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Study Identifies Genetic Mutations That Predict Response to Chemotherapy in Bladder Cancer

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Key Points

  • Genomic alterations in the DNA repair–associated genes ATM, RB1, and FANCC predicted response and clinical benefit after cisplatin-based chemotherapy in patients with muscle-invasive bladder cancer.
  • The study findings suggest that defective DNA repair renders tumors sensitive to cisplatin.
  • Genetic testing prior to chemotherapy may provide guidance in the selection of treatment strategies for individual patients, minimizing unnecessary treatments and side effects for those unlikely to benefit.

Although cisplatin-based neoadjuvant chemotherapy before cystectomy is the standard of care for muscle-invasive bladder cancer, only between 25% and 50% of patients achieve a pathologic response. A study investigating biomarkers that can predict response to chemotherapy in patients with muscle-invasive bladder cancer has found that mutations in DNA repair–associated genes ATM, RB1, and FANCC predicted responses after cisplatin-based chemotherapy. The findings suggest that genetic testing prior to chemotherapy may help guide the selection of treatment strategies for individual patients. The study by Plimack et al is published in European Urology.

Study Methodology

Pretreatment muscle-invasive bladder cancer tumor samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based neoadjuvant chemotherapy provided the discovery and validation biomarker sets in this study. Of these patients, 34 had received accelerated methotrexate, vinblastine, doxorubicin, and cisplatin therapy, and an additional 24 patients received dose-dense gemcitabine and cisplatin therapy.

DNA from the pretreated tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvement Amendments–certified laboratory.

The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set.

Study Findings

Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (P = .024) and validation (P =.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (P < .001; 87% sensitivity, 100% specificity) and better overall survival (P = .007). This test remained predictive for pathologic response in the validation set (P = .033), with a trend toward better overall survival (P = .055).

“Our discovery of a set of mutations that predict therapeutic response suggests that genetic testing prior to chemotherapy may help select appropriate candidates for this approach,” said Elizabeth R. Plimack, MD, MS, Attending Physician of Genitourinary Cancer and Director of Genitourinary Clinical Research at Fox Chase Cancer Center in Philadelphia, and first author of the study, in a statement. “This could help minimize unnecessary treatments and associated side effects for patients unlikely to benefit and improve overall prognosis and survival in patients predicted to benefit the most.”

“We expect that our ability to understand and define the capacity of individual tumors to repair chemotherapy-induced damage will evolve, ultimately leading to improvement and refinement of a predictive signature that can be clinically applied to select appropriate treatments for patients with urothelial and other advanced cancers,” concluded the study authors.

Dr. Plimack is the corresponding author of this European Urology article.

Funding for this study was provided by Fox Chase Cancer Center and the American Cancer Society. Dr. Plimack and Eric A. Ross, PhD, disclosed that they have a patent filing related to the study findings. The remaining study authors reported no conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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