Biology in prevention and treatment of brain metastases

Abstract

Brain metastases are common in cancer patients, may significantly diminish neurocognitive function and quality of life and carry a poor prognosis. Brain metastases differ from metastases in other organs such as liver, lung, lymph nodes and bone, both from a pathobiological and from a clinical perspective. Despite the high incidence of brain metastases, only relatively few studies aiming at better understanding of their pathobiology have been performed in the past. However, recently druggable targets have been identified in brain metastases of several tumor types and novel treatment approaches are becoming a feasible option for selected patients. In addition, scientific advances are elucidating some fundamental aspects of brain metastasis formation and may lead to effective strategies of drug-mediated prevention of metastatic brain invasion or inhibition of intracerebral outgrowth.

Keywords::

• biology
• brain metastases
• cancer
• prophylaxis
• therapy

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Brain metastases affect up to 40% of cancer patients and are 8–10-times more common than primary brain tumors.

• • Brain metastases are most common in lung cancer, breast cancer and melanoma.

• • Localization: 80% in cerebral hemispheres, 15% in cerebellum, 5% in the brainstem. Typically found at gray–white matter junctions and terminal watershed areas.

• • Brain metastases have high morbidity and mortality and are associated with poor quality of life.

• • Standard treatment options include neurosurgery, radiotherapy (whole-brain radiotherapy, stereotactic radiosurgery), while systemic cytotoxic chemotherapy seems to have limited efficacy.

• • The blood–brain barrier/blood–tumor barrier limits penetration of some systemic agents into the brain and may limit intracerebral efficacy.

• • Molecular targeted agents have shown evidence for clinical activity against brain metastases in specific patient populations: BRAF inhibitors and ipilimumab in melanoma, EGFR inhibitors in non-small-cell lung cancer, lapatinib in HER2-positive breast cancer.

• • Prevention of brain metastases by targeted agents may be feasible and this concept is being tested in clinical studies, for example, with chronic low-dose anti-angiogenesis.