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Results from a multi-institutional study led by a Cleveland Clinic researcher, DCSionRTĀ®, a biosignature based on multiple biomarkers, may hold the key to solving the treatment of ductal carcinoma in situ (DCIS). Chirag Shah, MD, coinvestigator, and director of Breast Radiation Oncology at Cleveland Clinic joins the Cancer Advances podcast to explain the study and findings that were presented at the American Society for Radiation Oncology annual meeting (ASTRO).

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Biosignature Predicts Benefit of Adjuvant Radiotherapy in Patients With DCIS

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research in clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma programs.

Today, I'm happy to be joined by Dr. Chirag Shah, Director of Breast Radiation Oncology and co-investigator of a clinical trial that we're going to discuss today. It was recently presented at the annual American Society for Radiation Oncology Meeting (ASTRO). Dr. Shah has been a guest on the previous episode of Cancer Advances, where he discussed the evolution of radiation for breast cancer. He's here today to talk to us about the research he presented on a biosignature that predicts benefit of adjuvant radiotherapy in patients with ductal carcinoma in situ. So, welcome, Chirag.

Chirag Shah, MD: Thanks. Thank you for having me back.

Dale Shepard, MD, PhD: Absolutely. So maybe you can start off, remind us a little bit about your role here at Cleveland Clinic. What do you do here?

Chirag Shah, MD: Sure. So, I'm a radiation oncologist in the Taussig Cancer Institute and I specialize in radiation therapy for breast cancer as well as soft tissue sarcomas. I serve as the director of breast radiation oncology, as well as the director of clinical research in our department.

Dale Shepard, MD, PhD: Excellent. Well, we're going to be talking about clinical research today. So tell us a little bit about the research that we're going to talk about today. What is the background? What question were you trying to answer and what were you hoping to find?

Chirag Shah, MD: Yeah. So, ductal carcinoma in situ, which is stage zero breast cancer, is a common cancer, so it's about 25% of all new breast cancer diagnoses. And over the past three decades, we've really tried to figure out how to thread the needle between over treating and under treating DCIS or ductal carcinoma in situ, and for a long time, the standard has been lumpectomy and radiation. We've done studies in the past looking to omit radiation, based on features we see in a pathology report, as well as patient factors such as age, but what we found time and time again is that the rates of recurrence are still quite substantial. And why that's important is that half of the recurrences we see in patients with DCIS are actually invasive recurrences, which can be associated with increased risk of breast cancer mortality.

So as we weren't able to find clinical and pathologic features that portended a higher risk of recurrence, we started looking at tumor genomics and biosignatures, and so that's where this project was really based. The idea was to look at a biosignature in patients with DCIS, to identify really three cohorts of patients. One cohort who have a low risk of recurrence and who most likely don't need radiation therapy, an elevated risk group of patients who have a good response, who would do well with lumpectomy and radiation, and those patients with elevated risk and a poor response subtype, which may require additional therapies, given persistently elevated rates of recurrence after standard treatment.

Dale Shepard, MD, PhD: So when you're talking about trying to avoid over or under treating, you're really trying to say, who do we need to treat and who don't we, and that's where we break into the good and bad response, for instance, for elevated risk. Now, where did you come up with the idea of what genes or what signatures might be important?

Chirag Shah, MD: Yeah. So, our study was based on a collaboration with a company called PreludeDX, which has created this assay called DCISionRT. And it includes multiple factors in genes, including Ki-67, which is a proliferation marker, as well as markers such as HER2, which we've obviously studied in breast cancer, as well as other genes including COX-2, CIA-2, FOXA1 and P16. So the idea was to create a assay and a biosignature that allows for the assessment of biologic risk. Dale Shepard, MD, PhD: And so, I mean, just give us an idea, take a step back about magnitude. You talk about some patients having a low risk already, but this being a common cancer and unfortunately, a lot of relapses, how many patients are we talking about a year?

Chirag Shah, MD: So in the United States, there's about 60,000 women diagnosed with DCIS each year.

Dale Shepard, MD, PhD: All right, so it's not an insignificant problem, and so if we can minimize the risk of side effects from treatment or make treatment better, that's certainly helpful. So how'd you do the research? What happened?

