blood sampling to 12 months (18 months if samples were missed due to COVID), and ctDNA+ patients were randomised 2:1; intervention:observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16/09/2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were i) ctDNA detection rate ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961). Results: 208 patients registered between 30/01/18 - 06/12/19, 185 had tumour sequenced, 171 (92·4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27·3% (44/161,95%CI:20·6-34·9). Seven patients relapsed without prior ctDNA detection. 45 patients entered the therapeutic component (intervention n=31; observation n=14; 1 observation patient was re-allocated to intervention following protocol amendment). Of patients allocated intervention, 72% (23/32) had metastases on staging at time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance. Conclusion: c-TRAK-TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes.

Item Type:Articles
Additional Information:This work was supported in part by Le Cure, the Royal Marsden Cancer Charity, and by provision of drug and funding by the Investigator-Initiated Studies Program of Merck Sharp & Dohme Limited. It was endorsed by Cancer Research UK (CRUKE/16/024) and the ICR Clinical Trials & Statistics Unit is supported by a core programme grant (grant number C1491/A15955) from Cancer Research UK.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacPherson, Professor Iain
Authors: Turner, N. C., Swift, C., Jenkins, B., Kilburn, L., Coakley, M., Beaney, M., Fox, L., Goddard, K., Garcia-Murillas, I., Proszek, P., Hall, P., Wynne, C. H., Hickish, T., Kernaghan, S., MacPherson, I. R., Okines, A., Palmieri, C., Perry, S., Randle, K., Snowdon, C., Stobart, H., Wardley, A., Wheatley, D., Waters, S., Winter, M., Hubank, M., Allen, S., and Bliss, J. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Annals of Oncology
Publisher:Elsevier
ISSN:0923-7534
ISSN (Online):1569-8041
Published Online:22 November 2022
Copyright Holders:Copyright © 2022 The Author(s).
First Published:First published in Annals of Oncology 34(2): 200-211
Publisher Policy:Reproduced under a Creative Commons license

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