Q&A: Guiding Breast Cancer Treatment With Genomic Risk Stratification

In this Q&A with Lee Schwartzberg, MD, FACP, he discusses how genomic testing with MammaPrint and BluePrint guides treatment decisions for patients with HR-positive, HER2-negative breast cancer. He explains how risk stratification helps determine when chemotherapy and anthracyclines are needed and when lower-intensity options are appropriate. Schwartzberg also highlights the role of multidisciplinary care, including pharmacists, in managing toxicities and supporting personalized treatment.

Pharmacy Times: How does the recent National Comprehensive Cancer Network (NCCN) update change the way clinicians determine which patients with HR-positive, HER2-negative early-stage breast cancer truly benefit from anthracycline-based chemotherapy?

Lee Schwartzberg, MD, FACP: This is an important area. So, HR+/HER2- breast cancer represents about 70% of early-stage breast cancer diagnoses, and that’s the largest group of breast cancer patients that we have. Up until now, we haven’t had firm evidence and guidance on how best to give particular chemotherapy to these patients.

We know that some of these patients do require chemotherapy, and that’s based on their clinical characteristics, the size of the tumor, and some patient characteristics, like the age of the patient. But mainly, it’s about the size of the tumor and their anatomic classification, as well as their genomic classification, if they’re high risk or low risk. We use biomarkers to help us determine that, but we haven’t been able to make a clear treatment decision or selection of which chemotherapy to use in these patients.

Based on the data that we have, we know that more aggressive chemotherapy, which includes the 2 major classes of agents that are effective, the anthracyclines and the taxanes, usually combined with Cytoxan or something called ATC, is essentially the most aggressive treatment we use in most of these patients. But we haven’t had a way to determine who really benefits from that.

Now we have NCCN guidelines that help us make this determination. As you know, the NCCN guidelines are really the key expertise that we look for to help us make these decisions. NCCN guidelines are based, for any given disease, on a group of experts from major cancer centers who come together and review all the evidence. They periodically update their guidelines based on high-quality data.

NCCN has just changed their guidelines to include MammaPrint as a way of [selecting] which patients would benefit from anthracyclines. This is a really big deal, because we could not have a good evidence base to determine who really benefits before this.

Now, NCCN has recognized the data that comes from the MammaPrint Blueprint registry called FLEX, which looked at a large number of patients—over 1200 patients—who either received anthracycline-based chemotherapy or received non-anthracycline-based chemotherapy. Typically, the non-anthracycline-based chemotherapy is taxane and Cytoxan alone.

There was a marked difference in the outcome in those patients in terms of their three-year invasive disease-free survival if they got anthracyclines and they had a MammaPrint high-risk classification, which is the more aggressive genomic classification that you get from patients who are subjected to MammaPrint Blueprint analysis.

Pharmacy Times: Anthracyclines can reduce recurrence and mortality but carry serious long-term risks. How does integrating MammaPrint into treatment decision-making help clinicians better balance benefit versus toxicity?

Schwartzberg: Anthracyclines have been around for a long time, for decades, actually, and were recognized to be a class of drugs that were very effective in breast cancer. However, they have serious complications.

The most important complication from anthracyclines is effects on the heart, and we know that there is, in most cases, a threshold of how much anthracyclines you can give a patient before they start to have problems with the heart. In addition, patients with anthracyclines have a small but real chance of getting a secondary leukemia down the road.

These are things, obviously, for healthy patients who have had breast cancer surgery, most of whom may not have the cancer come back, but we want to cut that risk as low as possible. We don’t want to give drugs that have long-term toxicity.

In addition, anthracyclines are highly mutagenic, and these patients have a lot of nausea and vomiting and fatigue and mucositis, so they are not the easiest drugs to use. There’s a reason that anthracyclines are called the “Red Devil.” They’re red, and we find that patients remember that.

When I ask a patient who got chemotherapy a long time ago, “Did you get a red medicine that caused a lot of problems?” they immediately remember it. It really stands out in terms of its toxicity, and we really don’t want to give any drug to any patient that’s not effective.

Over the last couple of decades in oncology, we’ve realized that in some cases, we can de-escalate chemotherapy and preserve the efficacy, and that’s a wonderful thing, because we really want to treat every patient in a personalized way. We want to give them the most effective therapy with the least short-term and long-term toxicity.

