Integrative Molecular Characterization of Sarcomatoid and Rhabdoid Renal Cell Carcinoma Reveals Determinants of Poor Prognosis and Response to Immune Checkpoint Inhibitors
David A. Braun,
Sachet A. Shukla,
Meng Xiao He,
Amin H. Nassar,
Sarah Abou Alaiwi,
John A. Steinharter,
Pier Vitale Nuzzo,
Jacob E. Berchuck,
Gwo-Shu Mary Lee,
Steven L. Chang,
Xiao X. Wei,
Bradley A. McGregor,
Lauren C. Harshman,
Michelle S. Hirsch,
Matthew L Freedman,
Michael B. Atkins,
Catherine J. Wu,
Thai H. Ho,
W. Marston Linehan,
David F. McDermott,
Daniel Y.C. Heng,
Srinivas R. Viswanathan,
Eliezer M Van Allen,
Toni K. Choueiri
Posted 30 May 2020
bioRxiv DOI: 10.1101/2020.05.28.121806
Posted 30 May 2020
Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors1−3, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD−L1 expression. Our findings shed light on the molecular drivers of aggressivity and responsiveness to immune checkpoint inhibitors of S/R RCC tumors. ### Competing Interest Statement ZB: reported nonfinancial support from Bristol-Myers Squibb and Genentech/ImCore. D.A.B. reported nonfinancial support from, Bristol-Myers Squibb, and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy, outside of the submitted work. S.A.S. reported nonfinancial support from Bristol-Myers Squibb, and equity in 152 Therapeutics outside the submitted work. X.G: Research Support to Institution: Exelixis. X.X.W: Research Support: BMS. B.A.M is a consultant for Bayer, Astellas, Astra Zeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech and EMD Serono. He received research support to Dana Farber Cancer Institute (DFCI) from Bristol Myers Squibb, Calithera, Exelixis, Seattle Genetics. L.C.H reports consulting fees from Genentech, Dendreon, Pfizer, Medivation/Astellas, Exelixis, Bayer, Kew Group, Corvus, Merck, Novartis, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), Jounce, EMD Serrano, and Ology Medical Education; Research funding from Bayer, Sotio, Bristol-Myers Squib, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer, Endocyte (Novartis), and support for research travel from Bayer and Genentech. M.B.A: Advisory Board participation: BMS, Merck, Novartis, Arrowhead, Pfizer, Galactone, Werewolf, Fathom, Pneuma, Leads BioPharma; Consultant: BMS, Merck, Novartis, Pfizer, Genentech-Roche, Exelixis, Eisai, Aveo, Array, AstraZeneca, Ideera, Aduro, ImmunoCore, Boehringer-Ingelheim, Iovance, Newlink, Pharma, Surface, Alexion, Acceleron, Cota, Amgen; Research Support to institution: BMS, Merck, Pfizer, Genentech. C.J.W: Co-founder of Neon Therapeutics, and is a member of its SAB. Receives research funding from Pharmacyclics. T.H.H: Advisory board participation: Surface Therapeutics, Exelixis, Genentech, Pfizer, Ipsen, Cardinal Health; research support-Novartis. D.F.M reports a consulting/advisory role for Bristol-Myers Squibb, Merck, Roche/Genentech, Pfizer, Exelixis, Novartis, Eisai, X4 Pharmaceuticals, and Array BioPharma; and reports that his home institution receives research funding from Prometheus Laboratories. D.H: consulting or research funding from Pfizer, Novartis, BMS, Ipsen, Exelixis, and Merck. S.S: Research support to Institution: Bristol-Myers Squibb, AstraZeneca, Novartis, Exelixis; Consultant: Merck, AstraZeneca, Bristol-Myers Squibb, AACR, and NCI; royalties: Biogenex. E.M.V: Advisory/Consulting: Tango Therapeutics, Genome Medical, Invitae, Illumina, Ervaxx; Research support: Novartis, BMS; Equity: Tango Therapeutics, Genome Medical, Syapse, Ervaxx, Microsoft; Travel reimbursement: Roche/Genentech; Patents: Institutional patents filed on ERCC2 mutations and chemotherapy response, chromatin mutations and immunotherapy response, and methods for clinical interpretation. T.K.C: Research (Institutional and personal): AstraZeneca, Alexion, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, Takeda, National Cancer Institute (NCI), National Institute of Health (NIH), Department of Defense (DOD).; Honoraria: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), Research to Practice, L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics, Lilly, ASCO, ESMO ; Consulting or Advisory Role: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, Tempest.; No speaker bureau; Stock ownership: Pionyr, Tempest.; No leadership or employment in for-profit companies. Other present or past leadership roles: Director of GU Oncology Division at Dana-Farber and past President of medical Staff at Dana-Farber), member of NCCN Kidney panel and the GU Steering Committee, past chairman of the Kidney Cancer Association Medical and Scientific Steering Committee); Patents, royalties or other intellectual properties: International Patent Application No. PCT/US2018/12209, entitled PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response, filed January 3, 2018, claiming priority to U.S. Provisional Patent Application No. 62/445,094, filed January 11, 2017 and International Patent Application No. PCT/US2018/058430, entitled Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, filed October 31, 2018, claiming priority to U.S. Provisional Patent Application No. 62/581,175, filed November 3, 2017; Travel, accommodations, expenses, in relation to consulting, advisory roles, or honoraria; Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, and others); The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter; CV provided upon request for scope of clinical practice and research; Mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components: Asmar Wood S.A.L. is a private company based in Beirut, Lebanon that will provide a total of $100,000 in salary support to Dr. Sarah Abou Alaiwi from 7/1/2018 to 7/1/2020 during her post-doctoral research fellowship at DFCI; Fondation Arc Pour La Recherche Sur Le Cancer is a not-for-profit foundation based in Villejuif, France that provides 2561.04 Euros per month in salary support to Dr. Ronan Flippot during his clinical training at DFCI from 5/2/2018 to 11/4/2018. The other authors declare no potential conflicts of interest.
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