Who Responds to Chemotherapy for Bladder Cancer?
(By Jeni Crockett-Holme)
Keywords: Bladder cancer, Biomarker, Chemotherapy, Genes, Cisplatin
Individual genes play roles in cancer [1,2]. Patients can be tested for specific genes, called biomarkers, to guide treatment for some types of cancer, but this type of genetic marker has been missing for bladder cancer [1,3]. When bladder cancer has spread to adjacent muscle (muscle-invasive bladder cancer), it tends to spread to other areas of the body (metastatic disease). Chemotherapy before surgery is given to prevent this spread, but it works in only about one-third of patients [3,4]. Biomarkers are needed to predict which patients will respond to and benefit from presurgical chemotherapy for muscle-invasive disease .
A study was performed to discover genes within bladder tumors that might predict which patients would respond to chemotherapy for muscle-invasive bladder cancer . The investigators analyzed genes in tumor tissue collected before patients received chemotherapy with the drug cisplatin. They sequenced the genes in the tumor tissue  and used statistical analysis to compare the association of individual gene mutations with patients’ response to chemotherapy.
Patients who had no tumor left or had a tumor that was less aggressive after chemotherapy were considered responders; patients whose tumors grew or did not change were considered nonresponders. One analysis was performed to discover genes that could be biomarkers, and another was performed to confirm the findings. The second analysis used tumor tissue from a group of patients that received a different but similar type of chemotherapy that also contained cisplatin.
The investigators found what they were looking for in three of the genes analyzed. DNA gives instructions to individual cells, and those instructions can become confused when DNA is damaged or broken, resulting in a mutation . The investigators found mutations in three genes, called ATM, RB1, and FANCC. The normal function of these three genes is to repair damaged DNA in other genes . Patients with a mutation in one or more of these genes were more likely to respond to chemotherapy and tended to live longer. Patients who had no tumor left after chemotherapy had more mutations in these genes than patients who still had a tumor following chemotherapy.
What do the results tell us?
ATM, RB1, and FANCC repair DNA, and when they are mutated, they are less effective at that job [2,3]. The investigators speculated that bladder cancer cells become vulnerable to damage from chemotherapy because their DNA cannot be repaired by the mutated genes.
The presence of these genetic mutations constitutes a biomarker for muscle-invasive bladder cancer. A patient who has this biomarker is more likely to respond to presurgical treatment with chemotherapy that contains the drug cisplatin. Testing for this marker before chemotherapy may help determine whether a patient is likely to benefit from chemotherapy—it will not determine who will not benefit over the long term. It is a marker of chemotherapy response, not resistance. Nevertheless, this approach can help guide and personalize treatment.
 The Cancer Genome Atlas. Impact of cancer genomics on precision medicine for the treatment of cancer. http://cancergenome.nih.gov/cancergenomics/impact. Accessed November 9, 2015.
 Cancer Research UK. Genes, DNS, and cancer. http://www.cancerresearchuk.org/about-cancer/what-is-cancer/genes-dna-and-cancer. Accessed November 9, 2015.
 Plimack ER, Dunbrack RL, Brennan TA, et al. Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Eur Urol 2015;68:959–67.
 Cancer Research UK. Types of bladder cancer: invasive bladder cancer. http://www.cancerresearchuk.org/about-cancer/type/bladder-cancer/about/types-of-bladder-cancer#invasive. Accessed November 9, 2015.
 National Human Genome Research Institute. DNA sequencing. https://www.genome.gov/10001177. Accessed November 16, 2015.