So, figuring out a way to avoid anthracyclines but still get great results has become an area that we’re very interested in. Now that we have this data from MammaPrint, we have a way of making that determination.

Pharmacy Times: The FLEX Study showed a marked difference in 3 year invasive disease-free survival among High 2 patients who did and did not receive anthracyclines. What stands out most to you about these real-world findings, and how should they influence practice?

Schwartzberg: So, FLEX is a registry that includes a group of patients who are being treated by their physicians based on their characteristics. It’s not mandating particular therapy. The strength of FLEX is that we’re collecting this data prospectively, and all of these patients in FLEX have had MammaPrint and BluePrint analysis, so we know their risk. It ranges from ultra-low to low to high, from what’s called the high-risk category 1 to the high-risk category 2.

When investigators looked at the FLEX data and focused on the patients who had the high-risk 2 category, they examined over 1200 patients. So, this was a large data set. They looked at patients who received anthracycline-containing regimens versus those that did not, and the patients who had the high-risk 2 category derived substantial benefit from adding the anthracycline. In fact, it was over a 10% three-year invasive disease-free survival benefit. That’s huge. That’s a very large differential.

That is data that, in my opinion, and in the opinion of the NCCN guideline committee, is resoundingly robust enough to incorporate into the guidelines to help you choose who needs anthracyclines. So, it’s that high-risk 2 category, and that kind of makes sense, because those are the patients who have the most aggressive cancers and might benefit from the addition of another class of agent that works in a slightly different way but is very active against aggressive breast cancers.

Conversely, patients in the high-risk 1 category are also patients who benefit from chemotherapy. We know clearly that they do benefit from chemotherapy, and we make the decision to give them chemotherapy based on whether they’re high 1 or high 2. All of those patients generally have been shown to benefit from chemotherapy.

But now, we can sub-stratify these patients. The high-risk 1 patients did not benefit from anthracyclines, and you can give them lower-intensity chemotherapy, like taxane and Cytoxan, like I talked about before, and spare them anthracyclines while still getting excellent results.

So that’s the key: preserving the efficacy by using the right chemotherapy, by looking at MammaPrint and stratifying the patients by their actual MammaPrint score—high 1 versus high 2.

Pharmacy Times: For patients classified as Low or Ultralow risk by MammaPrint, what reassurance does this data provide that anthracyclines can be safely avoided without compromising outcomes?

Schwartzberg: MammaPrint BluePrint is a great test to order on patients when you’re deciding whether or not they need chemotherapy.

So, in that large group of patients who are HR-positive, HER2-negative, we have to decide: should we give chemotherapy or not? That’s the first cut, if you will—do they need chemotherapy, or will they benefit from endocrine therapy only?

Because, as we all know, the foundation of treating HR-positive, HER2-negative patients is to give them endocrine therapy to block the effects of estrogen, because they are HR, meaning hormone receptor–positive, usually estrogen receptor–positive and progesterone receptor–positive. So the given is that they’re going to get endocrine therapy. The question is whether there is benefit from chemotherapy.

So, if you get a MammaPrint, as I mentioned, we get four categories: ultra-low, where they have a very low risk of recurrence and endocrine therapy adds a small amount of benefit; low, where endocrine therapy adds a lot of benefit and reduces their risk; and then high one and high two.

High one and high two have been shown, from both randomized clinical trials, previous registry data, as well as the data from FLEX, which now includes over 20,000 patients, that the benefit of chemotherapy starts in patients who have high-risk disease. Conversely, there is no benefit of chemotherapy in addition to endocrine therapy in patients who have low-risk disease or ultra-low–risk disease.

So, we break it into those four groups. First, the two lower groups don’t need chemotherapy, don’t get benefit from chemotherapy, have a better prognosis, and get benefit from endocrine therapy. Conversely, the high-risk patients get benefit from chemotherapy, and now we know that the high two patients at the highest risk get benefit from more aggressive chemotherapy that includes anthracyclines.

Pharmacy Times: As genomic testing increasingly guides chemotherapy selection, how can pharmacists support oncology teams in implementing these more personalized treatment strategies?

