Unmet Needs for Metastatic Breast Cancer

Transcript:Mark Pegram, MD: The unmet need is very clear. Unfortunately, we cure very few metastatic breast cancers. So, with rare exception, this remains a huge challenge. Moreover, we need to be concerned about quality of life and make sure that our treatments don’t negatively impact quality of life too severely to be tolerable. That’s a very fine balance, and I think the older I get—the more experience I have—the less ambitious I am in terms of using toxic therapies. I’ve become much more constrained over time in considering quality of life issues and introducing the concept of chemotherapy holidays from time-to-time, things like this.

Those are, really, very important to patients. It’s critical not to overtreat with chemotherapeutics. And from time-to-time when I do consultations from outside, clinicians referring patients, I see patients who have maybe crossed the boundary. They’ve been maybe overtreated—have too much peripheral neuropathy to be acceptable. For example, too many cytopenias.

So, I think it’s really critical to follow our patients very closely: make sure we understand what their lifestyle is, what their daily life activities are, and how the treatments are impacting their family situations; even simple things like transportation. Giving a weekly vinorelbine regimen is going to be more challenging than an every-3-week chemotherapy regimen, for example. And these are the things that patients use to weigh in on the decision. If you’re in an equipoise between 2 different future treatment options, that might be a deal breaker. If they live a great distance from clinic, it might be too much of a problem to do a weekly treatment. Simple things like that.

The IV access is sometimes a barrier. And as professionals, we don’t really think about those things because they’re so routine, they’re so automatic. But for patients, they’re extremely disruptive, and so we have active treatments. We certainly need to do better. There’s a lot of opportunity in terms of clinical research now for promising and hopeful new treatments for metastatic disease. But what the patients want and demand is a cure for metastatic breast cancer, and we’re just not there yet. Sadly, we’re not there. A lot more work needs to be done for advanced disease, and there’s a growing swell of enthusiasm to contribute more research dollars to the advanced disease state because of its overall poor prognosis and outcomes. Even though it’s better now than it has been historically, it’s still not good enough. It’s not acceptable, and we need to do better.

I think we are always going to need some cytotoxic treatment approaches. It has been, and remains, the backbone of treatment for advanced breast cancer for sure. And consequently, it’s very likely we’ll need new classes of cytotoxics. I don’t think the story is over yet for chemotherapy. I wish it was, but I don’t think it is. Ironically, if you really look critically at the mechanism of how most chemotherapeutics work, they are targeted agents. Their targets were well known to the people that invented them back in the day, and nowadays, we might call those targeted therapies instead of chemotherapy. CDK4 and CDK6 inhibition would be a classic example: if that molecule (palbociclib) were discovered in the 1970s instead of the 20-teens, it would have been another class of chemotherapeutics. We don’t call it that now, but if you really think about it, it has many chemotherapy-like attributes—neutropenia in particular.

I think that we’ll continue to evolve the story, and we are going to need cytotoxic mechanisms of action, probably in partnership with other targeted therapeutic approaches or immunotherapeutic approaches, to be sure. And also, for cytotoxic payloads and antibody drug conjugates, the field is very exciting and moving quickly, both in the HER2-positive space, where there are some new antibody drug conjugates that look to be more potent than TDM1 in preclinical models, and also in some new antibody drug conjugates with great promise in triple-negative disease that are really almost quite unexpected—that these targets would be important in that subset of patients with high unmet needs.

So, at the end of the day, antibody drug conjugates are cytotoxic chemotherapy—just a different nuance in the delivery mechanism. I think there’s also more need for orally bioavailable cytotoxics, to make it more convenient for patients not to have chronic parenteral access and the complications that can happen from central venous catheters, infection, blood clots, etc. I think the field will move forward. There will be new cytotoxics in our future, and they will most likely be partnered with other targeted therapeutic approaches. But at the end of the day, they will remain a backbone in the armamentarium for metastatic breast cancer.

Transcript Edited for Clarity