Dr. Robert Bristow On Genomics, Radiation Therapy + Prostate Cancer

Dr. Robert B. Bristow talks with Prostatepedia about the intersection of genomics and radiation therapy for prostate cancer.

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Let’s talk about genomics. Do we have a way of predicting who will respond to radiation? And who will have severe side effects?

Dr. Robert B. Bristow: The short answer is no. My work with my colleagues in Canada involved a huge effort to sequence the entire genome, or the entire DNA network within prostate cancer in patients in the localized setting. What we know in localized disease is that there are a number of patients that under the microscope look like they have the same Gleason score. When we do whole genome sequencing, we see that about a quarter of these actually have a number of genetic rearrangements and mutations within their tumor.

It’s quite clear that the patients who have more aggressive mutations and increased number of mutations actually do worse. The way that they do worse is that they actually fail radiotherapy quite quickly after treatment. We therefore think that genetic instability, or the increased burden of mutation, is associated with hidden metastases as opposed to information about responding to surgery versus radiotherapy.

We’ve looked very hard in the Canadian study for a predictor of who would respond to radiotherapy versus who would respond to surgery. Although some early leads suggested one gene or another, I’m not confident right now that we actually have a marker so that when a patient comes into the clinic, we could do a quick test to say whether his disease was more or less sensitive to radiotherapy. We hope that will change, of course, with further data. But we don’t have it yet.

The other aspect that you pointed out is whether or not radiation side effects are associated with germline or blood DNA. Some data suggests there are specific gene mutations associated with cell growth, the way the cells contact each other, or DNA repair that might put patients at risk for erectile dysfunction or rectal bleeding. A lot of validation studies still need to be completed. It is also not ready for prime time.

Something that has come up in the last two to three years is that patients can have defects in genes associated with DNA repair. Your readers will have heard about the BRCA1 and BRCA2 genes normally associated with ovarian and breast cancer. We now know if you are a male BRCA2 carrier you have an increased risk for prostate cancer and an increased risk of aggressive prostate cancer.

One Canadian study suggested that some of these localized cancers in BRCA carriers already had acquired resistance patterns to hormone therapy and other types of therapy even though they had never seen the therapy. They are almost primed for resistance.

We also know that maybe up to 15% of patients with metastatic castrate-resistance prostate cancer have DNA repair defects. This is important because it speaks to mechanisms of resistance and aggressiveness based on genes in your bloodline. The other important thing we’ve learned in the last five years is that prostate cancer patients with BRCA1 and BRCA2 DNA repair defects respond to PARP inhibitors.

This is a very exciting area of precision oncology using genomics to predict those patients that might respond to a molecular-targeted therapy in this case.

One can only assume that there might be other stories like the DNA repair defect story that would give us more information about different types of tumors.

Dr. Bristow: This comes back to what we were talking about before: carefully designing clinical trials to compare one treatment versus another in large numbers of patients in which there is high content information about the immune landscape, genetics of the tumor, genetics of their bloodline, and functional imaging of the tumors. This will allow us to start to put this information together to come up with a more precise way of treating our patients.

Cancer is complex. The complexities of cancer are for us to discover, but also for us to develop a number of tests that give us a sense of that complexity so that we can use the right treatment for the right patient at the right time.

The promise of genomics in the last decade is now leading to novel treatment for patients. There are still situations for which we don’t know the best treatments. In those cases, patients need to demand from their healthcare givers information about which clinical trials are available to them so that we can solve these questions together. The reality is that we do require clinical trials to answer them.

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