Circulating tumour DNA dynamics predict recurrence in stage III melanoma patients receiving neoadjuvant immunotherapy

J Exp Clin Cancer Res. 2024 Aug 21;43(1):238. doi: 10.1186/s13046-024-03153-1.

Abstract

Background: Neoadjuvant therapy improves recurrence-free survival (RFS) in resectable stage III cutaneous melanoma. However, accurately predicting individual recurrence risk remains a significant challenge. We investigated circulating tumour DNA (ctDNA) as a biomarker for recurrence in measurable stage IIIB/C melanoma patients undergoing neoadjuvant immunotherapy.

Methods: Plasma samples were collected pre-neoadjuvant treatment, pre-surgery and/or six weeks post-surgery from 40 patients enrolled in the OpACIN-neo and PRADO clinical trials. Patients received two cycles of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) before surgery. Cell free DNA (cfDNA) underwent unbiased pre-amplification followed by tumour-informed mutation detection using droplet digital polymerase chain reaction (ddPCR) with the Bio-Rad QX600 PCR system.

Results: Pre-treatment ctDNA was detectable in 19/40 (48%) patients. Among these, 17/19 (89%) zero-converted within six weeks of surgery and none recurred. Positive ctDNA post-surgery (N = 4), irrespective of pre-treatment ctDNA status, was 100% predictive of recurrence (sensitivity 44%, specificity 100%). Furthermore, ctDNA cleared prior to surgery in 7/9 (78%) patients who did not recur, warranting further investigation into ctDNA-guided surgical management.

Conclusion: Post-surgery ctDNA positivity and zero-conversion are highly predictive of recurrence, offering a window for personalised modification of adjuvant therapy.

Keywords: Circulating tumour DNA; Neoadjuvant therapy; Recurrence risk; Stage III melanoma.

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / blood
  • Circulating Tumor DNA* / blood
  • Circulating Tumor DNA* / genetics
  • Female
  • Humans
  • Immunotherapy* / methods
  • Male
  • Melanoma* / blood
  • Melanoma* / drug therapy
  • Melanoma* / genetics
  • Melanoma* / pathology
  • Melanoma* / therapy
  • Middle Aged
  • Neoadjuvant Therapy* / methods
  • Neoplasm Recurrence, Local*
  • Neoplasm Staging*
  • Skin Neoplasms / blood
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology
  • Skin Neoplasms / therapy

Substances

  • Circulating Tumor DNA
  • Biomarkers, Tumor