Utility of Prospective ctDNA Surveillance in Early TNBC and the Activity of Pembrolizumab in Patients with ctDNA Detected

In c-TRAK TN, first study to prospectively assess circulating tumour DNA (ctDNA) for molecular residual disease detection in patients with moderate- and high-risk early triple negative breast cancer (TNBC), ctDNA was detected at the rate anticipated, with 27.3% patients having ctDNA detected during the first 12 months, but far fewer patients than anticipated started treatment with pembrolizumab. The rapid relapsing nature of high-risk TNBC challenged implementation of molecular residual disease detection. The rate of metastatic disease detection at the point of ctDNA detection was substantially higher than anticipated, with additional patients not wishing to start treatment in part exacerbated by the COVID-19 pandemic. The findings are published by Prof. Nicholas C. Turner of the Institute of Cancer Research (ICR) and the Royal Marsden Hospital in London, UK and colleagues on 21 November 2022 in the Annals of Oncology.

The authors wrote in the background that neoadjuvant chemotherapy reduces the risk of relapse, and enables down-staging to reduce extent of surgery. The addition of carboplatin to neoadjuvant chemotherapy improves the rates of pathological complete response (pCR) and disease-free survival (DFS). The addition of pembrolizumab to a carboplatin containing regimen further improves pCR rates and DFS. With improved DFS rates using intensive neoadjuvant chemotherapy, the challenge now is to develop new methods to identify patients who remain at high risk of relapse after treatment completion, and who may therefore benefit from further treatment.

Post-treatment detection of ctDNA in patients with early stage TNBC predicts high risk of relapse. The c-TRAK TN study was designed to establish the potential for ctDNA guided treatment, and it is the first prospective study to assess whether ctDNA assays have clinical utility in guiding further treatment for patients with breast cancer.

It is a multicentre phase II study, with integrated prospective ctDNA surveillance by digital PCR. It 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-19), and ctDNA-positive patients were randomised 2:1 into 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 on 16 September 2020 closed the observation group and all subsequent ctDNA-positive patients were allocated to intervention. The study co-primary endpoints were ctDNA detection rate and sustained ctDNA clearance rate on pembrolizumab.

In total, 208 patients registered between 30 January 2018 and 6 December 2019; 185 patients had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (95% confidence interval 20.6-34.9). Seven patients relapsed without prior ctDNA detection.

A total 45 patients entered the therapeutic component, 31 to intervention 14 to observation, 1 patient was re-allocated from observation to intervention following protocol amendment. Of patients allocated to intervention, 23 of 32 (72%) had metastases on staging at time of ctDNA detection, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance.

The authors concluded that implementation of molecular residual disease detection with personalised assays was clinically achievable. 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. Treatment with pembrolizumab did not result in ctDNA clearance, although assessment was limited by small numbers of patients.

The authors commented that the approach piloted in this study would benefit from further investigation, with appropriate modifications to patient population and ctDNA testing, to select patients for adjuvant systemic treatment. A phase III study is assessing the potential for ctDNA to guide treatment in TNBC and BRCA1/2 germline mutation breast cancer with the PARP inhibitor niraparib.

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 and the ICR Clinical Trials & Statistics Unit is supported by a core programme grant from Cancer Research UK. This study represents independent research funded by the UK National Institute for Health Research Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and the ICR, London.

Reference

Turner NC, Swift C, Jenkins B, et al. 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; Published online 21 November 2022. DOI: https://doi.org/10.1016/j.annonc.2022.11.005

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