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. Researchers at Fox Chase Cancer Center have now identified genetic mutations that predict response to chemotherapy in patients with muscle-invasive bladder cancer, opening new avenues for personalized treatment approaches. The findings, published August 5 in European Urology, suggest that defects in the ability to repair DNA damage represent an Achilles heel for tumors, making them more vulnerable to DNA-damaging drugs.
“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, associate professor of medical oncology, and director of Genitourinary Clinical Research at Fox Chase. “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.”
Bladder cancer is the sixth most common cancer in the United States, accounting for about 74,000 new cases and 16,000 deaths each year. When the cancer invades a thick muscle deep in the bladder wall, known as the muscularis propria, the disease is much more likely to spread to other parts of the body. As a result, muscle-invasive cancer is generally treated more aggressively than nonmuscle-invasive cancer. The standard of care for patients with muscle-invasive bladder cancer is a chemotherapy regimen based on an FDA-approved, DNA-damaging drug called cisplatin, followed by bladder removal. However, only 40% of patients respond to this combination therapy, underscoring the importance of identifying molecular biomarkers that could predict responses to therapy.
To search for potential biomarkers, Plimack and her collaborators sequenced genomic DNA extracted from tumor tissue taken from chemotherapy-treated patients with muscle-invasive bladder cancer. Thirty-four of these patients received accelerated methotrexate, vinblastine, adriamycin, and cisplatin (AMVAC) therapy, and an additional 24 patients received dose-dense gemcitabine and cisplatin (DDGC) therapy.
The researchers found that mutations in DNA repair genes ATM, RB1, and FANCC predicted responses after chemotherapy. Eighty-seven percent of patients who responded to AMVAC therapy had an alteration in one or more of these genes, whereas none of the nonresponders had an alteration in any of the genes. Moreover, mutations in one or more of the genes predicted progression-free survival and overall survival in AMVAC-treated patients. Similar results were observed in the independent set of DDGC-treated patients, confirming the initial findings.
The findings could help guide the selection of treatment strategies for individual patients. “Candidates for therapy for muscle-invasive bladder cancer can be screened for mutations in these genes by quick panel testing,” said study author Erica A. Golemis, PhD, deputy chief scientific officer and vice president, and co-leader of Molecular Therapeutics at Fox Chase. “If they are mutated, the patient is likely to respond to AMVAC, making it a better choice. If they are not mutated, the doctor might consider using a different means of treatment, or up-front surgery.” Dr. Plimack notes that another application of these findings could be to allow patients to safely avoid surgery after chemotherapy. “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.”
Before the findings can be implemented in the clinic, the biomarkers will need to be validated in larger independent data sets collected prospectively from homogenously treated patients. “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 bladder and other advanced cancers,” Plimack said.
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Fox Chase Cancer Center, part of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence four consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. For more information, call 1-888-FOX CHASE or (1-888-369-2427).
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