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Genomic and clinical prognostic factors in patients with advanced urothelial carcinoma receiving immune checkpoint inhibitors

  • Author Footnotes
    † Neal Chawla, Nicolas Sayegh, and Nishita Tripathi contributed equally to this work as first authors.
    Neal S. Chawla
    Footnotes
    † Neal Chawla, Nicolas Sayegh, and Nishita Tripathi contributed equally to this work as first authors.
    Affiliations
    Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA
    Search for articles by this author
  • Author Footnotes
    † Neal Chawla, Nicolas Sayegh, and Nishita Tripathi contributed equally to this work as first authors.
    Nicolas Sayegh
    Footnotes
    † Neal Chawla, Nicolas Sayegh, and Nishita Tripathi contributed equally to this work as first authors.
    Affiliations
    Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
    Search for articles by this author
  • Author Footnotes
    † Neal Chawla, Nicolas Sayegh, and Nishita Tripathi contributed equally to this work as first authors.
    Nishita Tripathi
    Footnotes
    † Neal Chawla, Nicolas Sayegh, and Nishita Tripathi contributed equally to this work as first authors.
    Affiliations
    Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
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  • Ameish Govindarajan
    Affiliations
    Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA
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  • Zeynep B. Zengin
    Affiliations
    Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA
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  • Errol J. Phillip
    Affiliations
    Medicine, University of California San Francisco, San Francisco, California, USA.
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  • Nazli Dizman
    Affiliations
    Yale University School of Medicine, New Haven, CT, USA
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  • Luis Meza
    Affiliations
    Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA
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  • Ramya Muddasani
    Affiliations
    Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA
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  • Alexander Chehrazi-Raffle
    Affiliations
    Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA
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  • Jasnoor Malhotra
    Affiliations
    Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA
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  • JoAnn Hsu
    Affiliations
    Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA
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  • Author Footnotes
    ⁎ Neeraj Agarwal, Sumanta Pal, and Abhishek Tripathi contributed equally to this work as senior authors.
    Neeraj Agarwal
    Footnotes
    ⁎ Neeraj Agarwal, Sumanta Pal, and Abhishek Tripathi contributed equally to this work as senior authors.
    Affiliations
    Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
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  • Author Footnotes
    ⁎ Neeraj Agarwal, Sumanta Pal, and Abhishek Tripathi contributed equally to this work as senior authors.
    Sumanta K. Pal
    Footnotes
    ⁎ Neeraj Agarwal, Sumanta Pal, and Abhishek Tripathi contributed equally to this work as senior authors.
    Affiliations
    Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA
    Search for articles by this author
  • Author Footnotes
    ⁎ Neeraj Agarwal, Sumanta Pal, and Abhishek Tripathi contributed equally to this work as senior authors.
    Abhishek Tripathi
    Correspondence
    Corresponding Author: Abhishek Tripathi, Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, Office: (626) 256-4673, Fax: (626) 301-8233
    Footnotes
    ⁎ Neeraj Agarwal, Sumanta Pal, and Abhishek Tripathi contributed equally to this work as senior authors.
    Affiliations
    Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA
    Search for articles by this author
  • Author Footnotes
    † Neal Chawla, Nicolas Sayegh, and Nishita Tripathi contributed equally to this work as first authors.
    ⁎ Neeraj Agarwal, Sumanta Pal, and Abhishek Tripathi contributed equally to this work as senior authors.
Published:November 17, 2022DOI:https://doi.org/10.1016/j.clgc.2022.11.007

      Highlights

      • Genomic sequencing has gained a foothold in routine clinical care for mUC and may provide prognostic or predictive value with ICI therapy.
      • TERT promoter mutations are amongst the most commonly detected mutations in mUC and have been associated with ICI response in a prior study.
      • ATM mutations in particular are associated with poor outcomes in mUC, however there is data to suggest that DNA damage repair mutations may portend better responses with ICI.
      • Our study found no significant difference in outcomes with TERT mutations, while ATM mutations were significantly associated with poorer outcomes.

