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Comparing BRAF mutation status in matched primary and metastatic cutaneous melanomas: Implications on optimized targeted therapy

Experimental and Molecular Pathology

Abstract

Background

Selective BRAF inhibitors have shown dramatic results with regard to improving outcome in patients with melanoma. Testing the BRAF status in matched primary and metastatic melanomas to optimize individual targeted therapy is not well investigated.

Methods

Extended BRAF testing using PCR for 9 mutations and VE1 immunohistochemistry for BRAF V600E detection on 95 lesions including 40 primary melanomas with their matched metastases (n = 42), recurrences (n = 9) and second primaries (n = 4) was performed. Nine patients had multiple metastases.

Results

V600E was the only identified mutation type; 35.4% of primary vs. 18.9% of metastatic melanomas. The overall primary-metastatic BRAF status discordance rate was 32.3% using PCR and 27.5% with immunohistochemistry, and was significantly more frequent in primary lesions with mutant BRAF (67%). Males and patients with metastasis to lymph nodes were less likely to be discordant compared to females and those with metastasis to other sites (p = 0.023). Discordant BRAF mutation status was predicted by multivariate binary logistic regression: the presence of a mutant BRAF in the primary melanoma [OR (95% C.I.) = 23.4 (2.4–229.7)] and female gender [OR = 10.6 (1.08–95)]. Inter-metastases BRAF concordance was 100% (6 comparisons).

Conclusion

A high discordant rate implies the need for clinical trials addressing the response to targeted therapy in patients with discordant BRAF statuses between their primary and metastatic lesions.

Highlights

 

  • The primary-metastatic BRAF discordance rate was 27.5% (IHC)–32.3% (PCR).
  • Discordance was significantly more frequent in primary lesions with mutant BRAF (67%).
  • High inter-metastases concordance was observed.

Keywords: BRAF, Matched primary and metastatic melanomas, Targeted therapy.

Footnotes

a American University of Beirut Medical Center, Beirut, Lebanon

b Weill-Cornell Medical Center, New York, NY, United States

c Shaukat Khanum Memorial Cancer Center and Research Hospital, Lahore, Pakistan

d King Fahad Specialist Hospital, Dammam, Saudi Arabia

e Dhahran Health Center, SAMSO, Dhahran, Saudi Arabia

f King Abdul-Aziz Medical City, Jeddah, Saudi Arabia

g ViennaLab Diagnostics GmbH, Vienna, Austria

lowast Corresponding author at: American University of Beirut Medical Center, Department of Pathology & Laboratory Medicine, Cairo Street, Hamra, Beirut 1107 2020, Lebanon.