Breast Cancer Recurrence

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 one in sarcoma programs. Today I'm happy to be joined by Dr. Chirag Shah, a physician in the Cleveland Clinic's Department of Radiation Oncology and co-director of the Breast Cancer Program. He was here as a guest on this podcast twice in the past, once to talk about the evolution of radiation therapy for patients with breast cancer, and also to talk about a bio-signature to predict the benefit of adjuvant radiation on patients with DCIS. He's here today to talk to us about local and regional recurrence of breast cancer. So welcome back, Chirag.

Chirag Shah, MD: Thank you so much.

Dale Shepard, MD, PhD: So maybe just start out, you can remind us about your role here at Cleveland Clinic.

Chirag Shah, MD: Sure. So I'm a radiation oncologist who specializes in breast cancers and soft tissue sarcomas, and I have the pleasure of serving as the director of breast radiation and the co-director of the Breast Program here as well.

Dale Shepard, MD, PhD: Excellent. So happy to have you back. We're going to talk about breast cancer recurrence. When you talk about breast cancer recurrence, maybe just give us a broad overview. Maybe start out when people have recurrences and how common recurrence is. Just a really broad overview to start out.

Chirag Shah, MD: So when we talk to patients about recurrences, we really lump recurrences in breast cancer into two types of recurrences. One are called local regional, meaning recurrences happen on the breast or the chest wall, or in the lymph nodes adjacent under the armpit, above the collar, or in between the ribs. And they're distant, where the cancer is spread beyond this local regional phenomenon. And I think the great news across the board is these numbers continue to go down. To put it in perspective, when I trained more than 15 years ago, I would often quote women a 35% risk of local regional recurrence without radiation, and somewhere around 15% at 10 years. The most recent clinical trial published in Lancet showed a 4% local recurrence rate at 10 years. So even in just the 15 years, we've seen a massive reduction in local regional recurrences. Similarly, we've seen reductions in the rates of distant metastases as we've learned more about biology of cancers and targeting therapies and intensification to those patients at highest risk of developing distant metastases.

Dale Shepard, MD, PhD: And we'll talk a little bit more about this in detail, but it's pretty impressive to think that less than a third of the recurrences that you saw in the past. What's the biggest driver for that?

Chirag Shah, MD: I think it's multidisciplinary. I think it starts having surgical colleagues and standardized guidelines for margins, and making sure that we're doing lumpectomies and mastectomies with clean margins. I think it's advances in systemic therapy, which have been associated with reductions in local regional recurrences. And then I think it's in advances in radiation therapy allowing not only for the delivery of radiation, but such that the therapeutic ratios have gone up. So the benefit of radiation exists without as many of the long term side effects associated.

Dale Shepard, MD, PhD: And again, before we get into some specific research that you've participated in, who's most at risk?

Chirag Shah, MD: So when we think about patients who are highest risk of local regional recurrences, it tends to be driven by patient and disease factors. So younger women tend to be the higher risk for local regional recurrence and older patients with the same cancers. Patients who have high risk biologies, we tend to think of things like triple negative breast cancer as a higher risk biology. We also think about patients who have adverse features, so more advanced cancers, meaning cancers that present with more advanced involvement of the lymph nodes, more advanced cancer within the breast itself. Those tend to be the driving factors for recurrence when we look at these patients.

Dale Shepard, MD, PhD: All right. So this year at our annual oncology meeting, this ASCO meeting, there was some data that was presented about a bio signature. Give us a little bit of a background on that.

Chirag Shah, MD: Yeah, so this signature is something that we've been involved with in working on for the past few years, and the idea has really been to look at the risk of recurrences in a subset of breast cancer patients with DCIS or stage zero. And people often ask me, "Why does this matter in stage zero disease?" Well, the reason is that when you look at women who have DCIS who undergo lumpectomies, and they don't have adjuvant therapy, the risk of recurrence is double in the breast. But also half of those recurrences are invasive recurrences, and that's really the issue. So I tell patients we treat DCIS to avoid invasive recurrences, which have been shown in the NSABP trials to be associated with an increased risk of breast cancer mortality. That being said, we want to really tailor treatment to patients who are truly at risk of recurrence.

