Bi-weekly very-high-dose lapatinib: an easy-to-use active option in HER-2-positive breast cancer patients with meningeal carcinomatosis

Excerpt

The erbb2 gene, which encodes the growth factor receptor HER2, is amplified and overexpressed in 15–25 % of breast cancers, associated with poorer prognosis before the use of HER2 targeting agents. In patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel significantly improved the median overall survival to 56.5 months [1]. Prolonged survival combined with high neurotropism of HER2-amplified tumors results in increasing incidence of leptomeningeal metastases. Due to very limited options, this situation represents an emerging issue. The prognosis of breast cancer patients with meningeal carcinomatosis is very poor with a reported median survival of 4.5 months with high-dose intrathecal methotrexate [2]. Of crucial importance, comparison of HER2 statuses in cerebrospinal fluid-derived tumor cells from patients with metastatic breast cancer with leptomeningeal carcinomatosis and corresponding archival primary tumors revealed a very concordance rate [3]. Furthermore, because of the high molecular weight of trastuzumab and pertuzumab, unable to cross the blood–brain barrier, leptomeninges may be a sanctuary for cancer cells to monoclonal antibodies. Consequently, meningeal metastases may result from a pharmacokinetic limitation to treatment delivery rather than from a molecular resistance to HER2 blockade. The pulsatile administration of high doses of tyrosine kinase inhibitors is a potential way to obtain a very high plasma maximal concentration, resulting in active concentrations in the leptomeninges [4]. Lapatinib, a reversible dual tyrosine kinase inhibitor of EGFR and HER2, is active in patients with HER2-positive metastatic breast cancer. Because it has a small molecular weight and is lipophilic, we hypothesized that very high doses of lapatinib may circumvent the sanctuary effect in case of HER2-positive breast cancer with leptomeningeal metastases. …