Precision Medicine Circa 2017

Raoul S. Concepcion, MD

Over the years, the term “personalized medicine” has become part of the modern day lexicon in healthcare. In fact, has not medicine, in general, always been personalized? It is very rare that we follow the exact same script for every patient condition that we treat. Taken into account are a number of host factors that determine the optimal pathway: patient’s age, body type, allergies, current medicines, comorbid conditions, life expectancy, imaging findings, etc. At that point, we as physicians outline a treatment plan that will hopefully result in the best possible outcome and, most importantly, pair with patient expectations as a result (this latter point is often overlooked by many).

We are entering the era of molecular testing and screening, which is becoming more ubiquitous and does not require a second mortgage to obtain, as well as the ability to perform next generation sequencing (NGS) on tissue. Medicine, especially in cancer management, has entered the “precision” era. Clearly, our understanding of tumor biology has taken us into uncharted territory. We were prophetic in this column years ago that it would be less about the organ of origin and more about identifying particular pathways that result in these rogue tumor cells surviving, escaping the current therapeutic regimen, mutating, and ultimately causing the demise of our patients.

By now, I am sure many of you have read, or at least are aware of, the article published in the New England Journal of Medicine last year that examined the incidence of germline mutations in DNA repair genes among men with metastatic prostate cancer.¹ In summary, men with metastatic prostate cancer had a significantly higher incidence of germline mutations in DNA repair genes, including BRCA2, compared with men with localized prostate cancer than what was anticipated from prior data sets. In addition, the frequency of these mutations was not significantly different in men with or without a family history of prostate cancer. This finding, combined with the fact that the use of poly (ADP-ribose) polymerase inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC) who were identified by NGS to harbor mutations and deletions in DNA repair genes, heavily pretreated with androgen axis modulators (abiraterone acetate or enzalutamide) and/or taxane chemotherapy (docetaxel or cabazitaxel), showed a significant tumor response.²

The implications here are significant. For our patients with mCRPC, the addition of another mechanistically unique agent to our growing armamentarium of oncolytics, which now includes autologous immunotherapy, androgen synthesis inhibitors, androgen signaling/receptor inhibitors, radiopharmaceuticals and taxane-based chemotherapies, provides another option as we try and stay ahead of these mutational changes. As we are all well aware, the combination of agents, and most importantly, the ability to monitor therapies without tissue biopsy, remains a significant challenge.

But for the practicing urologist, even if you are not going to be actively engaged in treating and managing patients with mCRPC, understanding and appreciating these mutations is critical, especially when it comes to family counseling. In years past, we only concentrated on a family history of first degree relatives with prostate cancer and recommended early PSA screening for these patients. Now, we should also be focusing on obtaining detailed family histories for other heritable tumor types, including breast, ovarian, pancreatic, and others. What is going to be our role in obtaining molecular screening tests now being offered by many vendors across the United States? What would be the timing? Is it for all men that we discover a significant family history, or is it only in men with advanced and aggressive disease? And if we do adopt this philosophy of early testing, does the typical urology office have the bandwidth to manage the fallout and act on the data, specifically in family counseling?

These are all very important issues that as a specialty, we need to be addressing proactively if we want to be viewed as the experts in prostate cancer. Educating our patients and colleagues is a mandate that we should all embrace in order to stay cogent in this rapidly evolving area.

References

1. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453. doi: 10.1056/NEJMoa1603144.
2. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697-1708. doi: 10.1056/NEJMoa1506859.