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TERT Promoter Mutations and Other Prognostic Factors in Patients with Advanced Urothelial Carcinoma Treated with an Immune Checkpoint Inhibitor - Beyond the Abstract

Immune checkpoint inhibitors (ICI) have become an integral part of the treatment of locally advanced or metastatic urothelial carcinoma (aUC).1–5 A significant minority of patients (about 15-20%) may achieve durable responses, but unfortunately, this remains the case in only this small subset of patients. Although increased tumor PD-L1 expression and the presence of a high tumor mutation burden (TMB) have been identified as putative predictive biomarkers of response to ICI,6,7 a reliable way to identify these patients is still lacking. The recent approvals of targeted therapies and novel antibody-drug conjugates have further highlighted the need for robust and readily available biomarkers to better identify those patients most likely to benefit from ICI. In the present analysis, we hypothesized that genomic profiling could be used to predict clinical outcomes in patients with aUC treated with an ICI.


In this manuscript, we highlight a single-center retrospective study of patients who received ICI therapy for aUC at the University of California San Francisco. In addition to baseline demographic, clinical, and histopathologic variables, genomic profiling results were collected for all patients when available. We then tested for associations between baseline clinical/genomic characteristics and objective response, progression-free survival (PFS), and overall survival (OS) by logistic regression and Cox regression, respectively. Overall, we identified 119 aUC patients treated with an ICI at our institution from December 2014 to January 2020. Most received either pembrolizumab (68%) or atezolizumab (29%), and roughly half of all ICI therapy (51%) was administered in the post-platinum metastatic setting. Overall response rate was 29%, median PFS was 2.6 months, and median OS was 13.4 months. Genomic profiling results were available in two-third of cases (66%) and were primarily derived from FoundationOneTM or UCSF500--our institutional CLIA-certified platform. The most frequently detected alterations involved the TERT promoter, TP53, RB1, CKDN2A, and CDKN2B genes, consistent with prior data reported for aUC.

We first looked in our entire patient cohort for associations between baseline clinical characteristics and treatment outcomes. The presence of a favorable performance status (i.e. ECOG ≤1) at baseline was the only significant predictor of OS after adjusting for other pre-treatment clinical and laboratory variables (HR 0.46, 95% CI 0.23-0.90, p=0.03). We then looked at the subset of patients with available genomic profiling results and tested for associations between specific genomic alterations and clinical outcomes. Interestingly, we found that alterations in the TERT promoter gene were associated with an increased response rate (OR 1.33, 95% CI 1.08-1.65, p=0.01), longer PFS (HR 0.41, 95% CI 0.24-0.72, p=0.002), as well as a trend towards longer OS (HR 0.53, 95% CI 0.27-1.06, p=0.07) on univariable analysis. On multivariable analysis, the presence of a TERT promoter alteration remained predictive of outcomes, and in fact was the only clinical/genomic factor associated with improved PFS (HR 0.38, 95% CI 0.18 to 0.81, p=0.01) and OS (HR 0.32, 95% CI 0.10 to 0.93, p=0.04).

Although TERT promoter mutations are the most common genomic alteration in UC, relatively little is known about their prognostic and predictive significance in patients treated with ICI. Studies conducted in aUC patients receiving chemotherapy have either failed to show any significant association with clinical outcomes,8 or have suggested inferior outcomes in patients with TERT promoter mutations.9,10 Interestingly, the presence of a TERT promoter mutation has been associated with a lower risk of recurrence in patients with non-muscle invasive bladder cancer treated with BCG therapy.11  In our cohort, the presence of a TERT promoter mutation was an independent predictor of improved OS, and we hypothesized that these mutations may be associated with improved outcomes via increased tumor immunogenicity. We considered several potential mechanisms for this finding, including an association between TERT promoter mutations and PD-L1 expression or higher tumor mutation burden.12 However, tumor mutation burden and PD-L1 expression status were available only in a small subset of patients (62 and 21, respectively), and thus were not included in our multivariable analyses.

Overall, our study did not show most baseline clinical and laboratory variables (with the exception of ECOG performance status) to have prognostic value in patients with aUC receiving ICI therapy. However, the incorporation of genomic profiling results identified mutations in the TERT promoter gene as a novel and independent predictor of improved long-term outcomes (PFS and OS) in this patient population. These results are hypothesis-generating and will need to be validated in larger prospective cohorts alongside other putative biomarkers. Evaluation of TERT promoter mutation status in patients receiving non-ICI therapies will also help to determine whether these alterations have a predictive or purely prognostic role in aUC. Nonetheless, these findings suggest that genomic profiling can provide important prognostic information and potentially help guide treatment decisions as well as clinical trial selection and stratification in patients with aUC.

Written by: Ivan de Kouchkovsky and Vadim S. Koshkin, University of California San Francisco, Helen Diller Comprehensive Cancer Center

References:

  1. Bellmunt, J. et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N. Engl. J. Med. 376, 1015–1026 (2017).
  2. Rosenberg, J. E. et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387, 1909–1920 (2016).
  3. Sharma, P. et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 18, 312–322 (2017).
  4. Powles, T. et al. Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. JAMA Oncol. 3, e172411 (2017).
  5. Patel, M. R. et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 19, 51–64 (2018).
  6. Vuky, J. et al. Long-Term Outcomes in KEYNOTE-052: Phase II Study Investigating First-Line Pembrolizumab in Cisplatin-Ineligible Patients With Locally Advanced or Metastatic Urothelial Cancer. J. Clin. Oncol. 38, 2658–2666 (2020).
  7. Lavoie, J.-M., Black, P. C. & Eigl, B. J. Predictive Biomarkers for Checkpoint Blockade in Urothelial Cancer: A Systematic Review. J. Urol. 202, 49–56 (2019).
  8. Allory, Y. et al. Telomerase reverse transcriptase promoter mutations in bladder cancer: high frequency across stages, detection in urine, and lack of association with outcome. Eur. Urol. 65, 360–366 (2014).
  9. Wang, K. et al. TERT promoter mutations are associated with distant metastases in upper tract urothelial carcinomas and serve as urinary biomarkers detected by a sensitive castPCR. Oncotarget 5, 12428–12439 (2014).
  10. Isharwal, S. et al. Prognostic Value of TERT Alterations, Mutational and Copy Number Alterations Burden in Urothelial Carcinoma. Eur. Urol. Focus 5, 201–204 (2019).
  11. Batista, R. et al. TERT Promoter Mutation as a Potential Predictive Biomarker in BCG-Treated Bladder Cancer Patients. Int. J. Mol. Sci. 21, (2020).
  12. Li, H., Li, J., Zhang, C., Zhang, C. & Wang, H. TERT mutations correlate with higher TMB value and unique tumor microenvironment and may be a potential biomarker for anti-CTLA4 treatment. Cancer Med. 9, 7151–7160 (2020).

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