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Poster session 01

72P - Pan-tumor survey of RET fusions as detected by next-generation RNA sequencing identified RET+ colorectal carcinoma as a unique molecular subset of CRC

Date

10 Sep 2022

Session

Poster session 01

Topics

Pathology/Molecular Biology;  Targeted Therapy

Tumour Site

Thyroid Cancer;  Colon and Rectal Cancer;  Thoracic Malignancies

Presenters

Misako Nagasaka

Citation

Annals of Oncology (2022) 33 (suppl_7): S27-S54. 10.1016/annonc/annonc1037

Authors

M. Nagasaka1, D. Brazel2, Y. Baca3, J. Xiu4, M.N. Al-Hallak5, C. Kim6, J.J. nieva7, J.J. Swensen3, D. Spetzler3, W..M. Korn8, M.A. Socinski9, B. Halmos10, S.I. Ou11

Author affiliations

  • 1 Medicine, UCI Health - University of California Irvine, 92868 - Orange/US
  • 2 Medicine, UC Irvine Medical Center, CA 92868 - Orange/US
  • 3 Clinical And Translational, Caris Life Sciences, 85040 - Phoenix/US
  • 4 Clinical And Translational, Caris Life Sciences, 85054 - Phoenix/US
  • 5 Oncology, Karmanos Cancer Institute, 48201 - Detroit/US
  • 6 Oncology, Georgetown Lombardi Comprehensive Cancer Center, 20057 - Washington DC/US
  • 7 Oncology, USC - University of Southern California - Norris Comprehensive Cancer Center, 90033 - Los Angeles/US
  • 8 Medicine Department, UCSF-Diller Cancer Research Building, Mount Zion, 94115 - San Francisco/US
  • 9 Oncology, Florida Hospital Cancer Institute, 32803 - Orlando/US
  • 10 Oncology, Montefiore Medical Center, New York City/US
  • 11 Medicine Department, UCI Health Chao Family Comprehensive Cancer Center, 92868 - Orange/US
More

Abstract 72P

Background

Two selective RET tyrosine kinase inhibitors have been approved to treat RET fusion-positive (RET+) non-small cell lung cancer and well-differentiated thyroid cancer. However, RET fusions have been reported in other solid tumors.

Methods

To identify the full spectrum of RET+ solid tumors and their molecular characteristics, a retrospective analysis was executed on RET+ solid malignancies identified by targeted RNA sequencing and whole transcriptome sequencing of clinical tumor samples performed at Caris Life Science (Phoenix, AZ).

Results

A total of 378 RET+ solid malignancies were identified in 15 different tumor types and carcinoma of unknown primary (CUP) that underwent next-generation RNA sequencing. RET+ NSCLC and RET+ thyroid cancer constituted 66.9% and 11.1% of the RET+ solid malignancies respectively. RET+ colorectal adenocarcinoma and RET+ breast adenocarcinoma constituted 10.1% and 2.6% respectively. KIF5B (46.8%) is the most common fusion partner followed by CCDC6 (28.3%) and NCOA4 (13.8%) in RET+ solid tumors. KIF5B-RET is the dominant fusion variant in RET+ NSCLC, NCOA4-RET is the dominant variant in RET+ colorectal carcinoma, and CCDC6-RET is the dominant variant in thyroid cancer. Baseline characteristics of RET+ tumors by type is shown in the table. The mean junctional read per tumor sample was 45.2% +/- 42.6 standard deviation (SD) in NSCLC which was relatively similar to CUP which had 48.8% +/- 52.1 SD. The mean tumor mutation burden for all RET+ tumors is 5.48 +/- 6.51 (SD). The most common single gene alterations in RET+ tumors were TP53 (34.8%), ARID1A (10.8%) and RNF43 (6.7%). RET+ CRC had a median TMB of 20 Mt/Mb with MSI-H seen in 63%. There was no correlation between RET fusion partners and MSI status. Table: 72P

