Pre-operative ctDNA predicts survival in high-risk stage III cutaneous melanoma patients

J. H. Lee, R. P. Saw, J. F. Thompson, S. Lo, A. J. Spillane, K. F. Shannon, J. R. Stretch, J. Howle, A. M. Menzies, M. S. Carlino, R. F. Kefford, G. V. Long, R. A. Scolyer, H. Rizos

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: The outcomes of patients with stage III cutaneous melanoma who undergo complete surgical resection can be highly variable, and estimation of individual risk of disease recurrence and mortality remains imprecise. With recent demonstrations of effective adjuvant targeted and immune checkpoint inhibitor therapy, more precise stratification of patients for costly and potentially toxic adjuvant therapy is needed. We report the utility of pre-operative circulating tumour DNA (ctDNA) in patients with high-risk stage III melanoma.

Patients and methods: ctDNA was analysed in blood specimens that were collected pre-operatively from 174 patients with stage III melanoma undergoing complete lymph node (LN) dissection. Cox regression analyses were used to evaluate the prognostic significance of ctDNA for distant metastasis recurrence-free survival and melanoma-specific survival (MSS).

Results: The detection of ctDNA in the discovery and validation cohort was 34% and 33%, respectively, and was associated with larger nodal melanoma deposit, higher number of melanoma involved LNs, more advanced stage and high lactate dehydrogenase (LDH) levels. Detectable ctDNA was significantly associated with worse MSS in the discovery [hazard ratio (HR) 2.11 P <0.01] and validation cohort (HR 2.29, P = 0.04) and remained significant in a multivariable analysis (HR 1.85, P = 0.04). ctDNA further sub-stratified patients with AJCC stage III substage, with increasing significance observed in more advanced stage melanoma.

Conclusion: Pre-operative ctDNA predicts MSS in high-risk stage III melanoma patients undergoing complete LN dissection, independent of stage III substage. This biomarker may have an important role in determining prognosis and stratifying patients for adjuvant treatment.

LanguageEnglish
Pages815-822
Number of pages8
JournalAnnals of oncology : official journal of the European Society for Medical Oncology
Volume30
Issue number5
DOIs
Publication statusPublished - 1 May 2019

Fingerprint

Melanoma
Skin
Survival
DNA
Neoplasms
Lymph Node Excision
Recurrence
Poisons
L-Lactate Dehydrogenase
Therapeutics
Biomarkers
Regression Analysis
Neoplasm Metastasis
Mortality

Bibliographical note

Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • adjuvant therapy
  • circulating tumour DNA
  • melanoma
  • stage III
  • survival

Cite this

Lee, J. H. ; Saw, R. P. ; Thompson, J. F. ; Lo, S. ; Spillane, A. J. ; Shannon, K. F. ; Stretch, J. R. ; Howle, J. ; Menzies, A. M. ; Carlino, M. S. ; Kefford, R. F. ; Long, G. V. ; Scolyer, R. A. ; Rizos, H. / Pre-operative ctDNA predicts survival in high-risk stage III cutaneous melanoma patients. In: Annals of oncology : official journal of the European Society for Medical Oncology. 2019 ; Vol. 30, No. 5. pp. 815-822.
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title = "Pre-operative ctDNA predicts survival in high-risk stage III cutaneous melanoma patients",
abstract = "Background: The outcomes of patients with stage III cutaneous melanoma who undergo complete surgical resection can be highly variable, and estimation of individual risk of disease recurrence and mortality remains imprecise. With recent demonstrations of effective adjuvant targeted and immune checkpoint inhibitor therapy, more precise stratification of patients for costly and potentially toxic adjuvant therapy is needed. We report the utility of pre-operative circulating tumour DNA (ctDNA) in patients with high-risk stage III melanoma.Patients and methods: ctDNA was analysed in blood specimens that were collected pre-operatively from 174 patients with stage III melanoma undergoing complete lymph node (LN) dissection. Cox regression analyses were used to evaluate the prognostic significance of ctDNA for distant metastasis recurrence-free survival and melanoma-specific survival (MSS).Results: The detection of ctDNA in the discovery and validation cohort was 34{\%} and 33{\%}, respectively, and was associated with larger nodal melanoma deposit, higher number of melanoma involved LNs, more advanced stage and high lactate dehydrogenase (LDH) levels. Detectable ctDNA was significantly associated with worse MSS in the discovery [hazard ratio (HR) 2.11 P <0.01] and validation cohort (HR 2.29, P = 0.04) and remained significant in a multivariable analysis (HR 1.85, P = 0.04). ctDNA further sub-stratified patients with AJCC stage III substage, with increasing significance observed in more advanced stage melanoma.Conclusion: Pre-operative ctDNA predicts MSS in high-risk stage III melanoma patients undergoing complete LN dissection, independent of stage III substage. This biomarker may have an important role in determining prognosis and stratifying patients for adjuvant treatment.",
keywords = "adjuvant therapy, circulating tumour DNA, melanoma, stage III, survival",
author = "Lee, {J. H.} and Saw, {R. P.} and Thompson, {J. F.} and S. Lo and Spillane, {A. J.} and Shannon, {K. F.} and Stretch, {J. R.} and J. Howle and Menzies, {A. M.} and Carlino, {M. S.} and Kefford, {R. F.} and Long, {G. V.} and Scolyer, {R. A.} and H. Rizos",
note = "Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",
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doi = "10.1093/annonc/mdz075",
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Lee, JH, Saw, RP, Thompson, JF, Lo, S, Spillane, AJ, Shannon, KF, Stretch, JR, Howle, J, Menzies, AM, Carlino, MS, Kefford, RF, Long, GV, Scolyer, RA & Rizos, H 2019, 'Pre-operative ctDNA predicts survival in high-risk stage III cutaneous melanoma patients', Annals of oncology : official journal of the European Society for Medical Oncology, vol. 30, no. 5, pp. 815-822. https://doi.org/10.1093/annonc/mdz075

