Molecular alterations in clinical stage III cutaneous melanoma: Correlation with clinicopathological features and patient outcome

Piotr Rutkowski, Aleksandra Gos, Monika Jurkowska, Tomasz Switaj, Wirginiusz Dziewirski, Marcin Zdzienicki, Konrad Ptaszyński, Wanda Michej, Andrzej Tysarowski, Janusz A Siedlecki, Piotr Rutkowski, Aleksandra Gos, Monika Jurkowska, Tomasz Switaj, Wirginiusz Dziewirski, Marcin Zdzienicki, Konrad Ptaszyński, Wanda Michej, Andrzej Tysarowski, Janusz A Siedlecki

Abstract

The aim of the present study was to evaluate the frequency and type of oncogenic v-raf murine sarcoma viral oncogene homolog B1 (BRAF)/neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutations in cutaneous melanoma with clinically detected nodal metastases (stage IIIB and C) in relation to clinicopathological features and outcome. The clinicopathological data of 250 patients following therapeutic lymphadenectomy (LND) between 1995 and 2010, as well as BRAF/NRAS mutational status in corresponding nodal metastases, were analyzed. The median follow-up time was 53 months. BRAF mutations were detected in 154 (62%) cases (141 p.V600E, nine p.V600K and four others) and mutually exclusive NRAS mutations were detected in 42 (17%) cases. The presence of a BRAF mutation was found to correlate with patients of a younger age. The five-year overall survival (OS) rate was 33 and 43% for LND and primary tumor excision, respectively, and the five-year disease-free survival (DFS) rate for LND was 25%. No correlation was identified between BRAF/NRAS mutational status and RFS or OS (calculated from the date of the LND and primary tumor excision); for BRAF- and NRAS-mutated melanoma, the prognosis was the same for patients with wild-type (WT) melanoma. The important factors which had a negative impact on OS and DFS were as follows: Male gender, >1 metastatic lymph node and extracapsular extension of nodal metastases. The interval between the diagnosis of the initial melanoma to regional nodal metastasis (median, 10 months) was not significantly different between BRAF-mutant and -WT patients. Our largest comprehensive molecular analysis of clinical stage III melanoma revealed that BRAF and NRAS mutational status is not a prognostic marker in stage III melanoma patients with macroscopic nodal involvement, but may have implications for potential adjuvant therapy.

Keywords: lymph node; melanoma; metastases; molecular factors; neuroblastoma RAS viral (v-ras) oncogene homolog; v-raf murine sarcoma viral oncogene homolog B1.

Figures

Figure 1
Figure 1
Overall survival according to BRAF mutational status in clinical stage III melanoma calculated from (A) the date of the primary tumor excision (BRAF-mutants vs. wild-type) and (B) the date of lymph node dissection (BRAF p.V600E mutants vs. BRAF mutants, with the exception of p.V600E vs. wild-type). BRAF, v-raf murine sarcoma viral oncogene homolog B1.
Figure 2
Figure 2
Overall survival according to NRAS mutational status in clinical stage III melanoma calculated from (A) the date of the primary tumor excision and (B) the date of lymph node dissection. NRAS, neuroblastoma RAS viral (v-ras) oncogene homolog.
Figure 3
Figure 3
Disease-free survival according to BRAF and NRAS mutational status calculated from the date of the lymph node dissection. BRAF, v-raf murine sarcoma viral oncogene homolog B1; NRAS, neuroblastoma RAS viral (v-ras) oncogene homolog.

