PD12-12 PATIENT MATCHED GENOMIC ANALYSIS OF HIGH-GRADE NON-MUSCLE INVASIVE BLADDER CANCER SPECIMENS PRE- AND POST-BCG IMMUNOTHERAPY

Abstract

INTRODUCTION AND OBJECTIVE: High-grade non-muscle invasive bladder cancer (NMIBC) is treated with intravesical BCG immunotherapy. Unfortunately, 40% of patients develop recurrence with a subset progressing. Identification of genomic alterations associated with response to BCG could identify novel approaches to prevent or delay recurrence. To explore tumor evolution under the selective pressure of BCG therapy, we utilized targeted exon capture sequencing (IMPACT) to compare tumor collected pre- and post-BCG treatment. METHODS: High-grade NMIBC patients treated with BCG had IMPACT performed on pre- and post-treatment tumor. Patients were classified as having BCG unresponsive or late-relapsing disease. BCG unresponsive tumors were those with recurrent high-grade disease within 12 months after completion of adequate BCG. BCG late-relapsing tumors were those with high-grade recurrence over 12 months after BCG treatment. The association between patient characteristics, genomic profiles and tumor mutational burden (TMB) with high-grade recurrence following BCG was estimated. TMP pre- and post-treatment was compared using a paired Wilcoxon test. RESULTS: Matched specimens from 18 patients were analyzed. The median age at diagnosis was 60 years (IQR 50-75) and 15 (83%) were male. 11 patients (61%) were cTa, 6 (33%) cT1 and 1 cTis. The mutational concordance between pretreatment and posttreatment BCG specimens was 80% (IQR 65-96) (Figure 1). TMB between matched specimens was not significantly different with median 7 in both (p=0.88). Notably three patients gained a potentially actionable mutation post-BCG like patient 10 with a gain of a FGFR3 mutation after FACETS analysis. Univariable analysis did not detect statistically significant differences in BCG-unresponsive vs late-relapsing with respect to age, gender, number of tumors, smoker, tumor size or cT-stage. Comparing genomic alterations, a significant difference in the present of a CREBBP mutation was detected between these two cohorts (p=0.03). As a chromatin modifying gene, mutations in CREBBP may potentially be actionable with histone deacetylase inhibitors. CONCLUSIONS: With recurrent BCG shortages, further knowledge of resistance patterns can help guide clinical practice. We found a high concordance between tumor pre- and post-BCG treatment. The cohort identified here was small but there were some notable differences between pre- and post-treatment specimens, especially with gain of actionable mutations in post-BCG specimens. While we examined only patients with BCG recurrences, there were a number of actionable mutations that could serve as potential targets for novel therapies.Source of Funding: This work was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers, the Michael and Zena Wiener for Therapeutics Program in Bladder Cancer, Pin Down Bladder Cancer, Cycle for Survival, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, NIH/NCATS Grant Number UL1-TR002384, the National Cancer Institute Cancer Center Core Grant Number P30-CA008748 and by SPORE in Bladder Cancer P50-CA221745.