The emerging role of ctDNA in breast cancer

In the era of precision medicine for breast cancer, the application of circulating tumour DNA (ctDNA) assays is opening up multiple opportunities. Recipient of the ESMO Award for Translational Research 2023 Prof. Nicholas Turner from The Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research, and The Ralph Lauren Centre for Breast Cancer Research at The Royal Marsden NHS Foundation Trust, London, UK discusses how ctDNA assays can guide therapy for breast cancer and can detect disease recurrence far earlier than standard imaging methods.

What are the most important current challenges facing translational research in breast cancer?

The prognosis for women with early-stage breast cancer has been transformed over the past two decades, with a recent study demonstrating a five-year mortality rate of only 5% for women diagnosed between 2010 and 2015 (BMJ. 2023;381:e074684). Nevertheless, there remains a proportion of women who relapse despite our current treatment approaches, and outcomes for these patients are often poor (Curr Oncol. 2023;30:3829–3844). The most important challenge that we currently face in breast cancer is to identify these patients who are at risk of relapse. We need to strike the right balance between providing necessary treatment to those who require it, whilst avoiding overtreatment for those who are already cured. Distinguishing patients in need of additional treatment from those who are unlikely to relapse is a major motivator for my research and we are optimistic that ctDNA assays can play a pivotal role in predicting treatment responses and detecting disease recurrence.

What do you consider to be your key career achievements in translational research in breast cancer to date?

Historically, targetable mutations have been identified from tissue-based biopsies; however, these are invasive, can be limited by tissue heterogeneity and do not allow for real-time monitoring. As part of efforts to improve the utility of biomarkers, my research has focused on the use of liquid biopsies to guide therapy for breast cancer. For example, in the plasmaMATCH phase IIa study, we were able to show that ctDNA assays can detect targetable mutations with high sensitivity and accuracy (Lancet Oncol. 2020;21:1296–1308). Moreover, within this study, patients harbouring rare mutations in HER2 and AKT1, as identified by ctDNA analysis, had clinically important responses to HER2 and AKT inhibitors.

We have also been very interested in exploring the potential of ctDNA in predicting the risk of relapse among patients who have completed treatment for early-stage breast cancer. We conducted the c-TRAK TN phase II trial for patients with early-stage triple-negative breast cancer (Ann Oncol. 2023;34:200–211). This was the first study to prospectively assess ctDNA for molecular residual disease (MRD) in breast cancer, and reinforced the importance of early and frequent ctDNA testing for MRD detection. We are now conducting a trial that will determine whether ctDNA can be used to detect relapse at an early stage in patients with ER-positive breast cancer who are currently receiving hormone therapy (TRAK-ER study, NCT04985266). Patients enrolled in this study will undergo ctDNA testing every 3 months for up to 3 years. Those who test positive for ctDNA will then be randomised to either continue with standard endocrine therapy or receive additional treatments. We hope that this study will show that prognosis can be improved through early detection of recurrence and initiation of effective therapies.

What does the future hold for translational research in breast cancer?

As a result of advancements in hormone-based and targeted therapies, an increasing number of individuals are now surviving breast cancer. Moreover, the promise of immunotherapy is starting to be realised, especially in patients with triple-negative disease. However, a crucial question for the future will be how we can harness immunotherapy for other types of breast cancer. The emergence of cellular therapies and novel antibodies represents exciting developments in this regard, but the successful implementation of these therapies will depend on our ability to determine precisely which patients will derive the most benefit from these treatments.