Joyce O’Shaughnessy, MD: In ER [estrogen receptor]-positive, HER2 [human epidermal growth factor receptor 2]-negative metastatic breast cancer, the vast majority of breast cancers will be sensitive to endocrine therapy except for a small subpopulation. This is really resistant to endocrine therapy alone. Those patients resistant to endocrine therapy alone in the first-line metastatic setting would generally be patients whose breast cancer has recurred on adjuvant endocrine therapy. Those patients are absolutely manifesting disease that’s resistant. Their disease is actually progressing. That’s a very ominous sign for a woman with early breast cancer, to be on an adjuvant endocrine agent and to develop disease recurrence on that. It’s very unlikely, unfortunately, that this woman is going to benefit from another endocrine therapy alone. Those are patients who are at risk for having resistance even to an endocrine therapy plus a CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitor.

Regarding those patients with first-line metastatic disease that has recurred on an adjuvant endocrine agent, the majority of them will benefit from fulvestrant plus a CDK4/6 inhibitor, but there will probably be a third of patients who will not. They will really be very, very resistant to endocrine therapy and CDK4/6 inhibitors at that time, and will only benefit from chemotherapy. That’s probably the most important predictor: recurrence on adjuvant endocrine therapy. Rarely, you will have someone who isn’t recurring on adjuvant endocrine therapy and is some years out from her diagnosis, but who just develops very, very widespread disease in multiple organ sites involving ER-positive metastasis. They would be resistant. That’s a woman who would have relatively lower levels of estrogen receptor expression, progesterone receptor [PR]-negative breast cancer, liver metastasis, and higher-grade disease—grade 3—that’s more highly proliferative. That would be the picture of someone who may not benefit from endocrine therapy even with a CDK4/6 inhibitor added.

Looking at a woman who has ER-positive, HER2-negative metastatic breast cancer and really understanding what the natural history of her disease is going to be—the likelihood of her survival, the likelihood of her breast cancer being endocrine therapy-sensitive, the likelihood for her really being resistant and needing chemotherapy—the main things we look at are overall tumor burden and symptoms. If diseases come on very, very rapidly and are in multiple organ sites, that’s an ominous sign that she’s less likely to benefit from endocrine therapy. Those are much more concerning characteristics.

Sites of disease are also very important. There are sites of metastasis that are more endocrine therapy-sensitive: bone metastasis, lung metastasis, lymph node metastasis, soft tissue disease, chest wall recurrence, and in-breast recurrence tend to be endocrine therapy-sensitive organ sites. Conversely, liver metastases are less likely to be endocrine therapy-sensitive. They can be, but they’re less likely to be. Brain metastases can be, but are less likely to be. Grade of disease is also quite important. Grade 1/2 disease is much more likely to be endocrine therapy-sensitive, whereas grade 3 disease is less likely to be.

Progesterone receptor-positivity is also very important, particularly strongly progesterone receptor-positive disease. The estrogen receptor leads to the transcription of the progesterone receptor, so you really have an actively signaling estrogen receptor. Conversely, if the progesterone receptor is negative, it’s not being transcribed, so that breast cancer is not all about the estrogen receptor. There are other signaling pathways involved there, so it’s less likely to be endocrine therapy-sensitive.

Conversely, on the positive side, those patients with a smaller tumor burden, bone-only disease, lower grade disease, and strongly PR-positive disease are women who are very likely to benefit from endocrine therapy. We really do have a pretty good idea of which patients are likely to benefit from endocrine therapy and which patients we have to be more concerned about.

Transcript Edited for Clarity