No Impact of Germline Variants on RFS, PFS in NMIBC Patients Receiving Bacillus Calmette-Guerin

By Cecilia Brown - July 26, 2022

Pathogenic or likely pathogenic germline variants in DNA-damage response genes did not significantly impact recurrence-free survival (RFS) or progression-free survival (PFS) in patients with non-muscle invasive bladder cancer (NMIBC) who received bacillus Calmette-Guerin immunotherapy, according to a recent study. The study, led by Eugene Pietzak, MD, of the Memorial Sloan Kettering Cancer Center, was published in Clinical Cancer Research.

Germline analysis was performed on an initial cohort of patients with NMIBC (n = 99) and an expanded cohort of patients with NMIBC (n = 115). Investigators analyzed associations between the presence of pathogenic and likely pathogenic germline variants in ≥76 hereditary cancer predisposition genes and the patients’ clinicopathologic features and clinical outcomes. The frequency of pathogenic/likely pathogenic germline variants was similar between the initial (12%) and expanded cohorts (8.7%; P=.4).

Pathogenic/likely pathogenic variants were reported in 22 of 214 patients (10%) in a combined analysis of both cohorts. However, pathogenic/likely pathogenic variants were significantly more common in patients who had high-grade NMIBC (13.5%) than in patients with low-grade NMIBC (0%; P=.005).

Pathogenic/likely pathogenic germline variants in DNA-damage response genes were reported in 15 of the 22 patients (68%) with high-grade NMIBC. Most of the reported variants were in genes that play a role in nucleotide excision repair (ERCC2/3) and homologous recombination repair (BRCA1, NBN, RAD50) pathways.

When patients received bacillus Calmette-Guerin immunotherapy (n = 148) there was no statistically significant difference in RFS between patients with and without pathogenic/likely pathogenic germline variants in DNA-damage response genes (hazard ratio [HR], 0.98, P≥.9). RFS at one year was 62% (95% CI, 40-95%) in patients with DNA-damage response gene variants and was 67% (95% CI, 49-90%) in patients without those variants.

There were no statistically significant differences in biologic PFS (HR, 1.1, P=.9) or clinical PFS (HR, 1.14, P=.8) between patients with and without pathogenic/likely pathogenic germline variants in DNA-damage response genes when treated with bacillus Calmette-Guerin immunotherapy. The two-year biologic PFS was 77% (95% CI, 57-100%) in patients with DNA-damage response gene variants and was 83% (95% CI, 77-89%) in patients without those variants. The two-year clinical PFS was 77% (95% CI, 57-100%) in patients with DNA-damage response gene variants and was 80% (95% CI, 73-87%) in patients without those variants.

The results suggest bacillus Calmette-Guerin immunotherapy “may be protective against the adverse clinical outcomes previously reported for NMIBC patients” who have pathogenic/likely pathogenic germline variants in DNA-damage response genes, researchers reported.

Due to the prevalence of somatic mutations and pathogenic/likely pathogenic germline variants in DNA-damage response genes in patients who have high-grade NMIBC, the research has implications for future treatments and genetic screening options, investigators wrote.

“Our results support offering germline counseling and testing for all patients with high-grade bladder cancer, regardless of the initial tumor stage,” the authors concluded. “Therapeutic strategies that target impaired DNA repair may benefit patients with high-grade NMIBC.”

 

Reference

Pietzak EJ, Whiting K, Srinivasan P, et al. Inherited germline cancer susceptibility gene variants in individuals with non-muscle-invasive bladder cancer. Clin Cancer Res. 2022. doi:10.1158/1078-0432.CCR-22-1006

 

 

Advertisement
Advertisement