Top Advancements in Breast Cancer Care: What Can We Expect in the Next 5 Years?

Anthony Lucci, MD, The University of Texas MD Anderson Cancer Center, Houston, discusses 5 developments in breast cancer care he believes we will see within the next 5 years, including:

1. The de-escalation of breast cancer treatment;
2. Improved survival for patients with metastatic breast cancer, specifically those with HER2-positive disease and brain metastases;
3. The use of liquid biopsy to determine risk, monitor response to therapy, and guide therapy; increased use of immunotherapy in patients with breast cancer;
4. Increased use of immunotherapy in patients with breast cancer;
5. Survivorship, specifically improvements in the area of lymphedema among patients with breast cancer.

Transcript:

Hello, I am Dr Anthony Lucci. I am a professor of breast surgical oncology at the University of Texas, MD Anderson Cancer Center in Houston, Texas.

Today, we are going to talk about what I think might be 5 future developments in the world of breast cancer. There is obviously more than 5, there could be hundreds, but these are 5 interesting areas that appear to be on the horizon, and which could be realized within the next 5 years.

We will start off with what I think is obviously the most common theme pervading in breast cancer now, and that's the de-escalation of therapy. When I say de-escalation, that applies to the entire multidisciplinary treatment of breast cancer. We will go through each of those sub-points of the overlying theme of, number one, de-escalation of breast cancer treatment.

When we look at the de-escalation, first we could talk about surgery. Being a surgeon, that is a natural starting point. We have already seen an incredible amount of de-escalation by the surgeons. We have gone from axillary node dissections to sentinel node biopsy, to targeted node dissection for those patients who have positive nodes prior to neoadjuvant chemotherapy.

We can now spare the nodes in a significant number of patients who have a response in the nodal basin by removing the targeted or clipped nodes and the sentinel nodes. If those are negative, we can preserve nodes.

That is another kind of de-escalation that has been successful, but I think in the future, we are going to see even less axillary surgery. Why do I say that? There is already data to suggest that, especially in older patient, sentinel node biopsy may not offer a lot of value as far as use for guiding treatment.

If you look at the Society of Surgical Oncology in choosing wisely recommendations, already, there is discussion about possibly omitting sentinel node biopsy for patients over 70 years of age.

Also, when we have some of the data come out from Europe from, let's say, the SOUND trial in Italy, which looks at omitting sentinel node biopsy for select patients, we may find that there are a number of patients for whom we can omit sentinel node biopsy altogether.

People say, "Well, sentinel node biopsy, it is an innocuous procedure." Actually, no. If you look at the data, it is much better than an axillary node dissection, but you can still have chronic pain. You can still have seromas in a significant number of patients following the procedure.

If we could avoid it altogether, that would be another step forward. One thing is I think we will see less surgery. We may also see no surgery for the primary tumor.

There are trials right now looking at, instead of removing the primary tumor in patients who are likely to have a complete pathologic response, of course, that would normally be triple-negative breast cancers are HER2-positive breast cancers, after receiving appropriate therapy, there are trials where, instead of removing the tumor, multiple core biopsies are obtained of the tumor.

If those are negative, the patient can then omit surgery of the primary tumor and go on to radiation. Now, remember, these are studies. These are not standard practice currently. These are clinical studies. But this may actually identify a group of patients for whom we do not have to take out the primary tumor if they have had a complete pathologic response.

Again, I do not think that is too far-fetched. It may be in the near future, and so we may see less surgery on the breast and less surgery in the nodal basin as we discussed.

Now, what about chemotherapy? We are already seeing in the world of chemotherapy, we are becoming much better at directing therapy to those who are going to benefit. Let's take data from the TAILORx trial, and even from RxPONDER.

Here, we can use genomic assays like Oncotype, and in fact, what we can do is identify patients who simply do not derive benefit from chemotherapy. Clearly, in the past, we were treating almost all of those patients who had, let's say, a positive node, or if you look back at the old consensus statement, almost all patients were recommended to have chemotherapy if they had larger tumors.

Now, we can stratify patients. Let's say a patient, especially a postmenopausal patient with an ER-positive tumor and negative nodes, has an Oncotype with a low score. We know that is actually going to be 85% of the postmenopausal populations.

We can avoid chemotherapy because those patients with a score of 0-25 showed no benefit for chemotherapy. We will have much less need for chemotherapy in that group of patients, and even in the premenopausal group of patients or those who have low scores, let's say, especially 0-15, which is 50% of the premenopausal population, there was no benefit.

We are now seeing less use of chemotherapy, even in the premenopausal group if they have a low genomic assay score. More personalized therapy, rather than just giving chemotherapy to all patients.

What about node-positive disease? We actually saw in the RxPONDER study that patients who are postmenopausal and have an Oncotype 0-25, they did not receive benefit from chemotherapy. We can avoid more chemotherapy exposure and the morbidity that goes along with that in that postmenopausal group.

In the premenopausal, those patients did show benefit. Right now, those patients would receive chemotherapy, but we may look in the future and see things like trials where we can use courses of therapy and see if there is a reduction in the Ki67.

