IMPORTANCE: NRAS and BRAF mutations in melanoma inform current treatment paradigms but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. OBJECTIVE: To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. DESIGN SETTING AND PARTICIPANTS: A population-based study with median follow-up of 7.6 years for 912 patients with first primary cutaneous melanoma analyzed for NRAS and BRAF mutations diagnosed in the year 2000 from the United States and Australia in the Genes, Environment and Melanoma Study and followed through 2007. MAIN OUTCOMES AND MEASURES: Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. RESULTS: The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype). In a multivariable model including clinicopathologic characteristics, NRAS+ melanoma was associated (P<.05) with mitoses, lower tumor infiltrating lymphocyte (TIL) grade, and anatomic site other than scalp/neck and BRAF+ melanoma was associated with younger age, superficial spreading subtype, and mitoses, relative to wildtype melanoma. There was no significant difference in melanoma-specific survival for melanoma harboring mutations in NRAS (HR 1.7, 95% CI, 0.8-3.4) or BRAF (HR, 1.5, 95% CI, 0.8-2.9) compared to wildtype melanoma adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher risk (T2b or higher stage) tumors with NRAS (HR 2.9; 95% CI 1.1-7.7) or BRAF (HR 3.1; 95% CI 1.2-8.5) mutations but not for lower risk (T2a or lower) tumors (P=.65) adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. CONCLUSIONS AND RELEVANCE: Lower TIL grade for NRAS+ melanoma suggests it has a more immunosuppressed microenvironment, which may impact its response to immunotherapies. Further, the approximately three-fold increased death rate for higher risk tumors harboring NRAS or BRAF mutations compared to wildtype melanomas after adjusting for other prognostic factors indicates that the prognostic implication of NRAS and BRAF mutations deserves further investigation, particularly in higher AJCC stage primary melanomas.
AD - Departments of Dermatology (Dr. Thomas and Ms. Hao), Epidemiology (Dr. Conway), Pathology and Laboratory Medicine (Dr. Groben), and Surgery (Dr. Ollila, Ms. Frank, Ms. Bramson), Lineberger Comprehensive Cancer Center (Drs. Thomas, Ollila, and Conway and Ms. Edmiston, Ms. Alexander, and Ms. Parrish), University of North Carolina, Chapel Hill, North Carolina; Sydney School of Public Health (Drs. Armstrong, Kricker, and Cust), The University of Sydney, Sydney, New South Wales, Australia; Women's College Hospital (Dr. From), Toronto, Ontario, Canada; Departments of Pathology (Dr. Busam) and Epidemiology and Biostatistics (Drs. Orlow and Begg and Ms. Reiner), Memorial Sloan Kettering Cancer Center, New York, New York; University of California (Dr. Anton-Culver), Irvine, California; USC Norris Comprehensive Cancer Center (Dr. Gruber), University of Southern California, Los Angeles, California; Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL (Dr. Kanetsky); Cancer Care Ontario, Toronto, Ontario, Canada (Dr. Marrett); British Columbia Cancer Agency, Vancouver, British Columbia, Canada(Dr. Gallagher); Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy (Drs. Rosso and Zanetti); The George Institute for Global Health, Oxford Martin School, & Nuffield Department of Population Health, Oxford University, United Kingdom (Dr. Dwyer); Department of Medicine, Division of Epidemiology (Ms. Paine and Drs. Luo and Berwick) University of New Mexico, Albuquerque, New Mexico. AN - 26146664 BT - JAMA Oncology C2 - PMC4486299 C6 - Nihms667643 DP - NLM ET - 2015/07/07 LA - Eng LB - UK M1 - 3 N1 - Thomas, Nancy EIMPORTANCE: NRAS and BRAF mutations in melanoma inform current treatment paradigms but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. OBJECTIVE: To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. DESIGN SETTING AND PARTICIPANTS: A population-based study with median follow-up of 7.6 years for 912 patients with first primary cutaneous melanoma analyzed for NRAS and BRAF mutations diagnosed in the year 2000 from the United States and Australia in the Genes, Environment and Melanoma Study and followed through 2007. MAIN OUTCOMES AND MEASURES: Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. RESULTS: The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype). In a multivariable model including clinicopathologic characteristics, NRAS+ melanoma was associated (P<.05) with mitoses, lower tumor infiltrating lymphocyte (TIL) grade, and anatomic site other than scalp/neck and BRAF+ melanoma was associated with younger age, superficial spreading subtype, and mitoses, relative to wildtype melanoma. There was no significant difference in melanoma-specific survival for melanoma harboring mutations in NRAS (HR 1.7, 95% CI, 0.8-3.4) or BRAF (HR, 1.5, 95% CI, 0.8-2.9) compared to wildtype melanoma adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher risk (T2b or higher stage) tumors with NRAS (HR 2.9; 95% CI 1.1-7.7) or BRAF (HR 3.1; 95% CI 1.2-8.5) mutations but not for lower risk (T2a or lower) tumors (P=.65) adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. CONCLUSIONS AND RELEVANCE: Lower TIL grade for NRAS+ melanoma suggests it has a more immunosuppressed microenvironment, which may impact its response to immunotherapies. Further, the approximately three-fold increased death rate for higher risk tumors harboring NRAS or BRAF mutations compared to wildtype melanomas after adjusting for other prognostic factors indicates that the prognostic implication of NRAS and BRAF mutations deserves further investigation, particularly in higher AJCC stage primary melanomas.
PY - 2015 SN - 2374-2437 (Print) SP - 359 EP - 368 T2 - JAMA Oncology TI - Association Between and Mutational Status and Melanoma-Specific Survival Among Patients With Higher Risk Primary Melanoma VL - 1 ER -