Adding TKIs Could Increase Responses in Metastatic HER2+ Breast Cancer

A laboratory study found that combining anti-HER2 tyrosine kinase inhibitors (TKIs) with trastuzumab and pertuzumab can result in enhanced anticancer activity compared with those agents alone in HER2-positive breast cancer cell lines.

The addition of trastuzumab and pertuzumab for the treatment of HER2-positive breast cancer has dramatically changed outcomes in this malignancy. “However, for the overwhelming majority of patients with HER2-positive metastatic breast cancer, the disease remains fatal,” wrote study authors led by Alexandra Canonici, PhD, of Dublin City University in Ireland.

The researchers investigated whether adding targeted therapies including afatinib, lapatinib, and neratinib would have a synergistic effect along with the standard anti-HER2 therapies, using a number of HER2-positive cell lines. The results were published in Investigational New Drugs.

Seven of 11 cell lines tested were found to be sensitive to afatinib. The investigators combined afatinib with trastuzumab in four cell lines sensitive to both agents, in two lines resistant to both drugs, and in one cell line sensitive to afatinib but resistant to trastuzumab. They found that combining the agents in the four sensitive lines yielded significantly improved responses compared with either agent alone. In the resistant cell lines, this effect was diminished or not seen at all.

In trastuzumab-sensitive SKBR3 cells, all the TKIs tested enhanced the response to trastuzumab. Adding pertuzumab to trastuzumab did not have a synergistic effect, though when combined with lapatinib it did have such an effect. In two other cell lines that were resistant to trastuzumab, the TKIs inhibited cell growth, but adding them to the two HER2 antibodies did not improve the response.

At higher concentrations of the agents, the triple combination of trastuzumab, pertuzumab, and a TKI offered the most substantial inhibition of cell growth.

“Our results suggest that the addition of small molecular TKIs to antibody/chemotherapy-based therapies may result in improved antitumor activity in HER2-altered metastatic breast cancer,” the authors concluded. “We believe that there is a sound scientific rationale for performing a prospective clinical trial to test this hypothesis.” They noted, though, that “organizational hurdles” may make such trials difficult to conduct.