Liquid biopsies for residual disease and recurrence

Abstract

Detection of minimal residual disease in patients with cancer, who are in complete remission with no cancer cells detectable, has the potential to improve recurrence-free survival through treatment selection. Studies analyzing circulating tumor DNA (ctDNA) in patients with solid tumors suggest the potential to accurately predict and detect relapse, enabling treatment strategies that may improve clinical outcomes. Over the past decade, assays for ctDNA detection in plasma samples have steadily increased in sensitivity and specificity. These are applied for the detection of residual disease after treatment and for earlier detection of recurrence. Novel clinical trials are now assessing how assays for ''residual disease and recurrence'' (RDR) may influence current treatment paradigms and potentially change the landscape of risk classification for cancer recurrence. In this review, we appraise the progress of RDR detection using ctDNA and consider the emerging role of liquid biopsy in the monitoring and management of solid tumors. CIRCULATING TUMOR DNA AND LIQUID BIOPSIESCirculating fragments of cell-free DNA were first described in 1948 by Mandel and Me ´tais. 1 These were the subject of infrequent study; 2,3 however, that started to change after proof-of-principle studies demonstrated the potential clinical utility of detecting circulating tumor DNA (ctDNA) in the 1990s. For example, DNA fragments carrying mutations in the KRAS gene were identified in the plasma of patients with pancreatic cancer using allele-specific polymerase chain reaction (PCR). 4 Multiple studies, using sensitive mutation analysis in plasma of cancer patients and xenograft models, confirmed that ctDNA fragments are derived from cancer cells and could be used as a quantitative marker to assess cancer disease burden. [5][6][7] In parallel, the introduction of massively parallel or next-generation sequencing (NGS) 8 has enabled breathtaking progress in cancer genomics from both tissue and body fluid samples.Tissue samples are the gold standard for cancer diagnosis but are, in many cases, not available for analysis. In contrast, blood samples are minimally invasive and can be collected frequently, mitigating the practical limitations of tumor biopsy. ctDNA analysis may sample mutations released from genetically heterogeneous tumors, 9,10 though subclonal mutations can be challenging to detect in plasma. 11,12 Bloodbased genetic and genomic tests have emerged, now referred to as a ''liquid biopsy''. 13,14

Residual ctDNA after treatment predicts early relapse in patients with early-stage non-small cell lung cancer

“…Recent results support this approach in multiple cancer types. 23 , 26 In early-stage NSCLC treated by surgery and/or radiotherapy, several recent studies used high-sensitivity methods to test associations between ctDNA detection and patient outcomes after treatment with curative intent 21 , 39 , 40 (see Supplementary Information, available at https://doi.org/10.1016/j.annonc.2022.02.007 ). Here we applied high-sensitivity personalized assays to study a population with earlier stage disease, of whom 70% underwent surgical treatment, and observed lead times of ∼200 days from ctDNA detection to disease recurrence.…”

“… 4 With the development of highly-sensitive patient-specific assays, ctDNA has been used to detect MRD in patients with breast, colorectal, lung cancer and other solid tumours. 16 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 In NSCLC, Chaudhuri et al. 21 demonstrated that residual ctDNA could be detected in 94% of stage I-III patients treated predominantly (35/40 patients) by radiotherapy or CRT who subsequently recurred.…”

Circulating Histones to Detect and Monitor the Progression of Cancer

“…In the frame of malignant disease monitoring and progression, ctDNA has also been used as a marker for guiding therapy and minimal residual disease (MRD). The latter is used for the detection of residual disease, based on the presence of cancer-derived molecular biomarkers, when the bulk cancer is not detectable by conventional investigations, such as medical imaging, for instance, in melanoma and colorectal carcinoma (CRC) [ 6 , 7 , 8 , 9 , 10 , 11 ]. Unfortunately, ctDNA in the bloodstream has a very short half-life, ranging from 30 min to 2 h, causing problems in several areas, including tracking tumor heterogeneity, precision treatment, and rigid protocol standardization ( Table 1 ).…”

Utilizing Plasma Circulating Tumor DNA Sequencing for Precision Medicine in the Management of Solid Cancers

“…The ctDNA-based decision of adjuvant treatment did not adversely affect patient outcomes (2-year recurrence-free survival of 93.5% vs. 92.4%) in stage II colon cancer while reducing the number of patients receiving adjuvant chemotherapy (15% vs. 28%) compared to SoC. This trial successfully examined the impact of a ctDNA-based adjuvant treatment decision strategy compared to a standard adjuvant decision in stage II colon cancer, and many ongoing clinical trials are investigating whether adjuvant chemotherapy can be modified based on postoperative ctDNA MRD status in various types of early-stage solid cancers [79][80][81][82][83][84][85] (Table 1). The prospective randomized trials of MRD-guided adjuvant treatment can be roughly divided into those with a superiority design of escalation strategy, where intensified treatment regimens are compared with SoC in patients with positive postoperative MRD, and those with a non-inferiority design of de-escalation strategy, where de-intensified regimens (e.g., shortened treatment duration, or reduced dose or even treatment omission) are compared with SoC in patients with negative postoperative MRD.…”

“…In contrast, tumor-informed panels generally have a higher sensitivity by targeting a larger number of mutations. However, these methods are more expensive and take longer to generate results compared to tumor-agnostic panels [83,84], b)…”