Maybe you can identify groups of premenopausal patients, who will have an excellent response to endocrine therapy and may not need chemotherapy. That is on the horizon. Less use of chemotherapy, and I think we are going to see more use of targeted therapy.

We are already seeing approval of agents. We now can think of discussing things like PARP inhibitors for BRCA1 patients, and perhaps even introducing that as neoadjuvant in some trials, which will provide more light into, could we use more targeted therapies for these patients, and potentially improve their outcomes?

We are also looking at, which we will talk about in a little bit, some of the other options instead of just using chemotherapy but using different agents. We could spend the entire discussion on that topic alone, but we will move on just for the sake of time.

The other thing which we are going to see is more judicious or personalized use of radiation therapy. If you think about it, patients with, let's say, 1-3 positive nodes may very likely be recommended to have radiation therapy to that nodal basin.

There is data already, retrospective data, suggesting that if you take patients who by a personalized assay, again, using, let's say, an Oncotype of their primary tumor, and they are deemed low risk with a score of less than 18, they may not get benefit from regional nodal radiation.

In other words, based on retrospective data, the genomic assay may identify patients who are at low risk for local-regional recurrence as well as those who may be at lower risk for distant recurrence, or who, let's say will do well with endocrine therapy.

The MA39, the TAILOR RT study, is currently taking patients who are 1-3 node-positive who are low risk with a low Oncotype score, and they are getting randomized to radiation therapy or no radiation therapy of the nodal base.

This kind of personalized, directed approach to radiation therapy may very well come up in the future, where we can then identify patients who simply do not need aggressive radiation therapy.

The same thing could even apply to post-mastectomy radiation. If you look at some of the data from the NSABP studies, there is patients with low Oncotype scores who may have a lower local regional recurrence rate.

Could we possibly, in the future, incorporate that kind of thing into more judicious use of radiation therapy, and even, let's say, shorter courses? I think we are going to see that in the future. That is going to be a really important step for reducing morbidity.

Rather than spend the entire time on de-escalation, let's move on to a second area, and that is going to be improved survival for patients with metastatic breast cancer. Especially, we are going to talk about specifically those patients with HER2-positive disease and brain metastases.

Obviously, this is a big problem because if you look at the data, almost half of the patients with metastatic HER2-positive breast cancer can develop brain metastases at some point. This was a difficult area for quite a while.

I know there is a lot of work on developing better agents to cross the blood-brain barrier and try to prevent this before it happens, but one of the most important things which we have seen is the use of targeted therapy, TKIs, to reduce the risk and improve outcomes.

I would just talk about one study. If you look at the HER2CLIMB study, pretty amazing data. You have patients who have already been treated with trastuzumab and they have already received T-DM1.

These patients who, let's say, especially in the brain metastasis positive group within that study, those patients who received tucatinib had a 1-year CNS progression-free survival of about, I think it was around 40%, versus 0 for the placebo group. That is pretty amazing.

Also, the data showed improved overall progression-free survival for the tucatinib versus the placebo group. These are major improvements in the treatment of patients with metastatic HER2 breast cancer. I think we are going to see more of this in the future.

Think about it. A few years ago, these were patients who we felt there is maybe not much we could do systemically. Maybe you could try stereotactic radiosurgery or something like that.

Now, we have systemic agents which show efficacy. A huge improvement. I do not think we have ever seen anything like that in the past. That is a huge view for the future. Is improving the outcome for these patients with metastatic disease.

A third area, which I think is going to come up in the future, and obviously, I have a little bit of a individual vested interest in this, is the use of liquid biopsy to not only determine risk in patients with breast cancer but to monitor response to therapy and potentially even to guide therapy.

Why do I say this? There is already a lot of data to show that you can use tests like circulating tumor cells and potentially even circulating tumor DNA to identify patients who are at higher risk for relapse.

Prognostic information alone will not be useful. We need to move towards predictive benefit. Could we identify patients who are likely to respond to therapy, who are responding to therapy, monitoring response? I do think in the future, we will see that most of our patients - I would predict in the next 5 years - most of our patients with breast cancer will be monitored with liquid biopsy.

I know it is a pretty bold statement, but if you look at the data and you look at some of the information that is coming up, and the amount of money that industry in time and effort that is being put into this, it is not that far off.

That we will be able to, instead of putting needles into bone or liver to assess what is going on in the metastatic compartment, we could much more readily take a blood sample. Within that blood sample, identify what is going on in the whole body.

Since you have a pool now of data being put into the circulation, we could identify what is going on in the metastatic site. We can determine markers that may or may not be the same as what is in the primary tumor. Could that open up avenues for treatment?

Before we say that seems far out and too futuristic, think about it. It already happens in lung cancer. You can take a liquid biopsy and determine if EGFR is present. Then you can direct your therapy for that patient's lung cancer.

In breast cancer, we know it's not too far-fetched because, in the BELLE-3 study, you could look in the blood compartment and see if you could find mutation for Pyk3 kinase. Actually, it was able to be identified and could potentially be used in the future as a way to guide therapy.

When we get more technological advances for determining and identifying small volumes CTDNA and whether we can use CTCs to look at individual markers, I think in the future, that is going to be an important point for guiding personalized therapy.