Chirag Shah, MD: So the research is actually an analysis of three cohorts of patients treated in the United States, Australia, and Sweden. We initially started with 485 women in our study, and these were women who had long-term outcomes following treatment with DCIS available. We ran the DCISionRT analysis on them, and then what we wanted to look with was a group of patients who we almost always say, "Oh, you need treatment. You're high risk, you need treatment." So in DCIS that's typically patients with grade three disease and larger tumors, which is typically two and a half centimeters. And so we found about 250 women that matched those criteria, and we did the assay on them. And so about 72% of them were found to be elevated risk and the rest were found to be low risk. And in the low risk group, we looked at the role of radiation therapy and we found no benefit to radiation therapy with this low risk cohort.

Within the elevated risk cohort, we saw clear benefit to radiation and worse outcomes, as compared to the low risk group. But then when you look at the response subtype, this is where there's really some new findings. So within the elevated risk group that had a good response type, they had a substantial reduction in risk of recurrence with radiation. However, in the elevated group with a poor response subtype, no benefit the radiation was seen with quite elevated rates of recurrence of almost 25% at 10 years.

Dale Shepard, MD, PhD: So essentially, looking back at the data you presented, so clinically you would've expected some of these patients at high risk, but even there you found a fair number that probably didn't necessarily fit in that high risk group, right?

Chirag Shah, MD: Yeah. I think that's the key takeaway, Dale, is that we tend to assume homogeneity within patients having similar pathologic features, but what we're realizing is when you look at tumor genomics and biosignatures, there's actually true heterogeneity, even within perceived high risk patients with DCIS.

Dale Shepard, MD, PhD: And so really our ability to predict without these measures is not all that good.

Chirag Shah, MD: That's exactly right. I think that's the key takeaway, is I think sometimes, we rely on these clinical and pathologic features, but what this study and other studies in this area have shown is that, that we're not very good at prognosticating based on those features.

Dale Shepard, MD, PhD: And so what are some of the limitations? How do we move this forward and make this more of a mainstream diagnostic test?

Chirag Shah, MD: So the limitations are obviously, a 250 patient study is quite large, but still in the spectrum of DCIS, a relatively small study. The patients were followed for 10 years, so they were already treated in a previous kind of generation of treatment standards. How we move forward is we actually have prospective studies underway evaluating this, including one at the Cleveland Clinic, looking at this assay prospectively. We also have data being done on studies of patients that were randomized, so being able to use randomized data and then retrospectively running this assay in a randomized trial cohort, to look at this and provide long-term data as well. And those results are expected in the next year or two.

Dale Shepard, MD, PhD: All right. So, things are in the works and we'll find out more. Is it thought that there will be even additional genes or markers that we can look at that might further refine these groups and lead to even better outcomes?

Chirag Shah, MD: It's a great question. I think right now, the assay is showing itself to be quite good in terms of being predictive and prognostic, so I don't see us adjusting the biosignature at this time. That being said, as we learn more about how DCIS works, we may end up adding genes as those genes become identified and can then be added.

Dale Shepard, MD, PhD: So as a very, very practical question, woman shows up in a radiation oncologist's office, what's the biggest barrier, either from the patient standpoint or from the treating provider standpoint, in adopting some of these changes? So is it more trying to convince someone, either the patient or doctor, that there is no need for treatment, or is it trying to push people to get a therapy? Sometimes there's a thought that, well, I need more and maybe they don't. How do we approach that sort of real world clinical scenario?

Chirag Shah, MD: Yeah. So from the patient perspective, I run into two patient groups in this situation. So I have one patient group that are very motivated to get a test like this, who are saying, "If it's not going to help me, I'd prefer not to have treatment." And so they are actually championing tests like this to say, "Hey, I would love to have my own individual risk stratification, rather than using these kind of large generalized metrics." The other group are the patients who feel like more is more, even if it's only marginal, and I think with them, it's really educating them on the pros and cons of treatment and how, if this test, for example, shows they have little benefit to treatment, that the side effects may not be warranted, given that they have such a limited benefit.

On the clinician side, I think there's a fair amount of education that needs to be done, this is a relatively new area of work on the radiation oncology side. This has been part and parcel of our colleagues in the medical oncology side for some years now, and it's now finding its way into radiation. So I think educating clinicians on this test and how it can be used to help pick the best treatment for patients is really important in how it gives them another tool to really risk stratify their patients.

