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Genomic alterations predict chemotherapy response in muscle-invasive bladder cancer
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Genomic alterations in certain DNA repair-associated genes predicted response to and clinical benefit from neoadjuvant cisplatin chemotherapy for muscle-invasive bladder cancer, according to the results of a prospective study.
“Chemotherapy before surgery to remove the bladder improves the chance of cure for some patients with bladder cancer, but unfortunately not all patients benefit from this approach,” Elizabeth R. Plimack, MD, MS, associate professor of medical oncology and director of Genitourinary Clinical Research at Fox Chase Cancer Center, told HemOnc Today. “We set out to see whether genetic testing prior to chemotherapy could help select appropriate candidates for this approach. 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.”
Currently, between 25% and 50% of patients with muscle-invasive bladder cancer experience a pathologic response to neoadjuvant cisplatin chemotherapy, according to the researchers.
Plimark and colleagues collected pretreatment samples from patients with muscle-invasive bladder cancer enrolled in two separate clinical trials — forming the discovery and validation sets — of cisplatin-based neoadjuvant chemotherapy. Researchers sequenced DNA from pretreatment tumor tissues for the coding exons of 287 cancer-related genes and analyzed for base substitutions, copy number alterations and select rearrangements.
The study included data from a total of 34 patients in the discovery trial and 24 patients in the validation trial. The researchers observed a total of 728 alterations in 212 genes from the discovery trial and 434 alterations in 170 genes from the validation trial.
Patients who achieved a pathological complete response following neoadjuvant cisplatin chemotherapy had more alterations than those with residual tumor in the discovery (P = .024) and validation (P = .018) sets.
In the discovery set, alterations to one or more of the DNA repair genes ATM, RB1 and FANCC predicted pathologic response — with 87% sensitivity and 100% specificity (P < .001) — as well as improved OS (P = .0007)
The test remained predictive for pathologic response in the validation set (P = .033) and produced a trend towards improved OS (P = .055).
These findings justify further validation in additional sample sets, according to Plimack.
“If validated in larger studies, candidates for therapy for muscle-invasive bladder cancer could be screened for mutations in these genes by quick panel testing,” Plimack said. “Our next study will be to see if we can use this gene signature, in combination with biopsies and imaging of the bladder, to determine whether some patients’ cancers have been eradicated by chemotherapy. These patients may be able to keep their bladders and avoid surgery.” – by Cameron Kelsall
For more information:
Elizabeth R. Plimack, MD, MS, can be reached at Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111; email: elizabeth.plimack@fccc.edu.
Disclosure: Plimack and one other study researcher report a patent pending related to the findings of this study. The other researchers report no relevant financial disclosures.
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