Selecting Therapy for HR+ Breast Cancer


Stephen Johnston, MA, PhD, FRCP: I think understanding who we would deem to perhaps be a lower risk patient with ER [estrogen receptor]—positive breast cancer is a very important issue for oncologists today. We know that the distribution of disease is important, so somebody with bone metastases alone would be somebody who is deemed at lower risk. It might be somebody for whom an endocrine approach alone would be sufficient. I think one of the other key features is what we call the treatment-free interval: how long since their original diagnosis before they develop metastases.

We know if that timeframe is relatively short, 1 or 2 years, those patients might have a more aggressive phenotype where often, people have hitherto thought more along the lines of chemotherapy or targeted combination treatment. Whereas for a very long treatment-free interval of 5, 10, or 15 years with just very small sites of disease in the bone or soft tissue, those patients can have very endocrine-responsive disease, and endocrine monotherapy could be a very good treatment option for many of these ladies.

Joyce A. O’Shaughnessy, MD: It’s very interesting. It used to be that for first-line ER-positive metastatic breast cancer that was indolent with a long natural history and minimal sites of disease, those patients would just get endocrine therapy, and some would do well for many years. For patients with more sites of metastases, maybe some elevated liver function tests, and symptoms from the metastatic disease, we would give them chemotherapy, oftentimes single-agent, reserving combination chemotherapy for those patients who really were in very substantial life-threatening visceral crisis. That paradigm has really changed dramatically in the past few years with the introduction of the CDK4/6 inhibitors.

Patients whose breast cancer really is ER-driven—most endocrine therapy—sensitive disease with a long natural history, strongly positive bone-only disease, and lung disease tend to be ER driven—benefit greatly from the addition of a CDK4/6 inhibitor. It’s no longer endocrine therapy by itself; it’s combination therapy. And conversely, patients with a fair amount of metastatic disease—multiple sites involved, liver function abnormalities, symptoms from disease, short natural history, and fast development of metastatic disease—we’re treating as well with CDK4/6 inhibitors with endocrine therapy and not going to chemotherapy. With the benefits from the CDK4/6 inhibitors, they work just as quickly, it appears, as chemotherapy.

We don’t have randomized comparative data yet, but just looking at how quickly patients benefit, the response rates are at least as good if not better than even combination chemotherapy. But most important is the duration of benefits. The median progression-free survival is around 2 years in all the studies, which is much longer than we would get from chemotherapy. So we’re really reserving chemotherapy for those with the most immediately life-threatening disease, but even that may change over time. The CDK4/6 inhibitors may end up being superior even to combination chemotherapy.

Matthew P. Goetz, MD: We think of primary endocrine resistance as being mainly a clinical diagnosis. In the past, we’ve said if patients were receiving an adjuvant endocrine therapy and they progressed within the first 2 years of that adjuvant endocrine therapy, that would be associated with endocrine resistance. Similarly, in the metastatic setting, if a woman presented and was treated with endocrine monotherapy—such as letrozole for a postmenopausal woman—and she progressed within 6 months, that would be considered primary endocrine resistance. What are those factors that are associated with endocrine resistance? Well, we know things such as low levels of ER. Clearly, we know that in the past, it was overexpression of HER2.

There are data with regard to EGFR. We know that there are other factors, however, such as patients who have cyclin D1 amplification or patients who have other growth factor receptors activated, such as FGFR. There are a number of these factors. I didn’t mention P53 mutations, which are generally associated with a worse prognosis. But these are factors we’re identifying right now where if we knew about them up front in combination with those clinical factors, it might suggest that patient is at higher risk for primary endocrine resistance.

Now, in the setting of CDK4/6 inhibitors, we haven’t defined as of yet what primary and secondary resistance are to CDK4/6 inhibitor combinations. But I suspect, at least in the metastatic setting, we’re talking about progression in less than a year. If the median progression-free survival is 24 months, and someone progressed within 12 months, that might suggest, if you will, a primary resistance to CDK4/6 inhibitors. We’re increasingly understanding some of those factors that are associated with resistance to CDK4/6 inhibitors, but we still have quite a bit to learn.

Transcript Edited for Clarity

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