How Targeted Therapies Are Changing the Breast Cancer Treatment Landscape

Targeted therapies that attack cancer in a more precise way than traditional chemotherapy are being used more in the field of breast cancer, but the solution in utilizing them lies within the patient-oncologist relationship, according to Dr. Dejan Juric.

Juric, who is the director of the Termeer Center for Targeted Therapies at Massachusetts General Hospital Cancer Center in Boston, recently presented a session on how targeted therapies fit within the breast cancer treatment landscape at CURE®’s Educated Patient® Breast Cancer Summit.

After his presentation, Juric spoke with CURE® to discuss some specific targets that are used to treat breast cancer, the potential downsides to using targeted therapies, and what questions patients should be asking of their doctors when it comes to deciding if precision medicine is right for them.

CURE®: Can you offer some insight into what you mean when you talk about precision medicine, particularly in breast cancer?

Juric: Precision medicine is a new approach to treat cancers, by trying to match the right treatment with a patient, and do that at the right time in the course of the treatment, using novel genomic tools to help us understand what is unique about their cancer, what is the particular vulnerability of that cancer, so that we can increase the chance of treatment actually working.

Think of it as an inverted pyramid of biomarker driven treatments, where instead of the old school approach where we're treating a lot of patients with a drug for a small benefit, they (targeted therapies) are sort of flipping that upside down to get a small fraction of patients who are positive for a particular biomarker, and only those patients get the treatment. And then you have a much larger benefit in that highly selected group of patients, and you avoid exposing large fractions of patients who wouldn't benefit from the treatment to unnecessary side effects.

What are some particular targets right now that are being investigated that have some promise in breast cancer?

A really promising target is PIK3CA. This is the most commonly altered gene in a large subgroup of estrogen receptor-positive breast cancer, where about 40% of patients have activated mutations in that particular gene in their tumor. That mutation results in the activation of the entire pathway, and what we call aberrant or abnormal signaling, where now the cancer cells get a persistent message to grow, grow, grow. And by blocking that target, we are able to then turn that around and suppress the growth of the cancer cells.

Very recently, the first agent targeting PIK3CA, alpelisib (Piqray) has been approved by the FDA (Food and Drug Administration). But targeting PIK3CA remains a very important avenue of research because we can always do better. We can try to develop drugs that almost exclusively target the mutant protein, the one that's present in the cancer cells and try to completely spare the normal version of that protein. If we do that, then we can truly improve the treatment outcomes in PIK3CA-mutant breast cancer. So that's one target that deserves a lot of interest.

But also, this is really important, developing higher order combinations of these agents. Cancer is an extremely adaptable system. And it is a rule that the cancer cell will try to survive pretty much anything we throw at it. So, we need to surprise the cancer cells or preempt their reaction by attacking those cells, and the tumor, with not just one drug, not even two drugs. But hopefully three or four drugs, hoping that with combination therapy, we can close the so-called escape routes for cancer cells that can kind of get the cancer into the corner and have those cells die so they cannot negatively impact the patient’s life.

What are some of the downsides to targeted therapies?

Targeted therapies are not without side effects. They can still have so-called “on-target” and “off-target” side effects. They're just different from cytotoxic chemotherapy. But we still need to pay attention to those side effects.

The second component that I think is important to discuss is, by using targeted therapies, we are putting all our chips on one particular target, and it is possible that the cancer relies on redundant mechanisms. And for that reason, a targeted therapy may fail because of that adaptation or escape or quick switch that the cancer cells can go through to use a similar protein or in some other way bypass the action of the targeted treatment.

What are you most excited for in the future of this field?

I'm really excited with the pace of progress. When we started working with targeted therapies, I remember so vividly as a fellow, I would stare at the median overall survival (rate) for metastatic breast cancer patients, which was only 22 months for less than two years. And now, just with one treatment, we can ensure that the disease stays in control for three years or more. So, this is dramatic improvement.

I hope that as we continue to integrate this modern technology into clinical practice, we'll be able to develop better and better ways to select those patients (who) are truly most likely to benefit from (a) particular treatment. I think technological improvements in this area are moving so fast and no doubt these tools will enter the clinical practice and the same time the developments in machine learning and artificial intelligence, it will be essential to then use the wealth of data generated by these omics approaches to help us make these decisions quicker and for us to be overall smarter …. And I feel with improvements in both the technology used to analyze tumors, as well as machine learning approaches, I feel when we marry these two successfully, we'll be truly able to benefit patients tremendously.

What advice would you have for patients who are interested in learning more about how targeted therapies might fit into their treatment plan?

When you find yourself in a difficult position where you have to make a decision about your treatment, or about diagnostic approaches necessary to further characterize your disease, ask questions. Ask whether conventional approaches such as cytotoxic chemotherapy are truly the best way forward for you, or should you have a more precise treatment such as targeted therapy? Should gentle treatments such as hormonal therapy, be the way to go? Or should you engage the immune system and (use) immunotherapy to control your disease?

Also, ask your physician whether they know enough about your cancer. I say that to beat the enemy, (you) need to know the enemy. So, it's really essential to know as much as possible about what is really driving cancer. Why is it there in the first place? And how can we stop it? That will require often performing tissue biopsies, it may require getting a liquid biopsy, or it may require particular imaging tests to be done. And the more you know, and better (informed) the oncologist is by combining these diagnostic and analytical tools, hopefully (the more) better informed they'll be making these decisions.

But there's something sacred about the relationship between a physician and a patient. It's a bi-directional relationship. It's a partnership. And oncologists take cues not just from their colleagues from the broader community of other practicing oncologists and scientists. They're really also driven by the needs of their patients (and) their questions on their goals. And the more engaged a patient is in asking questions, the more motivated the physician is to answer them, and to go as deep as possible in understanding the disease and treating that patient better.

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