A major challenge in treating cancer is that people respond very differently to chemotherapy. Only about half the people with muscle-invasive bladder cancer respond to chemotherapy, and the cancer spreads uninhibited among the others. Now researchers have found a way to better identify who will benefit from chemotherapy. Ultimately, this will enable optimization of treatment, thereby avoiding overtreatment and unnecessary side effects. The method is currently being tested in a major clinical trial before potential clinical use.
Injecting chemotherapy into the arm of a person with bladder cancer is currently like a lottery. The right combination of genes and proteins enables cisplatin to eliminate the cancer cells. The wrong combination means that the chemical effects of this drug may do more harm than good to an already weakened body.
“We have studied changes in the cell’s key molecules – genes, RNA molecules and proteins – among 300 people with muscle-invasive bladder cancer. This clearly shows that chemotherapy reacts more efficiently to the cells with major changes in the genome and with repair mechanisms that do not function properly. In addition, we found that the immune system plays a major role. The chemotherapy was less effective on tumours that were unable to attract immune cells. In our future studies, we will screen patients for these molecular changes and test whether our predictions hold true, so that we ultimately can treat everyone optimally,” explains Lars Dyrskjøt Andersen, Professor, Department of Clinical Medicine, Aarhus University.
Works best in imbalance
The new results are based on molecular analysis of tumour tissue and blood samples collected from people with muscle-invasive bladder cancer over 20 years. The researchers carried out the most comprehensive analysis so far of the effectiveness of chemotherapy on this type of cancer: multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics).
“This means that we have studied different molecular layers and compared these to enable us to optimally characterize tumours. We have studied the genome, RNA molecules, which are copies of genes and templates for proteins, and specific proteins associated with the immune system. Finally, we performed epigenomic analysis, which examines changes on the surface of the genome,” says Lars Dyrskjøt Andersen.
Comparing the results from the various molecular layers of the tumours from the 300 patients enabled the researchers to determine which tumour biomarkers were associated with response to treatment with cisplatin, which is typically used to treat people with bladder cancer.
“Chemotherapy had a strong effect on cells with major imbalance in the genome in the form of a significantly higher number of “indels”, which are fragments of DNA that are either lost or inserted, and many mutations in genes such as BRCA2, which usually ensures that damaged DNA is repaired. These genomic changes may have also caused the cancer to develop more aggressively,” explains Lars Dyrskjøt Andersen.
Cisplatin chemically interferes with DNA replication and repair, leading to apoptosis (cell death). However, cisplatin must first enter the cells, and rapidly growing and dividing cells therefore normally absorb more of it, but some bladder cancer cells manage to resist this drug.
Reducing treatment time
The researchers also found that tumours with a high infiltration of immune cells responded better to the treatment. They especially found that the programmed cell death protein (PD-1), which is on the surface of immune cells and helps to regulate the immune system, was associated with better chemotherapy response.
“Our study indicates several complex molecular changes that can effectively differentiate people who respond well and poorly to chemotherapy. If our findings are validated, this could reduce treatment time for people predicted to respond poorly to chemotherapy, thereby avoiding the extensive side effects of chemotherapy,” says Lars Dyrskjøt Andersen.
People treated for bladder cancer typically receive chemotherapy before the bladder is removed and possibly at later stages of the disease if metastasis is detected. The researchers therefore hope that the new knowledge can save precious time, pain and weakening by identifying the people who will not respond to chemotherapy. These patients may instead proceed directly to surgery or receive other treatment such as immunotherapy.
“We have made such great progress that we are now testing our analysis in a large national prospective validation trial before potential clinical use. In the new study, immunotherapy is also given earlier than usual based on biomarkers in the blood,” concludes Lars Dyrskjøt Andersen.
“Molecular correlates of cisplatin-based chemotherapy response in muscle invasive bladder cancer by integrated multi-omics analysis” has been published in Nature Communications. The main authors are from Aarhus University: Ann Taber, PhD Fellow; Emil Christensen, Postdoctoral Fellow; and Philippe Lamy, Associate Professor. In 2017, the Novo Nordisk Foundation awarded a grant to Lars Dyrskjøt Andersen for the project Implementation of Predictive Biomarker Models for Stratifying Bladder Cancer Patients to Optimize Therapy (INSTRUCT).