Richard Finn, MD: I think it’s become somewhat of a patient and clinician preference as to whether patients start with an AI [aromatase inhibitor] or fulvestrant. We do have data that suggest that fulvestrant is active after patients have had an aromatase inhibitor. For patients who are progressing on an adjuvant AI, they would probably go to an AI and fulvestrant as their first-line treatment since they’re progressing on AIs. However, I think for most patients who have newly diagnosed advanced disease and who have not had an AI or endocrine treatment within the past year, many of us would favor going with a combined oral regimen. This would be either letrozole or anastrozole in combination with one of the CDK4/6 inhibitors. Again, for a patient who has had adjuvant aromatase inhibitors and has a short disease-free interval, less than a year, or is progressing already on that AI, then a fulvestrant-based CDK regimen would seem to be appropriate.

Harold Burstein, MD, PhD: The choice between an aromatase inhibitor or fulvestrant in the first-line setting depends on the patient’s prior therapy. If they have been on an aromatase inhibitor recently, or are currently on an aromatase inhibitor as part of their adjuvant treatment program at the time of cancer recurrence or the diagnosis of metastatic disease, then we usually go for fulvestrant. By contrast, if they are several years removed from treatment with an aromatase inhibitor, or if they’ve never had an aromatase inhibitor in the past, then we typically go with the aromatase inhibitor because of the convenience of the oral medication, as opposed to the intramuscular injection that is required for fulvestrant treatment.

We also mentioned briefly a moment ago the ESR1 mutation status. Increasingly, we are getting genomic sequencing of tumors at the time of recurrence, and that can be done either on a tissue biopsy, which is always a good idea to make sure you’re dealing with a known breast cancer recurrence, and to retest things like estrogen receptor and HER2 markers. But increasingly, we are doing genomic sequencing of those, or we are doing so-called liquid biopsies, where they look for circulating tumor DNA. In those specimens, you can analyze the tumor to see if there is acquisition of an ESR1 mutation. That’s a common finding in about half the cases that progress or recur on aromatase inhibitor therapy. And in such cancers, our general preference is to use fulvestrant or a SERD [selective estrogen receptor degrader] because we think the outcomes are better with the use of those drugs in the setting of an ESR1 mutation than with an aromatase inhibitor.

For nearly all patients who have ER [estrogen receptor]-positive metastatic breast cancer, we are including a CDK4/6 inhibitor as part of their first-line treatment in combination with endocrine therapy, be it either an aromatase inhibitor or fulvestrant. We do that because many studies have shown that each of the CDK4/6 inhibitors, when paired with an endocrine backbone, improve the progression-free survival. We also have data from all sorts of studies that it improves overall survival for women with ER-positive metastatic breast cancer. We’re now seeing median overall survival in excess of 5 years for many patients who are getting the combination of endocrine therapy plus a CDK4/6 inhibitor. That’s tremendous progress.

For most women, the CDK4/6 inhibitors are reasonably well tolerated, but there are few patients who might have adverse effect situations or other particular instances where we might not use a CDK4/6 inhibitor. One would be if there’s a particular concern about neutropenia. One of the adverse effects of CDK4/6 inhibitors is neutropenia. So, for a patient who has recently had surgery, or who has open skin wounds or skin tumor involvement, and you want to get an initial response with endocrine treatment, you might hold off on the CDK4/6 inhibitor for a little while. Some patients have minimal cancer burdens, a tiny lymph node, or a pulmonary nodule, or an isolated bone lesion. And for those patients, there’s always the opportunity to defer a CDK4/6-based regimen to second-line treatment. For many women, they might begin with endocrine therapy alone if they have a minimal cancer burden. Then you might add the CDK4/6 inhibitor later. But just to be clear, for the vast majority of patients, it’s combining a CDK4/6 inhibitor with their standard endocrine therapy.

There are 3 commercially available CDK4/6 inhibitors: abemaciclib, ribociclib, and palbociclib. In the metastatic setting, these drugs all look surprisingly similar in terms of their success rates for improving progression-free and overall survival. Palbociclib and ribociclib are really similar drugs. They are given on a very similar schedule of 3 weeks on and 1 week off, and their major adverse effects include neutropenia. They can also cause some diarrhea and some skin rashes, but those are less common. Abemaciclib is a slightly different product, it’s given twice a day, it’s given continuously, and it has diarrhea as a more common adverse effect than neutropenia. Though, you can see neutropenia with abemaciclib. We tend to use a lot of palbociclib, which was the first drug to market. Our teams have a lot of experience with it, and it’s generally a very well-tolerated drug. We know that the 125-mg dose can be safely lowered to 100 mg if patients have neutropenia without compromising the efficacy of the drug. I’ve got to say for our patients, it’s often a very well-tolerated drug with less diarrhea in particular than is occasionally seen with the abemaciclib. But there isn’t any reason to be dogmatic about choosing one of these drugs over another, and I know that different cancer centers might have preferences for different products.

Transcript edited for clarity.