By Scott Tagawa, M.D.
In casual conversations, chemotherapy is often referred to as one type of cancer treatment, but it actually refers to different classes of drugs/medications that work via a similar mechanism.
Taxanes are the only class of chemotherapy agents that have significantly improved survival in men with advanced prostate cancer. These include docetaxel (Taxotere ®) and cabazitaxel (Jevtana ®). Though there have been exciting advances in hormonal therapies, bone-targeted therapies, and immunotherapies that have led to a multitude of FDA-approved therapies for patients, chemotherapy is a mainstay.
Chemotherapy was initially approved because men with advanced prostate cancer felt better and in less pain after receiving it. In 2004, docetaxel chemotherapy was approved because it made men feel even better than the older chemotherapy and it also controlled the prostate cancer well enough to lead to longer lifespan. However, the use of chemotherapy was initially limited due to fears of side effects and since 2011, additional medicines have been approved.
The recent success in large clinical trials using taxane chemotherapy has demonstrated unprecedented survival advantages when these drugs are used early. The CHAARTED and STAMPEDE trials showed a much larger improvement in survival compared to any treatment that has been studied in the modern era. Additional trials of men with earlier stages of prostate cancer have also pointed towards patient benefit. However, not all men respond to this treatment and despite improvements in quality of life for symptomatic men with advanced cancer, side-effects do exist. As a result, there is interest in identifying markers that can more accurately identify patients who will respond to this treatment and those for whom taxane chemotherapy is less likely to work. Many efforts are already in the works and progress has already been made.
A genetic alteration known as TMPRSS2-ERG that was co-discovered by Weill Cornell Medicine (WCM)’s Dr. Mark Rubin, Director of the Caryl and Israel Englander Institute for Precision Medicine, is unique to prostate cancer and present in tumors in about 50% of men with prostate cancer. Interestingly, we later discovered that the protein created by this gene fusion called ERG binds to tubulin, which is the molecular target of taxane chemotherapy.
Because of this protein’s interaction with tubulin, there is interference with the “drug-target engagement” of taxanes, leading to resistance. With this scientific discovery, in addition to outlining the mechanism and demonstrating drug-resistance in lab experiments, WCM investigators in collaboration with a group in Sydney tested tumors from human patients that received docetaxel chemotherapy. In this small group of men, those whose tumors expressed ERG were less likely to respond to docetaxel.
In a recent publication, Spanish investigators built on this discovery and identified TMPRSS2-ERG as a biomarker present in the bloodstream, making it a potentially easy way to use a blood test to predict resistance to taxane chemotherapy. This group of scientists from Barcelona used a blood test in men with advanced prostate cancer prior to starting docetaxel or cabazitaxel chemotherapy to determine the presence of TMPRSS2-ERG. Their work confirmed that men with tumors harbouring the gene fusion have resistance to this type of chemotherapy.
Though additional research is ongoing (and needed), there are now a number of treatment choices available. In the near future, physicians might be able to pick the drug that is most likely to work on an individualized basis, perhaps even through a simple blood test. This is another step towards our goal of precision medicine: the right treatment for the right patient at the right time.