      ABSTRACT

      Background

      Recently reported data suggest that among other clinical parameters, TERT promoter mutations may portend superior outcomes with immune checkpoint inhibitor (ICI) therapy in mUC. In our retrospective analysis from two tertiary cancer centers, we assessed the predictive role of TERT promoter mutations along with other clinical and genomic data points.

      Methods

      Patient registries were queried for patients treated with ICI for mUC with available genomic and clinical data. Sex, Eastern Cooperative Oncology Group performance score (ECOG score), smoking history, hemoglobin level, albumin level, neutrophil to lymphocyte ratio (NLR), primary tumor site, histology, treatment modality, and setting were recorded. Tumor mutational burden (TMB), and mutational status of TERT, CDKN2A, CDKN2B, TMB, TP53, RB1, KMT2D, ARID1A, ERBB2, KDM6A, PIK3CA, FGFR3, and ATM were noted. These factors were subject to univariate analysis of significance concerning overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Parameters that met stasticial significance on univariate analysis were subject to multivariate analysis.

      Results

      In total, 113 patients were found to meet inclusion criteria. In our study cohort, ORR was 55%, median PFS was 5.1 months (0.2-71.8), and median OS was 13.4 months (0.2-84.8). On univariate analysis, female sex, NLR>5, and ATM mutation were significantly associated with inferior PFS and OS, whereas upper tract primary disease and ECOG score ≥ 2 were associated with worse OS. On multivariate analysis, NLR >5 was associated with worse PFS and OS whereas upper tract primary disease, albumin <3.4 g/dL, hemoglobin <10 g/dL and ATM mutation were significantly associated with worse OS on multivariate analysis. No significant differences were seen in ORR, PFS, or OS regarding other genomic factors, including TERT promoter mutations.

      Conclusion

      In our study, TERT promoter mutations were not significantly associated with any difference in outcome in patients treated with ICI in our annotated dataset. ATM mutations were associated with significantly worse outcomes.

