Genomic Predictors of BCG Response in High Risk Non Muscle Invasive Bladder Cancer
Alice Kennedy, BS, Zhong Jiang, MD, Xiuling Meng, MD, Vera Kazakova, MD, Jennifer Yates, MD, Loyd Hutchinson, MD, Kriti Mittal, MD.
University of Massachusetts Chan School of Medicine, Worcester, MA, USA.
Introduction: Approximately 75% of new bladder cancer patients have non-muscle invasive bladder cancer (NMIBC). Management of high risk NMIBC typically entails resection followed by intravesical BCG and close cystoscopic surveillance. Within five years, half of NMIBC patients experience recurrence; 20-30% progress to muscle invasive disease. High recurrence rates and BCG shortage continue to pose challenges for NMIBC management. Characterizing genomic markers of BCG refractoriness may optimize patient selection for initial and subsequent courses of BCG. Objectives: The purpose of this pilot study was to identify differential genomic profiles of bladder cancer tumors among patients demosntrating durable response to BCG compared to those with BCG-unresponsive disease. Methods: Records of high risk NMIBC patients who received intravesical BCG at our site between 10/1/2017 - 10/1/2022 were reviewed. Pre-treatment samples from 22 patients who were either exceptional responders (n=12; defined as no recurrence >pTa 12 months after BCG completion) or BCG-unresponsive (per AUA criteria1; n=10) were analyzed. Tissue diagnosis was confirmed by two independent pathologists. DNA was then extracted from paraffin-embedded (FFPE) tissue slides. Next generation sequencing (NGS) was performed using our institution's target-specific probes covering known hotspot mutations on 50 genes. Raw sequencing results were analyzed by two pipelines. Variants were reviewed and confirmed to be of pathologic potential using publicly available data. Statistical analyses were conducted using R4.2.2. Results: The study population had a mean age of 71.5 years, 86.4% with smoking history, and 72.7% male. All were diagnosed with Ta/T1 papillary urothelial carcinoma, majority with high grade histology. Baseline characteristics were consistent between groups (table 1). NGS revealed alterations with pathogenic potential in every specimen. TP53 mutation testing appeared to be predictive of BCG unresponsiveness with 60% of BCG failures demonstrating inactivating missense mutation in p53 compared to 17% of durable responders, though this trend did not reach statistical significance (p=0.07). 1.FGFR3 and TERT promoter mutations were present in 67% responders vs 40% BCG unresponsive (p = 0.39) and 58% responders vs 80% BCG unresponsive patients (p = 0.38) respectively. The impact of gene mutations on disease free survival did not reach statistical significance possibly due the limited sample size. Conclusions: The higher proportion of TP53 mutations within the BCG-unresponsive cohort suggests that the TP53 tumor suppressor may confer resistance to BCG therapy. Our pilot data underscores the feasibility of characterizing NMIBC tumors by NGS and the possibility of using genomic profile has the potential to be a predictive biomarker of BCG response. Future studies to evaluate the interaction between TP53 dysregulation, FGFR and TERT mutations and immune response mediated by BCG are warranted.
| BCG Responsive | BCG Unresponsive | p | |
| n | 12 | 10 | |
| Age at tissue diagnosis | 71.70 (11.14) | 71.19 (10.10) | 0.911 |
| Sex | |||
| Male | 8 ( 67.7) | 8 ( 80.0) | 0.827 |
| Female | 4 ( 33.3) | 2 ( 20.0) | |
| Smoking status (%) | |||
| Current | 1 ( 8.3) | 2 ( 20.0) | 0.204 |
| Former | 8 ( 66.7) | 8 ( 80.0) | |
| Never | 3 ( 25.0) | 0 ( 0.0) | |
| Prior Urothelial Cancer Diagnosis (%) | 1 ( 8.3) | 2 ( 20.0) | 0.865 |
| Multifocal disease (%) | 4 ( 33.3) | 8 ( 80.0) | 0.079 |
| Tumor size | |||
| >3cm (%) | 6 ( 50.0) | 7 ( 70.0) | 0.607 |
| <3cm (%) | 6 ( 50.0) | 3 ( 30.0) | |
| Perioperative instillation of chemotherapy (%) | 2 ( 16.7) | 1 ( 10.0) | 1 |
| T stage | |||
| T1 (%) | 5 ( 41.7) | 4 ( 40.0) | 1 |
| Ta (%) | 7 (58.3) | 6 (60.0) | |
| Grade | |||
| Low (%) | 1 ( 8.3) | 1 ( 10.0) | 1 |
| High (%) | 11 ( 91.7) | 9 ( 90.0) | |
| Cis | |||
| Present (%) | 2 ( 16.7) | 0 ( 0.0) | 0.542 |
| Absent (%) | 10 (83.3) | 10 (100.0) | |
| BCG Received | |||
| Induction only (%) | 5 ( 41.7) | 3 ( 30.0) | 0.903 |
| Induction and maintenance/reinduction (%) | 7 (48.3) | 7 (70.0) | |
| Number of additional OR procedures | 1.50 (2.32) | 3.40 (1.35) | 0.033 |
| Months between diagnosis and BCG initiation | 2.24 (1.26) | 2.49 (1.29) | 0.649 |
| Months of follow-up after BCG initiation | 44.23 (12.41) | 37.69 (17.52) | 0.318 |
Footnotes1 US Food and Drug Administration. Guidance document: bacillus Calmette-Guerin-unresponsive nonmuscle invasive bladder cancer: developing drugs and biologics for treatment guidance for industry. images/guidanceCompliance RegulatoryInformation/Guidances/UCM529600.pdf
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