Precision Medicine Advances in HR+/HER2- Breast Cancer

In Partnership With:

Partner | Cancer Centers | <b>Winship Cancer Institute of Emory University</b>

Jane Meisel, MD, provides insight on how genomic assays are helping to individualize treatment plans and strategies to determine the optimal duration of endocrine therapy.

Jane L. Meisel, MD

Genomic platforms are helping to personalize treatment decisions in patients with hormone receptor (HR)—positive, HER2-negative breast cancer, said Jane L. Meisel, MD, specifically whether or not chemotherapy can be omitted in those with low genomic risk.

“The key is sorting out which bucket your patient fits into and how to best manage them, how to treat them as much as they need to be treated and with the right treatments, but not overtreating and causing too much toxicity,” said Meisel. “Individualizing care and personalizing the treatment plan is a challenge, but it's what makes oncology so exciting and what makes it so rewarding to treat these patients.”

Meisel, an assistant professor, Department of Hematology and Medical Oncology and Department of Gynecology & Obstetrics, Winship Cancer Institute, Emory University School of Medicine, said that differentiating between when to use the Oncotype DX versus MammaPrint assays is especially important, as the results of these tests can help inform whether chemotherapy is necessary or not.

In an interview during the 2019 OncLive® State of the Science Summit™ on Breast Cancer, Meisel provided insight on how genomic assays are helping to individualize treatment plans and strategies to determine the optimal duration of endocrine therapy.

OncLive: What are some factors to consider when choosing whether or not to treat with chemotherapy?

Meisel: Where that question [becomes especially relevant] is in the patient who has some high-risk disease, but not full-blown stage III, or advanced stage II, node-positive breast cancer. There are some patients who you need to give chemotherapy to. We don't have the data—and won't have the data, at least for a very long time—[that says we should] not treat patients with multiple positive lymph nodes [with this approach]. However, for the patient who has a node-negative cancer and some high-risk features, genomic testing or other clinical features may play into a decision regarding whether to use chemotherapy or not.

You don't want to give patients [unnecessary] toxicity, but you also don’t want to look back at a time of metastatic recurrence and wish that you had used chemotherapy. As I said, those questions really come into play with the patients who have node-negative disease, but have some high-risk features—like maybe they are estrogen receptor (ER) positive, but progesterone receptor negative—or they have a high-grade cancer, or 1, 2, or 3 positive nodes. That's where you have to consider the chemotherapy decision carefully.

How are genomic platforms helping to inform that decision?

Oncotype DX has been around now for a while and all of us are very comfortable using it. Especially with the TAILORx data, there is now a smaller grey area in terms of women [for whom] we don't exactly know [how to approach treatment]. We need to focus on those women who are under 50 years and have recurrence score between 16 and 25; that's the group where we still have to use clinical factors, patient preference, and a lot of shared decision-making to decide whether to use chemotherapy or not. TAILORx has allowed us to omit chemotherapy in many node-negative patients who are over the age of 50 and have a score under 25. [The data also] made it clear that those patients who have higher scores really do benefit [from chemotherapy]; that has been really helpful.

MammaPrint is helpful in a different way. [For example], in those higher-risk patients, even those patients with 1 positive lymph node who may not be totally sold on chemotherapy, sometimes we can use MammaPrint to say, "Hey, this patient who is clinically a little high-risk, may actually be genomically low-risk and not benefit [from chemotherapy]." We’re also waiting for the RxPONDER to read out, so we can really understand whether Oncotype DX may play a role in those patients with 1 to 3 positive nodes; that will also be very helpful.

Could you expand on how the TAILORx findings changed practice?

TAILORx looked at women with an intermediate-risk recurrence score, between 11 and 25, and randomized them to receive either chemotherapy plus endocrine therapy or endocrine therapy alone. They found that women over the age of 50 who had a recurrence score less than 25 didn’t benefit from chemotherapy. Now we're able to omit chemotherapy with some certainty for those women.

Again, these are [women with] T1, T2 tumors and negative lymph nodes. [The trial also showed that] women under the age of 50 who had scores below 16 didn't benefit [from chemotherapy] either. There was some benefit seen with chemotherapy in women with scores ranging from 16 to 20, and then a little more benefit in women with scores ranging from 21 to 25; I believe that's the group where we still have a little bit of a grey zone.

A presentation at the 2019 ASCO Annual Meeting looked at combining clinical risk with Oncotype DX [score] for that population and seeing whether we can use clinical risk to help improve our ability to detect which of those women in that little grey zone need chemotherapy versus those who don't. There weren't any major conclusions drawn from that. I believe the women who are between 40 and 50 years, are premenopausal, are at high clinical risk, and have a higher Oncotype DX score, are probably those who benefit the most [from chemotherapy]. However, this is still an area where we're going to have to discuss the risks and benefits and weigh the pros and cons with the patient in order to make an individualized decision.

