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First-line Therapy for HR-Positive, HER2-Negative mBC


William J. Gradishar, MD and Joyce A. O’Shaughnessy, MD provide the setting for the role of first-line therapy for HR-positive, HER2-negative mBC.


Bruce Feinberg, DO: Bill, maybe you can give us an overview on how breast cancer is distinguished molecularly, particularly in the subset of patients who are hormone receptor-positive and HER2 negative. Tell us about traditional care and then the advent of CDK4/6 inhibitors and how it has changed the current guidelines, both NCCN [National Comprehensive Cancer Network] and others.

William J. Gradishar, MD: Sure. As clinicians, despite all the tools that we have available today, including sophisticated tests and molecular testing, we still fundamentally look at breast cancer and divide it up into just a couple of different buckets. Those are ER [estrogen receptor]-positive breast cancer, HER2-positive breast cancer, so-called triple-negative breast cancer, where the markers are absent, or some combination of ER or HER2 being positive. To a large degree, our treatment decisions are based on knowing which category a patient falls into. For those that have metastatic disease, unless there is some visceral crisis or the tempo of the disease is significantly rapid, we typically prefer to use anti-hormone therapy if the patient has hormone-sensitive breast cancer. The reason for that is because the toxicity associated with it as a general statement is much better than chemotherapy, and in that subset of cancer, we find that chemotherapy isn’t necessarily better. That perception, sometimes on patients’ parts or even on the part of their clinicians, that you must give chemotherapy because it’s the more potent way of treating the cancer, doesn’t necessarily translate into a better outcome.

With that said, we’ve typically tried to use single agents, whether it’s tamoxifen, aromatase inhibitors, or fulvestrant. We use them in sequence until the tempo of the disease has changed or until the patient becomes refractory to endocrine therapy, and then we go on to other treatments. More recently, we’ve started to see the introduction of partners to endocrine therapy. Before the CDK4/6 inhibitors, there was even an effort 20 or 30 years ago to combine endocrine therapy. That wasn’t particularly fruitful, so again, we used sequencing of single agents.

Probably a decade ago, we started to understand some of the molecular pathways a bit better, and the first drug that was introduced that we partnered with endocrine therapy was an mTOR inhibitor, everolimus. In combination with an aromatase inhibitor, that proved to be more effective than the aromatase inhibitor alone. More recently, where all the excitement is focused, and obviously the subject of much of what we’re talking about today, is the CDK4/6 inhibitors. Understanding how those work and then developing drugs that affected that pathway has proven to be very effective in the treatment of advanced breast cancer. I know we’ll probably get into some of the details about the individual trials. With the introduction of CDK4/6 inhibitors, that changed how we approach patients. Now, it’s somewhat standard to use a combination endocrine therapy with something else when treating patients with ER-positive metastatic breast cancer.

Bruce Feinberg, DO: Bill, you mentioned the visceral crisis as historically 1 of the reasons why chemotherapy might be used. Do we know if that paradigm has changed using a CDK4/6 in combination with an endocrine agent?

William J. Gradishar, MD: It probably still holds true. It’s also worth saying that a visceral crisis is sometimes in the eye of the beholder. Sometimes a medical oncologist will see 2 liver lesions and think, “That’s bad, we have to go to chemotherapy.” But what I’m referring to, and I’ll let Joyce comment on this herself, is usually when you see bulky disease and you have 1 opportunity to get things under control, otherwise the patient is going to decline rapidly. It’s that circumstance where things are changing rapidly, in which we’re more inclined to use chemotherapy. The presence of visceral disease alone does not dictate that you must give chemotherapy. You could use endocrine therapy in that setting.

Bruce Feinberg, DO: Joyce, that’s a great segue to bring you in. I do quite a bit of real-world evidence research, and I see huge variance in the first-line use of chemotherapy in the HR [hormone receptor]-positive metastatic breast population. It’s difficult to know. All of these patients clearly have lung and liver metastases, at least in their claims coding, but it’s hard to believe that crisis patients could be as many as 40%. I don’t know what that number should be. Is it 5%? Is it 10%? To address Steve’s prior comments, it seems that these are the kinds of areas where clinicians need to have a role. I think we’ve been too hesitant to let it be in the eye of the beholder versus providing some definition—bilirubin greater than 1.5, transaminases greater than 2 times normal—or something that might speak to the impact on an organ. Something that would say by adding this therapy, this is the cost, toxicity, and risk of hospitalization would play a role. I’m really curious to get your perspective and I wanted to set it up.

Joyce A. O’Shaughnessy, MD: Yes, it is puzzling to those of us who do a lot of breast cancer treatment. The data on the first-line CDK4/6 inhibitors basically shows that the median progression-free survival with an endocrine agent and CDK4/6 inhibitors is a bit over 2 years, sometimes approaching 30 months. That is 3 to 4 times longer than you’d get with even combination chemotherapy, and the CDK4/6 inhibitors are beginning to have a positive impact on overall survival. It’s actually puzzling why someone would use chemotherapy in the first line unless, as Bill put it, the organ dysfunction is so bad that you’ve got 1 shot to get that patient or that organ functioning, or else she’s not going to be well enough to get a second line of therapy. That’s where we should be confining our chemotherapy to. It is puzzling. Part of it may be an educational process, with the thinking that chemotherapy, particularly in a combination, may work faster than the CDK4/6 inhibitors, although they work very quickly. I think those data show that the tempo of them working in terms of the antiproliferative effect is as fast as chemotherapy. There just needs to be more educational digging to find out where that 30% to 40% comes from, because it’s not all visceral crisis. That’s for sure.

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