Therapy for advanced HER2+ breast cancer

1st line therapy:

a) (++) Taxanes (docetaxel, paclitaxel, or nab-paclitaxel) + dual blockade (Herceptin and Trastuzumab). With this type of therapy, 17% of patients have no disease progression after 8 years, and the survival rate is 37% (Cleopatra study).

b) (+) Vinorelbine can be used instead of taxanes.

In the event of disease progression (growth of metastases or appearance of new ones) 6 months or more after the start of first-line therapy, we begin second-line therapy.

2nd line therapy:

a) Trastuzumab emtansine (T-DM1). This is a new class of drugs that is a conjugate of the monoclonal antibody trastuzumab and the cytotoxic agent emtansine chemically linked together (Emilia study).

In the case of progression on the second-line therapy, we have the option of third-line therapy.

3rd line therapy:

a) (++) Tucatinib + Trastuzumab + Capecitabine. Tucatinib is a tyrosine kinase inhibitor specifically targeting HER2. Data from a study presented at the San Antonio Congress in the USA showed that survival in the tucatinib group after 12 months of treatment was almost three times higher compared to the control group (33% vs. 12%). In this study, 48% of patients had brain metastases. In the tucatinib group, after one year of treatment, 25% of patients with brain metastases had no disease progression, unlike the control group where all patients had disease progression. This indicates the good effectiveness of tucatinib in the treatment of brain metastases.

Thus, the combination of capecitabine, trastuzumab, and tucatinib presents a promising option for HER2+ metastatic breast cancer after dual blockade and T-DM1. The main side effects were diarrhea and elevated liver enzymes.

b) (+) Trastuzumab deruxtecan (T-Dxd). This is a conjugate of the monoclonal antibody trastuzumab and the cytotoxic agent deruxtecan (Dxd) chemically linked together. Compared to T-DM1, T-Dxd has a higher ratio of cytotoxic concentration to trastuzumab, and the connection of two molecules of T-Dxd is more stable, which facilitates the penetration of the cytotoxic agent into the cell and may also affect neighboring tumor cells. Deruxtecan is a topoisomerase 1 inhibitor. In large studies, disease-free progression was observed in 76.1% of patients (who had received an average of 6 different treatment regimens).

Common side effects included nausea, and less commonly, interstitial lung inflammation that responded well to treatment.

c) (+/-) other experimental combinations and treatment regimens.