Preoperative ctDNA Predictive for Survival in Stage III Melanoma

Patients with stage III melanoma who are at high risk of recurrence, such as those with lymph node involvement, typically undergo complete surgical resection followed by adjuvant-targeted therapy (BRAF V600 mutant) or immunotherapy. However, current strategies for estimating risk of recurrence are flawed, and it is difficult to accurately identify those patients for whom the benefit of adjuvant treatment outweighs the toxicity and cost of treatment. Presence of circulating tumor (ct)DNA is associated with shortened survival in patients with stage IV melanoma. To evaluate the prognostic significance of ctDNA as a biomarker for patients with stage III melanoma, a recent study by the Melanoma Institute Australia evaluated blood from 174 patients with American Joint Committee on Cancer (AJCC) stage IIIB/C/D melanoma with detectable BRAF, NRAS, or KIT mutations collected prior to completion lymph node dissection (CLND) and correlated presence or absence of ctDNA to patient outcomes.

A total of 119 patients from multiple centers were in the discovery cohort and a validation cohort included 55 patients from a single separate institution. Patients included in both cohorts were similar across all clinical and pathological characteristics. ctDNA was analysed in preoperatively collected blood specimens and was found to be present in 34% and 33% of patients in the discovery and validation cohorts, respectively. Presence of ctDNA in the discovery cohort was most commonly associated with larger nodal deposits, higher number of involved lymph nodes, and elevated levels of lactose dehydrogenase (LDH) (P<.01 for all). Similar associations were seen in the validation cohort, with the exception of LDH level. Patients with higher AJCC stage disease were more likely to have detectable ctDNA.

Patients with detectable ctDNA had significantly worse melanoma-specific survival (MSS) compared to patients with undetectable ctDNA (17.6 months vs 49.4 months; HR 2.11, P<.01) Similar results were observed in the validation cohort (HR 2.29, P = .04). In a multiple Cox regression analysis, presence of ctDNA and extranodal extension were found to be the only parameters significantly associated with decreased MSS. Patients with detectable ctDNA also had a shortened distant metastasis relapse-free survival (DM-RFS) compared to those with undetectable levels (6.2 months vs 13.9 months; HR 1.59, P = .027). MSS decreased from AJCC stage IIIB to IIIC to IIID (P = .02). The difference in MSS was greatest in 14 patients with stage IIID disease, where all 7 patients with detectable ctDNA died, while 4 of 7 patients with undetectable levels of ctDNA remained alive with 18.5-, 53.7-, 60-, and 80.2-month follow-up (HR for death 6.4, P<.01). The median overall survival (OS) was 4.9 months in patients with detectable ctDNA and unreached in patients with undetectable ctDNA.

The authors concluded that presence of preoperative ctDNA in patients with high-risk stage III melanoma with a driver mutation is an independent predictor of worse MSS in patients receiving no systemic therapy. They also stated that “when used in combination with AJCC staging, detectability of ctDNA may provide more precise risk stratification,” though they recognized that longer follow-up and a larger cohort of patients with prospective molecular testing and adjuvant therapy is needed for further validation.

Ann Oncol. 2019 Mar 12. [Epub ahead of print.]

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