TY - JOUR
T1 - Distinct molecular profiles and immunotherapy treatment outcomes of V600E and V600K BRAF-mutant melanoma
AU - da Silva, Inês Pires
AU - Wang, Kevin Y.X.
AU - Wilmott, James S.
AU - Holst, Jeff
AU - Carlino, Matteo S.
AU - Park, John J.
AU - Quek, Camelia
AU - Wongchenko, Matthew
AU - Yan, Yibing
AU - Mann, Graham
AU - Johnson, Douglas B.
AU - McQuade, Jennifer L.
AU - Rai, Rajat
AU - Kefford, Richard F.
AU - Rizos, Helen
AU - Scolyer, Richard A.
AU - Yang, Jean Y.H.
AU - Long, Georgina V.
AU - Menzies, Alexander M.
N1 - Funding Information:
J. Holst is an employee of and reports receiving other commercial research support from MetabloQ Pharmaceuticals. M.S. Carlino is a consultant/advisory board member for Bristol-Myers Squibb, MSD, Novartis, Amgen, and Pierre-Fabre. M. Wongchenko holds ownership interest (including patents) in Roche and Ariad Pharmaceuticals. Y. Yan holds ownership interest (including patents) in Genentech. D.B. Johnson reports receiving commercial research grants from Bristol-MyersSquibband Incyte, andis aconsultant/advisoryboardmember for Array, Bristol-Myers Squibb, Genoptix, Incyte, and Merck. R.F. Kefford is a consultant/advisory board member for Amgen and reports receiving other remuneration in the form of conference expenses from Bristol-Myers Squibb and Amgen. R.A. Scolyer is a consultant/advisory board member for Merck Sharp & Dohme and Novartis. G.V. Long is a consultant/advisory board member for Bristol-Myers Squibb, Novartis, Roche, Amgen, Pierre-Fabre, Array, and Merck. A.M. Menzies is a consultant/advisory board member for Bristol-
Funding Information:
The authors are thankful for the assistance of Jess Hyman, Hazel Burke, Alex Guminski, and Raghwa Sharma. J.S. Wilmott is supported by an NHMRC Research Fellowship. J.L. McQuade is supported by an ASCO/CCF Career Development Award, a Melanoma SPORE Developmental Research Program Award, and an NIH T32 Training Grant CA009666. R.A. Scolyer is supported by an NHMRC Practitioner Fellowship. J.Y.H. Yang is supported by NHMRC CDF and ARC Discovery Project grant (DP170100654). G.V. Long is supported by an NHMRC Practitioner Fellowship and the University of Sydney Medical Foundation. A.M. Menzies is supported by a Cancer Institute NSW Fellowship. This work was supported by a Pfizer Australia grant (WS2345795 to A.M. Menzies), and a Cancer Council NSW grant (RG17-04 to J. Holst, J.S. Wilmott, and A.M. Menzies). This research was also supported by an Australian National Health and Medical Research Council program grant. Assistance from other colleagues at Melanoma Institute Australia and the Royal Prince Alfred Hospital is also gratefully acknowledged.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/2/15
Y1 - 2019/2/15
N2 - Purpose: BRAF V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to BRAFiMEKi. We investigated mechanisms for this and explored whether genotype affects response to immunotherapy. Experimental Design: Pretreatment formalin-fixed paraffin-embedded tumors from patients treated with BRAFiMEKi underwent gene expression profiling and DNA sequencing. Molecular results were validated using The Cancer Genome Atlas (TCGA) data. An independent cohort of V600E/K patients treated with anti–PD-1 immunotherapy was examined. Results: Baseline tissue and clinical outcome with BRAFiMEKi were studied in 93 patients (78 V600E, 15 V600K). V600K patients had numerically less tumor regression (median, 31% vs. 52%, P ¼ 0.154) and shorter progression-free survival (PFS; median, 5.7 vs. 7.1 months, P ¼ 0.15) compared with V600E. V600K melanomas had lower expression of the ERK pathway feedback regulator dual-specificity phosphatase 6, confirmed with TCGA data (116 V600E, 17 V600K). Pathway analysis showed V600K had lower expression of ERK and higher expression of PI3K-AKT genes than V600E. Higher mutational load was observed in V600K, with a higher proportion of mutations in PIK3R1 and tumor-suppressor genes. In patients treated with anti–PD-1, V600K (n ¼ 19) had superior outcomes than V600E (n ¼ 84), including response rate (53% vs. 29%, P ¼ 0.059), PFS (median, 19 vs. 2.7 months, P ¼ 0.049), and overall survival (20.4 vs. 11.7 months, P ¼ 0.081). Conclusions: BRAF V600K melanomas appear to benefit less from BRAFiMEKi than V600E, potentially due to less reliance on ERK pathway activation and greater use of alternative pathways. In contrast, these melanomas have higher mutational load and respond better to immunotherapy.
AB - Purpose: BRAF V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to BRAFiMEKi. We investigated mechanisms for this and explored whether genotype affects response to immunotherapy. Experimental Design: Pretreatment formalin-fixed paraffin-embedded tumors from patients treated with BRAFiMEKi underwent gene expression profiling and DNA sequencing. Molecular results were validated using The Cancer Genome Atlas (TCGA) data. An independent cohort of V600E/K patients treated with anti–PD-1 immunotherapy was examined. Results: Baseline tissue and clinical outcome with BRAFiMEKi were studied in 93 patients (78 V600E, 15 V600K). V600K patients had numerically less tumor regression (median, 31% vs. 52%, P ¼ 0.154) and shorter progression-free survival (PFS; median, 5.7 vs. 7.1 months, P ¼ 0.15) compared with V600E. V600K melanomas had lower expression of the ERK pathway feedback regulator dual-specificity phosphatase 6, confirmed with TCGA data (116 V600E, 17 V600K). Pathway analysis showed V600K had lower expression of ERK and higher expression of PI3K-AKT genes than V600E. Higher mutational load was observed in V600K, with a higher proportion of mutations in PIK3R1 and tumor-suppressor genes. In patients treated with anti–PD-1, V600K (n ¼ 19) had superior outcomes than V600E (n ¼ 84), including response rate (53% vs. 29%, P ¼ 0.059), PFS (median, 19 vs. 2.7 months, P ¼ 0.049), and overall survival (20.4 vs. 11.7 months, P ¼ 0.081). Conclusions: BRAF V600K melanomas appear to benefit less from BRAFiMEKi than V600E, potentially due to less reliance on ERK pathway activation and greater use of alternative pathways. In contrast, these melanomas have higher mutational load and respond better to immunotherapy.
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U2 - 10.1158/1078-0432.CCR-18-1680
DO - 10.1158/1078-0432.CCR-18-1680
M3 - Article
C2 - 30630828
AN - SCOPUS:85061577843
SN - 1078-0432
VL - 25
SP - 1272
EP - 1279
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -