How Immunotherapy Is Making an Impact in Breast Cancer

Breast cancer continues to be a global health crisis. In 2018, there were an estimated 2.1 million new cases of breast cancer worldwide. In the United States alone, another life is lost to breast cancer every 15 minutes. Breast cancer comes in several forms, with triple-negative breast cancer being the most aggressive and hardest to treat. In all subtypes, once the cancer has metastasized, or spread from the breast to other organs, the odds are survival are significantly lower. These advanced breast cancers are also less likely to respond to traditional treatments.

New strategies are urgently needed to improve breast cancer care and increase patient survival. To that end, immunotherapy—a new class of treatments that help patients’ immune systems fight cancer—is one avenue that appears especially promising for patients. The U.S. Food and Drug Administration (FDA) has already approved one immunotherapy for a subset of patients with advanced breast cancer. In addition, immunotherapies are being evaluated in clinical trials for patients with nearly all types of breast cancer.

To better understand the current immunotherapy landscape in breast cancer and how these immune-based approaches are starting to improve care for some patients, we spoke with breast cancer expert Rebecca A. Shatsky, MD, a medical oncologist and assistant clinical professor of medicine in the University of California, San Diego (UCSD) Health System.

Arthur N. Brodsky, Ph.D.:

Let’s start by talking about the checkpoint inhibitor immunotherapies, especially those that block the PD-1/PD-L1 pathway, which have dominated advances in cancer treatment over the past few years. Could you discuss how these treatments work and how they’re being used to treat patients with breast cancer?

Rebecca A. Shatsky, M.D.:

PD-1 is a molecule that is expressed on T cells that essentially tells the immune system to be quiet and not attack things. PD-L1 is a molecule often expressed on tumor cells and works by engaging PD-1, which then shuts off immune cells. By blocking these signals with immunotherapy, you can wake up the immune system to potentially attack anything that could be dangerous.

Expressing high levels of PD-L1 is one way that tumors can evade the immune system. It’s a characteristic that aggressive tumors tend to have that helps them hide from the immune system. By treating patients with these antibodies that inhibit PD-1 and PD-L1, we can exploit that mechanism and wake up the immune system to target tumors.

The downside of that, however, is that when you wake up the immune system indiscriminately, you can get inflammatory responses and autoimmune diseases as your own immune system mistakenly attacks healthy tissue. It could be the liver, the lungs, the adrenal glands, the pituitary gland, the liver, the pancreas—anything. So it can lead to a lot of problems in certain patients. Thankfully, in general, patients tolerate these drugs pretty well.

Dr. Rebecca Shatsky speaks at the CRI Immunotherapy Patient Summit in San Diego on June 29, 2019.​

Arthur N. Brodsky, Ph.D.:

With respect to these side effects, when they crop up, how well can they be managed? Are there any steps that doctors can take once they recognize these side effects?

Rebecca A. Shatsky, M.D.:

Yes. We have enough experience using these treatments now that we have learned how to manage the majority of side effects. Usually it’s done with steroids, either administered orally or intravenously, sometimes along with some other immune modulatory agents. For example, if the side effect was severe diarrhea, which is common enough with checkpoint blockade, you start with steroids but you can also use infliximab (Remicade^®). For severe liver toxicity, we start with steroids, but we can also use other drugs. Some of the toxicities, however, are quite severe and, despite treatment with steroids, can lead to death. Usually those are ones that affect the heart, which can be really severe, or the lungs.

So if there is a serious complication, the most important thing is to treat it early. If there is any evidence of any kind of life-threatening heart toxicity, for example, you stop the immunotherapy and treat it with steroids as soon as it happens.

Arthur N. Brodsky, Ph.D.:

That makes sense. It’s my understanding that, at least in some cases, these types of immune responses that come with side effects can sometime, but not always, be a good sign of immune activity against the cancer. Obviously, the side effects are unfortunate and having them doesn’t always mean that an individual patient will respond to treatment, but I also understand that even if a patient has to be treated for these side effects or has to come off treatment because of them, it doesn’t necessarily mean the treatment isn’t working. Is that correct?

Rebecca A. Shatsky, M.D.:

Yes. We sometimes see these types of responses as a sign that the treatment is working. There is some correlation between immune-related adverse events and benefit from these medications. While immune checkpoint inhibitors can cause amazing responses in some patients, overall, response rates are still relatively low. So seeing somebody have some kind of response, even if it comes with negative side effects, does tell us that the treatment could be helping.

Arthur N. Brodsky, Ph.D.:

You mentioned that these checkpoint immunotherapies by themselves still don’t work for the vast majority of breast cancer patients. Combining checkpoint immunotherapies with other treatments, such as chemotherapy, seems to be a promising approach. How this strategy is being applied in the clinic?