      Keywords

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      REFERENCES

        • Bellmunt J
        • de Wit R
        • Vaughn DJ
        • et al.
        Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.
        N Engl J Med. 2017; 376: 1015-1026https://doi.org/10.1056/NEJMoa1613683
        • Sharma P
        • Retz M
        • Siefker-Radtke A
        • et al.
        Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial.
        Lancet Oncol. 2017; 18: 312-322https://doi.org/10.1016/S1470-2045(17)30065-7
        • Powles T
        • Park SH
        • Voog E
        • et al.
        Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma.
        N Engl J Med. 2020; 383: 1218-1230https://doi.org/10.1056/NEJMoa2002788
        • Pond GR
        • Niegisch G
        • Rosenberg JE
        • et al.
        New 6-factor prognostic model for patients (pts) with advanced urothelial carcinoma (UC) receiving post-platinum atezolizumab.
        J Clin Oncol. 2018; 36 (413-413)https://doi.org/10.1200/JCO.2018.36.6_suppl.413
        • Nassar AH
        • Mouw KW
        • Jegede O
        • et al.
        A model combining clinical and genomic factors to predict response to PD-1/PD-L1 blockade in advanced urothelial carcinoma.
        Br J Cancer. 2020; 122: 555-563https://doi.org/10.1038/s41416-019-0686-0
        • Marabelle A
        • Le DT
        • Ascierto PA
        • et al.
        Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study.
        J Clin Oncol. 2020; 38: 1-10https://doi.org/10.1200/JCO.19.02105
        • Powles T
        • Sridhar SS
        • Loriot Y
        • et al.
        Avelumab maintenance in advanced urothelial carcinoma: biomarker analysis of the phase 3 JAVELIN Bladder 100 trial.
        Nat Med. 2021; 27: 2200-2211https://doi.org/10.1038/s41591-021-01579-0
        • Loriot Y
        • Necchi A
        • Park SH
        • et al.
        Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma.
        N Engl J Med. 2019; 381: 338-348https://doi.org/10.1056/NEJMoa1817323
        • Crabb SJ
        • Hussain SA
        • Soulis E
        • et al.
        A randomized, double blind, biomarker selected, phase II clinical trial of maintenance PARP inhibition following chemotherapy for metastatic urothelial carcinoma (mUC): Final analysis of the ATLANTIS rucaparib arm.
        J Clin Oncol. 2022; 40 (436-436)https://doi.org/10.1200/JCO.2022.40.6_suppl.436
        • Rosenberg JE
        • Park SH
        • Dao TV
        • et al.
        BAYOU: A phase II, randomized, multicenter, double-blind, study of durvalumab (D) in combination with olaparib (O) for the first-line treatment of platinum-ineligible patients with unresectable, stage IV urothelial carcinoma (UC).
        J Clin Oncol. 2022; 40 (437-437)https://doi.org/10.1200/JCO.2022.40.6_suppl.437
        • Vignani F
        • Tambaro R
        • De Giorgi U
        • et al.
        Randomized phase II study of niraparib plus best supportive care (BSC) versus BSC alone as maintenance treatment in patients with advanced urothelial carcinoma (UC) whose disease did not progress after first-line platinum-based chemotherapy (PBCT): The Meet-URO12 trial.
        J Clin Oncol. 2022; 40 (442-442)https://doi.org/10.1200/JCO.2022.40.6_suppl.442
        • de Kouchkovsky I
        • Zhang L
        • Philip EJ
        • et al.
        TERT promoter mutations and other prognostic factors in patients with advanced urothelial carcinoma treated with an immune checkpoint inhibitor.
        J Immunother Cancer. 2021; 9e002127https://doi.org/10.1136/jitc-2020-002127
        • Dizman N
        • Lyou Y
        • Salgia N
        • et al.
        Correlates of clinical benefit from immunotherapy and targeted therapy in metastatic renal cell carcinoma: comprehensive genomic and transcriptomic analysis.
        J Immunother Cancer. 2020; 8e000953https://doi.org/10.1136/jitc-2020-000953
        • Nickerson ML
        • Witte N
        • Im KM
        • et al.
        Molecular analysis of urothelial cancer cell lines for modeling tumor biology and drug response.
        Oncogene. 2017; 36: 35-46https://doi.org/10.1038/onc.2016.172
        • Network Cancer Genome Atlas Research
        Comprehensive molecular characterization of urothelial bladder carcinoma.
        Nature. 2014; 507: 315-322https://doi.org/10.1038/nature12965
        • Eisenhauer EA
        • Therasse P
        • Bogaerts J
        • et al.
        New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).
        Eur J Cancer. 2009; 45: 228-247https://doi.org/10.1016/j.ejca.2008.10.026
        • Khaki AR
        • Li A
        • Diamantopoulos LN
        • et al.
        A New Prognostic Model in Patients with Advanced Urothelial Carcinoma Treated with First-line Immune Checkpoint Inhibitors.
