Additional study results showed that all of the HER2 activating mutations were found only in the tumor and were thus somatic and not inherited, according to Dr. Bose, who disclosed having no conflicts of interest related to the research.
The mutations clustered in two areas of the HER2 gene: one area affecting the tyrosine kinase domain of the protein (seen in 68% of cases) and another area affecting the extracellular domain (seen in 20%).
Laboratory analyses indicated that the mutations were indeed being expressed at the RNA level, that those affecting the kinase domain of the protein were associated with increased kinase activity, and that the mutations spurred tumor growth in nude mice.
"The majority of these HER2 mutations are activating events that cause cancerous growth of the cells in the lab, meaning that they stimulate the function of HER2 or turn on HER2’s activity in an excessive or inappropriate manner," Dr. Bose summarized. "Thus, we feel they are highly likely to drive the growth of these human breast cancers in which they occur."
In sensitivity testing, the six cases having the L755S mutation were resistant to the tyrosine kinase inhibitor lapatinib but sensitive to neratinib, an irreversible pan-ErbB tyrosine kinase inhibitor.
In fact, neratinib showed greater effectiveness than lapatinib at inhibiting cell growth in all of the mutated tumors tested, with several hundred to several thousand times greater concentrations of lapatinib needed to achieve the same level of inhibition.
Dr. Bose disclosed having no relevant conflicts of interest.