By: Danielle Ternyila
Most patients with breast cancer are curable, according to Hannah Linden, MD, and by identifying patients with mutations, targeted therapies can be used to help improve outcomes and survival in many patients.
“We are doing better for helping women with breast cancer, and it’s a more treatable disease,” said Linden. “Imaging, liquid biopsy, and molecular biology are evolving to allow us to identify important therapeutic strategies.”
Imaging, liquid biopsy, and tissue assays are able to determine the presence of various mutations in a patient that could help in predicting response to select therapies. The mutations identified with these tests can help guide therapy selection for each patient with breast cancer to deliver a more personalized approach to treatment.
With the growing understanding of different mutations in breast cancer, more targeted therapies are evolving in this space, including the emergence of CDK4/6 inhibitors for patients with ER-positive/HER2-negative patients. Targeted therapies are also becoming available for patients with breast cancer harboring a PI3K or ESR1 mutation.
“We have some work cut out for us to determine sequencing and timing, but it is truly promising to know that we have better treatments, and we have better ways of identifying which patient needs that treatment,” said Linden, a physician at Seattle Cancer Care Alliance; Athena Distinguished Professorship in the Division of Medical Oncology at the University of Washington School of Medicine; Associate Program Director of the Medical Oncology and Hematology Fellowship Program at Fred Hutch and UW Medicine; Member of the FHCRC; and Member of Brotman Baty Institute for Precision Medicine.
In an interview with Targeted Oncology, Linden discussed the current treatment landscape during Breast Cancer Awareness Month. She also highlighted the value of liquid biopsy, tissue biopsy, and imaging techniques in this space for identifying patients with targetable mutations and how these assays and techniques can further impact treatment and outcomes of these patients.
TARGETED ONCOLOGY: Could you provide an overview of the current outlook on patients with breast cancer and how this treatment landscape has evolved overtime?
Linden: Breast cancer, for many patients, is curable. We take care of many of those patients, and they are a member of advocacy groups, and those advocacy groups are very strong. That’s why you have comfort for reconstruction and other things that might not have happened without those advocacy groups that are so embedded now in all our research. That is a good thing because they keep our eye on the quality of life of the patient and the patient experience.
The patients who we spend the most time with, within medical oncology, are the people with metastatic breast cancer. Those are not curable, but they are very treatable. They’re becoming more and more treatable, and actually 1 of the advances in the past year has been using CyberKnife, a Gamma Knife procedure or surgery without surgery or radiation treatment, to a small number of 5 or less metastatic sites. You don’t cure all people with that approach, but you do cure some of them, so it does seem that sometimes people with stage IV disease, advanced disease, or disease that spreads outside the region of the breast are curable. The majority of patients, however, are treatable. I wouldn’t say it’s a chronic disease, but that is how some people want to see it. We give you a medication, you take it for the rest of your life, and you do very well on it for a long time. Certainly, if you are already older, you could have some other intervening [comorbidity] before the breast cancer takes your life.
We have better tools and better treatments for breast cancer, but we’ve always had good treatments. This has been going on for a long time. We have had estrogen receptor (ER) and HER2 as clear targets for therapy with good therapies targeting those receptors. It just keeps getting better. We keep identifying better ways to target the ER and HER2, and that definitely accounts for why more people are either cured or living longer.
TARGETED ONCOLOGY: What are the newer agents that are providing hope for this patient population?
Linden: Recent developments have helped us a bit in the group of people with the most common subtype of breast cancer, which we call ER-positive/HER2-negative. This means that the tumor is expressing ER, and it does not have this bad-acting protein called HER2. That’s the most common subtype of breast cancer, so on average if you have metastatic breast cancer, that is [likely] what you’re living with. There have been a couple types of therapies aimed at that group of patients that have improved outcomes for them both in quality of life and quantity of life. The interesting ones recently have been the CDK4/6 inhibitors, like palbociclib (Ibrance), abemaciclib (Verzenio), and ribociclib (Kisqali). Those are actually pretty tolerable drugs, and we are using them more and more and earlier and earlier in breast cancer, including now in trials of people who don’t have incurable disease but to increase the percentage that are going to be cured and not have the cancer come back. Stages I, II, and III are curable, but it’s a worsening scale on the way between stages I and III. For stage I, we don’t offer anything extra, but if you have a stage II or stage III cancer, you can now get CDK4/6 inhibitors in a clinical trial, randomized with a placebo, added to your care to see if we can actually increase the percentage of women that are durably cured. The odd thing about these cancers are the cancer can come back after the window of time that we all think of as the time you are cured. The thought here is if you take your anti-estrogen therapy for 5 years and it benefits you 25 years later when we look at your outcome. That’s kind of a magic trick because you are not taking anything, but you are still getting an advantage from something you’ve taken previously. We’re also looking at which patients need 5 versus 10 years of endocrine therapy.
