Charles Ryan: Hello, I'm sitting with Arjun Gupta from the University of Minnesota and Alicia Morgans from Dana-Farber, and we're talking about a really innovative study that they've just presented that looks at the role of the genetics of the patient and their response to painful stimuli, or cancer pain. Arjun, Alicia, great to see you. Tell us a little bit about the background of your work, Arjun, how you came about to study this interesting confluence of genetics and the pain experience or the experience of the patient.

Arjun Gupta: Thank you. So we know that in non-cancer populations that a patient's neurobiology, the level of neurotransmitters in their brain and genetic variants in these neurotransmitter metabolism genes can affect peoples response to placebo therapies. So what we know is that if a patient gets a placebo response, their experience, their subjective feeling, their quality of life can vary just by what their neurobiology is. But no one's ever really looked at this in a cancer population, and also hasn't looked at what the impact of a cancer treatment on this complex interplay with the genetics and the quality of life might be. So that's why we sought to explore this in a clinical trial.

Charles Ryan: So Alicia, you have been the mentor to Dr. Gupta here on this project. And tell us a little bit about how you decided where to look, because it's a challenging set of clinical scenarios in which you want to be able to tease out or find this effect.

Alicia Morgans: Sure. So really this work, which I am so appreciative, is funded by the Prostate Cancer Foundation, is based on trying to use data that has already been collected. Because to your point, this is information that wouldn't necessarily be something we would collect in routine clinical practice and is not captured in the majority of clinical trials. So what we needed was genetic information to understand the underlying biology of the patient. We needed a clinical trial that exposed the patient to some insult or some sort of exposure. In this case, either androgen deprivation therapy or ADT plus chemotherapy. And we needed, really, a robust capture from the patient's perspective of what the quality of life experience was during that treatment. And we hoped to see that people who had different polymorphisms of the COMT gene, and we'll hear more about this in a minute, might have different feelings or experiences during the exposure to treatment.

The trial that we really investigated for this work is the CHAARTED trial, which people might know from many years ago, was the initial study that looked at patients with metastatic hormone-sensitive prostate cancer and treated them with either ADT, or chemohormonal therapy, which is ADT and six cycles of docetaxel. And it was within that context that we were able to really pull out this information.

Charles Ryan: Clearly, a practice changing trial from many, many years ago. But we continue to be able to analyze data, which is in part because of the fact that it was sponsored by the National Cancer Institute, all these specimens were collected and available for you these many years later. So tell us about the COMT gene, and why does this matter for cancer patients?

Arjun Gupta: Of course. So all of us have dopamine in the brain. Dopamine is a chemical and neurotransmitter. Higher levels of dopamine are generally associated with better mood, better quality of life, better feelings in general, and less pain. And so the COMT gene or the Catechol-O-methyl transferase gene actually breaks down dopamine. So higher levels of COMT will actually drop your dopamine levels in the brain. So if you have a genetic polymorphism, which is inherited, it's in your body, that prevents COMT from acting, it actually raises dopamine levels in the brain.

So what we're seeing in these placebo studies in non-cancer populations was that if you had this specific variant in the COMT gene, the RS4860, it would actually lead to higher levels of dopamine in the brain and those patients would have a better placebo response or better quality of life. So a priori, we hypothesized that in the CHAARTED study, for patients who have this specific genetic polymorphism, their experience with pain and quality of life would be better compared to people who did not have the polymorphism.

And as Dr. Morgans pointed out, the CHAARTED study was collecting every three month quality of life data, including the brief pain inventory and the FACT-P, which is the functional assessment of cancer therapies, the prostate subscale, on all of these patients, so we could track that over time.

Charles Ryan: So this polymorphism is not rare.

Arjun Gupta: Yes, it's seen in approximately 40% of the Caucasian population.

Charles Ryan: So it's almost a 50/50 split. Some of us have the slow variant and some of us have the fast variant. It affects how we perceive pain, and really the world, and maybe even experience pleasure. So tell us what you found.

Arjun Gupta: Absolutely. So I'll broadly just recap. There were approximately 790 patients in the clinical trial. We had data available for 550 of them, and we analyzed their longitudinal pain and quality of life scores for patients in the ADT alone arm, who were just getting androgen deprivation therapy. We found that patients with the COMT variant of interest had improved quality of life and less pain. So things looked great. So the COMT was actually predictive of better quality of life. But in patients in the ADT plus docetaxel arm, there was no such difference. And so this benefit of COMT was limited to the ADT alone arm.

Charles Ryan: So does this mean that docetaxel was an effective enough therapy to essentially eradicate any difference that could emerge from this genetic variant?

Arjun Gupta: I think we don't know what exactly the mechanism was. It may be that docetaxel was interacting with this neurobiology in some way that we don't exactly know. I think this work is still very preliminary. We've just looked at two PROs, or patient-reported outcomes in a single trial. I think this is hypothesis generating work, for now.

Charles Ryan: So Alicia, how can you integrate this into the broader field of cancer survivorship, and the biology of survivorship?

Alicia Morgans: Well, I think certainly we would want to assess this in other treatment categories and actually see if we can replicate this initial finding in other studies. So we certainly are going to be reaching out to collaborators to see if those with access to things like STAMPEDE might be amenable to looking within their data sets. One thing that I think is important to consider is that the symptom burden related to treatment with docetaxel is pretty pronounced in the CHAARTED study, and I wouldn't say that it's any different than in our clinical practices, but it does cause meaningful changes in the patient reported outcome measures. And that was certainly reported from the CHAARTED data years and years ago.

That more dramatic shift in patient experience related to exposure to chemotherapy may have been enough to overcome any benefit that we might see from an underlying genetic sort of resilience or inherited resistance to feeling those symptoms. And so it may be that in some treatment combinations we see that COMT may play more of a role, whereas in others, the symptom burden related to the treatment itself may overpower that. So I think it's important to investigate across the board, but the first thing we need to do is replicate the findings.

Charles Ryan: Yeah. Really fascinating findings. I love the idea of integrating the biology of the patient with the therapy that's being given, and the patient outcome. It really is a very interesting story and we'll really want to follow that. And congratulations on the results and best of luck with the future research.

Alicia Morgans: Thank you.

Arjun Gupta: Thank you for the support.