ctDNA as a Biomarker of Recurrence and Prognosis in Early-Stage CRC

Adjuvant chemotherapy is standard of care for stage III colorectal cancer (CRC) and high-risk stage II CRC. However, decision making for adjuvant therapy is imperfect and based on risk stratification by stage and clinical risk factors. In recent years, circulating tumor DNA (ctDNA) has emerged as a promising noninvasive and dynamic biomarker for monitoring genomic evolution and development of resistance in metastatic CRC. Furthermore, presence of ctDNA in the blood of patients with CRC after surgical resection has shown to be associated with higher risk of recurrence in several patient case studies. Assays to detect ctDNA are highly sensitive and can detect residual tumor cells several months before they become radiographically visible. Two studies published in a recent edition of JAMA Oncology evaluated the potential of ctDNA as a biomarker of recurrence and outcomes in patients with stages I to III CRC.

A prospective, multicenter cohort study from Denmark evaluated longitudinal plasma samples from 125 patients with early-stage CRC to determine the associations between ctDNA detection, risk of recurrence, and patient outcome. Plasma samples were collected before surgery, 30 days after surgery, and then every 3 months for up to 3 years. ctDNA was detected with a personalized, tumor-specific, multiplex polymerase chain reaction (PCR)–based next- generation sequencing (NGS) method. The majority of patients (88.5%) had detectable ctDNA prior to surgery, while only 10.6% were ctDNA-positive following surgery. ctDNA-positive patients had a significantly higher recurrence rate compared to ctDNA-negative patients (70.0% vs 11.9%; HR 7.2, P<.001) and had significantly reduced relapse-free survival (RFS, HR 7.2; P<.001). In a multivariate analysis that included ctDNA status and known clinicopathologic risk factors, ctDNA status was the only significant prognostic factor associated with RFS. Among patients who underwent adjuvant chemotherapy following surgery (n = 52), ctDNA positivity was associated with a significantly higher risk of recurrence (HR 17.5, P<.001). Of 10 patients who were ctDNA-positive at the start of adjuvant chemotherapy, 3 became ctDNA-negative during treatment. Interestingly, patients who were ctDNA-negative had a relapse rate of 12%, regardless of whether or not they received adjuvant chemotherapy, suggesting adjuvant chemotherapy may not be necessary in this population. Of note, serial ctDNA analysis revealed disease recurrence at an average of 8.7 months before recurrence was detected by radiologic imaging.

A second study compared ctDNA results to outcomes in 58 patients with stage I-III CRC who underwent surgical resection in four hospitals in Sweden. 18 patients (31%) also received adjuvant chemotherapy following surgery. Blood samples for ctDNA analysis were collected at 1 month after surgery and then every 3 to 6 months. Among 13 patients with detectable ctDNA, 10 patients recurred (77%), while none with negative ctDNA relapsed. The median time to recurrence after surgery was 9 months. Among the 40 patients (69%) who did not receive adjuvant therapy, 8 patients, all of whom were ctDNA positive, relapsed. In the subset of patients who received adjuvant chemotherapy, 2 patients who had positive ctDNA postchemotherapy relapsed. Importantly, ctDNA was detectable 3 months before clinical or radiological signs of recurrence, suggesting ctDNA may be used as an early marker of recurrence. However, 3 patients with positive ctDNA did not relapse, though their ctDNA fell to undetectable levels during follow-up.

In an accompanying editorial, the authors pointed out that both of these studies indicate that presence of ctDNA after standard treatment for early stage CRC is associated with increased risk of recurrence. They indicate that ctDNA can be used as a biomarker to aid in treatment decision-making in this population and is likely better than commonly used clinical and pathological risk factors.

JAMA Oncol. 2019 May 9. [Epub ahead of print.]

ctDNA-for-CRC-recurrence-prognosis

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