I think that we have already seen, like I said, in other disease systems, so I do not think it is too far off. I would stand by that prediction. That within 5 years, we will be able to use that routinely.

For instance, you can give a patient a neoadjuvant therapy, you could take a blood sample potentially based on changes in the midpoint or the after neoadjuvant sample, determine whether or not you have reduced the microscopic burden in the blood, and potentially determine whether or not you are successfully reducing the microscopic burden of disease.

We have already seen data that if patients have residual disease after neoadjuvant chemotherapy, for instance, in triple-negative cancers, if you find evidence or inflammatory cancers, you find evidence in the blood of CTCs or CTDNA, that could be a predictor of relapse. Even after a complete response in the primary tumor. Even though that sounds far-fetched, it has been reproduced.

Finally, if you look at data presented a couple of years ago at San Antonio Breast Cancer Conference by Joseph Sparano, MD, showed that if you take patients who are 5 years out from their diagnosis, and you take a blood sample and they still have evidence of microscopic disease in the blood, let's say circulating tumor cells, those patients had up to 18 fold relapse risk versus those that did not have evidence.

We could potentially even use it as an indicator of late relapse. I am going to stand by the prediction that I think in the next 5 years we will have some useful liquid biopsies to help guide our treatment of patients with breast cancer.

Number 4 is going to be the increased use of immunotherapy in patients with breast cancer. This is not a very bold statement because we already saw the recent approval of pembrolizumab plus chemotherapy after KEYNOTE-522. It is not a huge going out on a cliff statement. Interestingly, I think that we will start to see even more of this.

In that study, adding pembrolizumab plus chemotherapy to a combination of placebo and chemotherapy increased the pathologic complete response rate to almost 65% from, I believe it was about 56% in the placebo group. Based on that we already have an approval to utilize this in our triple-negative breast cancer patients.

In the near future, we are going to see more use of immunotherapy in breast cancer. Whether that be in triple-negative alone, we will have to wait and see. I would even make one other statement. Interestingly, there might be some data emerging that you could potentially even use injectable therapy.

There is a small paper from Moffitt Cancer Center looking at a pilot study of using T-VEC, is an injectable agent, into let's say, triple-negative breast cancer to elicit a more robust immune response and you can get this abscopal effect where you can not only inject in local area but get a systemic effect as well.

Mixing that with other immunotherapy agents might not be such a crazy idea for these triple-negative breast cancers. This is something we will see more of in the future. Clearly, we have set the pathway in melanoma, where we can do the same kind of thing, inject patients with things like T-VEC plus an immune checkpoint inhibitor and see amazing responses.

Breast cancer is not the same as melanoma, there is not the same immune basis, but in triple-negative, the data is starting to emerge. I don't think it is too far-fetched, and so we may see an increased use in the future. We already just saw a recent approval that has changed neoadjuvant protocols for triple-negative breast cancer considerably.

I do not think it is too far-fetched and too far out. We will have to wait and see. I do think it will be interesting to see, can we combine immune checkpoint inhibitors with chemotherapy in different combinations? Could we see improved outcomes?

The fifth thing is I think we should also just touch on survivorship. In that area, I would say, what's going to be interesting is our improvements in the area of lymphedema. We are already starting to delve into surgical procedures.

Now, we are doing lymphovenous bypass as a procedure for patients who we deem to be at potentially high risk for lymphedema after an axillary node dissection. We are actually doing that upfront and then gathering the data to see, can we reduce the incidence of lymphedema afterwards?

We have also lymph node transfer, and we have gotten much better not only at identifying patient lymphedema but getting physical therapy involved early using conservative therapies initially, massage, compression, hydrotherapy, all kinds of things, and then moving on to more invasive therapies like surgical therapies, even potentially liposuction.

We have seen a lot of different combinations, so we are gathering a lot of data on that. I wanted to touch on one thing that, for survivorship, it is important we consider quality of life after we successfully treat the patient for breast cancer. One of the most feared things, believe me as a surgeon, we hear about, is lymphedema.

Looking at reduced axillary interventions, reduced axillary node dissection, even potentially reduce sentinel node, which is not high risk for lymphedema but certainly can cause axillary pain, and then by looking at better identification and treatment of lymphedema upfront, I think we have the potential in the next 5 years to improve the quality of life outcomes for patients with breast cancer.

That is going to be important because even if you cure patients, no one wants to have a swollen arm. Whatever we can do in that area, and I will be interested to see the data that we get from using lymphovenous bypass.

We are doing it now. We are doing several per week, and I know it is caught on around the country, and I will be hopeful that we are seeing durable improvement in lymphedema. That would be a major improvement from what we were seeing years ago with patients having to deal with a swollen arm.

I would predict in the next 5 years, that is my last prediction, is we will see improvements in management of lymphedema. That translates into improved quality of life.

Those are my ideas for the 5 areas that I think will take shape in breast cancer. Obviously, we did not touch on everything. There are so many more things we could have, but then just in the sake of time, we tried to find 5 things that we think are likely to occur.

I hope that is helpful, and I hope that over the next 5 years, we actually see these come to fruition. Thank you for taking the time to listen today.