Molecular Residual Disease and Adjuvant Trial Design in Solid Tumors

Abstract

Advances in diagnosis and treatment have resulted in a high rate of survival for many patients with early-stage cancers. However, identifying who is at ongoing risk of relapse remains of high priority to direct subsequent adjuvant therapy. Multiple recent retrospective studies have shown that detection of tumor-derived materials in blood, in particular with circulating tumor DNA (ctDNA) analysis, can identify patients with residual disease before clinical or radiological evidence of metastatic disease, anticipating relapse with relatively high sensitivity and high specificity. We discuss how these emerging technologies are defining new subgroups of patients with "Molecular Residual Disease" and "Molecular Relapse." We outline how novel clinical trials in the adjuvant setting designed for these new subgroups of patients may improve selection for adjuvant therapies, and provide new surrogate endpoints that may allow for early registration of adjuvant therapies and novel clinical trial designs in the adjuvant setting. We discuss the current limitations of these techniques and the routes to clinical implementation.

Prognostic significance of postsurgery circulating tumor DNA in nonmetastatic colorectal cancer: Individual patient pooled analysis of three cohort studies

“…[12][13][14][15][16] Prospective trials have now been initiated to explore how ctDNA status could optimally inform adjuvant therapy decision-making and ultimately improve patient outcomes. 17 Future prospective studies might be informed by consolidating lessons learnt from completed nonrandomized studies. Important questions include those about the optimal timing of blood collection after surgery, whether quantitative measurement of ctDNA mutation burden can provide further risk stratification when ctDNA is detectable, the predictive performance of ctDNA compared to known clinicopathologic risk factors, the impact of ctDNA mutation burden on…”

“…This promise has been further demonstrated in nonmetastatic CRC 8‐11 and many other solid tumor types 12‐16 . Prospective trials have now been initiated to explore how ctDNA status could optimally inform adjuvant therapy decision‐making and ultimately improve patient outcomes 17 …”

Circulating tumor DNA in advanced solid tumors: Clinical relevance and future directions

“…2). Such an approach is not dissimilar from ongoing studies of minimal residual disease in which ctDNA‐positive patients receive ongoing therapy whereas ctDNA‐negative patients are permitted a treatment break 136 …”

Detection of Circulating Tumor DNA in Solid Tumors

“…The majority of the studies on solid tumors have been conducted with the specific aim of detecting molecular residual disease (MRD) after the completion of definitive therapy. This technique was applied successfully for MRD detection in several solid tumors, including colorectal cancer, breast cancer, lung carcinoma, pancreatic carcinoma, and nasopharyngeal carcinoma [22].…”

“…The pioneering study by Diehl et al demonstrated the feasibility of ctDNA detection in a significant cohort of cancer patients [22]. The study also demonstrated that ctDNA in the plasma has a short half-life (of <2 h), although the ctDNA levels may be elevated 24 h following surgical tumor resection, apparently due to the release of ctDNA from the damaged tissue [23].…”