Pre-operative ctDNA predicts survival in high-risk stage III cutaneous melanoma patients. / Lee, J. H.; Saw, R. P.; Thompson, J. F.; Lo, S.; Spillane, A. J.; Shannon, K. F.; Stretch, J. R.; Howle, J.; Menzies, A. M.; Carlino, M. S.; Kefford, R. F.; Long, G. V.; Scolyer, R. A.; Rizos, H.

In: Annals of oncology : official journal of the European Society for Medical Oncology, Vol. 30, No. 5, 01.05.2019, p. 815-822.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Pre-operative ctDNA predicts survival in high-risk stage III cutaneous melanoma patients

AU - Lee, J. H.

AU - Saw, R. P.

AU - Thompson, J. F.

AU - Lo, S.

AU - Spillane, A. J.

AU - Shannon, K. F.

AU - Stretch, J. R.

AU - Howle, J.

AU - Menzies, A. M.

AU - Carlino, M. S.

AU - Kefford, R. F.

AU - Long, G. V.

AU - Scolyer, R. A.

AU - Rizos, H.

N1 - Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Background: The outcomes of patients with stage III cutaneous melanoma who undergo complete surgical resection can be highly variable, and estimation of individual risk of disease recurrence and mortality remains imprecise. With recent demonstrations of effective adjuvant targeted and immune checkpoint inhibitor therapy, more precise stratification of patients for costly and potentially toxic adjuvant therapy is needed. We report the utility of pre-operative circulating tumour DNA (ctDNA) in patients with high-risk stage III melanoma.Patients and methods: ctDNA was analysed in blood specimens that were collected pre-operatively from 174 patients with stage III melanoma undergoing complete lymph node (LN) dissection. Cox regression analyses were used to evaluate the prognostic significance of ctDNA for distant metastasis recurrence-free survival and melanoma-specific survival (MSS).Results: The detection of ctDNA in the discovery and validation cohort was 34% and 33%, respectively, and was associated with larger nodal melanoma deposit, higher number of melanoma involved LNs, more advanced stage and high lactate dehydrogenase (LDH) levels. Detectable ctDNA was significantly associated with worse MSS in the discovery [hazard ratio (HR) 2.11 P <0.01] and validation cohort (HR 2.29, P = 0.04) and remained significant in a multivariable analysis (HR 1.85, P = 0.04). ctDNA further sub-stratified patients with AJCC stage III substage, with increasing significance observed in more advanced stage melanoma.Conclusion: Pre-operative ctDNA predicts MSS in high-risk stage III melanoma patients undergoing complete LN dissection, independent of stage III substage. This biomarker may have an important role in determining prognosis and stratifying patients for adjuvant treatment.

AB - Background: The outcomes of patients with stage III cutaneous melanoma who undergo complete surgical resection can be highly variable, and estimation of individual risk of disease recurrence and mortality remains imprecise. With recent demonstrations of effective adjuvant targeted and immune checkpoint inhibitor therapy, more precise stratification of patients for costly and potentially toxic adjuvant therapy is needed. We report the utility of pre-operative circulating tumour DNA (ctDNA) in patients with high-risk stage III melanoma.Patients and methods: ctDNA was analysed in blood specimens that were collected pre-operatively from 174 patients with stage III melanoma undergoing complete lymph node (LN) dissection. Cox regression analyses were used to evaluate the prognostic significance of ctDNA for distant metastasis recurrence-free survival and melanoma-specific survival (MSS).Results: The detection of ctDNA in the discovery and validation cohort was 34% and 33%, respectively, and was associated with larger nodal melanoma deposit, higher number of melanoma involved LNs, more advanced stage and high lactate dehydrogenase (LDH) levels. Detectable ctDNA was significantly associated with worse MSS in the discovery [hazard ratio (HR) 2.11 P <0.01] and validation cohort (HR 2.29, P = 0.04) and remained significant in a multivariable analysis (HR 1.85, P = 0.04). ctDNA further sub-stratified patients with AJCC stage III substage, with increasing significance observed in more advanced stage melanoma.Conclusion: Pre-operative ctDNA predicts MSS in high-risk stage III melanoma patients undergoing complete LN dissection, independent of stage III substage. This biomarker may have an important role in determining prognosis and stratifying patients for adjuvant treatment.

KW - adjuvant therapy

KW - circulating tumour DNA

KW - melanoma

KW - stage III

KW - survival

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UR - http://purl.org/au-research/grants/nhmrc/1093017

UR - http://purl.org/au-research/grants/nhmrc/1130423

UR - http://purl.org/au-research/grants/nhmrc/1104503

U2 - 10.1093/annonc/mdz075

DO - 10.1093/annonc/mdz075

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EP - 822

JO - Annals of Oncology

T2 - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

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ER -