NSCLC Thyroid Colorectal Breast CUP Pancreatic
N 253 42 38 10 10 8
Age
Median (range) 66 (27-89) 81.0 (9-84) 72.5 (34-88) 59.5 (35-75) 71.5 (41-87) 68.5 (55-81)
Mean (SD) 64.7 (12.02) 51.1 (21.1) 67.9 (12.7) 58.8 (15.7) 68.8 (13.9) 67.3 (9.0)
Sex
Male 113 14 15 0 6 5
Female 140 28 23 10 4 3
Fusion partner
KIF5B- 173 1 0 0 0 0
CCDC6- 56 26 8 3 3 2
NCOA4- 5 10 24 4 2 2
ERC1- 3 0 0 0 0 1
KIF13A- 5 0 0 0 0 0
GPHN- 0 0 2 0 0 0
Sequencing methods
Targeted RNA (Archer) 44 3 2 3 2 0
WTS 209 39 36 7 8 8
Mean junction read (SD) 45.2 (42.6) 18.7 (35.9) 22.7 (26.8) 16.7 (10.8) 48.8 (52.1) 38.4 (80.9)
PD-L1 (22C3)
<1% 70 NA NA 2 NA NA
1-49% 71 NA NA 2 NA NA
>= 50% 92 1 NA 0 NA NA
TMB
0-5 174 39 9 6 7 6
>5-10 55 0 4 4 2 2
>10 4 1 22 0 1 0
Microsatellite
Stable 244 41 14 10 9 8
Unstable 1 0 24 0 1 0

Conclusions

Outside of approved indications of NSCLC and thyroid cancers, RET fusions were identified in multiple tumor types such as colorectal, breast, cancer of unknown primary and pancreatic cancer.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M. Nagasaka: Financial Interests, Personal, Advisory Board: AstraZeneca, Caris Life Sciences, Daiichi Sankyo, Novartis, EMD Serono, Janssen, Pfizer, Genentech, Mirati, Regeneron, Silverback; Financial Interests, Personal, Speaker’s Bureau: Takeda, Blueprint Medicines; Financial Interests, Personal, Expert Testimony: Lilly; Financial Interests, Personal, Other, Travel: AnHeart. Y. Baca: Financial Interests, Personal, Stocks/Shares: Caris Life Sciences. J. Xiu: Financial Interests, Personal, Stocks/Shares: Caris Life Sciences. M.N. Al-Hallak: Financial Interests, Personal, Speaker’s Bureau: Ipsen. C. Kim: Financial Interests, Personal, Advisory Board: Novartis, Janssen, AstraZeneca, Sanofi, PierianDx, Diffuse Pharmaceuticals, Mirati; Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb, Novartis, Genentech, Regeneron, Debiopharm, Karyopharm. J.J. Nieva: Financial Interests, Personal and Institutional, Research Grant: Merck, Genentech; Financial Interests, Personal, Advisory Board: Mindmed, AstraZeneca, Naveris, G1 Therapeutics, Aadi Biosciences; Financial Interests, Personal, Ownership Interest: Epic Sciences, Quantgene, Indee Bio. J.J. Swensen: Financial Interests, Personal, Stocks/Shares: Caris Life Sciences. D. Spetzler: Financial Interests, Personal, Stocks/Shares: Caris Life Sciences. W.M. Korn: Financial Interests, Personal, Stocks/Shares: Caris Life Sciences. M.A. Socinski: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Bayer, Roche, Celgene, Bristol Myers Squibb, Takeda, Genentech, Novartis, Lilly; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca, Roche, Takeda. B. Halmos: Financial Interests, Personal and Institutional, Research Grant: Boehringer Ingelheim, AstraZeneca, Merck, Bristol Myers Squibb, Advaxis, Amgen, AbbVie, Daiichi Sankyo, Pfizer, GSK, Beigene, Janssen; Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Veracyte, Janssen, Takeda, Merck, Bristol Myers Squibb, Genentech, Pfizer, Eli Lilly. S.I. Ou: Financial Interests, Personal, Invited Speaker: Pfizer, Roche; Financial Interests, Personal, Advisory Board: JNJ/Janssen, Elevation Oncology; Financial Interests, Personal, Stocks/Shares: Turning Point Therapeutics, Elevation Oncology; Financial Interests, Institutional, Invited Speaker: Pfizer, Mirati, JNJ/Janssen, Merus. All other authors have declared no conflicts of interest.

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