Evolving Therapeutic Landscape in Breast Cancer

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The current standard of treating estrogen receptor (ER)-positive breast cancer involves anti-estrogen therapy, although distinct treatments are not always easily determined, especially in asymptomatic patients. Adam Brufsky, MD, describes a clinical scenario that concerns a woman with disease that has metastasized, despite presenting with no symptoms. She is stabilized on anti-hormonal therapy, but a follow-up scan 1 year later reveals an enlarged tumor. Brufsky notes that clinicians struggle with whether they should proceed with chemotherapy under these circumstances.

Newer targeted therapies are available for ER-positive refractory breast cancer, such as the mTOR inhibitor everolimus. Therapies currently under investigation include cyclin-dependent kinase 4/6 inhibitors, PI3 kinase inhibitors, and selective estrogen receptor degraders. Harold Burstein, MD, notes PI3 kinase mutations may be the most frequently acquired mutation in ER-positive breast cancer, estimating that 30% to 40% of ER-positive breast cancers express abnormalities in the PI3 kinase pathway. Burstein adds that potent single-agent activity has yet to be seen in current data, and that these therapies are not without serious side effects.

Brufsky mentions that obstacles such as testing for HER2-positive disease and knowing when to introduce an anti-HER2 agent remain a challenge for practitioners. A tremendous amount of investigation has focused on HER2-active medications in breast cancers, as there have been many success stories involving the use of anti-HER2 agents. Pertuzumab, the dual anti-HER2 and anti-HER3 monoclonal antibody, has improved overall survival when used as first-line therapy.

Second-line therapy with trastuzumab emtansine (TDM1), or ado-trastuzumab, has demonstrated a survival advantage compared with the previous standard, capecitabine and lapatinib. The combination of TDM1 with pertuzumab has been proposed as potential first-line treatment, which would be an appealing approach that would allow clinicians to circumvent the use of chemotherapy as first-line treatment.

Treatment of individuals with triple-negative disease continues to be a clinical challenge, observes Burstein. Brufsky elaborates that choosing the best treatment approach in a younger patient with a small, high-risk triple-negative tumor is particularly difficult. It is important to consider whether it is worthwhile to initiate standard chemotherapy or opt for a milder treatment in these situations. Regarding future direction, Burstein mentions that triple-negative breast cancer is a variant of breast cancer with the most mutations and has shown to involve tumor-infiltrating lymphocytes, lending itself to an immunologic approach.