COMMENTARY

Will Immunotherapy Be a PANACEA for Breast Cancer?

Sherene Loi, MBBS (Hons), FRACP, PhD, FAHMS ; Kathy D. Miller, MD

Disclosures

January 02, 2018

Kathy D. Miller, MD: Hi. I am Dr Kathy Miller, professor of medicine at the Indiana University School of Medicine in Indianapolis. Welcome to Medscape Oncology Insights, coming to you from another rainy day at the 2017 San Antonio Breast Cancer Symposium (SABCS).

From monoclonal antibodies to checkpoint inhibitors and maybe even cellular immunotherapy, immunotherapy continues to redefine the treatment of breast cancer. My guest is at the forefront of that field, and she is here to highlight those developments, including results of a study she presented yesterday. Dr Sherene Loi is associate professor and consultant medical oncologist at the Peter MacCallum Cancer Centre at the University of Melbourne in Melbourne, Australia. Welcome, Sherene.

Sherene Loi, MBBS (Hons), FRACP, PhD, FAHMS: Thank you for having me.

Immunotherapy for HER2-Positive Breast Cancer

Dr Miller: We have come a long way in thinking about immunotherapy for breast cancer. What do you think were the most important results in that area from this year's meeting?

Dr Loi: We have come a long way, but we still have a long way to go in the development of immunotherapy for breast cancer. The study[1] I presented yesterday was the first study in HER2-positive breast cancer. In my opinion, that is the most immunogenic of all the breast cancer subtypes.

This was a proof-of-concept study to investigate whether pembrolizumab has activity in a trastuzumab-resistant, metastatic HER2-positive [breast cancer] population. We designed this study many years ago after observing that HER2-positive breast cancer has large amounts of T-cell infiltration, that trastuzumab has immune mechanisms of action, and that tumor-infiltrating lymphocytes (TILs) are prognostic in HER2-positive breast cancer. This study looked at pembrolizumab as monotherapy with trastuzumab.

We observed durable responses. The response rate in the overall population was 15%. We noticed that patients with metastatic disease have very low levels of TIL infiltrate. We believe that if we select patients who have a high level of TIL infiltrate, we can enrich this population for respondents. Among those patients, we saw a higher rate of respondents. Those patients had a year of treatment on average with just pembrolizumab and trastuzumab, which were well-tolerated. So, they experienced durable control without chemotherapy.

Immunogenicity of Breast Cancer

Dr Miller: I want to ask you a bunch of questions about the underlying biology and your results. It was interesting that you think HER2-positive disease is the most immunogenic, because that is certainly not where the early studies were done and where we saw the first results almost 2 years ago. If HER2-positive disease is the most immunogenic, why have we been spending 2 years talking about triple-negative disease?

Dr Loi: There is obviously much higher need in triple-negative breast cancer (TNBC), because that is the area in which we do not have any effective therapies resulting in durable, long-term control. Triple-negative primary breast cancer also has high levels of TIL infiltrate, and we do see a similar signal in TNBC as in HER2, with regard to associations with prognosis and TIL infiltrate. However, TNBC is a more aggressive disease. Baseline therapy for HER2-positive breast cancer is trastuzumab, and that seems to be able to reactivate the immune system to some degree in many patients.

We already have proof of concept in HER2-positive breast cancer that trastuzumab is effective. Also, it allows us to get the immunotherapy in and allows patients the time to respond in the advanced setting. Whereas in TNBC, in the context where we have been evaluating checkpoint inhibition, often the disease is very advanced and is often very aggressive at that point.

We have not given immunotherapy enough time in the populations we have evaluated to date, for us to really understand whether checkpoint inhibition is having any effect at all. Studies in the first-line setting in metastatic TNBC have been far more promising,[2] and we are beginning to get a hint in the neoadjuvant setting,[3,4] where we see the highest levels of immune infiltrate. Perhaps that is where we need to go to implement this therapy.

Dr Miller: You mentioned that in the metastatic setting, there is not much immune infiltrate. There has always been a bit of an inconsistency in my mind between thinking that the tumors with the most genetic aberrations are the most likely to be recognized by the immune system and be the most immunogenic. If that is correct and you assume that the tumors become more aberrant and accumulate more mutations over time, why do those seem to be going in different directions?

Dr Loi: From a mutational burden point of view, breast cancer has far fewer mutations than the other, more immunogenic tumor types, such as melanoma and lung cancer. We are talking an order of magnitude of 10 times, 100 times less than some of the tumor types that have already had pembrolizumab or nivolumab approval. On the whole, breast cancer is less mutationally burdened. That could be because those other tumor types are carcinogen-induced, with smoking or ultraviolet light [exposure].

Triple-negative breast cancer has a higher mutational burden, and that may explain some degree of the immune infiltrate we see. The concept is that for TNBC breast cancer to actually relapse, there must be a degree of immune invasion or immune suppression that has gone on during that progression from primary to metastatic disease.

It makes sense to me that in the metastatic setting, these patients have tumors that have worked out how to invade or suppress the immune system. That may explain why these patients have less immunogenic disease in the advanced setting. As you go along with multiple lines of therapy, that seems to be even more the case.

