Personalized Medicine in Prostate Cancer: Now More Precise

Over the past decade, we have witnessed an explosion of molecular testing in the urology world that will help us better diagnose and manage prostate cancer across the spectrum of the disease. All of us recognize that we have fallen behind our colleagues who treat other tumor types and for whom routine lab and tissue testing is the requirement or norm for optimal therapeutic choices. However, we are making progress.

We know that prostate cancer is an endocrine disease and the androgen receptor (AR) plays a major role in disease progression, even when serum testosterone is at castration levels of the hormone. Androgen deprivation therapy (ADT) continues to be the foundation of treatment on which all other oncolytics are layered as the patient begins to progress. However, treatment pressure selection and tumor heterogeneity will result in cellular mutagenesis that makes ultimately eradicating the disease a daunting task. In patients with metastatic castration resistant prostate cancer, a number of these mutations, which will inevitably confer resistance to therapy, have been discovered. For example, prostate cancer cells that have been long exposed to ADT and are now starved of their fuel for survival can produce their own ligands to survive. This is comparable to a car that could produce its own gasoline (or electricity)—very nice if you are the automobile owner—but the reality is not so desirable for the patient with cancer. AR, the very target of ADT, can undergo genetic alterations that will result in downstream changes leading to resistance and cell survival.

Fortunately, we are in the early stages of developing biomolecular markers that will help the clinician to choose better therapies to try to stay ahead of these mutations. The ability to measure circulating tumor cells has led to the development and marketing of commercial assays to detect these aberrations—AR splice variants—that may be predictive of what agent should be used next in the treatment paradigm. In addition, patients who harbor homozygous mutations of inherited DNA repair genes, most notably BRCA2, may in fact respond to PARP inhibition therapy. Also, DNA sequencing to test for these gene mutations can now be clinically implemented in the appropriate patient.

Thus, just as it is difficult to keep track of all the FDA-approved therapies, their mechanisms of action, adverse event profiles, and current approval status, we are additionally challenged to stay up-to-date with the molecular tests that may ultimately be required to determine when and where to use these drugs in the appropriate sequence for each patient. The vernacular commonly used in the press is the “era of personalized medicine.” I will argue that the art of medicine has always been personalized. We as providers do not adhere to a single agent, from an antibiotic to an antihypertensive to an oncolytic, for all patients. All of us consider the patient’s medical history and comorbidities and a host of other factors to best determine which agent to prescribe in hopes of achieving the best outcome. Now, given the complexity in understanding these malignancies and their ability to undergo evolutionary mutations to survive, we must clearly understand how to accurately test and target these dynamics to stay ahead of the changing tumor environment. Personalized yet ever more precise at the tumor level—precision medicine. This is how all of us will need to practice moving forward to continue making strides in advancing cancer care.