Abstract 573P
Background
The recent development and approvals of anti-RET targeted therapies in TC and NSCLC has spurred interest in studying the landscape of RET genomic alterations (GA) in all-types of TC.
Methods
We performed hybrid capture-based comprehensive genomic profiling (CGP) on 1,377 clinically advanced/metastatic TC to detect genomic alterations (GA) including short variant (SV) mutations, copy number changes (CN) and rearrangements/fusions (FUS). Analyses included quantifying tumor mutational burden (TMB) and evaluating PD-L1 expression (Dako 22C3) with low expression defined as 1-49% and high expression as ≥50% tumor cell staining.
Results
231 (17%) of all TC featured RET GA with 163/163 (100%) of medullary TC (MTC) (71% of RET+ TC) and 68/1,146 (6%) of non-MTC including 71 papillary TC (PTC), 3 follicular TC (FTC), 4 poorly differentiated TC (PDTC) and 5 anaplastic TC (ATC). In the 68 cases of TC with RET FUS+, 56 (81%) were PTC; the remaining cases included 3 FTC, 4 PDTC, 5 ATC and 1 MTC. In contrast, 161/163 (99%) of non-FUS RET GA were in MTC (99% SV, 1% CN). 6/163 (4%) MTC had germline RET SV mutations. There were no germline RET GA in non-MTC samples. RET FUS+ patients were more often female (P=.001) and younger (P<.0001) than the RET SV+ patients. BRAF co-mutations were not identified in RET GA+ TC. CDKN2A/B (P=.04) and MTAP deletions were more common in RET FUS+ TC as were TERT GA (P<.0001). TMB was low and no cases were MSI-H. RET FUS+ non-MTC and RET SV+ MTC had similar rates of low-level PD-L1 expression, but the RET SV+ non-MTC cases had a significantly higher PD-L1 High expression frequency (P<.0001). Table: 573P
| All RET FUS + | All RET SV+ | P value | |
| Number of cases | 68 | 163 | |
| Females/Males | 62%/38% | 37%/73% | .001 |
| Mean Age (range) | 42 (9-81) | 55 (8-89) | <.0001 |
| GA/tumor | 2.3 | 1.8 | NS |
| BRAF | 0% | <1% | NS |
| CDKN2A | 15% | 6% | .04 |
| CDKN2B | 10% | 3% | .04 |
| MTAP | 7% | 3% | NS |
| RBM10 | 1% | 6% | .03 |
| VHL | 0% | 3% | NS |
| TERT | 30% | 1% | .0001 |
| MSI High | 0% | 0% | NS |
| Median TMB | 1.0 | 1.3 | NS |
| TMB > 10/mut/Mb | 0% | 0% | NS |
| PD-L1 IHC Low | 35% | 33% | NS |
| PD-L1 IHC High | 26% | 2% | <.0001 |
Conclusions
RET FUS is almost exclusively found in non-MTC and associated with younger patient age and female gender. RET altered TC do not feature BRAF co-mutations, but RET FUS+ feature more GA in CDKN2A/B and TERT than RET SV+ and more often had high PD-L1 expression. Further study of GA in RET driven TC to design potential therapy combinations for patients who become refractory to anti-RET therapies appears warranted.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Foundation Medicine Inc.
Disclosure
N.A. Danziger: Financial Interests, Personal, Full or part-time Employment, null: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares, null: F. Hoffman La-Roche LTd. D. Pavlick: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. J.S. Ross: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. All other authors have declared no conflicts of interest.