Determining What Is 'Driving the Immune Infiltrate'

Dr Miller: Have we been able to look at any samples from studies—whether in HER2 or triple-negative disease—to try to understand the difference between tumors with a rich T-cell infiltrate and those that are very bland? How much is it a tumor factor? How much is it a host factor?

Dr Loi: That is an excellent question. Studies are ongoing, but the main issue in all of these studies is the analyses were done not on the metastatic lesion, but on the primary lesions. It is really important now that we start collecting more metastatic lesions. The studies to date suggest that we do not really understand what is driving the immune infiltrate.

We have looked at mutational burden in particular, and there does not seem to be a very strong correlation. Again, we have not really looked at the metastatic lesion. The TIL infiltrate certainly seems to be a T-cell infiltrate, so for those patients who do have immune cells present, it seems to be the right type of immune cells, but they are pretty rare. There are gene signatures that have looked at these tumors, but again, it's mainly the immune signal that comes out. We do not really understand what is going on in the tumor, and that is a very unclear question at the moment.

Dr Miller: Are there any measures of immune activation that, even after short-term treatment with a checkpoint inhibitor, might allow us to distinguish those patients who are attempting to mount an immune response to their tumor versus those for whom this is just not successful?

Dr Loi: That is a great question as well. Can we take a biopsy after, for example, an immunotherapy or chemotherapy to see who has been able to mount an immune response? That is something that we should be doing. Sometimes it's really hard to get that biopsy in patients who are responding, because the tumor disappears.

We have to look at the baseline biopsy, and obviously it's hard to get multiple metastatic biopsies on people. There is work looking at plasma, correlates of the T-cell receptor, and peripheral blood, for example. Hopefully, as those studies come through, we will be able to understand who is responding early on and be able to modify the trial therapy on the basis of that.

Are We Asking Immunotherapy to 'Do Too Much'?

Dr Miller: Where do you see the next iteration, the next important results of studies looking at immunotherapy in breast cancer? Where should our listeners be focusing their attention?

Dr Loi: Some important studies are going to be reported in the near future, in particular in metastatic TNBC in the first-line setting in combination with chemotherapy. For example, we need to understand whether chemotherapy can help some patients mount an immune response that can be enhanced with a checkpoint inhibitor. The first question for me is, what is chemotherapy doing in this context? Ultimately, we will need to develop more effective antitumor therapies in order to relieve or break down that really immunosuppressive microenvironment and allow those T cells to get in. It comes down to more effective therapies, and for TNBC, that may be other things apart from chemotherapy.

Dr Miller: It almost sounds like you are saying that we are asking immunotherapy to do too much —that we need other effective therapies, and then let immunotherapy clean up what is left.

Dr Loi: In the advanced setting, that is certainly the case. Tumor burden is just too much for your little T cells to cope with, even if you might try to boost them or if you take them out and boost them up. That is my impression, at the moment, with breast cancer, because the tumor microenvironment is just too difficult for some of these T cells to get in and work. I believe we do need to break down tumor. However, in the primary setting, the breast cancer may be a little bit easier; there is less tumor overall. We know in the neoadjuvant setting that we can get higher rates of pathologic complete response in some patients. That may be an easier target and potentially lead to regimens with less chemotherapy. All of these need further investigation, but that could be promising for future breast cancer patients.

Cellular Immunotherapy

Dr Miller: We should think at least a little bit about cellular immunotherapy, which has been recently approved in the United States, though not for breast cancer. There are very different questions for cellular therapy, but is that one that may have a role in breast cancer?

Dr Loi: If your T cells are not functional, can you take them out, genetically modify them, and put them back inside? There is a lot of activity in this space. Hematologic cancers are very different from solid tumors because you do not have that microenvironment you need to tackle. In blood cancers, they travel around your system, and get to your lymph nodes and then get back out to where they are needed, but in solid cancers, that is a very different story. I think we will be left with the fact that we still have to penetrate this very immune, hostile microenvironment. We will probably have to combine it with effective antitumor therapies.

Dr Miller: This is such a fascinating shift in perception, because earlier in my career, we used to talk about chemotherapy being immunosuppressive. Yet you are talking about chemotherapy as a way to lift the immunosuppressive effect on the tumor so that the immune therapy can have an effect.

Dr Loi: Yes. I think that concept needs to be revisited a little bit. Obviously, chemotherapy can be very myelosuppressive, so you do not want to be killing your T cells as they are trying to generate. That is poorly understood. Perhaps the chemotherapy is stimulating an immune response by being myelosuppressive, and it's decreasing your neutrophils as well, which potentially can be immunosuppressive.

There are lots of things we do not quite understand about chemotherapy. Some chemotherapies probably promote more immune response compared with other chemotherapies. We need to do a lot of work to investigate that.

Dr Miller: It's clear that we are still in early days of immunotherapy for breast cancer. We are still a little bit behind some of the other solid tumors, but it's fantastic to finally start seeing results.

Dr Loi: It's great to see these durable responses. Certainly, we have seen that in other solid tumor types, so it's very promising that we can do the same thing for breast cancer patients. It's just working out how we can improve on what we have seen so far.

Dr Miller: Thank you for joining us today to talk through some of these results, and we will look forward to learning more.

Dr Loi: Thank you very much for having me.

Dr Miller: To our listeners, thank you for joining us as well. This is Dr Kathy Miller, coming to you from SABCS.

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