Harold Burstein, MD, PhD: The first thing to say is that estrogen receptor [ER]-positive, HER2-negative breast cancer is the most common kind of both early stage and metastatic breast cancer. Treating patients with this variant or flavor of breast cancer is a really important public health issue, as well of course, as an issue for individual clinical teams, and obviously for patients themselves. We usually begin treatment with anti-estrogen therapies. This can be an aromatase inhibitor, or if the patient has had adjuvant therapy with an aromatase inhibitor, it often is a so-called SERD [selective estrogen receptor degrader], such as fulvestrant. Nowadays, we tend to combine these with targeted treatments.

A typical first-line regimen would be either an aromatase inhibitor or fulvestrant in combination with a CDK4/6 inhibitor, because many studies have now shown that the addition of the CDK4/6 inhibitors will improve progression-free and overall survival. In the second line of treatment, we often continue that combination of endocrine therapy with a targeted drug. There are products like everolimus, which is an mTOR inhibitor that can extend the utility of endocrine therapy. Similarly, for women whose tumors harbor a PIK3CA mutation, there is the option of alpelisib, which is another targeted therapy used in combination with endocrine treatment. A small number of patients will be candidates for multiple lines of endocrine therapy. But after adjuvant treatment and then usually a couple of lines of endocrine treatment in the metastatic setting, most patients whose tumors are resistant to endocrine therapy at that point will need to consider chemotherapy. There are many lines of chemotherapy that we use to control ER-positive hormone therapy-resistant metastatic breast cancer for such patients. That’s what our standard approaches look like circa 2022.

There’s a lot of heterogeneity in the first-line setting because it depends on what the patient has had in the early stage or adjuvant setting. The majority of patients who are diagnosed with metastatic breast cancer have previously been diagnosed with early stage breast cancer and then have had adjuvant treatment. And despite that adjuvant treatment, they have subsequently had a recurrence of the breast cancer. For many women that will mean that they’ve already had, for instance, either tamoxifen or an aromatase inhibitor, or some combination of tamoxifen and aromatase inhibitor. If that’s the case, then we often go with fulvestrant as our endocrine backbone in the first line of therapy, and we would pair that with a CDK4/6 inhibitor. If the patient has truly de novo disease, or if it has been a long time since they were exposed to either tamoxifen or an aromatase inhibitor, we will typically go with an aromatase inhibitor in the first-line setting because of the convenience of the oral medication. Some women are premenopausal at the time of diagnosis of metastatic ER-positive breast cancer. If that’s the case, then one of the other first things we do is suppress ovarian function so they are essentially postmenopausal, and then they are candidates for either an aromatase inhibitor or fulvestrant.

There are many different challenges of managing hormone receptor-positive metastatic breast cancer. One of the common questions is, does a patient need chemotherapy or hormonal therapy initially? Many women who present with metastatic disease will have somewhat limited metastatic disease, bone dominant, or bone-only metastatic disease, or limited sites of disease elsewhere in the body. For most of those women, endocrine therapy should be the initial therapy. A few patients will present with more extensive cancer burdens, particularly including extensive disease in the lung or the liver. Sometimes because of the extent of visceral disease, you have to start with chemotherapy to get control of the cancer, drive down the overall tumor burden, and then switch to a sort of maintenance phase of endocrine therapy, if you will.

The second, larger biological issue is the fundamental problem of resistance to endocrine therapy. We know clinically that many tumors become resistant to endocrine treatment, and we’re learning more about the biology of that resistance mechanism. For women who’ve been on an aromatase inhibitor, a mutation in the estrogen receptor gene called an ESR1 mutation is a frequent contributor to resistance to aromatase inhibitor therapy. In the setting of an ESR1 mutation, the tumor cell has acquired the capacity to have the estrogen receptor in the on position, if you will, even though there’s no estrogen present because the patient is on the aromatase inhibitor. Sometimes I describe that to patients as like having a gas pedal stuck to the floor. The car is always accelerating forward, even though you don’t seem to be stepping on the gas. That is a mutation that limits the effectiveness of endocrine therapies, and particularly limits the effectiveness of aromatase inhibitors in the treatment of metastatic breast cancer.

Transcript edited for clarity.