Clearing the Smoke: Underreporting of Smoking Status in Food and Drug Administration–Approved Bladder Cancer Therapeutic Trials

You have accessJournal of UrologyJU Forum1 Apr 2024Clearing the Smoke: Underreporting of Smoking Status in Food and Drug Administration–Approved Bladder Cancer Therapeutic Trials Hannah Kay, Richard S. Matulewicz, and Marc A. Bjurlin Hannah KayHannah Kay , Richard S. MatulewiczRichard S. Matulewicz , and Marc A. BjurlinMarc A. Bjurlin Corresponding Author: Marc A. Bjurlin, DO, MSc, Department of Urology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 101 Manning Dr, 2nd Floor, Chapel Hill, NC 27514 ([email protected]) View All Author Informationhttps://doi.org/10.1097/JU.0000000000003853AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail SMOKING AFFECTS BLADDER CANCER TREATMENTS AND OUTCOMES Cigarette smoking is the most common modifiable risk factor for the development of bladder cancer, accounting for 50% of all cases. Continued smoking after a bladder cancer diagnosis leads to an increased risk of second primary tumors, attenuates treatment efficacy and toxicity/morbidity, and worsens quality of life and overall survival. Despite the negative associations continued smoking has with bladder cancer outcomes, details regarding clinical trial participants' smoking status and history remain largely understudied. There is an imperative need to collect and report a detailed tobacco use history in clinical trials to understand its potential impact on bladder cancer therapeutic outcomes. THE BLADDER CANCER GENOMIC LANDSCAPE IS DISTINCT ACCORDING TO SMOKING STATUS Patient smoking history is associated with markedly distinct changes to a patient's tumor molecular biology. Therefore, the therapeutic implications of smoking-related epigenetic modifications in bladder cancer are diverse and include changes in gene expression, gene mutation, and mutational signatures. Bladder cancers in smokers are generally correlated with increased tumor mutational burden and higher PD-L1 expression (≥50%), which has been shown to modulate the efficacy of several immunotherapy drugs. A recent meta-analysis of patients treated for metastatic lung cancer found that pembrolizumab and nivolumab, both of which are immunotherapies approved for advanced bladder cancer, significantly prolonged overall survival in smokers but not in never smokers.1 Smoking impacts oncogenic characteristics in bladder cancer as well with lower proportions of patients with TP53, PIK3CA, and ERBB2 (HER2) amplification seen in nonsmokers compared to smokers. Conversely, the GPR15 gene is upregulated and the mutational signature BLCA.4 is enriched in bladder tumors of patients who smoke.2 Taken together, oncogenic differences seen in smokers may be a pathway towards precision selection of therapeutics, and further investigation into differences in bladder cancer treatment efficacy should be pursued. TOBACCO-RELATED CARCINOGENS IN CIGARETTE SMOKE IMPACT THE PHARMACOKINETICS OF BLADDER CANCER THERAPEUTICS Cigarette smoke contains many substances that can modulate the pharmacokinetics of anticancer drugs and may change their efficacy. Polycyclic aromatic hydrocarbons, a compound commonly found in cigarette smoke, are known cytochrome P450 (CYP) 1A2 inducers. CYP-dependent drugs, such as erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, are predominately metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP1A1 and undergoes rapid clearance among smokers. Therefore, a higher dose would be required to reach equivalent systemic exposure among current smokers compared with nonsmokers. In a phase 2 trial of neoadjuvant erlotinib in patients with muscle-invasive bladder cancer undergoing radical cystectomy, the effect of smoking on pathological outcomes suggested a worse response (lower pT0 rates) in patients who were current smokers.3 Overexpression of cytidine deaminase, similarly, induced by smoking, may also lead to increased catabolism and reduced efficacy of gemcitabine in smokers and former smokers. Cigarette smoke has been shown to reduce the efficacy of cisplatin, a standard of care chemotherapeutic agent for the treatment of muscle-invasive and advanced bladder cancer, by influencing the expression of ABCG2-transporters involved in multidrug resistance. Bladder cancer patients who smoke have been observed to have a higher sensitivity to gemcitabine, Wnt-C59, JAK1_8709, LY2109761, and KRAS (G12 C) Inhibitor-12, and lower sensitivity to AZ960 and buparlisib.4 Additionally, smoking may reduce the efficacy of intravesical bacillus Calmette-Guérin immunotherapy, resulting in higher disease-recurrence rates compared to never and former smokers.5 SMOKING IS UNDERREPORTED IN BLADDER CANCER CLINICAL TRIALS COMPARED TO OTHER SMOKING-RELATED MALIGNANCIES There have been 9 new bladder cancer drugs approved by the Food and Drug Administration (FDA) over the past 10 years (2013-2023), largely the result of efforts to better understand the genetic drivers and pathophysiology of this disease. Given the impact of smoking on multiple facets of bladder cancer drug treatment and outcomes, we sought to better understand how smoking is evaluated within the clinical trial context by comparing newly FDA-approved bladder cancer drug trials to lung cancer drug trials (small-cell lung cancer [SCLC] and nonsmall-cell lung cancer [NSCLC]), as lung cancer is another well-established smoking-related malignancy. We evaluated the 9 FDA-approved bladder cancer drugs (17 trials), 10 FDA-approved