We want to avoid overtreatment and we want to avoid undertreatment, so we can really optimize the therapeutic ratio and thread that needle of not over or undertreating patients. And that's where the bio-signature comes in. We've previously looked at this bio signature and said we created three groups. One is a low risk group, one is an elevated group and one is a residual risk group. And low risk has been shown to have really no benefit to radiation post lumpectomy. Elevated has been shown to have a benefit to radiation post lumpectomy with respect to recurrences. And residual has been shown to have increased risk of recurrence even after lumpectomy and radiation, suggesting further intensification of therapies being needed. The next part of this question is how does endocrine therapy play into all of this? We have good studies showing that endocrine therapy reduce the risk of recurrence in the breast, as well as in the contralateral breast.

And so it's commonly offered to women post lumpectomy for DCIS. What our study looked at was how the bio-signature really assessed endocrine therapy and the improvement in outcomes. For low risk patients, what the study showed is that irrespective a receipt of radiation, there was no benefit to the addition of endocrine therapy with respect to recurrence as at 10 years. So even in patients who didn't get radiation, there was still no benefit to endocrine therapy. Interesting on the other side, when you look at patients who are elevated or residual risk, they did have a benefit to radiation... Sorry, benefit to endocrine therapy, but when those patients got radiation, the benefit to endocrine therapy disappeared. And so there's some suggestion that when these patients benefit from radiation, they may not need endocrine therapy. And conversely, if they choose not to accept radiation therapy, that we really should consider endocrine therapy for those patients, helping to risk stratify treatments and make patients able to make decisions on which treatments they prefer and which they don't, to minimize their risk of recurrence while considering toxicity profiles.

Dale Shepard, MD, PhD: And so if we look at that group where there's a benefit to endocrine therapy or radiation therapy, how are those decisions made and who's making those decisions?

Chirag Shah, MD: I think that's the privilege of working at a place like the Cleveland Clinic. I think it's done in a multidisciplinary fashion. It's done in conjunction with the patient using really an informed decision making model. We talk about the pros, the cons of each treatment approach. We talk about the data supporting it, and then we work with the patient to make a decision that's most aligned with their values and their goals of care.

Dale Shepard, MD, PhD: So when we think about this signature, and you've used it in a number of settings, what's next within this group? Are there further questions we're going to be looking into in this particular group of patients?

Chirag Shah, MD: Yeah, I mean, I think the biggest remaining question from my vantage point are these patients who have perceived higher rates of recurrence even after we do everything. So how do we get recurrence rates down on people where we have thrown everything we have, surgery, radiation, even endocrine therapy, and they still have high rates of recurrence? What is next? And one suggestion has been, there was a large trial that looked at this, but it looked at all patients with DCIS, is the concept of doing HER2 directed therapies in patients with this residual risk. And so there's some consideration of looking at that as a strategy for these patients who seem to have high rates of recurrence even after standard therapies.

Dale Shepard, MD, PhD: And you've mentioned before about pros and cons of each therapy. Maybe in general, mind it's from an endocrine therapy versus radiation therapy, what are the risks and when do those risks occur?

Chirag Shah, MD: These constantly evolve as we get better and better with our therapies. In terms of radiation therapy, for most patients, I now offer five days of radiation rather than the five weeks. So in terms of pros, it's typically five treatments of radiation. It's often targeted radiation. In terms of side effects, are minor fatigues and minor redness of the skin. And then long term we use techniques to reduce the risk of any harder long side effects. And we're not treating lymph nodes or anything like that, so really no risk of lymphedema. But it does require six visits, one for the CAT scan and five for the treatments, which each take about 20, 30 minutes. On the other side, you have endocrine therapy typically given daily for five years in women with DCIS. The pros are it's convenient. You don't have to come in for extra visits and all you do is take a pill every day.

There's also some data on using lower doses of endocrine therapy which have been published, so that helps reduce the side effects. The most common side effects I see in patients taking endocrine therapy is hot flashes, joint aches and myalgia, so those are the most common. And in some women they do get concerned because there's the potential for a little bit of weight gain. So those are the ones that we tend to see the most, though they're not uniform for all patients. The other thing that we've seen is compliance rates. With the shorter courses of radiation, the compliance rates really are around a 100%, whereas with endocrine therapy, there's data suggesting long term outside of a clinical trial, compliance is somewhere between 50 and 70%.

Dale Shepard, MD, PhD: And so how common has five days of therapy instead of five weeks of therapy been adapted?

Chirag Shah, MD: So five days of therapy at the Cleveland Clinic has really become our standard for low risk DCIS. I would say most women over the age of 50 who have low risk DCIS are treated with five days of radiation nowadays.

Dale Shepard, MD, PhD: And is that common in other centers?

Chirag Shah, MD: It's something that's slowly becoming more and more common? I would say we were certainly on the forefront of implementing five fraction radiation as the data came out. I think we're starting to see it incorporated in more centers throughout the Midwest and also nationally. In Europe, it is considered standard of care. And now with recent study, 60 to 70% of patients in the United Kingdom got five treatments of radiation for their breast cancer.

Dale Shepard, MD, PhD: That's great. Are there further innovations that we're considering in terms of delivery of radiation for this group?

Chirag Shah, MD: Yeah, so we actually have a study that just opened looking at the use of CPAP, which is often used for sleep apnea. And the idea is the CPAP machine during radiation will expand the lungs and pull the breasts away from the heart and lungs to further reduce dosing to the heart and lungs. So that clinical trial is open now with the clinic. The other thing we're looking at is to start considering these shorter courses of radiation in patients with more advanced cancers. This is already starting to be done in Europe, and we're looking to bring that here to the US.

Dale Shepard, MD, PhD: Excellent. Discussions we've had about this bio-signature have revolved around DCIS. Has this been incorporated into other uses of radiation and breast cancer?

Chirag Shah, MD: Yeah, so we're starting to see trials look at different types of bio-signatures in invasive cancers because they have slightly different risks. But we are starting to use tumor genomics and tumor bio-signatures. For example, there's a currently open clinical trial, the NRG-BR007 trial, which uses a different tumor genomics assay and randomizes patients with a low risk tumor genomics assay and invasive cancers to receive radiation or not receive radiation.

Dale Shepard, MD, PhD: So a lot of effort to select the right patients to get the right therapies. Looks like a good effort that has led to reduction in recurrence. If patients have recurrence, what are some of the exciting things in radiation therapy for those patients?

Chirag Shah, MD: Yeah, I mean I think when it comes to managing recurrences, it really is a team sport and I think that's one of our really big strengths beyond just radiation. We have surgeons who are able to do repeat lumpectomies. We have plastic surgeons able to do lymphovenous bypasses. In cases that are more advanced, we have thoracic surgeons able to do chest wall reconstructions and resections. In terms of radiation therapy, I think the biggest thing we're going to highlight at the symposium this year is that radiation can be given again and that it's been shown to be safe and effective. So when women who've had a local recurrence in the breast after previous radiation, we've often told them you can't have radiation again, you need to have a mastectomy. But now we have national level data from a phase two trial showing that you can do repeat lumpectomy and radiation. And we also have data from the Cleveland Clinic showing that when you do repeat lumpectomy and radiation, it's safe and effective.

So that's one thing we're offering. For more advanced recurrences, we've also been able to show that you can give repeat radiation for lymph node recurrences, as well as skin recurrences and actually have excellent outcomes, even though in the past we thought that was not really something that was appropriate to do. So we've really expanded the horizons on re-radiation in the setting of recurrences.

Dale Shepard, MD, PhD: You mentioned about the symposium. Tell me a little bit about that.

Chirag Shah, MD: The Breast Cancer Symposium was on August 12th. But for those who have been unable to attend, they'll be able to participate virtually online through the Cleveland Clinic Continuing Medical Education platform.

Dale Shepard, MD, PhD: So it looks like a lot of things going on in a lot of different areas. What are the biggest gaps? How do we get to that next plateau of success in terms of treating these patients?

Chirag Shah, MD: I think the next step is using all this really big data that we're starting to generate and using tumor genomics to pick out the patients that need escalation up front, the patients that need de-escalation. There's been some great work for my colleague, Dr. Jacob Scott, on the concept of GARD, which is genomic associated radiation dose. Right now we give the same dose of radiation to patients in breast cancer radiation, but we know that some of them still fail locally and the question is why. And so his work has been able to show that there are subsets of breast cancers that need higher doses of radiation, and there are also subsets that may need lower radiation. So I think it goes back to really targeting therapies to the risk that the patient's cancers present.

Dale Shepard, MD, PhD: Anything else from the standpoint of the bio-signature that we're going to be pursuing?

Chirag Shah, MD: I think that from the bio-signature standpoint, I think that we're going to try to expand this obviously potentially into other realms, including potentially invasive cancers. And then also looking at those patients that fail and say, why are they failing when we use the bio-signature, and trying to understand that to continue to refine.

Dale Shepard, MD, PhD: Chirag, thanks for being with us today. You're doing great work to pick the right treatments for the right patients. Appreciate you being with us today.

Chirag Shah, MD: Thank you so much, Dr. Shepherd.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled. 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 real-time 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.