Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma

doi:10.1038/bjc.2014.287

. 2014 Jul 15;111(2):292-9.

doi: 10.1038/bjc.2014.287. Epub 2014 Jun 10.

Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma

M S Carlino¹, L E Haydu², H Kakavand³, A M Menzies⁴, A L Hamilton⁵, B Yu⁶, C C Ng⁷, W A Cooper⁸, J F Thompson⁹, R F Kefford¹, S A O'Toole¹⁰, R A Scolyer¹¹, G V Long⁴

Affiliations

¹ 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia [3] Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia [4] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
² 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
³ 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
⁴ 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
⁵ 1] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [2] Department of Medical Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
⁶ 1] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [2] Department of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
⁷ Department of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
⁸ 1] Department of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia [2] Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia [3] School of Medicine, University of Western Sydney, Sydney, NSW, Australia.
⁹ 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [3] Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
¹⁰ 1] Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [2] Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia [3] The Kinghorn Cancer Centre and Cancer Program Garvan Institute of Medical Research, Victoria Street, Darlinghurst, New South Wales, Australia.
¹¹ 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [3] Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.

PMID: 24918823
PMCID: PMC4102942
DOI: 10.1038/bjc.2014.287

Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma

M S Carlino et al. Br J Cancer. 2014.

. 2014 Jul 15;111(2):292-9.

doi: 10.1038/bjc.2014.287. Epub 2014 Jun 10.

Authors

M S Carlino¹, L E Haydu², H Kakavand³, A M Menzies⁴, A L Hamilton⁵, B Yu⁶, C C Ng⁷, W A Cooper⁸, J F Thompson⁹, R F Kefford¹, S A O'Toole¹⁰, R A Scolyer¹¹, G V Long⁴

Affiliations

¹ 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead, New South Wales, Australia [3] Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia [4] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
² 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
³ 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
⁴ 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
⁵ 1] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [2] Department of Medical Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
⁶ 1] Discipline of Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [2] Department of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
⁷ Department of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
⁸ 1] Department of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia [2] Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia [3] School of Medicine, University of Western Sydney, Sydney, NSW, Australia.
⁹ 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Surgery, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [3] Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
¹⁰ 1] Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [2] Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia [3] The Kinghorn Cancer Centre and Cancer Program Garvan Institute of Medical Research, Victoria Street, Darlinghurst, New South Wales, Australia.
¹¹ 1] Melanoma Institute Australia, Sydney, New South Wales, Australia [2] Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia [3] Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.

PMID: 24918823
PMCID: PMC4102942
DOI: 10.1038/bjc.2014.287

Abstract

Background: The prognostic significance of BRAF and NRAS mutations in metastatic melanoma patients remains uncertain, with several studies reporting conflicting results, often biased by the inclusion of patients treated with BRAF and MEK (MAPK) inhibitors. We therefore interrogated a historical cohort of patients free of the confounding influence of MAPK inhibitor therapy.

Methods: Patients with available archival tissue first diagnosed with metastatic melanoma between 2002 and 2006 were analysed. Mutational analysis was performed using the OncoCarta Panel. Patient characteristics, treatment outcome and survival were correlated with BRAF/NRAS mutation status.

Results: In 193 patients, 92 (48%) melanomas were BRAF-mutant, 39 (20%) were NRAS-mutant and 62 (32%) were wild-type for BRAF/NRAS mutations (wt). There was no difference in response to chemotherapy based on mutation status (35-37%). The distant disease-free interval (DDFI) was significantly shorter in patients with wt melanoma (27.9 months vs 35.1 for BRAF and 49.1 for NRAS) although this was not significant in multivariate analysis. Survival from stage IV melanoma diagnosis was not significantly different based on mutation status. The DDFI was significantly shorter in patients with BRAF(V600K/R) versus BRAF(V600E) melanoma in univariate and multivariate analyses.

Conclusions: BRAF and NRAS mutation status does not influence survival in metastatic melanoma.