Rebecca A. Shatsky, M.D.:

I think it’s a big misconception that chemotherapy only harms the immune system. What we actually find is that it can make immunotherapy work better. Chemo attacks cancer directly, bursting open tumor cells and exposing proteins that the immune system recognizes as dangerous. That’s actually quite beneficial when the immunotherapy comes in to boost the immune system. We’ve seen some of the best clinical trial results in breast cancer where chemo is combined with immunotherapy.

In triple-negative breast cancer, a subtype of breast cancer that doesn’t have the three most common receptors targeted by current therapies and is therefore typically unresponsive to treatment, somewhere between eight to eighteen percent of women respond. But when you combine it with chemotherapy, half of patients or more respond.

Another factor with checkpoint inhibitors is that they can take a bit of time to really kick in and reach their maximum function. Unfortunately, in breast cancer it’s really hard to wait that long. Treatments that take months to kick can only really be effective for diseases that are slow growing or stable. So another benefit of combining checkpoint immunotherapy with chemotherapy is that you’re treating the cancer and preserving organ function right away while the immunotherapy has a chance to work. So it’s sort of a two-fold benefit that way.

Arthur N. Brodsky, Ph.D.:

One of these immunotherapy-chemotherapy combinations was recently approved for some breast cancer patients, correct?

Rebecca A. Shatsky, M.D.:

Yes. Late last year saw the first really positive results from a clinical trial in which triple-negative breast cancer patients treated in the first-line metastatic setting with the combination of chemotherapy (Abraxane®, or nab-paclitaxel) plus atezolizumab, which is a PD-L1 inhibitor. It was the first immunotherapy study to show improved overall survival in breast cancer, which was really impressive, and it led to a recent FDA approval for patients with metastatic triple-negative breast cancer that expresses the PD-L1 marker.

Now, that’s really important because not all triple-negative breast cancers, and certainly not all breast cancers, are PD-L1-positive, but those are the patients that truly have the most benefit from this therapy.

Dr. Rebecca Shatsky leads a breakout session focused on breast cancer at the CRI Immunotherapy Patient Summit in San Diego on June 29, 2019.

Arthur N. Brodsky, Ph.D.:

Of course, that approval is a great start, but like you mentioned, for now it still only covers a small portion of all the patients with breast cancer. Beyond this checkpoint immunotherapy and chemotherapy combination, what other strategies are being explored in clinical trials for patients with other types of breast cancer, such as those that express HER2 or those that are hormone receptor-positive?

Rebecca A. Shatsky, M.D.:

In other types of breast cancer, in both early and late stages of disease, we’re looking at combinations of targeted therapy, immunotherapy, and chemotherapy. I believe that those are going to provide the most promising overall outcomes because the more ways that we can target the tumor and prevent tumor growth, the more the treatment tends to help the patient. Attacking tumors from more than one angle can also help to prevent the tumor from developing resistance in other ways.

So in the metastatic setting, combinations of targeted therapies plus immunotherapies and chemotherapies are being explored. One example of targeted therapy are PI3K inhibitors, which block the activity of enzymes that are important for cell growth.

PARP inhibitors, which can disrupt the genomes of tumors, are another type of targeted therapy being used. We know that these PARP inhibitors are effective as single therapies in patients who have BRCA1 and BRCA2 gene mutations, and now we’re looking at them in combination with chemo and immunotherapy in patients with all types of breast cancer, including those whose tumors are unable to repair their DNA. (Editor’s note: Women and men carrying BRCA1/2 mutations are more likely to develop breast and other cancers; tumor cells can also acquire BRCA mutations during their development.)

We’re also looking at targeted therapies called CDK4/6 inhibitors, which target enzymes important in cell division, in combination with immunotherapy. It’s tough to combine those drugs with chemotherapy because it can deplete certain types of immune cells in a significant way. However, we do know that CDK4/6 inhibitors are really effective in certain patients with estrogen-positive, HER2-negative tumors. Now, we’re investigating which other subsets of breast cancer patients they might be helpful for.

The combination of immunotherapy plus radiation can be beneficial too, due to something called the abscopal effect. Here, radiation can have similar effects to chemotherapy in terms of destroying cancer cells and alerting the immune system. That aspect of radiation can make this immunotherapy potentially more effective and is why we are continuing to explore these types of strategies for patients in the clinic.

There are also a lot of other immune-modulating molecules that are being looked at. There are IDO inhibitors [that interfere with cell metabolism], drugs targeting the STING pathway [involved in immune cell activation], all kinds of novel immune pathways that we’re exploring. A lot of these are going to be combination therapies, so it’s not likely any will be hugely successful by itself, but I think some of these treatment combinations are going to be transformative in the future of breast oncology.

