Joyce O’Shaughnessy, MD: In ER [estrogen receptor]-positive, HER2 [human epidermal growth factor receptor 2]-negative metastatic breast cancer, when we’re thinking about what therapy to give a woman, there are multiple factors we consider. The natural history of her disease is probably most important. The most important prognostic factor is probably how long it took the metastatic disease to develop after that primary diagnosis. Or, is it a de novo metastatic cancer, which also has a more favorable prognosis among metastatic breast cancer. So, we consider the disease-free interval, treatment-free interval, and how long the woman was on endocrine therapy before her cancer recurred. For example, recurring on adjuvant endocrine therapy is a poor prognostic sign. That’s really quite resistant to endocrine therapy.

Maybe she completed her endocrine therapy, and she’s been off for 5 or 10 years. That’s a favorable sign. We consider that disease-free interval, whether or not the breast cancer recurred on endocrine therapy, and overall tumor burden, or how many sites of metastatic disease are involved. Is there liver metastasis? What’s the extent of disease within the liver? Is there end-organ function? How symptomatic is the woman? Then on rebiopsy, we ask how strong that estrogen receptor is, making sure that HER2 positivity has not emerged as a resistance mechanism. Then, of course, we consider her overall health, her comorbidities, and of course her overall wishes and desires—her particular goals, as well.

In ER-positive, HER2-negative metastatic breast cancer for patients in the first-line metastatic setting, we could choose endocrine therapy alone, such as an aromatase [AI] inhibitor or fulvestrant, or combinations: usually a nonsteroidal aromatase inhibitor with a CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitor or chemotherapy. Probably the easiest decision is on chemotherapy. Increasingly, because the CDK4/6 inhibitors can work so quickly even in patients with concerning clinical characteristics, chemotherapy should probably be reserved for patients who have substantial organ dysfunction from metastatic breast cancer. Patients with significant dyspnea or significantly abnormal liver function tests in particular would be the group that we’d be more likely to utilize combination chemotherapy in. I think that group is shrinking because of the effectiveness of the CDK4/6 inhibitors.

On the other end of the spectrum, endocrine therapy alone would only be used in a very limited fashion. The only scenario where I can honestly think about using endocrine therapy alone in first-line metastatic disease is with a woman who has very small-volume disease and predicted endocrine therapy-sensitive disease, with either a long natural history or de novo metastatic, strongly ER/PR [progesterone receptor] positive, lower grade, more slowly proliferative disease. Comorbidities that would make you want to keep the therapeutic regimen as simple as possible with the fewest possible [adverse] effects for someone whose life span was very limited by other comorbidities, such as severe heart disease, lung disease, or CNS [central nervous system] disease, etc.

The addition of a CDK4/6 inhibitor to a nonsteroidal AI in first-line metastatic disease, even in the de novo metastatic population, generally does extremely well compared to endocrine therapy alone. If you add a CDK4/6 inhibitor to that frontline setting, patients do so much better with regard to improving their progression-free survival with relatively little toxicity. Even in the most endocrine therapy-sensitive population, I still think a strong argument can be made for adding a CDK4/6 inhibitor. In fact, some of the CDK4/6 inhibitors like palbociclib may preferentially benefit patients who have that more indolent, luminal A-type biology. I would recommend a CDK4/6 inhibitor even in the most endocrine therapy-sensitive population and confine AI use alone for patients who have very endocrine therapy-sensitive disease, asymptomatic disease, and substantial comorbidities, where you really want to absolutely minimize adverse effects for patients.

Transcript Edited for Clarity