Interview With Dr Cesar Santa-Maria

Hot Breast Tumors See More Immunotherapy Action

Faye Nourollahi, MS


February 21, 2019

Editor's Note: Cesar Santa-Maria, MD, is a breast cancer oncologist based at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. In the following interview, he details the latest clinical treatment and research breakthroughs in breast cancer, particularly immunotherapy.

Medscape: Please tell us a little about yourself, particularly your area of cancer specialty and your clinical and research work.

Santa-Maria: I'm an assistant professor at Johns Hopkins. My clinical and research interests are in breast cancer, and on the research front, I'm particularly interested in developing immunotherapies for breast cancer and understanding the tumor microenvironment and relevant immune biomarkers.

Medscape: You recently wrote a review on this.[1] Does your current research focus mostly on biomarkers that are in the tumor microenvironment, or biomarkers that are involved in immune system response?

Santa-Maria: I just published some updates [on that review] in the Journal of the National Comprehensive Cancer Network with Rita Nanda.[2] I have also published an original research study where we looked at PD-L1 and CTLA-4 inhibition of metastatic breast cancer.[3]

In the original research study that looked at PD-L1 and CTLA-4 inhibition in metastatic breast cancer, we had a really comprehensive overview of various immune genomic biomarkers, [looking at] such things as tumor mutational burden [and] T-cell receptor repertoires with T-cell receptor sequencing. We looked at various gene expression profiles, and we did this sequentially. We had a baseline assessment, and then after 2 months, we repeated the biopsies to see how changes may have been affected.

Medscape: Affected by progression of the tumor, or affected by treatment?

Santa-Maria: Affected by treatment. There are different kinds of biomarkers that can serve different functions. There are biomarkers that can, potentially, prior to starting on treatments be associated with people more likely to respond. For example, I think tumor mutational burden has that.

I don't think we know enough about medications that would show that there are drugs that change tumor mutational burden, although obviously there are some genetic syndromes that may be associated with that—for example, microsatellite instability.

Then there are immune biomarkers that are really more pharmacodynamic. So basically, we look at [biomarkers] at two various time points, and [then] we look at changes that we think might be related to the treatment.

I think T-cell receptor sequencing, or tumor infiltrate and lymphocytes, are biomarkers in the sense that these are things that can potentially be modified by treatment. We're looking at the reflections of what is happening in the immune microenvironment with these surrogates, be it T-cell receptor sequencing or tumor-infiltrating lymphocytes. I see those as surrogates of creating a more inflamed, or "hot," immune phenotype.

Sometimes baseline assessments, or these pharmacodynamic assessments (so the change, not just the baseline, but also the change), can be important in identifying patients we think may be more likely to respond. On the basis of the study that we published in Oncotarget, with the PD-L1/ CTLA-4 inhibition, what we found is just that.[3]

Tumor mutation burden at baseline was associated with immune sensitivity. [With] the T-cell receptor repertoire, in particular, the baseline assessment actually did not correlate very well with responses. If you looked at the delta—the difference between T-cell receptor repertoire from baseline to 2 months in this particular study—we found that patients who underwent an oligoclonal shift are more likely to respond. Those people had the immune-sensitive phenotype, and I think [that] was quite clear in the pharmacodynamic change that we are seeing.

Medscape: Are the drugs developed specifically to bind to the receptor?

Santa-Maria: I think these drugs have an impact on the tumor microenvironment. In that particular study, we looked at PD-L1 and CTLA-4. No amount of preclinical data has really surfaced—CTLA-4 may be something that can increase PD-L1 expression, for example, and might be sensitizing to anti–PD-L1 inhibitors in that fashion.

In another study that I'm currently running, we are looking at CDK4/6 inhibitors.[4] Those are also drugs that are of interest, because we think they might affect the tumor microenvironment in terms of activating the T cells, but also [it is possible that] the way they kill cells [may cause them] to be releasing certain cytokines that can attract T-cells into the tumor microenvironment, hopefully resulting in responses to immunotherapy.

Medscape: From 2015 to now, what biomarkers do you think have changed the most both in terms of our understanding of what they represent, as well as potential new biomarkers that have come up in the field? Is there a particular field that you think represents certain things that have changed recently, that you think more researchers should shine their focus toward?

Santa-Maria: I am going to answer that question in the context of the most relevant immunotherapy study in breast cancer to date. That is that the IMpassion130 Study, which is the first phase III study in metastatic triple-negative breast cancer, or actually any breast cancer.

This particular study focused on triple-negative breast cancer and demonstrated a clinical benefit of combination immunotherapy. In this particular case, it was atezolizumab, a PD-L1 inhibitor, in combination with paclitaxel.[5]

The research found that compared with the chemotherapy alone, the chemoimmunotherapy resulted in improvements in progression-free survival. There is an exploratory analysis that suggests the benefit was particularly pronounced in PD-L1–positive patients.

We just had an article published in the New England Journal of Medicine.[6] These are our first data in breast cancer that are positive, so we are really excited about them, but there are several caveats to the study. I think this is going to be a real poster child for why biomarkers are so important.