Schwartzberg: One of the great changes in treating breast cancer over the last years has been the development of multidisciplinary teams to help guide care, and it really does take a village to make decisions for breast cancer patients.

They get surgery, they sometimes get chemotherapy, they get endocrine therapy in most cases, and sometimes they get biological therapy. They will have reconstruction, and they will have radiation therapy. Sometimes they need additional people helping them.

Part of the multidisciplinary team that’s critical is the pharmacist. When we meet every week to go over our new cases, our pharmacist is there and is an integral component of the team. As we’re making these decisions, the pharmacist is really critical.

Number one, they can help determine and might talk about getting a genomic test. We value everyone’s opinion as we’re thinking about who we should test to figure out what treatment to give. Then, if we decide on chemotherapy, the pharmacist’s role is critical in helping the patient understand the toxicity of the chemotherapy.

Our pharmacists help with chemo education and help monitor patients who are undergoing chemotherapy. Adjuvant chemotherapy for breast cancer can be rough on patients. We get them through it, but it really takes a lot of attention.

The pharmacist is a critical component of that part of our care as well, making sure that all toxicities and adverse events that a patient has are managed correctly so we can deliver effective chemotherapy and reduce their chance of breast cancer ever coming back.

Pharmacy Times: When discussing treatment options with patients, how do you explain that avoiding anthracyclines in certain cases reflects precision medicine rather than undertreatment?

Schwartzberg: That’s a great question. So, the way I approach the discussion with the patient is to tell them that they have, in this case, HR+/HER2- breast cancer, and that we have some decisions to make about how best to treat them to reduce their risk of the cancer coming back.

We want to make that decision as personalized as possible, and today we have tools to help us do that. Those tools include genomic profiles like MammaPrint and BluePrint, which give us individual characteristics of that cancer.

So, we use the genomic information from MammaPrint in addition to the clinical information: the size of the tumor, whether or not lymph nodes are involved, the characteristics of the tumor, the estrogen receptor, the progesterone receptor, the HER2 receptor, and the patient characteristics—what their age is and what their comorbidities are. All of these are integrated together to make a decision.

I start by telling the patient that we have a lot of information that we’re going to integrate to come up with the best possible approach. When we get a MammaPrint BluePrint test, we then know the category that they’re in.

When I meet with the patient again with their MammaPrint results, I can say something like, “We did this test on your tumor, and despite the fact that you didn’t have lymph nodes involved, perhaps, or maybe you had one positive node, and we were making a decision about what type of chemotherapy to give, we now have information that shows us that anthracyclines will benefit you and markedly reduce your risk of this cancer coming back.”

So that’s the kind of chemotherapy regimen I want to give to you, and that’s why I want to give it. It does have some toxicities that are specific to anthracyclines. It means a little more aggressive treatment, but we can manage these toxicities safely.

We have a whole team working together to manage this: besides me, my advanced practice provider, my nurse practitioner, my nurse, and my pharmacist. We’ll work together as a team to manage it.

When you finish this chemotherapy, which in your case, if you have a high-risk two cancer by MammaPrint, will include anthracyclines, you’ll finish, you’ll get over the side effects, and you can feel comfortable that you have the lowest risk of the cancer coming back.

Pharmacy Times: Do you want to add anything else?

Schwartzberg: I would just say that the use of tests like MammaPrint BluePrint has really transformed the way we make decisions, and these tests can help us make a lot of decisions.

The most recent decision, as in the NCCN guidelines, is on anthracyclines, but they can also help us make a decision, as I mentioned, about whether or not to give chemotherapy at all and how long to continue endocrine therapy. In some cases, we give five years, and sometimes we give more extended endocrine therapy.

We get a wealth of information from a MammaPrint BluePrint test, which helps us plan at the very beginning, from the original tumor, even sometimes before surgery: whether to give chemotherapy upfront, whether to give chemotherapy afterward, how long to give endocrine therapy, and whether we need to add other drugs in the adjuvant setting because the risk is high.

So, it has really transformed our approach from just looking at the tumor, the size of the tumor, and the lymph nodes to now understanding the biology of the cancer. This allows us to give patients a personalized recommendation with the least toxicity possible while getting the most benefit.