PubMed Disclaimer

Figures

**Figure 1**
**Impact of mutation status on DDFI and survival from stage IV melanoma.** (A) DDFI from culprit primary melanoma based on *BRAF* and *NRAS* status. (B) Survival from diagnosis of stage IV melanoma based on *BRAF* and *NRAS* mutation status. (C) DDFI from culprit primary melanoma based on *BRAF* mutation genotype. (D) Survival from diagnosis of stage IV melanoma based on *BRAF* mutation genotype.

See this image and copyright information in PMC

Cited by

BRAF Alteration in Central and Peripheral Nervous System Tumors.
Srinivasa K, Cross KA, Dahiya S. Srinivasa K, et al. Front Oncol. 2020 Sep 15;10:574974. doi: 10.3389/fonc.2020.574974. eCollection 2020. Front Oncol. 2020. PMID: 33042847 Free PMC article. Review.
Targeted Therapy for Melanomas Without BRAF V600 Mutation.
Choi JS, Chandra S. Choi JS, et al. Curr Oncol Rep. 2022 Dec;24(12):1873-1881. doi: 10.1007/s11912-022-01306-z. Epub 2022 Nov 26. Curr Oncol Rep. 2022. PMID: 36435868 Review.
The Hidden Story of Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma-Association with Clinical Outcome and Tumor Phenotypes.
Betancourt LH, Szasz AM, Kuras M, Rodriguez Murillo J, Sugihara Y, Pla I, Horvath Z, Pawłowski K, Rezeli M, Miharada K, Gil J, Eriksson J, Appelqvist R, Miliotis T, Baldetorp B, Ingvar C, Olsson H, Lundgren L, Horvatovich P, Welinder C, Wieslander E, Kwon HJ, Malm J, Nemeth IB, Jönsson G, Fenyö D, Sanchez A, Marko-Varga G. Betancourt LH, et al. Cancers (Basel). 2019 Dec 9;11(12):1981. doi: 10.3390/cancers11121981. Cancers (Basel). 2019. PMID: 31835364 Free PMC article.
Assessment of clinical outcomes with immune checkpoint inhibitor therapy in melanoma patients with CDKN2A and TP53 pathogenic mutations.
DeLeon TT, Almquist DR, Kipp BR, Langlais BT, Mangold A, Winters JL, Kosiorek HE, Joseph RW, Dronca RS, Block MS, McWilliams RR, Kottschade LA, Rumilla KM, Voss JS, Seetharam M, Sekulic A, Markovic SN, Bryce AH. DeLeon TT, et al. PLoS One. 2020 Mar 20;15(3):e0230306. doi: 10.1371/journal.pone.0230306. eCollection 2020. PLoS One. 2020. PMID: 32196516 Free PMC article.
BRAF V600E Mutations and Beyond: A Molecular Perspective of Melanoma from a Tertiary Cancer Referral Center of India.
Vengurlekar V, Shetty O, Gurav M, Bapat P, Karnik N, Wagh G, Epari S, Rekhi B, Ramadwar M, Desai S. Vengurlekar V, et al. South Asian J Cancer. 2023 Mar 2;12(4):359-370. doi: 10.1055/s-0043-1760759. eCollection 2023 Oct. South Asian J Cancer. 2023. PMID: 38130275 Free PMC article.

