Metastatic melanoma (MM) is widely treated with both kinase inhibitors and immunotherapies, providing meaningful survival benefit. Contrasting CGP and TMB results across MM subtypes provides a blueprint for rational decision making in light of increasing effective therapeutic options.
CGP for 2,225 MM evaluated up to 315 genes plus introns of 28 genes commonly rearranged in cancer using hybrid-capture, adaptor ligation-based libraries (mean coverage >620X). TMB was calculated from ∼1.1 Mb of sequenced DNA. Base substitutions, insertions and deletions (short variants; SV); rearrangements; and copy number changes were assessed.
We evaluated 9 MM subtypes: routine cutaneous (CT), desmoplastic (DM), acral lentiginous (AL), Spitzoid (SP), gynecologic mucosal (GMC), head and neck mucosal (HN), anorectal (ARM) and ocular (OC). Each group harbored characteristic genomic alterations (GA) (Table). BRAF was mutated in 38% of CT (92% SV; 8% amplifications, fusions or cases with >1 BRAF GA). Patients with TMB ≥20 mut/Mb were common in CT and DM, but 5% or less in all other subtypes. The frequency of BRAF GA was lower in AL, GMC, HN, ARM and OC. SP commonly harbored fusions in BRAF (60%) and other kinases. KIT GA were prominent in GMC and AL. Key findings include novel drivers of BRAF inhibitor resistance including BRAF rearrangements, kinase duplications and MEK GA.Table:
|BRAF GA||38%||0%||18%||60% (Fusion)||15%||13%||0%||2%|
|Other driver GA||NF1 (21%) PTEN (12%) KIT (5%)||TP53 (75%) NF1 (50%)||NF1 (18%) PTEN (18%) KIT (18%)||Fusions in: ROS1 (3%) RET (3%) NTRK1 (1%) ALK (1%)||NF1 (32%) KIT (25%) PTEN (13%)||NF1 (18%) PTEN (9%) EGFR (5%) NTRK1 (5%)||NF1 (43%) NTRK1 (14%) BRCA2 (14%)||NF1 (2%) (BAP1, GNAQ, GNA11 or MYC found in 100%)|
|TMB ≥10 mut/Mb||61%||92%||NA||NA||3%||5%||14%||3%|
|TMB ≥20 mut/Mb||42%||83%||NA||NA||0||5%||0%||1%|
In the largest cohort of MM with CGP to date, genomic profiles and TMB differ across MM subtypes. Highly prevalent BRAF GA in CT and high TMB in CT and DM permit effective use of targeted and immunotherapies, although novel BRAF inhibitor resistance mechanisms were observed. In addition, a variety of non-BRAF kinase targets are apparent in some MM subtypes.
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Legal entity responsible for the study
Jeffrey S Ross
J.S. Ross: Employee, leader and owns stock in Foundation Medicine J.A. Elvin: Employee and owns stock in Foundation Medicine J-A. Vergilio, J. Suh, S. Ramkissoon, E. Severson, S. Daniel, S.M. Ali, A.B. Schrock, D. Fabrizio, G.M. Frampton, L.M. Gay: Employee and owns stock in Foundation medicine V.A. Miller, P.J. Stephens: Employee, leader and owns stock in Foundation medicine All other authors have declared no conflicts of interest.