Investigational chemotherapy and novel pharmacokinetic mechanisms for the treatment of breast cancer brain metastases

Abstract

In women, breast cancer is the most common cancer diagnosis and second most common cause of cancer death. More than half of breast cancer patients will develop metastases to the bone, liver, lung, or brain. Breast cancer brain metastases (BCBM) confers a poor prognosis, as current therapeutic options of surgery, radiation, and chemotherapy rarely significantly extend life and are considered palliative. Within the realm of chemotherapy, the last decade has seen an explosion of novel chemotherapeutics involving targeting agents and unique dosage forms. We provide a historical overview of BCBM chemotherapy, review the mechanisms of new agents such as poly-ADP ribose polymerase inhibitors, cyclin-dependent kinase 4/6 inhibitors, phosphatidyl inositol 3-kinaseinhibitors, estrogen pathway antagonists for hormone-receptor positive BCBM; tyrosine kinase inhibitors, antibodies, and conjugates for HER2 BCBM; repurposed cytotoxic chemotherapy for triple negative BCBM; and the utilization of these new agents and formulations in ongoing clinical trials. The mechanisms of novel dosage formulations such as nanoparticles, liposomes, pegylation, the concepts of enhanced permeation and retention, and drugs utilizing these concepts involved in clinical trials are also discussed. These new treatments provide a promising outlook in the treatment of BCBM.

G2M Cell Cycle Pathway Score as a Prognostic Biomarker of Metastasis in Estrogen Receptor (ER)-Positive Breast Cancer

“…In order to test this hypothesis, we identified two independent cohorts with previously published primary tumor gene expression and site-specific metastasis-free survival data (Gene Expression Omnibus studies GSE12276 [17] and GSE2034 [18]). We focused on the lung, brain, and bone as specific metastasis sites as distant metastasis is most common at these sites in breast cancer [19]. Primary tumors with a high G2M score had a significantly shorter overall as well as lung-specific (both logrank test p < 0.001), but not for brain-or bone-specific metastasis-free survival in the GSE12276 cohort ( Figure 3A).…”

Method of establishing breast cancer brain metastases affects brain uptake and efficacy of targeted, therapeutic nanoparticles

“…Currently, as many as half of patients with HER2‐positive, metastatic breast cancer develop brain metastases over time . Treatment of these brain tumors is a growing clinical challenge, in large part due to the poor penetration of HER2‐targeted agents through the blood–brain barrier (BBB) …”

“…4 Treatment of these brain tumors is a growing clinical challenge, in large part due to the poor penetration of HER2-targeted agents through the blood-brain barrier (BBB). 4,5 There is considerable debate in the literature regarding the extent to which the BBB remains intact with brain metastases (in the form of the blood-tumor barrier [BTB]). In general, chemotherapy has not proven to be effective in the clinic.…”

Central nervous system metastases in triple‐negative breast cancer: A step in the right direction

“…These include cyclophosphamide, methotrexate, fluorouracil (CMF), temozolomide with whole brain radiotherapy, capecitabine alone or with radiotherapy, or combinations. For example, lapatinib and capecitabine, trastuzumab, and trastuzumab emtansine for HER2 overexpressing brain metastases . Also, combinations of cyclin‐dependent kinase 4, 6 inhibitors and PI3‐kinase inhibitors with endocrine therapy in breast cancer patients with estrogen receptor positive brain metastases …”

“…Checkpoint inhibition of programmed cell death proteins (ie , PD‐1 and PD‐L1) is a treatment strategy in this subgroup under clinical investigation (see www.Clinical Trials.gov for comprehensive list of phase I and II trials of patients with TNBC and brain metastases). Finally, new delivery systems such as liposomes and nanoparticles are under investigation …”