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ePoster Display

694P - Methylthioadenosine phosphorylase (MTAP) deletion is more common in sarcomatoid (srcRCC) than in clear cell renal cell carcinoma (ccRCC)

Date

16 Sep 2021

Session

ePoster Display

Presenters

Andrea Necchi

Citation

Annals of Oncology (2021) 32 (suppl_5): S678-S724. 10.1016/annonc/annonc675

Authors

A. Necchi1, P. Grivas2, P.E. Spiess3, J. Jacob4, E. Sokol5, S. Ramkissoon6, E. Severson6, R.S.P. Huang6, D.I. Lin6, D.A. Mata6, B. Decker7, K. Mcgregor8, N.A. Danziger6, J.S. Ross9, G. Bratslavsky9

Author affiliations

  • 1 Medical Oncology, Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS, 20133 - Milan/IT
  • 2 Medicine/oncology Department, University of Washington Seattle Cancer Care Alliance, 98109-4405 - Seattle/US
  • 3 Gu Oncology, H. Lee Moffitt Cancer Center & Research Institute - Magnolia Campus, 33612 - Tampa/US
  • 4 Urologic Oncology, Upstate Medical University, 13202 - Syracuse/US
  • 5 Cancer Genomics Research, Foundation Medicine, Inc., Cambridge/US
  • 6 Pathology Department, Foundation Medicine, Inc, 02141 - Cambridge/US
  • 7 Foundation Medicine, Foundation Medicine, 02141 - Cambridge/US
  • 8 Medical Affairs, Foundation Medicine, Inc, 02210 - Boston/US
  • 9 Urology, SUNY Upstate Medical University, 13210 - Syracuse/US
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Abstract 694P

Background

srcRCC is an aggressive variant of RCC that frequently presents as advanced-stage disease refractory to traditional systemic treatments for ccRCC. Emerging potential treatment strategies for metastatic srcRCC include immune checkpoint inhibitors (ICPIs) and novel synthetic lethality agents that exploit the genomic loss of MTAP.

Methods

66 srcRCC and 841 ccRCC underwent hybrid-capture based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3).

Results

MTAP deletion was significantly enriched in srcRCC compared to ccRCC (15% vs. 6%, P=.005). CDKN2A/B co-deletion was frequent in MTAP-deleted tumors as a consequence of single 9p21 deletion events. VHL and PBRM1 GAs were significantly increased in MTAP-intact ccRCC, but not in MTAP-intact srcRCC (see the table). Frequency of GAs in SETD2, BAP1, TP53, and TERT did not significantly differ between the groups. NF2 GAs were more frequent in both MTAP-deleted srcRCC (P=.054) and ccRCC (P=.004). All cases were MS stable and exhibited low TMBs. PD-L1 IHC low- and high-positive expression was variable in the cohorts but did not reach significance in statistical comparisons. Table: 694P

MTAP-deleted srcRCC (n=10) MTAP-intact srcRCC (n=56) P value MTAP-deleted ccRCC (n=46) MTAP-intact ccRCC (n=795) P value
Males/Females 80%/20% 68%/32% NS 85%/15% 70%/30% NS
Median age (range), yrs 59 (32-75) 61 (30-89) NS 59 (31-81) 62 (24-89) NS
CDKN2A 100% 25% <.0001 94% 7% <.0001
CDKN2B 90% 20% <.0001 85% 5% <.0001
VHL 70% 52% NS 59% 76% .01
PBRM1 20% 18% NS 28% 47% .01
SETD2 0% 18% NS 17% 29% NS
BAP1 10% 18% NS 17% 15% NS
TP53 30% 39% NS 13% 13% NS
PTEN 0% 18% NS 20% 12% NS
TERT 0% 20% NS 17% 8% NS
NF2 40% 13% .05 11% 2% .004
MET 0% 7% NS 6% 2% NS
Median TMB 3.8 3.8 NS 1.3 2.8 NS
TMB ≥10 mt/Mb 0% 7% NS 0% 1% NS
PD-L1 Low (1-49%) 50% (4) 19% (16) NS 28% (25) 28% (300) NS
PD-L1 High (≥50%) 25% 44% NS 12% 4% NS

Conclusions

MTAP deletion is significantly enriched in srcRCC versus ccRCC and is accompanied by increased GAs in NF2. Studies of anti-PRMT5 drugs that exploit MTAP deletion in the treatment of clinically advanced srcRCC appear warranted.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Foundation Medicine Inc.

Disclosure

A. Necchi: Financial Interests, Personal, Research Grant: Merck Share & Dohme; Financial Interests, Personal, Other, Consulting fees: Merck Sharp & Dohme; Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal, Other, Consulting fees: Roche; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Consulting Fees: AstraZeneca; Financial Interests, Personal, Research Grant: Millenium Pharmaceuticals; Financial Interests, Personal, Research Grant: Amgen; Financial Interests, Personal, Research Grant: Novartis. P. Grivas: Financial Interests, Personal, Other, Consulting fees: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Personal, Other, Consulting fees: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Consulting fees: Clovis Oncology; Financial Interests, Institutional, Research Grant: Clovis Oncology; Financial Interests, Personal, Other, Consulting fees: Bayer; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Personal, Other, Consulting fees: Genentech; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Personal, Other, Consulting fees: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Personal, Other, Consulting fees: Merck; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Personal, Other, Consulting fees: Mirati; Financial Interests, Institutional, Research Grant: Mirati; Financial Interests, Personal, Other, Consulting fees: Pfizer; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Other, Consulting fees: QED therapeutics; Financial Interests, Institutional, Research Grant: QED therapeutics; Financial Interests, Institutional, Research Grant: Bavarian nordic; Financial Interests, Institutional, Research Grant: Debiopharm; Financial Interests, Institutional, Research Grant: Immunomedics; Financial Interests, Institutional, Research Grant: OncoGenex Pharmaceuticals; Financial Interests, Personal, Other, consulting fees: EMD Serono; Financial Interests, Personal, Other, consulting fees: Exelixis; Financial Interests, Personal, Other, consulting fees: F. Hoffman La Roche; Financial Interests, Personal, Other, consulting fees: Foundation Medicine Inc.; Financial Interests, Personal, Other, consulting fees: Genzyme; Financial Interests, Personal, Other, Consulting fees: Heron Therapeutics; Financial Interests, Personal, Other, Consulting fees: Janssen; Financial Interests, Personal, Other, Consulting fees: Seattle Genetics. P.E. Spiess: Non-Financial Interests, Personal, Leadership Role: NCCN Panel on bladder and penile cancer; Non-Financial Interests, Personal, Leadership Role: Global Society of Rare GU Tumors. E. Sokol: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. S. Ramkissoon: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. E. Severson: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. R.S.P. Huang: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. D.I. Lin: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. D.A. Mata: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. B. Decker: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. K. Mcgregor: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La Roche Ltd. N.A. Danziger: 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.

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