In late-stage HR+/HER2- breast cancer, the addition of CDK4/6 inhibitors to a backbone of antiestrogen therapy has profoundly altered the treatment landscape. Three CDK4/6 inhibitors are available that have shown improvements in progression-free survival (PFS) and objective response. There is strong evidence that ribociclib and abemaciclib improve the OS of patients, but there is not clear evidence for this with palbociclib. It is not clear whether these differences are due to differences in efficacy between the drugs or in the patient population, but they may be clinically meaningful enough to favor ribociclib and abemaciclib over palbociclib. 

Biomarker evaluation is essential for patients in the second-line metastatic setting, including to assess for activating PIK3CA mutations that are predictive of response to the PIK3CA inhibitor alpelisib and for ESR1 mutations that are associated with sensitivity to selective estrogen receptor (ER) downregulators such as elacestrant. There are other rare mutations, such as HER2 mutations, which occur in approximately 2% of tumors. HER2 mutations are predictive of sensitivity to neratinib. NTRK mutations identify patients who can benefit from NTRK inhibitors, and BRCA1/2 mutations can confirm sensitivity to a PARP inhibitor, particularly in patients who have a strong family history of cancer or in patients for whom a family history is unknown and other treatment options have been exhausted. 

Right now, the only molecular alterations that impact adjuvant therapy are germline BRCA1/2 mutations, which could potentially benefit from a 1-year course of adjuvant olaparib after the completion of adjuvant chemotherapy. However, this would only be for higher-risk patients. The optimal choice for patients who have a BRCA1 mutation and are candidates for a CDK4/6 inhibitor is unknown and requires further evaluation.

In the metastatic setting, CDK4/6 inhibitors plus hormonal therapy are firmly entrenched as the standard of care because these drugs improve response rates and prolong PFS and OS. Several questions remain: How do we identify the small subset of patients who progress quickly and gain little, if any, benefit from CDK4/6 inhibitors? Further, for patients who have been taking a CDK4/6 inhibitor for a prolonged period of time, can we identify the biomarkers and pathways that are associated with the development of acquired resistance? Finally, there may be a small group of patients with a highly endocrine-responsive breast cancer who may do well with single-agent aromatase inhibitor therapy. However, at this time, we do not have validated biomarkers to identify these individuals. These are important topics and are areas of substantial research. 

For patients with early-stage HR+/HER2- breast cancer, the most important guiding principle is that adjuvant hormonal therapy greatly reduces the risk for recurrence and prolongs survival. Notably, the benefit of hormonal therapy is seen whether the patient is positive for the progesterone receptor or not. However, those who have progesterone receptor–negative tumors often have a worse prognosis and a higher risk for recurrence. These tumors are likely to harbor higher-risk genomic signatures, and, for these patients, adjuvant chemotherapy or perhaps even a CDK4/6 inhibitor (based on tumor stage) could be considered.

There remains great interest in identifying which patients with HR+/HER2- disease benefit from adjuvant chemotherapy, so a deeper understanding of the molecular features of early-stage breast cancers is critical to help guide therapeutic decisions. Over the years, many studies have found that the addition of chemotherapy to hormonal therapy is beneficial, even if the absolute benefit is relatively small. However, we now have level 1 data from the TAILORx and the RxPONDER studies identifying that many postmenopausal patients with low- or intermediate-risk signatures can avoid chemotherapy. Although there are also tumors with innate or primary endocrine resistance where the ER is expressed, blocking the ER is inadequate because other pathways are driving the growth of the cancer. Even if these patients are treated with adjuvant hormonal therapy in combination with chemotherapy, some individuals still remain at high risk for recurrence. This is where we now have exciting data demonstrating antitumor activity of CDK4/6 inhibition in this higher-risk group of patients with early-stage HR+ breast cancer. 

Great advances have been made in understanding the molecular pathways that promote tumor growth, and these advances have led to the development of targeted agents that block those pathways. What has really revolutionized the treatment of advanced HR+/HER2- breast cancer is the combination of CDK4/6 inhibitors with an endocrine therapy backbone. This combination has been shown to be beneficial for PFS and OS across all patient groups, including both pre- and postmenopausal women. For example, in the MONALEESA-7 trial, which looked specifically at pre- and perimenopausal women with advanced HR+/HER2- breast cancer, the use of ribociclib plus endocrine therapy was associated with superior OS compared with endocrine therapy alone.

Progression of disease on CDK4/6 inhibitors plus endocrine therapy continues to be a crucial area of research. In patients with advanced HR+/HER2- breast cancer, data from the phase 2 MAINTAIN trial suggested that switching endocrine therapy for those with progression on endocrine therapy plus CDK4/6 inhibitor therapy may allow for a continued response. In MAINTAIN, patients who had progressed on CDK4/6 inhibitors and endocrine therapy who were switched to fulvestrant or exemestane plus ribociclib had an improvement in PFS compared with those receiving fulvestrant or exemestane alone, although the absolute difference was small. These data really highlight the need to understand how to sequence CDK4/6 inhibitors with other therapies. While women stay on treatment with CDK4/6 inhibitors plus endocrine therapy for a median of 2 years, we need to understand the best treatment options available when their disease progresses. We know that tumors can change over time, under the pressure of cancer drugs. Thus, when a patient's disease progresses, it is vital to biopsy a metastatic site of disease (liquid biopsy if bone-predominant disease) in order to perform next-generation sequencing to identify actionable mutations, such as ESR1 and PI3K, for which there are currently approved treatment options.