Brain metastases
Epidemiology
Classification
Scales
Trials
Despite the frequency of brain metastases, prospective trials in this patient population are limited, and the criteria used to assess response and progression in the CNS are heterogeneous 1).
This heterogeneity largely stems from the recognition that existing criteria sets, such as RECIST 2) 3).
Genes involved
Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown.
Brastianos et al. detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases 4).
COX2
HBEGF
ST6GALNAC5
HK2
FOXC1
HER2
VEGFA
LEF1
CDH2, KIFC1, and FALZ3
STAT3
αvβ3
Molecular Biology
Brain metastasis is a complex process where cancer cells from a primary tumor spread to the brain and establish secondary tumors. The molecular biology of brain metastasis involves multiple steps, including:
Intravasation: cancer cells break away from the primary tumor and enter the bloodstream.
Circulation: cancer cells circulate through the bloodstream and eventually reach the brain.
Extravasation: cancer cells leave the bloodstream and enter the brain tissue.
Colonization: cancer cells establish themselves in the brain and begin to grow.
Evasion of immune response: cancer cells evade the immune system and avoid destruction by immune cells.
The molecular biology of brain metastasis is influenced by many factors, including the characteristics of the primary tumor, the genetic makeup of the cancer cells, and the microenvironment of the brain. Understanding the molecular biology of brain metastasis is important for the development of new treatments that can effectively target and eliminate cancer cells in the brain.
Molecular biology, genetics, and epigenetics are rapidly expanding, enabling us to advance our knowledge of the underlying mechanisms involved. Research approaches using cell lines that preferentially metastasize in vivo to the brain and in vitro tissue-based studies unfold new molecular leads into the disease. It is important to identify and understand the molecular pathways of the metastatic cascade in order to target the investigation and development of more effective therapies and research directions 5).
Clinical Features
Diagnosis
Differential diagnosis
Treatment
Outcome
Recurrence
Randomized controlled trials
There is a lack of prospective randomized studies. Based on retrospective case series, international guidelines recommend the harvesting (if required, stereotactically guided) of tissue for histological and molecular diagnosis in cases of unknown or possibly competing for underlying systemic malignant diseases, in cases of suspected tumor recurrence, and with regard to the evaluation of targeted therapies taking into account molecular heterogeneity of primary and secondary tumors. Surgical resection is particularly valuable for the treatment of up to three space-occupying cerebral metastases, especially to achieve clinical stabilization to allow further non-surgical treatment For cystic metastasis, a combination of stereotactic puncture and radiotherapy may be useful. Meningeal carcinomatosis can be treated with intrathecal medication via an intraventricular catheter system. Ventriculoperitoneal shunts represent an effective treatment option for patients with tumor-associated hydrocephalus.
Neurosurgical procedures are of central importance in the multimodal treatment of cerebral metastases. The indications for neurosurgical interventions will be refined in the light of more effective radiation techniques and systemic treatments with new targeted therapeutic approaches and immunotherapies on the horizon 6).
Case series
Research
Zhu et al. reported a medium-throughput drug screening platform (METPlatform) based on organotypic cultures that allow evaluating inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastases, they identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastases, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. The work validates METPlatform as a potent resource for metastases research integrating drug screening and unbiased omics approaches that are compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere 7).
Case reports from the HGUA
71-year-old male
Past medical History:
Arterial hypertension. Type 2 diabetes with polyneuropathy. dyslipidemia - digital agenesis MSD of birth - intermittent claudication.
Operated on cervical disc herniation, Peripheral arterial disease
Confusional picture, gait instability and hoarseness of 2 weeks evolution.
Two lesions left posterior parietal and occipital region, suggestive of brain metastases and a 6-mm pulmonary nodule in LSD and a 13-mm thyroid nodule in LTD, both with non-specific characteristics