Dale Shepard, MD, PhD: And I guess, again, just to frame the importance of this. So oftentimes, the therapies that we give aren't exactly benign, and so as we try to avoid having women get radiation that they might ordinarily not need because of this, what are the side effects? Why would we necessarily not want someone to get radiation?

Chirag Shah, MD: So obviously, radiation techniques have evolved over the years and in the past, we had more toxicity concerns, but even still, there are some side effects that can be associated with modern radiation. Side effects we commonly see is some mild fatigue during radiation, some redness of the skin, in rare cases some peeling of the skin under the fold of the breast and the corner of the arm, which typically heals within a few weeks. And again, while we've done a lot to advance cardiac and pulmonary radiation sparing techniques, there is still some dose that's given to the heart and lungs, and in theory that may be associated with heart and lung side effects downstream.

Dale Shepard, MD, PhD: And so this particular work is focusing on DCIS. Other areas of breast cancer that we're going to be working on similar questions?

Chirag Shah, MD: Yeah. There's actually a large amount of study on an early stage invasive cancers using this type of biosignature, as well as other biosignatures. And I think the same idea is that in early stage breast cancers, if we can pick out the patients who don't really derive a benefit from radiation, that we can omit radiation in them and follow them closely with surveillance, mammograms, and/or MRIs. So that work is also underway using multiple different assays at this time.

Dale Shepard, MD, PhD: And then to even take that a step further, is there any role for predicting, for palliative therapy for metastatic disease, for instance, or any other settings? I mean, do we think we're going to get to a world where we pretest people to assess their responsiveness to radiation?

Chirag Shah, MD: Yeah. It's a great question, and I think that we're starting to see more of that, not as much in the metastatic space yet, or oligometastatic space, but definitely in the Stage I to III setting. So for example, we have a national cooperative group trial open at the clinic looking at this question in Stage I patients, where the assay's done prior to decision on radiation. And we have a trial open as well for Stage III patients, looking at the role of radiation in limited nodal involvement, so one to three lymph nodes involved, using again, common tumor assays such as Oncotype. So I think that's definitely in the works. I think that in the years to come, we'll probably also see similar assays to look in patients with oligometastatic breast cancer, to see if aggressive treatments like SBRT will be beneficial.

Dale Shepard, MD, PhD: And so, having just mentioned things like SBRT, and since we have you available to give us some information about radiation and breast cancer, is there anything related to changes in techniques that might impact us as well?

Chirag Shah, MD: Yeah. So we've seen advances in radiation therapy, and particularly stereotactic body radiation therapy, which is SBRT, and this allows for a very high doses of radiation to be given to very small, finite areas with very low dose elsewhere. And so this technique can be used to treat limited metastatic disease or oligometastatic disease. There was recently the publication of the NRG-BR001 trial, which demonstrated the safety and efficacy of this approach in women with oligometastatic breast cancer. We also have data from the SABR-COMET trial, which demonstrated a substantial benefit to the use of SBRT in oligometastatic cancer, with 20% of those patients being breast cancer patients. So this innovation in breast radiation and radiation therapy in general, is allowing for ablation of limited metastatic disease using these techniques with very low side effect profiles.

Dale Shepard, MD, PhD: Well, it sounds like you're doing great work to try to find the right therapy for the right patients in the right setting, so I certainly appreciate all the work you're doing. Any other insights?

Chirag Shah, MD: I mean, I think the biggest insight is that we're really trying to use new radiation techniques, to provide patients individualized radiation therapy plans based on their disease, as well as their wishes with respect to balancing treatment efficacy and side effects. I think radiation's evolved dramatically, to the point where we can use things like cardiac and pulmonary sparing, breast radiation and SBRT to not only improve outcomes, but improve quality of life for patients undergoing treatment.

Dale Shepard, MD, PhD: That's outstanding. Well, thanks Chirag. Appreciate you being with us today.

Chirag Shah, MD: Thank you Dr. Shepard.

Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget, you can access realtime updates from Cleveland Clinic's Cancer Center experts, on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening, please join us again soon.

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