CDK4/6 inhibitors plus endocrine therapy remain a standard approach in the first-line treatment of hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) metastatic breast cancer. The field is rapidly evolving, and clinicians seek to further optimize therapy by understanding and addressing the mechanisms of resistance and tailoring therapy to the individual patient.

When assessing patients who have metastatic breast cancer, it is important to consider their overall disease burden, the location of the disease, and the burden of disease. It is also important to identify if an individual has comorbidities such as heart disease, diabetes, hypertension, and dyslipidemia, all of which can influence how well patients tolerate treatment. In the absence of major comorbidities and frailty, CDK4/6 inhibitor–plus-endocrine therapy is the standard of care for patients with estrogen receptor–positive (ER+)/HER2- metastatic breast cancer, as it improves progression-free and overall survival. However, for patients with poor performance status, health care providers may need to be more cautious (eg, starting with a single-agent aromatase inhibitor) in order to avoid significant treatment-related toxicity. For these individuals, clinicians can consider adding a CDK4/6 inhibitor later if endocrine therapy has been well tolerated. So, it is important not only to understand the recommended treatment options for individuals with ER+/HER2- metastatic disease but also to consider how these options will impact a patient’s quality of life.

Patients may present with oligometastatic disease, for which more aggressive therapy may be recommended. I do not believe that the current data support a radical approach to treatment. There may be some cases in which it is reasonable to treat small areas of disease, such as in patients with bone-predominant disease. But, at the end of the day, metastatic breast cancer is a systemic disease, and it is not known whether treating areas of disease will prolong the disease-free interval. That is why we discuss the situation with patients, because the last thing we want to do is to harm them with radical therapy that does not achieve our goals.

For patients with HR+/HER2- breast cancer as their initial manifestation of metastatic disease, the current standard of care in the first line is an aromatase inhibitor plus a CDK4/6 inhibitor. This is also the standard treatment for patients who relapse more than 1 year after completing a course of adjuvant endocrine therapy. And, in the premenopausal patient, there would also be ovarian function suppression.

For patients who progress on a CDK4/6 inhibitor, we test for PIK3CA mutations and can offer the PI3K inhibitor alpelisib to those who are mutation positive. Patients without PIK3CA mutations can be offered everolimus plus fulvestrant or a selective ER degrader (SERD) such as elacestrant. For those who need third-line therapy, antibody-drug conjugates such as trastuzumab deruxtecan and sacituzumab govitecan are good options, although chemotherapy with oral capecitabine can also be used.

In the current paradigm, the general treatment strategy is not necessarily to always use the most effective therapies early on, but rather to sequence therapies in a way that gets the most out of each one for each individual patient. For example, if a patient did very well on a CDK4/6 inhibitor for 2 to 3 years before slowly progressing with minimal symptoms, you might try a course of capecitabine rather than an antibody-drug conjugate.

Regarding the use of local therapies for metastatic disease, there is controversy about whether local therapy such as radiation is beneficial. Although it can improve the local control of the disease, there does not seem to be a survival benefit when adding local therapy to systemic therapy. A common scenario in which local therapy may be appropriate is for a patient with a chest wall recurrence. In this situation, you could give local radiation after a mastectomy and before systemic therapy. Another scenario would be for someone with an occurrence of primary or locoregional oligometastatic disease in the breast.

The standard of care for HR+/HER2- breast cancer in the first- or second-line metastatic setting is a CDK4/6 inhibitor that is proven to prolong survival (ie, abemaciclib or ribociclib) in combination with hormonal therapy. If a patient progresses on an aromatase inhibitor in the adjuvant setting, the current standard is to use fulvestrant plus a CDK4/6 inhibitor. If they have been off the aromatase inhibitor for 1 year or longer and then progress, it is reasonable to put them back on an aromatase inhibitor along with the CDK4/6 inhibitor. A major question is: Does the type of hormone therapy that is combined with the CDK4/6 inhibitor matter? Some would argue that SERDs are really the better drugs; therefore, we should be combining fulvestrant with a CDK4/6 inhibitor in all patients. The data so far have not demonstrated that, but several ongoing trials are looking into these questions.

A new research focus is to adapt the type of hormonal therapy combined with the CDK4/6 inhibitor based upon early blood-based detection of the biomarker that is associated with resistance. A key question is: Should the biomarker-selected therapy be started when there is radiographic progression (current standard of care) or when the blood-based biomarker first emerges? The ongoing phase 3 SERENA-6 trial (NCT04964934) is an example of a study that is testing the benefit of switching from an aromatase inhibitor to camizestrant at the time when the biomarker first emerges in the blood. In contrast, another phase 3 trial, ELAINE-3 (NCT05696626), is testing whether the combination of lasofoxifene along with abemaciclib is superior to fulvestrant plus abemaciclib in patients with radiographic progression on first-line CDK4/6 inhibitor–based therapy and in those patients with a detectable ESR1 mutation (either by tumor biopsy or blood).

There are 2 important aspects when considering local therapies for metastatic breast cancer. First, surgical removal of the primary tumor in addition to systemic therapy does not improve survival and should not be recommended. Second, radiation or ablation of an isolated lesion, either of a primary tumor or an oligometastatic lesion, has also not been demonstrated to improve survival. However, these local therapies are clearly indicated when there is a need for palliation.