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|Year : 2019 | Volume
| Issue : 3 | Page : 755-756
Brain metastasis: Momentum towards understanding the molecular milieu
Srinivas Chilukuri, Rakesh Jalali
Department of Radiation Oncology, Apollo Proton Cancer Centre, 100 Feet Road Tharamani, Chennai, Tamil Nadu, India
|Date of Web Publication||23-Jul-2019|
Dr. Rakesh Jalali
Department of Radiation Oncology, Apollo Proton Cancer Centre, 100 Feet Road Tharamani, Chennai - 600 113, Tamil Nadu
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Chilukuri S, Jalali R. Brain metastasis: Momentum towards understanding the molecular milieu. Neurol India 2019;67:755-6
Brain metastases are the most common and devastating neurologic complications of systemic cancer that occurs in approximately 20% of patients with cancer., However, the incidence of brain metastases is increasing because of better detection from improved imaging techniques, a lower threshold of magnetic resonance imaging (MRI) for screening and follow-up, more effective loco-regional and systemic treatment regimens that can prolong life, as well as permitting the cancer to disseminate to the brain, a sanctuary site. The common sources of primary cancers that result in brain metastases include lung, breast, an unknown primary, colorectal, melanoma, and renal cell carcinoma. Until the recent past, outcomes in patients with brain metastases were universally dismal with considerable nihilism in the management recommendations, and the patients were treated with palliative intent only. More definitive treatments, such as surgical resection and stereotactic radiosurgery, were used occasionally till reports of much better outcomes for select populations were noted. The number of brain metastasis, the source of the primary tumor, the volume and stage of the extracranial disease, the timing of brain metastasis with respect to the diagnosis of the primary lesion, the disease free interval, the patient's age, the performance status and the type of treatment received have been some of the important predictors for outcome. Data-driven prognostication tools for patients with brain metastases, including the recursive partitioning analysis (RPA) score, have been used to prognosticate and select patients suitable for aggressive treatments such as surgery and/or radiosurgery. Most of these traditional tools have been dependent on clinical parameters rather than biological factors. Although these are reasonably robust, we now know that there are inherent biological factors at play. Graded Prognostic Assessment (GPA), which includes histology-specific information and driver mutation status, is already being used in the assessment of lung and breast cancer., The molecular signature of the tumour, especially the status driver mutations, have been increasingly recognized to impact the outcome of these patients. For example, in patients with non-small-cell lung carcinoma (NSCLC) brain metastases, the presence or absence of mutations in epidermal growth factor receptor (EGFR) and translocations of anaplastic lymphoma kinase positive (ALK) gene can influence survival. The tumour subtype can also substantially affect the prognosis for patients with breast cancer who have brain metastases.
Understanding the prognosis of those patients with brain metastases requires an in-depth knowledge of the disease complexity at a molecular level. Although multiple hypotheses have been proposed to explain the unique metastatic patterns of various primary cancers, including the importance of the nature of the primary malignant cell [seed] and the organ to which the cancer cells metastasize [soil], or the variations in circulatory patterns between the common primary and metastatic sites, evidence supports a dynamic interplay between metastatic cells and the tumour microenvironment that is crucial for growth after cell seeding. For us to be successful in eliminating metastasis, our treatment solutions for these heterogeneous cancers will need to adapt to the unique biological susceptibilities of each tumour type and to the molecular signature of both the primary tumour and its metastases. In addition, the tumour micro-environmental factors that limit the efficacy of treatments, irrespective of the relative sensitivity of the tumour cell itself, must be recognized. In this context, the diagnosis of brain metastasis, especially with histopathological and molecular data, paves the way for better understanding of the biology as well as clinicopathological factors predicting clinical outcomes.,,
The article by Sangati et al., is among the few articles from India with a detailed histopathological data on brain metastases. The authors demonstrated that lung and breast cancers were the most common primaries in men and women, respectively, as had been noted in previous studies from India.,,, It is interesting to note that 52.7% of patients did not have a known primary, and brain metastasis was the first manifestation of a malignancy, as was shown in another recent series from India (Singh, et al., noted that 67% patients did not have a known primary). This seems to be higher than the figure of 15-20% that is typically reported in the literature. The authors  have also performed a battery of immunohistochemistry investigations to confirm and further subtype the cancers, which is critical to planning an appropriate evidence-based oncology care for these patients. It is also used to make distinctions between metastases, malignant gliomas, meningiomas, lymphomas and other rare entities. Further immunohistochemical markers are particularly useful among poorly differentiated subtypes that are difficult to diagnose without molecular characterization. While this data and the clinical outcome data, and its correlation with histopathology, would have been interesting to see, the study is still a very useful one. We also know now through data from whole-exome sequencing that the clonally related primary and brain metastasis share a common ancestry, yet a distinct evolution pattern occurs at the metastatic site. For example, distinct mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A) and anti-phosphoinositide-3-kinase, catalytic, alpha polypeptide antibodies (PIK3CA), loss of phosphatase and tensin homolog (PTEN), amplifications of v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2) and activating proto-oncogene Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations have been noted in secondaries but not their respective primaries. The authors  need to be commended for their efforts in bringing up this data that hopefully will encourage more centres to analyze the molecular milieu among brain metastases, which can potentially pave the way for personalized therapies for patients with brain secondaries.
Despite the quintessential need for the tissue, most patients of brain metastases will not undergo a biopsy or surgery, especially in those patients with known primaries and unambiguous radiological features. As the mutational signature can evolve over time in response to treatment, it will be important to safely obtain tissue in a minimally invasive manner to document the evolution in mutational burden over time, which can, in turn, guide clinical decisions regarding the selection of targeted therapies. Progress in molecular imaging and 'liquid biopsies' [using peripheral blood or cerebrospinal fluid (CSF)] are important advances that can potentially bypass some of the challenges associated with direct tissue sampling. A role for liquid biopsy of CSF has been suggested as a minimally invasive means to assess the presence of key genetic alterations of cerebral metastases in lung (EGFR mutation), breast cancers [Her2 amplification] and melanomas (BRAF [v-Raf murine sarcoma viral oncogene homolog B] mutation) as well as drug resistance mutations in patients with disease progression despite treatment. However, prospective studies are needed to validate this technology.
In the future, clinical trials focusing on tumour subtypes will need to meticulously report molecularly stratified outcomes as these data will be critical to the development of precision medicine in patients in whom molecular analyses are possible. As these discoveries move from the bench to bedside, the future for patients with brain metastases will most certainly be brighter and better.
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