1217PD - Comprehensive Genomic Profiling (CGP) and Tumor Mutational Burden (TMB) Assessment in Subtypes of Metastatic Melanoma

Date 11 September 2017
Event ESMO 2017 Congress
Session Melanoma and other skin tumours
Topics Cancer in Adolescents
Melanoma and other Skin Tumours
Personalised Medicine
Presenter Jeffrey Ross
Citation Annals of Oncology (2017) 28 (suppl_5): v428-v448. 10.1093/annonc/mdx377
Authors J.S. Ross1, J.A. Carlson1, J.A. Elvin2, J. Vergilio2, J. Suh2, S. Ramkissoon2, E. Severson2, S. Daniel2, S.M. Ali2, A.B. Schrock3, D. Fabrizio2, G.M. Frampton2, V.A. Miller2, P.J. Stephens2, L.M. Gay4, D.B. Johnson5
  • 1Pathology, Albany Medical Center, 12208 - Albany/US
  • 2R & D, Foundation Medicine, 02141 - Cambridge/US
  • 3Clinical Development, Foundation Medicine, MA 02141 - Cambridge/US
  • 4Pathology, Foundation Medicine, 02141 - Cambridge/US
  • 5Medical Oncology, Vanderbilt Ingram Cancer Center, 37232 - Nashville/US

Abstract

Background

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.

Methods

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.

Results

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:

1217PD

CTDMALSPGMCHNARMOC
Samples199112222244227105
BRAF GA38%0%18%60% (Fusion)15%13%0%2%
Other driver GANF1 (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/Mb61%92%NANA3%5%14%3%
TMB ≥20 mut/Mb42%83%NANA05%0%1%

Conclusions

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.

Clinical trial identification

Legal entity responsible for the study

Jeffrey S Ross

Funding

None

Disclosure

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.