Arthur N. Brodsky, Ph.D.:

That’s great to hear. Speaking of novel immunotherapy approaches, I know that one of the most exciting new approaches is cell therapy. Could you talk about some of the advances that are being made with these cellular immunotherapies in breast cancer?

Rebecca A. Shatsky, M.D.:

Yes, that is a really exciting area of ongoing research. These cell therapies were first developed for patients with melanoma. It involves taking immune cells from patients’ tumors [because we know they can already recognize and attack the tumors] and multiplying them outside of the patient to get higher numbers of them, and then re-infusing them into the patient to fight their cancer. In breast cancer, these cell therapies have been spearheaded by Steven Rosenberg at the [National Cancer Institute]. There is one patient, Judy Perkins, who had stage 4 breast cancer, and after being treated with her own tumor-targeting T cells, she’s now been disease-free for about two years.

While this therapy is very exciting, I think the challenge is the personalization process. Picking the right targets for the design of adoptive T cell transfer is really challenging because everybody person’s tumor is very unique, just as unique as our own DNA. There are also financial limitations associated with the cost of having to personalize a therapy for each patient. The progress is definitely exciting, though. Many cancer centers around the country right now are actively expanding their cell therapy programs, so that this treatment can be more feasible in the future.

Arthur N. Brodsky, Ph.D.:

Another important consideration is that most new treatments, including immunotherapy, are usually evaluated first in patients who have advanced, late-stage disease. The approval you mentioned for triple-negative breast cancer, for example, covers patients for whom surgery isn’t an option. But there’s a lot of evidence that these checkpoint immunotherapies might work even better when they’re applied earlier in the course of treatment, especially in combination with some of the other approaches you mentioned. Can you talk about some of these recent advances and why exactly immunotherapy might work better when used earlier?

Rebecca A. Shatsky, M.D.:

Of course. The greatest example of the positive results that we’ve had in this situation is with the I-SPY 2 clinical trial in breast cancer. Our results from 2017 proved that using chemo and immunotherapy together, at least in some of the triple-negative breast cancer patients, doubled the overall response rates or overall pathologic complete response rates, which is how we measured the benefit for early-stage aggressive breast cancer. [Editor’s note: pathologic complete response means that patients responded to immunotherapy prior to surgery, to the point that their tumors had shrunk considerably by the time they were removed.]

So we’ve known for a while that the addition of immunotherapy [to chemotherapy] can be quite beneficial. Early trials in metastatic cancer involved patients who had already received multiple rounds of chemotherapy, and whose bodies and immune systems weren’t always in the best overall shape. As a result, these patients weren’t likely to benefit from immunotherapy alone.

One of my colleagues liked to use the analogy that, “it’s really hard to stop a moving freight train.” Because once the tumor has kind of taken over the body and a lot of the organ function, reversing that is the number one priority. Sometimes you don’t have time to wait for the immunotherapy kick in. Sometimes the patient’s disease is just too advanced, too, and even something as powerful as targeting an immune checkpoint isn’t enough to reverse all of the damage that’s been done.

The I-SPY 2 trial has really shown that immunotherapy for aggressive breast cancer in the early-stage setting is quite beneficial. However, we don’t yet have long-term overall survival data, so it may take longer to figure out how to best apply these insights in the clinic. But at this point, we know that earlier treatment for patients with hormone-positive and triple-negative breast cancer doubles the pathologic complete response rate, which we know translates into a decreased risk of relapse and better overall survival.

Arthur N. Brodsky, Ph.D.:

Hopefully, as more of these trials start to read out their data, doctors can get a better idea of the effectiveness of different strategies as well as clues about the patients for whom they might be most effective.

So with respect to improving the benefits of immunotherapy for breast cancer patients, in your opinion, what are some of the most pressing questions that need to be answered?

Rebecca A. Shatsky, M.D.:

One of the biggest issues in breast cancer is the low overall response rates, so one of the greatest challenges is how do we increase that. And the answer is using biomarkers.

We talk about tumors as kind of being “cold” or “hot”—hot meaning that they already have been infiltrated by a lot of immune cells and they’re likely to respond well to these checkpoint immunotherapies. Some of these tumors are also PD-L1 positive, and some have high numbers of mutations, which are both predictors of potential immunotherapy benefit.

But what do we do for the patients who don’t have any of those biomarkers? What do we do about cold tumors? How do we make their tumors hot?

One strategy being explored is to use immune-stimulating vaccines that are delivered directly into the tumor to see if they may be able induce stronger immune responses. More generally, though, we know that the average metastatic breast cancer patient won’t respond to checkpoint immunotherapy alone, so we need to figure out how we can expand the general benefit of immunotherapy to reach that average metastatic breast cancer patient whose options are limited once they run out of hormonal therapies and chemotherapies.