References

    1. Leiter U, Meier F, Schittek B, Garbe C. The natural course of cutaneous melanoma. J Surg Oncol. 2004;86:172–178.
    1. Balch CM, Gershenwald JE, Soong SJ, et al. Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol. 2010;28:2452–2459.
    1. Balch CM, Gershenwald JE, Soong SJ, et al. Final Version of 2009 AJCC Melanoma Staging and Classification. J Clin Oncol. 2009;27:6199–6206.
    1. Hocker TL, Singh MK, Tsao H. Melanoma genetics and therapeutic approaches in the 21st century: moving from the benchside to the bedside. J Invest Dermatol. 2008;128:2575–2595.
    1. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–954.
    1. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135–2147.
    1. Garrido MC, Bastian BC. KIT as a therapeutic target in melanoma. J Invest Dermatol. 2010;130:20–27.
    1. Kumar R, Angelini S, Snellman E, Hemminki K. BRAF mutations are common somatic events in melanocytic nevi. J Invest Dermatol. 2004;122:342–348.
    1. Gorden A, Osman I, Gai W, et al. Analysis of BRAF and N-RAS mutations in metastatic melanoma tissues. Cancer Res. 2003;63:3955–3957.
    1. Satyamoorthy K, Li G, Gerrero MR. Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res. 2003;63:756–759.
    1. Gray-Schopfer VC, da Rocha Dias S, Marais R. The role of B-RAF in melanoma. Cancer Metastasis Rev. 2005;24:165–183.
    1. Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29:1239–1246.
    1. Rubinstein JC, Sznol M, Pavlick AC, et al. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med. 2010;8:67.
    1. Michaloglou C, Vredeveld LC, Soengas MS, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005;436:720–724.
    1. Pollock PM, Harper UL, Hansen KS, et al. High frequency of BRAF mutations in nevi. Nat Genet. 2003;33:19–20.
    1. Edlundh-Rose E, Egyházi S, Omholt K, Mansson-Brahme E, Platz A, Hansson J, Lundeberg J. NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. Melanoma Res. 2005;16:471–478.
    1. Goel VK, Lazar AJ, Warneke CL, Redston MS, Haluska FG. Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J Invest Dermatol. 2006;126:154–160.
    1. Poynter JN, Elder JT, Fullen DR, et al. BRAF and NRAS mutations in melanoma and melanocytic nevi. Melanoma Res. 2006;16:267–273.
    1. Omholt K, Platz A, Kanter L, Ringborg U, Hansson J. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res. 2003;9:6483–6488.
    1. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–2516.
    1. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–365.
    1. Jakob JA, Bassett RL, Jr, Ng CS, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2012;118:4014–4023.
    1. Karakousis CP. Therapeutic node dissections in malignant melanoma. Semin Surg Oncol. 1998;14:291–301.
    1. Eggermont AMM, Suciu S, MacKie R, et al. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomized controlled trial. Lancet. 2005;366:1189–1196.
    1. Nowecki ZI, Rutkowski P, Michej W. The survival benefit to patients with positive sentinel node melanoma after completion lymph node dissection may be limited to the subgroup with a primary lesion Breslow thickness greater than 1.0 and less than or equal to 4 mm (pT2-pT3) Ann Surg Oncol. 2008;5:2223–2234.
    1. Berd D, Mastrangelo MJ, Sato T. Calculation of survival of patients with stage III melanoma. J Clin Oncol. 2005;23:9427.
    1. Gos A, Jurkowska M, Siedlecki JA, Michej W, Wiater K, Switaj T, Kosela H, Rutkowski P. Comparison between two widely used laboratory methods in BRAF V600 mutation detection rate in FFPE clinical samples of stage III cutaneous melanoma metastases to the lymph nodes. 17th ECCO-38thESMO-32ndESTRO European Cancer Congress; 2013. Abstract P465.
    1. Lee JH, Choi JW, Kim YS. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol. 2011;164:776–784.
    1. Colombino M, Capone M, Lissia A, et al. BRAF/NRAS Mutation Frequencies Among Primary Tumors and Metastases in Patients With Melanoma. J Clin Oncol. 2012;30:2522–2529.
    1. Pont-Kingdon G, Gedge F, Wooderchak-Donahue W, et al. Design and analytical validation of clinical DNA sequencing assays. Arch Pathol Lab Med. 2012;136:41–46.
    1. Liu W, Kelly JW, Trivett M, et al. Distinct clinical and pathological features are associated with the BRAF(T1799A(V600E)) mutation in primary melanoma. J Invest Dermatol. 2007;127:900–905.
    1. Viros A, Fridlyand J, Bauer J, Lasithiotakis K, Garbe C, Pinkel D, Bastian BC. Improving melanoma classification by integrating genetic and morphologic features. PLoS Med. 2008;5:e120.
    1. Ellerhorst JA, Greene VR, Ekmekcioglu S, et al. Clinical Correlates of NRAS and BRAF Mutations in Primary Human Melanoma. Clin Cancer Res. 2011;17:229–235.
    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;125:312–317.
    1. Houben R, Becker JC, Kappel A, et al. Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. J Carcinog. 2004;3:6.
    1. Moreau S, Saiag P, Aegerter P, et al. Prognostic Value of BRAFV600 Mutations in Melanoma Patients After Resection of Metastatic Lymph Nodes. Ann Surg Oncol. 2012;19:4314–4321.
    1. Rutkowski P, Nowecki ZI, Zdzienicki M, et al. Cutaneous melanoma with nodal metastases in elderly people. Int J Dermatol. 2010;49:907–913.
    1. Kretschmer L, Starz H, Thoms KM, et al. Age as a key factor influencing metastasizing patterns and disease-specific survival after sentinel lymph node biopsy for cutaneous melanoma. Int J Cancer. 2011;129:1435–1442.
    1. Macdonald JB, Dueck AC, Gray RJ, Wasif N, Swanson DL, Sekulic A, Pockaj BA. Malignant Melanoma in the Elderly: Different Regional Disease and Poorer Prognosis. J Cancer. 2011;2:538–543.
    1. Menzies AM, Haydu LE, Visintin L, et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res. 2012;18:3242–3249.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться