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Precision medicine biomarkers in brain metastases: applications, discordances, and obstacles.

ABSTRACT: Brain metastases (BM) present a common cause of mortality and morbidity in several metastatic cancer entities. New therapeutic developments during the last decades, including targeted and immune-related therapies, have shown considerable extra- and intracranial response rates in specific subgroups of BM patients. However, differences in the molecular alteration in the BM tumor tissue compared to extracranial tumors leads to heterogeneous therapeutic responses. Therefore, an accurate molecular analyzation of BM tissue, if possible, has become an essential part in therapeutic decision making in BM patients. The concordance of predictive molecular biomarkers between multiple sites including extracranial and intracranial tumor tissue have been analyzed for some but not all biomarkers routinely applied in modern precision medicine approaches. In the present review, we summarize the current evidence of predictive biomarkers for personalized therapy approaches in the treatment of parenchymal BM.

SUBMITTER: Steindl A

PROVIDER: S-EPMC8633753 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Precision medicine biomarkers in brain metastases: applications, discordances, and obstacles.

Steindl Ariane A Brastianos Priscilla K PK Preusser Matthias M Berghoff Anna S AS

Neuro-oncology advances 20211127 Suppl 5

Brain metastases (BM) present a common cause of mortality and morbidity in several metastatic cancer entities. New therapeutic developments during the last decades, including targeted and immune-related therapies, have shown considerable extra- and intracranial response rates in specific subgroups of BM patients. However, differences in the molecular alteration in the BM tumor tissue compared to extracranial tumors leads to heterogeneous therapeutic responses. Therefore, an accurate molecular an ...[more]

PMID: 34859231

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Project description:ObjectiveTo broadly review the modern management of brain metastases.BackgroundBrain metastases are the commonest neurological manifestation of cancer and a major cause of morbidity in cancer patients. Brain metastases are increasing in frequency, as a result of longer life expectancy of cancer patients, more sensitive methods for brain metastasis detection and an ageing population. The proportional incidence of brain metastases according to cancer of origin, from greatest to least, is lung cancer, melanoma, renal, breast and colorectal cancers. Patients with lung cancer and melanoma are most likely to have brain metastases at diagnosis. Brain metastases cause a variety of symptoms, depending on their size and location, whether they cause mass effect and oedema, compression of the brain parenchyma, or focal neurological deficits. The major differential diagnoses of brain metastases include primary tumours and vascular/inflammatory lesions. Prognosis is dependent on the site, number and volume of lesions, the patients' performance status, age and the activity and extent of extracranial disease.MethodsEnglish literature articles in PubMed from 1950 to June 2021 were reviewed. Article bibliographies provided further references.ConclusionsTreatment of brain metastasis patients has moved from considering them as a homogenous population of patients, to individualised treatment. In those brain metastases patients of satisfactory performance status with a solitary lesion, especially one in a non-eloquent/accessible area causing significant mass effect and/or raised intracranial pressure or for whom the diagnosis is in doubt (histology needed), surgical resection is usually the treatment of choice. For multiple brain metastases, radiotherapy with or without systemic therapies are usually employed. For relatively fit patients with limited numbers of brain metastases (e.g., 4 or less), stereotactic radiosurgery is standard of care. Current clinical trials are testing the efficacy of stereotactic treatment alone for >4 brain metastases (although it is increasingly used for such patients in many centres) as well as integration of local therapies with targeted and immunological therapies in appropriately selected cases. In certain circumstances, cranial irradiation can be omitted.

Project description:The development of novel therapies for brain metastases is an unmet need. Brain metastases may have unique molecular features that could be explored as therapeutic targets. A better understanding of the drug sensitivity of live cells coupled to molecular analyses will lead to a rational prioritization of therapeutic candidates. We evaluated the molecular profiles of 12 breast cancer brain metastases (BCBM) and matched primary breast tumors to identify potential therapeutic targets. We established six novel patient-derived xenograft (PDX) from BCBM from patients undergoing clinically indicated surgical resection of BCBM and used the PDXs as a drug screening platform to interrogate potential molecular targets. Many of the alterations were conserved in brain metastases compared with the matched primary. We observed differential expressions in the immune-related and metabolism pathways. The PDXs from BCBM captured the potentially targetable molecular alterations in the source brain metastases tumor. The alterations in the PI3K pathway were the most predictive for drug efficacy in the PDXs. The PDXs were also treated with a panel of over 350 drugs and demonstrated high sensitivity to histone deacetylase and proteasome inhibitors. Our study revealed significant differences between the paired BCBM and primary breast tumors with the pathways involved in metabolisms and immune functions. While molecular targeted drug therapy based on genomic profiling of tumors is currently evaluated in clinical trials for patients with brain metastases, a functional precision medicine strategy may complement such an approach by expanding potential therapeutic options, even for BCBM without known targetable molecular alterations.SignificanceExamining genomic alterations and differentially expressed pathways in brain metastases may inform future therapeutic strategies. This study supports genomically-guided therapy for BCBM and further investigation into incorporating real-time functional evaluation will increase confidence in efficacy estimations during drug development and predictive biomarker assessment for BCBM.

Project description:Bone metastasis is a major cause of morbidity within solid tumours of the breast, prostate, lung and kidney. Metastasis to the skeleton is associated with a wide range of complications including bone fractures, spinal cord compression, hypercalcaemia and increased bone pain. Improved treatments for bone metastasis, such as the use of anti-bone resorptive bisphosphonate agents, within post-menopausal women have improved disease-free survival; however, these treatments are not without side effects. There is thus a need for biomarkers, which will predict the risk of developing the spread to bone within these cancers. The application of molecular profiling techniques, together with animal model systems and engineered cell-lines has enabled the identification of a series of potential bone-metastasis biomarker molecules predictive of bone metastasis risk. Some of these biomarker candidates have been validated within patient-derived samples providing a step towards clinical utility. Recent developments in multiplex biomarker quantification now enable the simultaneous measurement of up to 96 micro-RNA/protein molecules in a spatially defined manner with single-cell resolution, thus enabling the characterisation of the key molecules active at the sites of pre-metastatic niche formation as well as tumour-stroma signalling. These technologies have considerable potential to inform biomarker discovery. Additionally, a potential future extension of these discoveries could also be the identification of novel drug targets within cancer spread to bone. This chapter summarises recent findings in biomarker discovery within the key bone metastatic cancers (breast, prostate, lung and renal cell carcinoma). Tissue-based and circulating blood-based biomarkers are discussed from the fields of genomics, epigenetic regulation (micro-RNAs) and protein/cell-signalling together with a discussion of the potential future development of these markers towards clinical development.

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Precision medicine biomarkers in brain metastases: applications, discordances, and obstacles.

Publications

Precision medicine biomarkers in brain metastases: applications, discordances, and obstacles.

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