TARGETED ONCOLOGY: Besides ER and HER2, what other sub-populations can we target in breast cancer now?
Linden: The other new class of drugs that is something to talk about is for patients who seem to quite specifically overcome anti-estrogen therapy with a PI3K mutation. That specific mutation gives the cells an advantage, and we now have something to actually target that mutation. For the CDK4/6 inhibitors, we know there is some sort of proliferative signal, but we don’t actually have a molecular signature to help us identify which patients are going to benefit. However, with this PI3K mutation, we actually know those patients are going to benefit from a newly FDA-approved drug called alpelisib (Piqray). That’s a little more toxic, but it’s not that toxic. It’s tolerable. What’s exciting there is it is targeting something specific about 40% of these metastatic breast cancers that are more advanced, and it’s a way to avoid chemotherapy. It’s probably a better choice than chemotherapy for many patients. That’s the exciting news.
TARGETED ONCOLOGY: How do you see the role of liquid biopsy evolving in the breast cancer space?
Linden: Liquid biopsy is an emerging technology, and it’s not entirely standard for anything yet, although I think in the lung cancer world, it’s becoming more standard. Our suspicion is it will become more standard for breast cancer. The way it is likely to become more standard is these mutations that the tumor picks up overtime, we need a way to monitor them. There are 2 mutations, including the PI3K mutation and ESR1 mutation. Both of those are probably clinically relevant, meaning we have an indication to change therapy if we detect those mutations. The liquid biopsy advantage is you can check it out in the middle of things without putting a needle deeply inside anyone. It’s just a blood test. It’s a way to see what’s happening with the tumor overtime, and as tumors develop resistance to the therapy you’re actually on, it’s a way to monitor what we might do about that and give us another therapy that we can aim at that target.
TARGETED ONCOLOGY: Besides these assays, what other techniques can be used to capture the molecular biology of a patient?
Linden: We do functional imaging with ER imaging. We developed that at the University of Washington Molecular Imaging Group. It’s a great complement to biopsy because it’s non-invasive. It’s virtual. It’s not just showing you the shape of the tumor, but it’s showing you what the tumor can do. In this case, it’s whether or not the tumor can bind estrogen. We are also looking to see how these 3 different types of assays—liquid, tissue, and imaging—can complement each other and give us the best way to develop an effective strategy to manage the patient’s tumor. I think in the coming year, it is likely and in part because of the work we have done here, the FDA will approve the tracer and it will become commercially available.
TARGETED ONCOLOGY: How are these biomarkers impacting treatment decisions now in breast cancer?
Linden: We have ER and HER2. Those have been long-established, very robust markers in breast cancer, and we measure them in the tissue. Those have gotten us a lot, and breast cancer has had precision medicine approaches for a long time. I think we need to find newer targets that won’t replace those targets, but they’ll add to the utility of those targets.
For the ER-positive patients, we will look at the PI3K and ESR1 as evolving targets that can further narrow your choices for therapy. For HER2-positive tumors, there are probably some HER2 activating mutations that are relevant for us to target with different HER2-directed therapies that are also emerging, like neratinib (Nerlynx).
TARGETED ONCOLOGY: In honor of breast cancer awareness month, what message would you like to share with community oncologists that are treating patients with breast cancer?
Linden: We are doing a good job. We are doing better for helping women with breast cancer, and it’s a more treatable disease. Imaging, liquid biopsy, and molecular biology are evolving to allow us to identify important therapeutic strategies. We have some work cut out for us to determine sequencing and timing, but it is truly promising to know that we have better treatments and we have better ways of identifying which patient needs that treatment.
It’s also important to talk about the BRCA mutation. There are targetable germline mutations that are not about the tumor, but it’s about the genes of the patient. Those patients who have a risk of breast cancer and get breast cancer, there is a new targeted therapy for them too.
I think the message for the community oncologist is you’re doing a great job. All of the great therapies we have out there are good and should be used. There may be refinements now that we can make to identify more targeted therapies for women and men with breast cancer to spare them the toxicity of chemotherapy. Liquid and tissue molecular assays are also going to help.
Barbara Jacoby is an award winning blogger that has contributed her writings to multiple online publications that have touched readers worldwide.