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ctDNA predicts recurrence in nonmetastatic colorectal cancer

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ctDNA could revolutionize postoperative management of early-stage CRC

Based on recent findings of a study conducted by Wang et al. and an increasing amount of research, circulating tumor DNA (ctDNA) testing “will likely revolutionize” postoperative management for patients with early-stage colorectal cancer (CRC), according to Van Morris, MD; Arvind Dasari, MD; and Scott Kopetz, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

“The ability to optimize adjuvant chemotherapy recommendations for patients with resected CRC has been historically limited by the use of clinicopathologic characteristics, which imperfectly prognosticate the risk for recurrence,” the doctors wrote in a JAMA Oncology editorial accompanying the article by Wang et al.

In the study by Dr. Wang and associates, “clinical recurrence was strongly linked with ctDNA detection at the time of recurrence,” the doctors wrote, adding that “the absence of ctDNA was highly associated with excellent oncologic outcomes.” These associations translated to predictive advantages, as “[ctDNA] status outperformed traditional risk factors, including the pathological stage, in stratifying patients’ risk for recurrence.”

“With the implications of ctDNA status for recurrence risk, the question remains regarding how this exciting technology can be used to improve the standard practices for CRC,” the authors of the editorial wrote, noting that the National Comprehensive Cancer Network currently recommends monitoring with imaging studies, carcinoembryonic antigen (CEA) tests, and endoscopies. “ctDNA positivity may eventually serve as a biomarker for high-risk patients for whom a more aggressive systemic treatment against residual micrometastatic disease may be advantageous,” they wrote.

They also highlighted how, in the Wang et al. study, chemotherapy was associated with conversion from ctDNA positivity to negativity in one patient, a phenomenon that has been observed in other trials. “Interpretation of these data is limited by a small sample size of patients,” the doctors wrote, “but these findings nonetheless begin to provide important insight into the ability of chemotherapy to clear minimal residual disease, as tracked by serial changes in ctDNA status over time, which is associated with favorable prognostic implications for patients with early-stage CRC. Future trials in CRC and other solid cancers should assess ctDNA clearance more robustly as a surrogate marker for disease-free survival in patients undergoing definitive therapies for their solid tumors.”

“At present, payers in the United States have not yet approved the routine use of ctDNA technologies in patients with early-stage CRC after resection,” the doctors wrote. “However, compelling data on ctDNA as a robust prognostic marker should be a reason to reassess coverage.”

“[With payer support and improved techniques], then this exciting ctDNA technology will likely revolutionize the routine postoperative management of early-stage CRC by providing a reliable, objective tool for oncologists,” they concluded.

Dr. Morris, Dr. Dasari, and Dr. Kopetz are affiliated with the University of Texas MD Anderson Cancer Center in Houston. Dr. Morris reported financial relationships with GuardantHealth and Array Biopharma. Dr. Kopetz reported relationships with Symphogen, Amgen, Merck, and Holy Stone.


 

FROM JAMA ONCOLOGY

Circulating tumor DNA (ctDNA) could be used to predict disease recurrence in patients with nonmetastatic colorectal cancer (CRC), according to investigators following an observational study.

About three out of four patients with a positive ctDNA test went on to have disease recurrence, reported lead author Yuxuan Wang, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, and her colleagues. On average, positive tests preceded clinical and radiologic evidence of recurrence by 3 months.

“[T]he optimal protocol for surveillance of resected colorectal cancer remains uncertain,” the investigators wrote in JAMA Oncology.

“The only recommended blood marker for CRC surveillance is serum [carcinoembryonic antigen (CEA)], an oncofetal protein that is elevated in the serum of patients with a variety of disease conditions, including CRC. Unfortunately, its utility is limited by the lack of sensitivity and specificity.” Although computed tomography and magnetic resonance imaging can improve disease detection, these techniques also have their own shortcomings, the investigators noted, setting the stage for the present study.

The investigators recruited 63 patients with stage I, II, or III CRC who underwent surgical resection in Sweden between 2007 and 2013. Blood samples for ctDNA testing were collected 1 month after surgery, then every 3-6 months. CT was performed every 6-12 months. During this process, 5 patients were excluded, leaving 58 patients in the final dataset, 18 (31%) of whom received adjuvant chemotherapy. Patients were followed until metastasis or a median of 49 months.

Among all patients, 13 tested positive for ctDNA, and 10 of these relapsed (77%), with a median time of 3 months between ctDNA positivity and CT or clinical evidence of recurrence. Three of the 48 patients (6%) who did not relapse had a positive ctDNA result that later dropped to an undetectable level. Of the 45 patients who tested negative for ctDNA, none had recurrence, although 1 was positive for CEA.

Results were also divided into patients who received or did not receive adjuvant chemotherapy. Among the 40 patients who did not receive chemotherapy, 8 had disease recurrence after a positive ctDNA test, although only 5 tested positive for CEA. Among the 18 patients who did receive chemotherapy, 2 tested positive for ctDNA and later relapsed, although only 1 tested positive for CEA. These figures translated to a ctDNA sensitivity for recurrence of 100%, compared with 60% for CEA testing.

“Serial ctDNA levels during follow-up can precede disease recurrence prior to routine radiographic imaging,” the investigators concluded. “Because ctDNA measurements can be obtained from blood samples collected during routine follow-up, they may be easily incorporated into routine follow-up to complement a CEA test, radiographic imaging, and other conventional modalities to help stratify patients on the basis of the risk of disease recurrence. Such a personalized surveillance strategy may allow for earlier detection of relapse and minimize unnecessary testing.”

The study was funded by the Virginia and D.K. Ludwig Fund for Cancer Research, the Commonwealth Foundation, the John Templeton Foundation, and others. The investigators reported financial relationships with PapGene, Sysmex, Eisai, and others.

SOURCE: Wang et al. JAMA Onc. 2019 May 9. doi: 10.1001/jamaoncol.2019.0512.

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