Regarding the RxPONDER trial, what is the hope for that research?

Many of us feel in our gut that we may be overtreating some of these patients with low-grade, strongly ER-positive breast cancers, who have involved lymph nodes. Right now, we don't have the strong data to omit chemotherapy for those patients. However, I believe there's a sense that the biology of those tumors may be different; that those are patients who are going to respond better to endocrine therapy compared with chemotherapy and that chemotherapy really may be overtreatment. When the PALLAS trial—which is the trial of patients with estrogen-sensitive breast cancer who are stage II/III and are being randomized to either standard endocrine therapy versus endocrine therapy plus 2 years of a CDK4/6 inhibitor—reads out, it may be that those patients benefit more from a more aggressive endocrine approach.

Regardless, many of us feel like we may be overtreating or just giving the wrong treatment with chemotherapy, but the problem is, we don't have the data to omit chemotherapy in those patients, and they are higher risk. That’s where RxPONDER will help; it will tell us if there is a subset of patients with node-positive disease for whom we can safely omit chemotherapy if they have a lower Oncotype DX score. Just as the TAILORx has done for the Oncotype DX score under 25 population, RxPONDER may allow us to draw more of “a line in the sand” for a certain subgroup of node-positive, ER-positive patients for whom we can omit the chemotherapy.

What are some ways to optimize the use of these genomic assays in practice?

Thinking carefully about who you use [these assays] in [is important]. What are you going to do with the results? Are they going to inform your management? Giving the patient and the provider more confidence about the treatment choice is always what we're looking to do; we're always looking to personalize therapy and these tests help us do that.

Oncotype DX is a test [that’s more for] thinking about endocrine sensitivity and omission of chemotherapy, while MammaPrint is a test that's more for the higher clinical risk patient; [it can be used] to determine whether there are patients within that high-risk clinical group who may have low genomic risk and then we can omit chemotherapy. We need to be judicious about which test we use and when. When differentiating between whether to use Oncotype DX or MammaPrint, a lot of clinicians go with what they know. If they started using Oncotype DX, they use a lot of Oncotype DX. If their institution is more familiar with MammaPrint, then they use a lot of [that assay].

What I was hoping to get across today, and what I believe is true, is that there's probably a place for both of them—you just have to be judicious. Are you using a test to potentially omit chemotherapy in a patient with lower clinical risk? Or, are you thinking about a patient who may be of higher clinical risk for which you would really like to omit chemotherapy if you could? Then you can use a MammaPrint test, even in those patients who are maybe node-negative but high-grade or have even 1 positive node to help you determine, "Hey, this is a patient who is genomically low risk and can, therefore, omit chemotherapy."

What should your colleagues take home in terms of endocrine therapy and optimal duration of treatment?

It's a tough area where the pendulum keeps swinging. We do have data showing that extended therapy is better in terms of reduced risk of recurrence, and it even improves survival in some situations. The standard of care has always been 5 years. The challenge is that there are definitely a large group of patients for whom 5 years of endocrine therapy is enough. We know that 10 years of therapy, while it is better for some patients, is also more toxic. In terms of aromatase inhibitors, they are more osteoporosis and [cause] more fractures. When you're thinking about more tamoxifen, it has higher rates of endometrial cancer and diabetes . Then, it's harder to quantify, but for clinicians who are seeing these patients every day, [there is] the weight gain, the hot flashes, and the vaginal dryness; the things that people don't talk about as much but really do impact quality of life.

The point that's important to make is that there are some patients who probably significantly benefit from extending [treatment], but it probably is those patients with either just a higher bulk of disease at diagnosis, those with more than 4 positive lymph nodes, or those who are more high-risk in terms of genomics.

There will be more tools that will come to light in the future and are already starting to—the Breast Cancer Index and others—that may help us better understand, even within those node-positive cases, which patients are going to benefit the most. It is definitely still an area where patient preference and tolerance play a huge role in decision making. I have patients with stage I or early stage II tumors who have tolerated their endocrine therapy beautifully and feel like they would lose sleep if they stopped it because they want to benefit from as much as possible.

We know that if you monitor the adverse events, it is safe to continue. Therefore, I have allowed some of those women to continue to 10 years, even though they aren't necessarily the people for whom I would strongly recommend [this duration]. I have others who just can't tolerate [endocrine therapy] another day and they have to go off treatment. Then we just say, "We understand where you are with that and we just have to watch you closely." It all boils down to shared decision making and using these clinical and genomic tools where we can in an effort to make the best treatment decision for each individual woman.