Overview Breast cancer, including patients with brain metastases.

As per the the Duke Center for Brain and Spine Metastases studies, Breast cancer is the most common cancer in women, with 276, 480 new cases predicted for the year 2020 in the United States alone.1 It is also the second most common cause of brain metastases (BrM), with different reports indicating variable 10% to 30% incidence in breast cancer patients. The risk of BrM is subtype specific, with higher incidence among patients with human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer. In the HER2+ subtype of breast cancer, a diagnosis of BrM is common, affecting 25% to 50% of women with advanced disease. While the high incidence of BrM in the HER2-subtype is likely multifactorial, it became more apparent after the arrival of trastuzumab, a HER2-targeting monoclonal antibody (MAb) that improves survival and control of systemic disease but has low central nervous system (CNS) penetrance, and is relatively ineffective at treating Brain Metastases. 

Targeted therapy treatment

Lapatinib

Lapatinib is a small molecule tyrosine-kinase inhibitor (TKI) of EGFR and HER2, and is able to cross the BTB.

Trastuzumab deruxtecan

Trastuzumab deruxtecan, initially known as DS-8201, is the second ADC to be FDA approved as third line therapy for metastatic HER2+ BC, based on the impressive results of the phase II DESTINY trial.

Tucatinib

The FDA approved the medicine, Tucatinib, a TKI that inhibits HER2 in a reversible way. Tucatinib is sold under the brand name Tuksya. It has shown promising activity in combination with capecitabine and trastuzumab in a phase I trial, which included a notable response in BrM. 

Tucatinib comes in 50 mg and 150 mg tablets. Healthcare professionals recommend the dosage of Tucatinib is 300 mg taken orally twice daily with or without food. Tucatinib comes in the form of tablets to administer orally via the mouth. Tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation, and showed antitumor activity in HER2 expressing tumor cells. In vivo, Tucatinib inhibited the growth of HER2 expressing tumors. The combination of tucatinib and trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either drug alone. 

Conclusion

BrM are a frequent clinical challenge for patients with advanced HER2+ breast cancer. The continuous development of newer, brain permeable, anti-HER2 therapeutic options has steadily improved the impact of systemic therapy for patients with metastatic HER2+ breast cancer.