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The treatment of HER2-positive breast cancer has benefited from a number of targeted agents. Although adjuvant trastuzumab has dramatically reduced progression—making metastatic disease far less common today—newer treatment advances are also impacting this disease. Dual targeting with pertuzumab and trastuzumab can extend the survival of metastatic disease by more 16 months, but despite such success, resistance to HER2 targeting remains a challenge. Drugs in the pipeline, such as neratinib, may help meet this therapeutic demand. In addition to anti-HER2 agents, chemotherapy is beneficial to patients with tumors 1 cm or larger, but the optimal treatment of smaller tumors is still a work in progress.

The management of advanced hormone receptor–positive disease has evolved with the emergence of CDK4/6 inhibitors. Improvements in progression-free survival of approximately 10 months were noted in pivotal trials of palbociclib. Strong efficacy was also seen with ribociclib, which was recently approved by the FDA. In the adjuvant treatment setting of hormone receptor–positive disease, an important issue for consideration is the duration of endocrine therapy.

Many newer agents in combination are being studied in the front-line treatment of women with HER2-positive metastatic breast cancer (MBC), but the story in the endocrine arena is more about the wise use of new strategies to overcome endocrine resistance, because no new antihormonal agents have been approved in the past decade. During his presentation at the NCCN 19th Annual Conference, Dr. William Gradishar explored what’s new in the treatment of MBC, focusing primarily on enhancing the effect of endocrine therapy to overcome resistance with newer targeted agents such as everolimus, reevaluating the role of rebiopsy on disease progression and measuring circulating tumor cells as a surrogate of response to treatment, and reviewing the effective treatment regimens for HER2-positive disease.

Metastatic hormone receptor–positive, HER2-negative breast cancer treatment is increasingly individualized as more of the tumor landscape is described and targeted therapies are developed. CDK4/6 inhibitors have demonstrated consistency in prolonging progression-free survival across several clinical trials in advanced disease. Research in endocrine therapy highlighted the noninferiority of fulvestrant compared with aromatase inhibitors after disease progression. Studies such as the PEARL and Young-PEARL trials challenged the superiority of chemotherapy over endocrine therapy in certain populations, including premenopausal women. Sequential CDK4/6 inhibitor therapy after disease progression showed potential benefits, though definitive data are lacking. Targeting the PI3 kinase pathway, particularly with capivasertib in patients with pathway alterations, showed significant improvements in progression-free survival. ESR mutations have been identified as a key factor in resistance to endocrine therapy, with elacestrant showing promise in overcoming this challenge. Finally, in early-stage cancer, the question of whether ovarian suppression along with endocrine therapy can show the same results as chemotherapy is being explored, but the answer remains to be seen.

Recent advances in the understanding of the molecular underpinnings of metastatic breast cancer have led to the identification of novel therapeutic targets. The latest update to the NCCN Guidelines for Breast Cancer reflects a rapidly evolving treatment landscape, highlighting the growing importance of combination therapies and personalized medicine in managing estrogen-receptor (ER)–positive, HER2-positive, and triple-negative subtypes. For patients with ER-positive disease, the standard of care remains combination therapies involving cyclin-dependent kinase 4/6 inhibitors, endocrine therapy, and PI3 kinase. In patients with HER2-positive disease, the use of fam-trastuzumab deruxtecan-nxki and tucatinib have demonstrated improved outcomes. For those with triple-negative breast cancer, pembrolizumab, PARP inhibitors, and antibody–drug conjugates (eg, sacituzumab govitecan-hziy) have shown activity.

Treatment for metastatic HER2-negative breast cancer is becoming increasingly individualized as more of the tumor landscape is described and drugs are developed to target its pathways. Survival can be prolonged by CDK4/6 inhibitors in patients with hormone receptor–positive tumors and by immunotherapy in those with triple-negative disease. In patients with BRCA1/2 mutations, PARP inhibitors delay disease progression. Antibody–drug conjugates are expected to become critical components of the treatment landscape, and targeted drugs are proving to benefit small subsets of patients.

Systemic treatment for metastatic breast cancer now incorporates many targeted agents and a plethora of combinations specific to the breast cancer subtype. New to the treatment paradigm are fam-trastuzumab deruxtecan-nxki, and tucatinib for HER2-positive disease; the PI3K inhibitor alpelisib in combination with fulvestrant for estrogen receptor–positive and PIK3CA-mutated tumors; PARP inhibitors for patients with germline BRCA1/2 mutations; and the anti–PD-L1 agent atezolizumab in combination with albumin-bound paclitaxel for triple-negative disease with PD-L1 mutations in tumors. In addition, for estrogen receptor–positive disease, the role of CDK4/6 inhibitors increased substantially during the past year, as overall survival results have emerged. These targeted agents are greatly improving patient outcomes, and thus have all been incorporated into the NCCN Guidelines for Breast Cancer.

The question of combination versus single-agent chemotherapy in the setting of metastatic breast cancer (MBC) is an often-debated issue. Many single agents have activity in this setting and the potential for significant synergism between chemotherapy agents has led to many combination chemotherapy trials. This article defends the position that combination chemotherapy is the optimal approach for patients with MBC.

The recent approval of 4 agents for the treatment of patients with metastatic HER2-positive breast cancer has led to expanded recommendations in the NCCN Guidelines for treatment of this disease. For triple-negative disease, immunotherapy continues to gain traction in this challenging subtype, both in the preoperative and metastatic settings, though not yet as adjuvant treatment. Sacituzumab govitecan is another new agent with strong utility in triple-negative disease, and PARP inhibitors are recommended options in BRCA-mutated disease.