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Frequency and Nature of Genomic Alterations in ERBB2-Altered Urothelial Bladder Cancer

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Abstract

Background

Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the ERBB2 gene have been shown to play an oncogenic role similar to ERBB2 amplification.

Objective

To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2-altered (mutations, amplification) and ERBB2 wild-type UBC.

Patients and Methods

Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by ERBB2 alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher’s exact tests.

Results

A total of 602 (6.3%) UBC cases featured ERBB2 extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured ERBB2 kinase domain SV GA (KDmut+), 866 (9.1%) cases had ERBB2 amplification (amp+), and 7797 (81.9%) cases were ERBB2 wild-type (wt). European genetic ancestry of ECDmut+ was higher than ERBB2wt. Numerous significant associations were observed when comparing GA by group. Notably among these, CDKN2A/MTAP loss were more frequent in ERBB2wt versus ECDmut+ and amp+. ERBB3 GA were more frequent in ECDmut+ and KDmut+ than ERBB2wt. TERT GA were more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. TOP2A amplification was significantly more common in ECDmut+ and amp+ versus ERBB2wt, and TP53 SV GA were significantly higher in ERBB2 amp+ versus ERBB2wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in ERBB2wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus ERBB2wt. MSI-high status was more frequent in KDmut+ versus ERBB2wt, and in ERBB2wt than in amp+.

Conclusions

We noted important differences in co-occurring GA in ERBB2-altered (ECDmut+, KDmut+, amp+) versus ERBB2wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for ERBB2-altered UBC.

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Author information

Author notes

  1. Jeffrey Ross, Rafee Talukder and Petros Grivas contributed equally to this work as co-senior authors.

Authors and Affiliations

  1. Department of Medicine, University of Washington, Seattle, WA, USA

    Jacob B. Leary, Thomas Enright, Dimitra Rafailia Bakaloudi & Petros Grivas

  2. SUNY Upstate Medical University, Syracuse, NY, USA

    Alina Basnet, Gennady Bratslavsky & Joseph Jacob

  3. Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL, USA

    Philippe E. Spiess & Roger Li

  4. Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy

    Andrea Necchi

  5. Vita-Salute San Raffaele University, Milan, Italy

    Andrea Necchi

  6. MD Anderson Cancer Center, Houston, TX, USA

    Ashish M. Kamat

  7. Foundation Medicine, Cambridge, MA, USA

    Dean C. Pavlick, Natalie Danziger, Richard S. P. Huang, Douglas I. Lin & Jeffrey Ross

  8. Department of Pathology and Laboratory Medicine, Warren Alpert Medical School at Brown University, Providence, RI, USA

    Liang Cheng

  9. Legoretta Cancer Center at Brown University, Providence, RI, USA

    Liang Cheng

  10. Lifespan Academic Medical Center, Providence, RI, USA

    Liang Cheng

  11. Baylor College of Medicine, Houston, TX, USA

    Rafee Talukder

  12. Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Petros Grivas

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Corresponding author

Correspondence to Petros Grivas.

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Funding

No external funding was used in the preparation of this manuscript.

Conflicts of Interest (In Prior 3 Years)