        Eur Urol Oncol. 2021; 4: 464-472https://doi.org/10.1016/j.euo.2020.12.006
        • Shariat SF
        • Sfakianos JP
        • Droller MJ
        • Karakiewicz PI
        • Meryn S
        • Bochner BH.
        The effect of age and gender on bladder cancer: a critical review of the literature.
        BJU Int. 2010; 105: 300-308https://doi.org/10.1111/j.1464-410X.2009.09076.x
        • Dobruch J
        • Daneshmand S
        • Fisch M
        • et al.
        Gender and Bladder Cancer: A Collaborative Review of Etiology, Biology, and Outcomes.
        Eur Urol. 2016; 69: 300-310https://doi.org/10.1016/j.eururo.2015.08.037
        • Jain RK
        • Ross JS
        • Necchi A
        • Spiess PE.
        Should Upper-tract Urothelial Carcinoma and Bladder Carcinoma Be Treated the Same or Different?.
        Eur Urol Oncol. 2021; 4: 180-181https://doi.org/10.1016/j.euo.2021.01.009
        • Banna GL
        • Di Quattro R
        • Malatino L
        • et al.
        Neutrophil-to-lymphocyte ratio and lactate dehydrogenase as biomarkers for urothelial cancer treated with immunotherapy.
        Clin Transl Oncol Off Publ Fed Span Oncol Soc Natl Cancer Inst Mex. 2020; 22: 2130-2135https://doi.org/10.1007/s12094-020-02337-3
        • Manzano RG
        • Catalan-Latorre A
        • Brugarolas A.
        RB1 and TP53 co-mutations correlate strongly with genomic biomarkers of response to immunity checkpoint inhibitors in urothelial bladder cancer.
        BMC Cancer. 2021; 21: 432https://doi.org/10.1186/s12885-021-08078-y
        • Joshi M
        • Vasekar M
        • Grivas P
        • et al.
        Relationship of smoking status to genomic profile, chemotherapy response and clinical outcome in patients with advanced urothelial carcinoma.
        Oncotarget. 2016; 7: 52442-52449https://doi.org/10.18632/oncotarget.9449
        • Risdon EN
        • Chau CH
        • Price DK
        • Sartor O
        • Figg WD.
        PARP Inhibitors and Prostate Cancer: To Infinity and Beyond BRCA.
        The Oncologist. 2021; 26: e115-e129https://doi.org/10.1634/theoncologist.2020-0697
        • Tutt ANJ
        • Garber JE
        • Kaufman B
        • et al.
        Adjuvant Olaparib for Patients with BRCA1 - or BRCA2 -Mutated Breast Cancer.
        N Engl J Med. 2021; 384: 2394-2405https://doi.org/10.1056/NEJMoa2105215
        • Hussain M
        • Mateo J
        • Fizazi K
        • et al.
        Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer.
        N Engl J Med. 2020; 383: 2345-2357https://doi.org/10.1056/NEJMoa2022485
        • Teo MY
        • Bambury RM
        • Zabor EC
        • et al.
        DNA Damage Response and Repair Gene Alterations Are Associated with Improved Survival in Patients with Platinum-Treated Advanced Urothelial Carcinoma.
        Clin Cancer Res Off J Am Assoc Cancer Res. 2017; 23: 3610-3618https://doi.org/10.1158/1078-0432.CCR-16-2520
        • Teo MY
        • Seier K
        • Ostrovnaya I
        • et al.
        Alterations in DNA Damage Response and Repair Genes as Potential Marker of Clinical Benefit From PD-1/PD-L1 Blockade in Advanced Urothelial Cancers.
        J Clin Oncol Off J Am Soc Clin Oncol. 2018; 36: 1685-1694https://doi.org/10.1200/JCO.2017.75.7740
        • Yin M
        • Grivas P
        • Emamekhoo H
        • et al.
        ATM/RB1 mutations predict shorter overall survival in urothelial cancer.
        Oncotarget. 2018; 9: 16891-16898https://doi.org/10.18632/oncotarget.24738
        • Dratwa M
        • Wysoczańska B
        • Łacina P
        • Kubik T
        • Bogunia-Kubik K.
        TERT—Regulation and Roles in Cancer Formation.
        Front Immunol. 2020; 11589929https://doi.org/10.3389/fimmu.2020.589929
        • Shammas MA.
        Telomeres, lifestyle, cancer, and aging.
        Curr Opin Clin Nutr Metab Care. 2011; 14: 28-34https://doi.org/10.1097/MCO.0b013e32834121b1
        • Roggisch J
        • Ecke T
        • Koch S.
        Molecular identification of telomerase reverse transcriptase (TERT) promotor mutations in primary and recurrent tumors of invasive and noninvasive urothelial bladder cancer.
        Urol Oncol. 2020; 38 (77.e17-77.e25)https://doi.org/10.1016/j.urolonc.2019.08.007
        • Martin JW
        • Jefferson FA
        • Huang M
        • et al.
        A California Cancer Registry Analysis of Urothelial and Non-urothelial Bladder Cancer Subtypes: Epidemiology, Treatment, and Survival.
        Clin Genitourin Cancer. 2020; 18: e330-e336https://doi.org/10.1016/j.clgc.2020.01.002
        • Nagumo Y
        • Kawai K
        • Kojima T
        • et al.
        Prognostic significance of non-urothelial carcinoma of bladder: analysis of nationwide hospital-based cancer registry data in Japan.
        Jpn J Clin Oncol. 2020; 50: 1068-1075https://doi.org/10.1093/jjco/hyaa072