Circulating tumour DNA in the evolving treatment landscape of locally advanced rectal cancer: where does it fit in?

Abstract

The management of locally advanced rectal cancer (LARC) requires multimodality treatment, typically with neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision. However, the treatment landscape is rapidly evolving with total neoadjuvant therapy and non-operative management for selected patients emerging as other novel treatment approaches. With so many treatment options, there is a need for biomarkers to direct a more personalised treatment strategy for patients with LARC. In this review, we summarise the available data regarding the use of circulating tumour DNA (ctDNA) in patients with LARC, as both a marker of treatment response to neoadjuvant therapy and as a marker of minimal residual disease (MRD) after patients have completed definitive local treatment. To date, the ability of ctDNA status to predict for pathologic complete response at any timepoint during multimodality treatment has been variably reported. The most consistent finding across available studies is the ability of ctDNA to detect MRD after CRT and surgery, the presence of which confers a significantly poor prognosis, with increased risk of cancer recurrence and worse overall survival. It is yet to be determined if providing additional therapies to patients with MRD improves outcomes. The available studies assessing the potential utility of ctDNA in LARC are limited by significant heterogeneity in the choice of ctDNA assay, timepoint at which ctDNA was collected, treatment that patients received and length of follow-up, leading to uncertainties about how to implement it into daily clinical practice. As the treatment landscape evolves, larger randomised trials assessing the role of ctDNA in LARC are needed.

Keywords: chemotherapy; predictive biomarker; prognostic biomarker; radiotherapy; rectal cancer.

Figure 1.

Prognostic and predictive roles of ctDNA in locally advanced rectal cancer. Source: Image created with BioRender.com. CRT, chemoradiotherapy; ctDNA, circulating tumour DNA; pCR, pathologic complete response; LARC, locally advanced rectal cancer; MRD, minimal residual disease.

Figure 2.

Potential ways that the role of ctDNA could be studied in patients being treated for LARC. For patients who have received induction chemotherapy and then planned to receive neoadjuvant radiotherapy, the remaining neoadjuvant treatment could be (de)-intensified according to postinduction chemotherapy ctDNA status. Similarly, for patients whose first modality of treatment is radiation, consolidation chemotherapy could be (de)-intensified according to post-radiation ctDNA status. Patients with detectable ctDNA following TNT and surgery are at high risk of recurrence and the potential role of additional novel therapies in such patients has not yet been studied. The potential role of ctDNA in the surveillance of patients who achieve a complete clinical response and do not proceed to surgery has also not yet been well studied. For patients receiving neoadjuvant CRT and surgery, a risk-adapted approach to adjuvant therapy according to post-operative ctDNA status is being studied in clinical trials but results are yet to be published. Source: Image created with BioRender.com. CRT, chemoradiotherapy; ctDNA, circulating tumour DNA; LARC, locally advanced rectal cancer; SRT, short course radiation; TNT, total neoadjuvant therapy.