What this study looked at was PD-L1 levels in immune cells versus tumor cells (which, I think, is really the predominant way, if you look back in earlier studies). Back in 2015, we were looking at PD-L1 expression mostly on tumor cells, but it seems that at least according to this study, PD-L1 status of immune cells may be more important.

Medscape: Can you tell us a little about that cohort of patients that was treated in this study?

Santa-Maria: In terms of PD-L1 expression and specific patient cohorts, to my knowledge it hasn't been looked at. PD-L1 expression seems to be highest amongst patients with triple-negative breast cancer and lowest among those with hormone receptor-positive breast cancer.

I think we have a way of thinking about breast cancer as breast oncologists, but I think when we are starting to develop immunotherapies, we have to reset how we define breast cancers in terms of immunophenotype. I'm not sure it is necessarily going to correlate with some of our traditional biomarkers or traditional parameters that we look at.

Medscape: In your personal practice of oncology, you had mentioned you were working on some trials. Can you tell me a little bit about them and what you are hoping to see?

Santa-Maria: Let me tell you about the CTLA-4 study, a study that is open for entry at Johns Hopkins. It's for patients with estrogen receptor (ER)-positive breast cancer. We treat them before surgery and then will assess response rates. The reason for ER-positive breast cancer is because this [type of] breast cancer [is] least responsive to immunotherapy. We think ER-positive breast cancers are predominantly a "cold" immunophenotype.

The idea is if we give patients with ER-positive breast cancers a drug that can "warm up" a tumor—go from a cold to a hot tumor—that these tumors will be more responsive to immunotherapy. This study is in stage II and III ER-positive breast cancer. Before surgery, patients are randomly assigned to receive tamoxifen versus tamoxifen plus palbociclib. Palbociclib is a CDK4/6 inhibitor.

After a run of exactly 1 month, both arms are then treated with avelumab. We will continue treatment of randomized on avelumab and a PD-L1 inhibitor for an additional 3 months—so a total of 4 months in therapy—and then patients will undergo surgery.

We'll be able to measure rates of clinical complete response, but very importantly, this study has a lot of translational correlatives to assess the changes within the tumor microenvironment along the way. I mentioned there was a run-in period of 1 month. We are actually collecting another biopsy sample, so we will have a baseline and a 1-month biopsy.

Then we are going to look at biomarkers at the time of surgery as well. So we'll have three different types that we will be able to interrogate through a microenvironment. The biomarkers of interest in this particular study are going to be tumor infiltrate lymphocytes.

We'll be looking at T-cell receptor sequencing as well. Then we are going to be looking at multiplex biomarkers, including multiplex gene expression assays, such as the nanostring assay and also the multiplex immunochemistry assay, that's going to look at various immune cells in the microenvironment.

Medscape: When do you anticipate your earliest results will come in?

Santa-Maria: Probably in about a year or year and a half, I will get my very earliest results. There are a total of 40 patients. We have three patients onboard. If there are any patients interested in the Washington, DC, area, please feel free to reach out.[7]

My other experience in terms of treating patients with breast cancer with immunotherapy is from the initial trial I did looking at combinations of immunotherapy. We found, very similar to other diseases, that the vast majority of patients do not respond. Those who do respond can experience very durable responses. In fact, on the clinical trial that we initially ran (this opened in 2015) in patients with metastatic breast cancer, I have two patients who are still doing well. This is now 3 years later, both with metastatic-negative breast cancer.

We do see that—when it works, it works great. Again, it really highlights the importance of biomarkers to identify those patients where these potentially toxic therapies can really work wonderfully.

Medscape: Is this where the future of breast cancer care is headed?

Santa-Maria: I think the future directions of breast cancer treatment are going to be looking at combinatorial strategies and the ways of warming up these cold tumors.

The vast majority of breast cancers are cold immunophenotypically, and through a variety of different treatments—chemotherapy, radiation therapy, targeted therapies—there may be a way of warming these tumors up, which can result in better responses to immunotherapy. So I think it is a really important development and therapeutic consideration. And again, I think that understanding the tumor microenvironment, these biomarker changes, is really going to be important here.

A lot of patients do not respond, so we want to identify the responders, but also, we want to learn from the nonresponders and see why they are not responding. That is going to help generate the next generation of studies and, hopefully, develop treatments for those patients as well.

Medscape: Because you clearly have a population of patients who respond to immunotherapy, though it's a small percentage that responds, what follow-up are you doing to try to elucidate which biomarkers are relevant to the cancer? Are you still using these patients as follow-up to try to get as much information out as possible? Are you planning on maintaining them on the current therapy?

Santa-Maria: That is a good question. That's more relevant to the metastatic setting, in the neoadjuvant study, it defines treatment course, and after surgery, they are done with immunotherapy. In the metastatic setting, we treat patients longer. The way the study was designed the treatment has a maximum of only 2 years. You cannot give it for more than that.

What we're finding is that using avelumab, those who responded, are still doing great. The cool thing about their immune system is that it has memory. We think that—we have seen it in other cancer types—even after cessation of therapy, if the therapy is working, you can still experience control for long periods of time even after cessation of therapy. That's what we are seeing in breast cancer too.

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