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Characterizing the Genomic Landscape of the Micropapillary Subtype of Urothelial Carcinoma of the Bladder Harboring Activating Extracellular Mutations of ERBB2 - Beyond the Abstract

Our study illustrates the importance of next-generation sequencing in urothelial bladder cancer (UBC) to enhance patient selection for ERBB2/HER2-targeting agents and to identify additional genomic co-alterations that have been associated with tumor progression, therapeutic response, and treatment resistance.

UBC can exhibit a wide spectrum of histological subtypes that have traditionally relied on morphological features for classification. At the molecular level, a high percentage of the micropapillary subtype of urothelial carcinoma of the bladder (MPUC), a histological subtype of UBC that is associated with poor prognosis, contain oncogenic activating mutations in the extracellular domain (ECD) of ERBB2 (S310F/Y).1 Given the high rate of ERBB2 genomic alterations in MPUC, there is significant interest in ERBB2-targeting agents to treat this aggressive subtype of UBC.

Historically, clinical trials for ERBB2 therapy in UBC have led to suboptimal outcomes.2-4 One key issue lies in the heterogeneity of UBC as variable rates of ERBB2 protein expression have been described.5,6 Furthermore, patient selection has been based on ERBB2 fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) criteria established in breast cancer, further complicating the translation of successful criteria between these distinct malignancies. Thus, insufficient patient stratification and a limited understanding of the intricate molecular landscape of bladder cancer contribute to the difficulty in identifying individuals who would benefit most from ERBB2-targeted therapies. Therefore utilizing ERBB2 FISH and/or IHC for patient selection may not be ideal for patients with UBC, particularly in cases with a component of MPUC since the association between ERBB2 expression and amplification in this subtype is not linear7. Next-generation sequencing of tumors in UBC may enhance patient selection for ERBB2-targeting agents to improve patient outcomes.

We performed comprehensive genomic profiling in a large cohort of 5,485 UBC cases and identified 219 ERBB2 ECD-mutated tumors (S310F/Y) of which 63 (28.8%) featured MPUC histology. The main differences between ERBB2 ECD-mutated MPUC compared to non-MPUC tumors were KMT2D, RB1, and MTAP alterations. KMT2D and RB1 are tumor suppressor genes. MTAP loss is an emerging biomarker for new synthetic lethality based anti-cancer drugs (PRMT5 and MAT2A inhibitors) and clinical trials in solid tumors with MTAP deletion (including UBC) are currently in progress (NCT04794699). ERBB2 mutation and ERBB2 amplification are distinct oncogenic drivers and represent specific molecular and therapeutic targets8. Our study also identified 548 cases with ERBB2 amplification and we are further examining this cohort to determine the genomic differences between UBC with ERBB2 ECD-mutations compared to ERBB2 amplification. The ERBB2-directed antibody and topoisomerase inhibitor conjugate trastuzumab deruxtecan (T-DXd, Enhertu) is in active clinical trial testing (NCT04482309) and preliminary results showed an improved overall response rate across multiple ERBB2-expressing tumors including UBC9.

In summary, ERBB2 ECD-mutation-driven UBC featured an enrichment of MPUC histology with a unique genomic landscape. We identified additional genomic alterations in ERBB2-ECD mutated MPUC that may drive tumor progression and dictate treatment response to therapeutic approaches. Although clinical outcome data was not available for this patient cohort, we currently have a study in progress to look at the overall prognosis and response to targeted therapies in ERBB2-mutation-positive UBC. Better patient selection, through utilization of next-generation sequencing assays that detect specific genomic alterations and novel therapy combinations that include ERBB2–targeting agents (with immunotherapy or other treatment modalities) may lead to improved outcomes in ongoing and future clinical trials in UBC. Thus, genomic profiling of MPUC may not only improve our fundamental knowledge about this aggressive morphological subtype of UBC but also have the potential to guide a personalized approach focused on actionable therapeutic targets.

Written by: Jessica M. Posada,1 Jeffrey S. Ross,2,3 Liang Cheng1

  1. Department of Pathology and Laboratory Medicine, The Warren Albert Medical School of Brown University, Lifespan Academic Medical Center, and the Legorreta Cancer Center at Brown University, Providence, RI, USA
  2. Upstate Medical University, Syracuse, NY, USA
  3. Foundation Medicine Inc., Cambridge, MA, USA
References:

  1. Ross JS, Wang K, Gay LM, et al. A high frequency of activating extracellular domain ERBB2 (HER2) mutation in micropapillary urothelial carcinoma. Clin Cancer Res. 2014;20(1):68-75.
  2. Hussain MH, MacVicar GR, Petrylak DP, et al. Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J Clin Oncol. 2007;25(16):2218-2224.
  3. Oudard S, Culine S, Vano Y, et al. Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2. Eur J Cancer. 2015;51(1):45-54.
  4. Powles T, Huddart RA, Elliott T, et al. Phase III, Double-Blind, Randomized Trial That Compared Maintenance Lapatinib Versus Placebo After First-Line Chemotherapy in Patients With Human Epidermal Growth Factor Receptor 1/2-Positive Metastatic Bladder Cancer. J Clin Oncol. 2017;35(1):48-55.
  5. Behzatoglu K, Yorukoglu K, Demir H, Bal N. Human Epidermal Growth Factor Receptor 2 Overexpression in Micropapillary and Other Variants of Urothelial Carcinoma. Eur Urol Focus. 2018;4(3):399-404.
  6. Moktefi A, Pouessel D, Liu J, et al. Reappraisal of HER2 status in the spectrum of advanced urothelial carcinoma: a need of guidelines for treatment eligibility. Mod Pathol. 2018;31(8):1270-1281.
  7. Sanguedolce F, Zanelli M, Palicelli A, et al. HER2 Expression in Bladder Cancer: A Focused View on Its Diagnostic, Prognostic, and Predictive Role. Int J Mol Sci. 2023;24(4).
  8. Li BT, Ross DS, Aisner DL, et al. HER2 Amplification and HER2 Mutation Are Distinct Molecular Targets in Lung Cancers. J Thorac Oncol. 2016;11(3):414-419.
  9. Li BT, Meric-Bernstam F, Puvvada SD, et al. A phase 2, multicenter, open-label study evaluating trastuzumab deruxtecan (T-DXd) for the treatment of solid tumors harboring specific HER2-activating mutations (DESTINY-PanTumor01). Journal of Clinical Oncology. 2021;39(15_suppl):TPS3162-TPS3162.
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