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Updated: Jun 21, 2025
Magnetic Resonance Imaging Assessment of Carcinogen-induced Murine Bladder Tumors
Published on: March 29, 2019
Correlative Analysis of ATM, RB1, ERCC2, and FANCC Mutations and Pathologic Complete Response After Neoadjuvant
Elizabeth R Plimack1, Catherine Tangen2, Melissa Plets3
1Fox Chase Cancer Center, Temple Health, Philadelphia, PA, USA.
Abstract:
We previously reported that tumors harboring any one of four gene mutations (ATM, RB1, FANCC, or ERCC2) were likely to respond to neoadjuvant cisplatin-based chemotherapy (NAC), resulting in cancer-free surgical specimens at the time of cystectomy (pT0). Here, we report our validation of this finding. Using the CARIS 592 Gene Panel (Caris Life Sciences, Phoenix, AZ, USA), we analyzed 105 pre-NAC tumor specimens from a large multicenter trial (S1314) of either neoadjuvant gemcitabine and cisplatin (GC), or dose-dense methotrexate, vinblastine, Adriamycin, and cisplatin (DDMVAC). We found that a mutation in any one of these four genes predicted for pT0 at surgery (odds ratio = 5.36; 95% confidence interval [CI] 2.05, 14.02; two-sided p = 0.0006). The biomarker was better at predicting the presence of disease (negative predictive value for pT0 86%; 95% CI 73%, 94%) than the absence of disease (positive predictive value for pT0 48%; 95% CI 35%, 62%). There was no evidence of an interaction between the treatment arm (DDMVAC vs GC) and the genetic variant in terms of pT0. When combined with clinical assessment, these findings help inform patient selection for bladder preservation after cisplatin-based chemotherapy.
Insights
Tumors with mutations in ATM, RB1, FANCC, or ERCC2 genes predict a positive response to neoadjuvant cisplatin-based chemotherapy (NAC), leading to cancer-free surgical specimens. This genetic marker aids in selecting patients for bladder preservation strategies.
Area of Science:
- Oncology
- Genetics
- Chemotherapy
Background:
- Previous research identified four key gene mutations (ATM, RB1, FANCC, ERCC2) associated with positive responses to neoadjuvant cisplatin-based chemotherapy (NAC).
- A complete response (pT0) indicates cancer-free surgical specimens after NAC, crucial for bladder preservation strategies.
Purpose of the Study:
- To validate the predictive value of specific gene mutations for pT0 response to NAC.
- To assess the efficacy of these genetic markers in patient selection for bladder preservation.
Main Methods:
- Analysis of 105 pre-NAC tumor specimens from the S1314 multicenter trial using the CARIS 592 Gene Panel.
- Patients received either neoadjuvant gemcitabine and cisplatin (GC) or dose-dense methotrexate, vinblastine, Adriamycin, and cisplatin (DDMVAC).
- Statistical analysis to determine the association between gene mutations and pT0 response.
Main Results:
- A mutation in any of the four genes (ATM, RB1, FANCC, ERCC2) significantly predicted pT0 at surgery (OR=5.36, p=0.0006).
- The biomarker demonstrated a high negative predictive value (86%) for pT0, indicating its strength in predicting response.
- The positive predictive value for pT0 was 48%, suggesting it is more reliable for ruling out residual disease than confirming it.
- No significant interaction was found between the treatment arm (GC vs. D糰MVAC) and the genetic variant's effect on pT0.
Conclusions:
- The presence of ATM, RB1, FANCC, or ERCC2 mutations is a validated predictor of pT0 response to NAC.
- This genetic biomarker, combined with clinical assessment, can improve patient selection for bladder preservation after chemotherapy.
- Further integration of genetic profiling into treatment decisions can optimize outcomes in bladder cancer management.