J.B.L., T.E., D.R.B., A.B., and R.T. declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. G.B.: no financial interests; member of NCI GU Steering Committee, Renal Task Force. J.J.: has served in a consulting/advisory role for Janssen and Pfizer. P.E.S.: no financial interests; Vice Chair of NCCN Bladder and Penile Cancer Panel. R.L.: has received research support from Predicine, Veracyte, CG Oncology, Valar Labs, and Merck; serves on clinical trial protocol committees for CG Oncology, Merck, and Janssen and has served in a consulting/advisory role for Bristol Myers Squibb, Merck, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence, CG Oncology, and Janssen. A.N.: has received honoraria from Roche, MSD, AstraZeneca, Janssen, Foundation Medicine, Bristol Myers Squibb, and Astellas Pharma; has served in a consulting or advisory role for MSD, Roche, Bayer, AstraZeneca, Clovis Oncology, Janssen, Incyte, Seattle Genetics/Astellas, Bristol Myers Squibb, Rainier Therapeutics, Bicycle Therapeutics, GlaxoSmithKline, Basilea Pharmaceutica, and Catalym; has received research funding from MSD, AstraZeneca, Ipsen, and Gilead; has received travel, accommodations, and expenses from Roche, MSD, AstraZeneca, Janssen, Rainer Therapeutics, and Pfizer; and has employment and stock ownership (spouse) in Bayer. A.M.K.: has grants or contracts from FKD Therapies (now Ferring), Patient-Centered Outcomes Research Institute (PCORI), Photocure, Seagen, EnGene, Arquer Diagnostics, and SWOG; has roles on advisory board or has received consulting fees from Astellas Pharma, Biological Dynamics, Bristol Myers Squibb, CG Oncology, Cystotech, Eisai, EnGene, Ferring, Imagin Medical, Imvax, Incyte, Janssen, Medac, Merck, Nonagen Bioscience, Pfizer, Photocure, Protara Therapeutics, Roche, Seagen, Sesen Bio (now Carisma Therapeutics), Theralase, Urogen Pharma, US Biotest, and Vivet Therapeutics; holds patent for CyPRIT (Cytokine Predictors of Response to Intravesical Therapy), a joint patent with MD Anderson Cancer Center; and has leadership or fiduciary roles at European Urology Oncology, International Bladder Cancer Group (IBCG), International Bladder Cancer Network (IBCN), Journal of Urology, and UroToday. D.C.P., N.D., R.S.P.H., D.I.L. are employees of Foundation Medicine Inc., a wholly owned subsidiary of Roche, and receive equity from Roche. J.R. is an employee of Foundation Medicine Inc., a wholly owned subsidiary of Roche and receives equity from Roche, and has served in a consulting role for Tango Therapeutics and Celsius Therapeutics. P.G.: has served in a consulting role for 4D Pharma, Aadi Bioscience, Abbvie, Asieris Pharmaceuticals, Astellas, AstraZeneca, BostonGene, Bristol Myers Squibb, CG Oncology, Dyania Health, Exelixis, Fresenius Kabi, G1 Therapeutics, Genentech, Gilead Sciences, Guardant Health, ImmunityBio, Infinity Pharmaceuticals, Janssen, Lucence, Merck KGaA, Mirati Therapeutics, MSD, Pfizer, PureTech, QED Therapeutics, Regeneron, Roche, Seattle Genetics, Silverback Therapeutics, Strata Oncology, and UroGen Pharma; has received research funding from ALX Oncology, Acrivon Therapeutics, Bavarian Nordic, Bristol Myers Squibb, Debiopharm Group, Genentech, G1 Therapeutics, Gilead Sciences, GSK, Merck KGaA, Mirati Therapeutics, MSD, Pfizer, and QED Therapeutics.

Ethics Approval

Approval for this study, including a waiver of informed consent and a HIPAA waiver of authorization, was obtained from the Western Institutional Review Board (protocol no. 20152817) given the retrospective nature of this clinical study and deidentification was ensured for each tumor sample. The study was conducted in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

Consent to Participate

A waiver of informed consent and a HIPAA waiver of authorization was obtained from the Western Institutional Review Board (protocol no. 20152817) given the retrospective nature of this clinical study.

Consent for Publication

Not applicable.

Availability of Data and Material

Data are available on request from the authors.

Code Availability

Not applicable.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by D.C.P., D.R.B., and R.T. The first draft of the manuscript was written by J.B.L. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Leary, J.B., Enright, T., Bakaloudi, D.R. et al. Frequency and Nature of Genomic Alterations in ERBB2-Altered Urothelial Bladder Cancer. Targ Oncol (2024). https://doi.org/10.1007/s11523-024-01056-x

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