The detection of circulating tumor DNA (ctDNA) before surgery independently predicted survival outcomes among patients with high-risk stage III melanoma in a study recently published in the Annals of Oncology.1 Although further validation is required, the study findings, along with the growing body of evidence that shows the prognostic utility of ctDNA in melanoma, reinforce the need for ctDNA analysis to be included in clinical trial design.2,3

“Patients with melanoma that has spread to nearby lymph nodes undergo surgery to remove the cancer followed by systemic treatment to reduce the risk of cancer recurrence,” explained Helen Rizos, PhD, faculty of medicine and health sciences, Macquarie University, Sydney, Australia, during an interview with Cancer Therapy Advisor. “Selecting the best follow-up treatment for each patient — that is, an effective treatment with the fewest side effects — is particularly important, as some patients may be cured by surgery alone,” she said.

To determine the predictive utility of ctDNA, blood samples were collected from 174 patients with stage III melanoma one month before complete lymph node dissection. In total, 119 patients were allocated to the discovery cohort and 55 to the validation cohort. Melanoma-specific survival (MSS) was assessed as the primary outcome measure.

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The percentage of patients with detectable ctDNA in each cohort was approximately one-third. A multivariate analysis revealed that the detection of ctDNA correlated with significantly worse MSS (hazard ratio [HR], 1.85; P =.04). MSS declined with each subsequent American Joint Committee on Cancer (AJCC) stage (ie, IIIB to IIIC to IIID), and the detection of ctDNA-stratified patients within the AJCC stage III.

The most pronounced differentiation was among the 14 patients in the AJCC stage IIID group, for which detectable ctDNA significantly increased the likelihood of death (HR, 6.4; 95% CI, 1.63-25.04; P <.01).

For the 7 patients who had detectable ctDNA, all died; 4 of those deaths due to melanoma were within 6 months after surgery. In contrast, for the 7 patients with undetectable ctDNA, 4 remain alive at 18.5, 53.7, 60, and 80.2 months.

“Detectable levels of ctDNA prior to surgery was an independent predictor of worse survival in 2 independent patient cohorts,” said Dr Rizos. “This means that ctDNA may help guide each patient’s surgery and systemic treatment.” 

The study researchers showed that ctDNA correlates with the survival “really” well, said Diwakar Davar, MBBS, MSc, medical oncologist, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, during an interview with Cancer Therapy Advisor. Dr Davar, who was not involved in the study, noted that compared with radiographic assessment, ctDNA is a “far more” objective assessment of cancer growth.

“We have made an important first step in exploring the value of preoperative ctDNA in stage III melanoma, but there is much more to do,” said Dr Rizos. “Improving the sensitivity of ctDNA is perhaps the most critical next step,” she said. For example, ctDNA was not detected in patients enrolled in the study whose largest melanoma deposit was smaller than 10 mm in diameter. “We need to overcome this barrier if ctDNA is to become a personalized profiling tool for cancer patients,” she said.

In addition, Dr Rizos and Dr Davar each expressed the need for ctDNA to be incorporated into clinical trial design for melanoma. “We suggest that ctDNA analysis, which is a very simple test requiring only a 10-milliliter blood sample, should be a standard test incorporated in all future clinical trials,” said Dr Rizos. The incorporation of ctDNA in clinical trials would allow investigators to further establish the prognostic utility of ctDNA.


  1. Lee JH, Saw RP, Thompson JF, et al. Pre-operative ctDNA predicts survival in high-risk stage III cutaneous melanoma patients. Ann Oncol. doi: 10.1093/annonc/mdz075
  2. Santiago-Walker A, Gagnon R, Mazumdar J, et al. Correlation of BRAF mutation status in circulating-free DNA and tumor and association with clinical outcome across four BRAFi and MEKi clinical trials. Clin Cancer Res. 2016;22(3):567-574.
  3. Lee JH, Long GV, Boyd S, et al. Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic melanoma. Ann Oncol. 2017;28(5):1130-1136.