NSCLC drugs (22 trials), and 4 FDA-approved SCLC drugs (9 trials). Smoking status was reported in 41.2% of bladder trials, compared to 86.3% of NSCLC trials and 100% of SCLC trials. These results highlight an important discrepancy in reporting smoking status in bladder cancer drug trials. The difference becomes even more striking when 4 of the studied drugs (atezolizumab, pembrolizumab, durvalumab, and nivolumab) have been approved for both bladder cancer and NSCLC and/or SCLC, but smoking status was reported in only 44% of the bladder cancer trials while 100% of the lung cancer trials reported smoking status. This may reflect the differential public and scientific perception of the relationship between smoking and lung cancer compared with bladder cancer. Nonetheless, this clear difference in how smoking is reported in cancer therapeutic trials, even among the same drug for different malignancies, deserves further investigation. FUTURE DIRECTIONS In 2013, the National Cancer Institute–AACR (American Association for Cancer Research) Cancer Patient Tobacco Use Assessment Task Force was established to recommend the timing of tobacco use assessment in cancer clinical trials. In 2020, the FDA, IASLC (International Association for the Study of Lung Cancer), and AACR cosponsored the Workshop to Address the Criticality of Tobacco Use Assessment in Oncology Therapeutic Trials. The workshop's purpose was to generate discussion of tobacco assessment in clinical trials and improve understanding of the significance of continued tobacco use on health outcomes. Most recently, in 2023 the IASLC put out a position statement on the documentation of tobacco use in clinical trials. This statement encourages the documentation of use (including electronic cigarettes and heated tobacco products) at regular intervals throughout the clinical trial, any smoking cessation methods used, and analysis of the effect of tobacco use on clinical trial outcomes including response rate, progression-free and overall survival, treatment-related toxicity, adverse events, and quality of life. To further improve bladder cancer treatment interventions in an ever-evolving drug landscape, it is critical for clinical trials to uniformly assess tobacco use and evaluate its impact on bladder cancer therapeutic outcomes. Broad adoption of a standardized tobacco use assessment, such as the Cancer Patient Tobacco Use Questionnaire, may help advance knowledge regarding the clinical significance of persistent tobacco use and cessation in the bladder cancer treatment setting. REFERENCES 1. . The effect of smoking status on efficacy of immune checkpoint inhibitors in metastatic non-small cell lung cancer: a systematic review and meta-analysis. EClinicalMedicine. 2021; 38:100990. Crossref, Medline, Google Scholar 2. . Molecular footprints of muscle-invasive bladder cancer in smoking and nonsmoking patients. Urol Oncol. 2019; 37(11):818-825. Crossref, Medline, Google Scholar 3. . A phase II trial of neoadjuvant erlotinib in patients with muscle-invasive bladder cancer undergoing radical cystectomy: clinical and pathological results. BJU Int. 2010; 106(3):349-354. Crossref, Medline, Google Scholar 4. . Smoking-related epigenetic modifications are associated with the prognosis and chemotherapeutics of patients with bladder cancer. Int J Immunopathol Pharmacol. 2023; 37:3946320231166774. Crossref, Google Scholar 5. . Smoking reduces the efficacy of intravesical bacillus Calmette-Guérin immunotherapy in non-muscle-invasive bladder cancer. Eur Urol. 2012; 62(6):1204-1206. Crossref, Medline, Google Scholar Funding/Support: This work was supported by NCI # K08 CA259452 and MSK Core Grant # P30 CA008748 (Dr Matulewicz). Conflict of Interest Disclosures: The Authors have no conflicts of interest to disclose. Ethics Statement: In lieu of review board approval, the Principles of the Helsinki Declaration were followed. Author Contributions:Conception and design: Bjurlin, Kay, Matulewicz. Data analysis and interpretation: Bjurlin, Kay, Matulewicz. Data acquisition: Bjurlin, Kay. Drafting the manuscript: Bjurlin, Kay. Critical revision of the manuscript for scientific and factual content: Bjurlin, Kay, Matulewicz. Statistical analysis: Kay. Supervision: Bjurlin, Matulewicz. © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 4April 2024Page: 611-613 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Keywordsbladder cancersmokingtobaccodrugclinical trialMetrics Author Information Hannah Kay More articles by this author Richard S. Matulewicz More articles by this author Marc A. Bjurlin Corresponding Author: Marc A. Bjurlin, DO, MSc, Department of Urology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 101 Manning Dr, 2nd Floor, Chapel Hill, NC 27514 ([email protected]) More articles by this author Expand All Funding/Support: This work was supported by NCI # K08 CA259452 and MSK Core Grant # P30 CA008748 (Dr Matulewicz). Conflict of Interest Disclosures: The Authors have no conflicts of interest to disclose. Ethics Statement: In lieu of review board approval, the Principles of the Helsinki Declaration were followed. Author Contributions:Conception and design: Bjurlin, Kay, Matulewicz. Data analysis and interpretation: Bjurlin, Kay, Matulewicz. Data acquisition: Bjurlin, Kay. Drafting the manuscript: Bjurlin, Kay. Critical revision of the manuscript for scientific and factual content: Bjurlin, Kay, Matulewicz. Statistical analysis: Kay. Supervision: Bjurlin, Matulewicz. Advertisement Advertisement PDF downloadLoading ...