Epigenomic ctDNA Assay Predicts Recurrence in Resected Melanoma

Detection of circulating tumor DNA (ctDNA) with a tissue-free epigenomic assay after surgery was associated with a substantially higher risk of recurrence and death in patients with resected stage II-III melanoma, according to an interim analysis published in Cancer Research Communications.¹

In the prospective, multicenter COSMOS-MEL01 study (UMIN000042040), 6 of 47 evaluable patients (13%) had ctDNA detected with the Guardant Reveal assay approximately 28 days after surgery. In models adjusted for age, sex, stage, melanoma type, and adjuvant treatment, a positive day 28 result was associated with recurrence (HR, 11.70; 95% CI, 3.09-43.76; P <.001) and death (HR, 31.14; 95% CI, 5.37-221.1; P <.001). With serial testing, cumulative surveillance sensitivity for distant recurrence was 81% (13 of 16 patients), and specificity was 100% across 84 posttreatment samples from 19 patients who remained recurrence free.

“These results show that ctDNA detection using a tissue-free assay was associated with a substantially increased risk of recurrence and melanoma-related death and often preceded clinical detection of disease,” said Yoshiaki Nakamura, MD, PhD, corresponding author of the study and former chief of the International Research Promotion Office at National Cancer Center Hospital East in Chiba, Japan, in a news release from Guardant Health.²

Study Design and Population

COSMOS-MEL01 is an ongoing observational study at centers in Japan.¹ From July 2021 through March 2023, it enrolled 53 treatment-naive adults with clinical stage II-III cutaneous or mucosal melanoma who were planned for resection; 48 were included in the postoperative analyses. Of these, 52% had non-acral cutaneous melanoma, 31% had acral melanoma, and 17% had mucosal melanoma. Pathologic stage IIIB/C disease was present in 55%, and BRAF V600E/K mutations were present in approximately 19%. Adjuvant therapy was given to 28 patients (58%): 25 with anti–PD-1 antibodies and 3 with dabrafenib (Tafinlar) plus trametinib (Mekinist); none received neoadjuvant treatment.¹

Plasma was drawn before surgery, at about day 28, and every 3 to 6 months for up to 3 years, whereas imaging followed Japanese guidelines at roughly 6-month intervals. Samples were analyzed retrospectively, and results were not shared with treating physicians. The assay that was used evaluates more than 20,000 cancer-associated differentially methylated regions, using a melanoma-specific algorithm trained on more than 500 samples from patients with melanoma and more than 6000 from individuals without cancer. The assay is currently offered for minimal residual disease detection in early-stage colorectal, breast, and lung cancers.

At a median follow-up of 34.6 months, 27 patients had recurrent disease (16 distant, 10 regional, and 1 local), and all 11 deaths were attributed to melanoma.

Surveillance Findings

The assay returned results for 278 of 279 surveillance samples (99.6%), with a median of 6 draws per patient. Sensitivity was lower for locoregional recurrence, at 45% (5 of 11 patients). Among patients with any detectable ctDNA, the signal appeared a median of 70.5 days before clinical recurrence (IQR, 22.8-140.8 days), with a maximum of 273 days.

Overall, 21 of 47 patients (45%) had ctDNA at 1 or more postoperative time points, a proportion that rose from 13% at 1 month to more than 40% within 2 years. Of those 21, 18 (86%) recurred, 13 at distant sites. Among the 26 patients who never tested positive, distant disease recurred in 3 (12%) and locoregional disease in 6 (23%). All 17 patients with ctDNA detected after completing treatment recurred, while 3 positive patients who did not recur cleared ctDNA during or after adjuvant immunotherapy.

In landmark analyses at 12 months, surveillance ctDNA detection was associated with any recurrence (adjusted HR, 5.16; 95% CI, 1.53-17.36) and distant recurrence (adjusted HR, 8.66; 95% CI, 1.74-43.00).

Day 28 Outcomes

Five of the 6 patients with detected ctDNA at day 28 had disease recurrence within 6 months of surgery, including 3 who received adjuvant therapy, and 4 died of melanoma within 2 years. Median recurrence-free interval from sample collection was 3.6 months for ctDNA-positive patients vs 27.8 months for ctDNA-negative patients. The association with distant recurrence alone did not reach significance (HR, 3.87; 95% CI, 0.79-15.14; P =.089). Among ctDNA-negative patients, the 12-month recurrence-free rate was 70.7% and the 24-month OS rate was 92.7%.

Limitations and Next Steps

The authors described the sample as modest, particularly the number of ctDNA-positive patients at day 28, which is reflected in the wide CIs. Treatment was not adjusted according to ctDNA status, and the authors stated that no data support deescalating adjuvant therapy for ctDNA-negative patients. A separate study, COSMOS-MEL02 (UMIN000051210), is evaluating patients with BRAF-mutant melanoma, as only 9 of these patients were included in this trial and ctDNA could potentially be valuable in guiding treatment selection between BRAF inhibitors and immune checkpoint inhibitors, the investigators stated.¹

Kenjiro Namikawa, MD, PhD, first author of the study and chief of the Department of Dermatologic Oncology at National Cancer Center Hospital in Tokyo, Japan, stated in the news release: “Further studies will be important to determine whether and how ctDNA results could be incorporated into postoperative treatment and surveillance decisions.”²

REFERENCES

1. Namikawa K, Ogata D, Nakano E, et al. Melanoma recurrence prediction using a tissue-free epigenomic molecular residual disease assay: a multicenter prospective observational study (COSMOS-MEL01). Cancer Res Commun. Published online October 5, 2026. doi:10.1158/2767-9764.CRC-26-0388

2. Guardant Health COSMOS Study Published in Cancer Research Communications Validates Utility of Guardant Reveal® Liquid Biopsy Test for Predicting Recurrence in Melanoma. News release. Guardant Health, Inc. October 5, 2026. Accessed October 9, 2026. https://tinyurl.com/482ctaym