In solid tumor oncology, circulating tumor DNA (ctDNA) is poised to transform care through accurate assessment of minimal residual disease (MRD) and therapeutic response monitoring. To overcome the sparsity of ctDNA fragments in low tumor fraction (TF) settings and increase MRD sensitivity, we previously leveraged genome-wide mutational integration through plasma whole-genome sequencing (WGS). Here we now introduce MRD-EDGE, a machine-learning-guided WGS ctDNA single-nucleotide variant (SNV) and copy-number variant (CNV) detection platform designed to increase signal enrichment. MRD-EDGE^SNV uses deep learning and a ctDNA-specific feature space to increase SNV signal-to-noise enrichment in WGS by ~300× compared to previous WGS error suppression. MRD-EDGE^CNV also reduces the degree of aneuploidy needed for ultrasensitive CNV detection through WGS from 1 Gb to 200 Mb, vastly expanding its applicability within solid tumors. We harness the improved performance to identify MRD following surgery in multiple cancer types, track changes in TF in response to neoadjuvant immunotherapy in lung cancer and demonstrate ctDNA shedding in precancerous colorectal adenomas. Finally, the radical signal-to-noise enrichment in MRD-EDGE^SNV enables plasma-only (non-tumor-informed) disease monitoring in advanced melanoma and lung cancer, yielding clinically informative TF monitoring for patients on immune-checkpoint inhibition.

(2020). IMPROVE-IT2: implementing noninvasive circulating tumor DNA analysis to optimize the operative and postoperative treatment for patients with colorectal cancer – intervention trial 2. Study protocol. Acta Oncologica. Ahead of Print.

The fraction of patients who are cancer‐free survivors 5 years after curative‐intended surgery for colorectal cancer (CRC) is increasing, suggesting that extending surveillance beyond 5 years may be indicated. Here we estimate the incidence of late recurrence, metachronous CRC, and second primary cancers 5–10 years postoperative. All patients resected for UICC stage I–III CRC in Denmark through 2004–2013 were identified. Through individual‐level linkage of nationwide health registry data, recurrence status was determined using a validated algorithm. Cancer‐free survivors 5 years after surgery, were included. Cumulative incidence functions (CIF) of late recurrence, metachronous CRC, and second primary cancer 5–10 years postoperative were constructed. Subdistribution hazards ratios (sHR) were computed using Fine‐Gray regression. Among 8883 patients, 370 developed late recurrence (5–10‐year CIF = 4.1%, 95%CI: 3.7%–4.6%), 270 metachronous CRC (5–10‐year CIF = 3.0%, 95%CI: 2.7%–3.4%), and 635 a second primary cancer (5–10‐year CIF = 7.2%, 95%CI: 6.7%–7.7%). The risk of late recurrence was reduced for patients operated in 2009–2013 compared to 2004–2008 (2.9% vs. 5.6%, sHR = 0.52, 95% CI: 0.42–0.65). The risk of metachronous CRC was likewise reduced from 4.1% to 2.1% (sHR = 0.50, 95%CI: 0.39–0.65). While the risk of second primary cancer did not change between 2009–2013 and 2004–2008 (7.1% vs. 7.1%, sHR = 0.98, 95% CI: 0.84–1.15). Using nation‐wide 10‐year follow‐up data, we document that the incidences of late recurrence and metachronous CRC are low and decreasing from 2004 to 2013. Thus, despite increasing numbers of long‐term cancer survivors, the data do not advocate for extending CRC‐specific surveillance beyond 5 years.

Objective: Circulating tumor DNA (ctDNA) is a candidate biomarker of cancer with practice-changing potential in the detection of both early and residual disease. Disease stage and tumor size affect the probability of ctDNA detection, whereas little is known about the influence of other tumor characteristics on ctDNA detection. This study investigates the impact of tumor cell whole-genome doubling (WGD) on the detection of ctDNA in plasma collected preoperatively from newly diagnosed colorectal cancer (CRC) patients. Methods: WGD was estimated from copy numbers derived from whole-exome sequencing (WES) data of matched tumor and normal DNA from 833 Danish CRC patients. To explore if tumor WGD status impacts ctDNA detection, we applied tumor-informed ctDNA analysis to preoperative plasma samples from all patients. Results: Patients with WGD+ tumors had 53% increased odds of being ctDNA positive (OR = 1.53, 95%CI: 1.12–2.09). After stratification for UICC stage, the association persisted for Stage I (OR = 2.44, 95%CI: 1.22–5.03) and Stage II (OR = 1.76, 95%CI: 1.11–2.81) but not for Stage III (OR = 0.83, 95%CI: 0.44–1.53) patients. Conclusion: The presence of WGD significantly increases the probability of detecting ctDNA, particularly for early-stage disease. In patients with more advanced disease, the benefit of WGD on ctDNA detection is less pronounced, consistent with increased DNA shedding from these tumors, making ctDNA detection less dependent on the amount of ctDNA released per tumor cell.

The incidence of colorectal cancer (CRC) in individuals younger than 50 years of age (early-onset CRC) is increasing. Early-onset CRC often present at advanced stage, suggesting a more aggressive cancer course compared to late-onset CRC (age 50–79). This nationwide cohort study estimates the incidence of recurrence following early-onset CRC and late-onset CRC. The study included all Danish patients <80 years old operated for first-time Union for International Cancer Control (UICC) stage I–III CRC between January 2004 and December 2019. Recurrence status was determined by applying a validated algorithm to individual-level data from nationwide health registries. The 5-year cumulative incidence functions (CIF) of recurrence were reported for early-onset versus late-onset CRC. The difference in time to recurrence was estimated as a time ratio (TR) using an accelerated failure time model. Among 25,729 CRC patients, 1441 (5.6%) had early-onset CRC. Compared to late-onset CRC, early-onset was associated with advanced disease stages and higher treatment intensity. The 5-year CIF of recurrence was 29% (95% CI: 26%–31%) in early-onset versus 21% (95% CI: 21%–22%) in late-onset CRC. The higher CIF of recurrence for early-onset patients persisted in stage-stratified analysis. Time to recurrence was shorter in early-onset versus late-onset patients with TR = 0.76 (95% CI: 0.67–0.85). The 5-year CIF of recurrence decreased from 2004 to 2019 for both early- and late-onset patients–most prominent for early-onset patients. Early-onset CRC was associated with higher incidence of recurrence at all disease stages. Indicating that the increased risk is not explained by delayed diagnosis. The excess risk diminished from 2004 to 2019, suggesting that early-onset CRC may achieve a similar recurrence risk as late-onset CRC in a contemporary setting. 10.13039/100007605 Aarhus University , 10.13039/501100009708 Novo Nordisk Foundation , 10.13039/100012774 Innovation Fund Denmark , and the 10.13039/100008363 Danish Cancer Society .