Arthur N. Brodsky, Ph.D.:

In terms of addressing that challenge, it may not always be clear just how important clinical trials are in all of this. Could you talk a little bit about how trials help advance the field and ultimately help improve treatments for patients?

Rebecca A. Shatsky, M.D.:

I’m glad you asked that question because clinical trials are of such pivotal importance to moving the field of cancer research forward. As a lead on several investigator-initiated trials of metastatic and early-stage breast cancer, I just can’t stress enough how patient participation in clinical trials really allows us to see what therapies work and allows us to save lives on a daily basis.

If there’s ever a clinical trial that I think may benefit one of my patients more than the standard of care is likely to, then that’s always my go-to. There’s a lot of misconceptions among the public about what cancer clinical trials involve. Some may think, “oh, I’ll just get placebo or something like that.” And that’s really not the case. You’re going to get the standard of care or potentially something better in a clinical trial.

I also try to promote which clinical trials are available, not just at my own institution, but also what’s available in the local area or even further if it might be possible for my patients to feasibly enroll.

It’s not always possible for patients to travel far to enroll in something, but if they are interested in that, I am always happy to help them investigate what I think might be potentially beneficial. But even locally, I maintain as much as I can, good relationships and contacts with my local institutions, academic and otherwise, that may have beneficial trials open so that my patients always have that option. And I help them navigate how we use these therapies so that they have the most beneficial response possible.

Arthur N. Brodsky, Ph.D.:

That’s great to hear. Finally, I know that many patients find self-empowerment and self-education very helpful on their journey, but with how rapidly the field of breast cancer immunotherapy is evolving, I imagine that can also feel overwhelming at times. So with this in mind, what advice would you give to patients in terms of tips for talking to their oncologist and helping to make themselves an equal partner in their care?

Rebecca A. Shatsky, M.D.:

I think that more education is always better. Knowledge is power. I encourage my patients to actually look on social media a little bit. Twitter is an amazing resource for anything new for patients, especially with advanced breast cancer.

You can go to @breastclinicaltrials and #bcsm (#breastcancersocialmeda). Patients can meet other patients that way. They can learn what questions other people are asking their oncologist that they may want to ask their own. They can be more informed and more aware of what’s going on out there. There’s also a ton of breast cancer advocacy groups that are really supportive and helpful. I have a few patients that literally travel around the country as breast cancer advocates and are both learning and educating other patients about this process. Because that’s sort of the best way to stay informed, is to be aware of what’s going on, be aware of what the research is showing.

If they find a new treatment or have read something in the news or the media that they’re interested in, they should have the kind of relationship with their oncologist where they can just ask about it and get a reasonable response. If their oncologist doesn’t even know what they’re talking about, then they’ll at least look it up.

Also sometimes if you’re getting treated in the community, having just a one-time consult by a breast cancer specialist can be helpful to see what kind of investigational or experimental options are out there, if they’re just being treated with standard of care.

Again, there are excellent community programs and not everyone needs to be treated at an academic center, but that’s always an option to explore and become empowered just to see what else is out there.

Arthur N. Brodsky, Ph.D.:

Are there any other resources you’d recommend to patients that might help them in their quest to educate themselves about their options, especially in clinical trials?

Rebecca A. Shatsky, M.D.:

I definitely find websites to be of huge benefit to my patient population. One is Facing Our Risk, which is specifically for people who are BRCA carriers. Also, the Breast Cancer Research Foundation, Susan B. Komen, these are all kind of institutions that are really helpful. The Cancer Research Institute (CRI) has an Immunotherapy Clinical Trial Finder that is a fantastic resource that patients can use to determine which trials they might be eligible for.

CRI also hosts an Immunotherapy Patient Summit series, with several events each year. Last time I spoke at it, in San Diego, we did a breakout session specifically for breast cancer, and I was amazed by the amount of really incredible women who were there looking to educate themselves and looking to expand their options. I ended up getting a lot of new patient consults, so I was able to help a lot of women and was really pleased with the event. I think this upcoming summit on June 29 in San Diego is going to be just as successful. I’ve had nothing but fantastic feedback about it when I did it the last time. It’s a really positive experience.

Arthur N. Brodsky, Ph.D.:

That’s great to hear. Thank you so much, Dr. Shatsky, for taking the time to speak with me today.

Rebecca A. Shatsky, M.D.:

My pleasure. If you or anyone reading this want to follow me on Twitter, I have a professional account, @Dr_RShatsky. where I tweet on evidence-based breast cancer on clinical trials, new data, and more.