See all "Cited by" articles

References

1. Akslen LA, Angelini S, Straume O, Bachmann IM, Molven A, Hemminki K, Kumar R. BRAF and NRAS mutations are frequent in nodular melanoma but are not associated with tumor cell proliferation or patient survival. J Invest Dermatol. 2005;125 (2):312–317. - PubMed
1. Amanuel B, Grieu F, Kular J, Millward M, Iacopetta B. Incidence of BRAF p.Val600Glu and p.Val600Lys mutations in a consecutive series of 183 metastatic melanoma patients from a high incidence region. Pathology. 2012;44 (4):357–359. - PubMed
1. Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, Blank CU, Hauschild A, Beck JT, St-Pierre A, Niazi F, Wandel S, Peters M, Zubel A, Dummer R. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14 (3):249–256. - PubMed
1. Brissy S, Gaudy-Marqueste C, Mallet S, Monestier S, Hesse S, Koeppel M-C, Rojat-Habib M-C, Nanni I, Loundou A, Lh Ouafik, Bonnet N, Richard M-A, Grob JJ. BRAF mutation as a pejorative marker in metastatic melanoma. J Clin Oncol. 2012;30 (suppl):abstr 8555.
1. Bucheit AD, Syklawer E, Jakob JA, Bassett RL, Jr, Curry JL, Gershenwald JE, Kim KB, Hwu P, Lazar AJ, Davies MA. Clinical characteristics and outcomes with specific BRAF and NRAS mutations in patients with metastatic melanoma. Cancer. 2013;119 (21):3821–3829. - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

[1] Akslen LA, Angelini S, Straume O, Bachmann IM, Molven A, Hemminki K, Kumar R. BRAF and NRAS mutations are frequent in nodular melanoma but are not associated with tumor cell proliferation or patient survival. J Invest Dermatol. 2005;125 (2):312–317. - PubMed

[2] Akslen LA, Angelini S, Straume O, Bachmann IM, Molven A, Hemminki K, Kumar R. BRAF and NRAS mutations are frequent in nodular melanoma but are not associated with tumor cell proliferation or patient survival. J Invest Dermatol. 2005;125 (2):312–317. - PubMed

[3] Amanuel B, Grieu F, Kular J, Millward M, Iacopetta B. Incidence of BRAF p.Val600Glu and p.Val600Lys mutations in a consecutive series of 183 metastatic melanoma patients from a high incidence region. Pathology. 2012;44 (4):357–359. - PubMed

[4] Amanuel B, Grieu F, Kular J, Millward M, Iacopetta B. Incidence of BRAF p.Val600Glu and p.Val600Lys mutations in a consecutive series of 183 metastatic melanoma patients from a high incidence region. Pathology. 2012;44 (4):357–359. - PubMed

[5] Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, Blank CU, Hauschild A, Beck JT, St-Pierre A, Niazi F, Wandel S, Peters M, Zubel A, Dummer R. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14 (3):249–256. - PubMed

[6] Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, Blank CU, Hauschild A, Beck JT, St-Pierre A, Niazi F, Wandel S, Peters M, Zubel A, Dummer R. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14 (3):249–256. - PubMed

[7] Brissy S, Gaudy-Marqueste C, Mallet S, Monestier S, Hesse S, Koeppel M-C, Rojat-Habib M-C, Nanni I, Loundou A, Lh Ouafik, Bonnet N, Richard M-A, Grob JJ. BRAF mutation as a pejorative marker in metastatic melanoma. J Clin Oncol. 2012;30 (suppl):abstr 8555.

[8] Brissy S, Gaudy-Marqueste C, Mallet S, Monestier S, Hesse S, Koeppel M-C, Rojat-Habib M-C, Nanni I, Loundou A, Lh Ouafik, Bonnet N, Richard M-A, Grob JJ. BRAF mutation as a pejorative marker in metastatic melanoma. J Clin Oncol. 2012;30 (suppl):abstr 8555.

[9] Bucheit AD, Syklawer E, Jakob JA, Bassett RL, Jr, Curry JL, Gershenwald JE, Kim KB, Hwu P, Lazar AJ, Davies MA. Clinical characteristics and outcomes with specific BRAF and NRAS mutations in patients with metastatic melanoma. Cancer. 2013;119 (21):3821–3829. - PubMed

[10] Bucheit AD, Syklawer E, Jakob JA, Bassett RL, Jr, Curry JL, Gershenwald JE, Kim KB, Hwu P, Lazar AJ, Davies MA. Clinical characteristics and outcomes with specific BRAF and NRAS mutations in patients with metastatic melanoma. Cancer. 2013;119 (21):3821–3829. - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma

Affiliations

Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma

Authors

Affiliations

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous