Anatomical and Topographical Variations in the Distribution of Brain Metastases Based on Primary Cancer Origin and Molecular Subtypes: A Systematic Review

Abstract Background While it has been suspected that different primary cancers have varying predilections for metastasis in certain brain regions, recent advances in neuro-imaging and spatial modeling analytics have facilitated further exploration into this field. Methods A systematic electronic database search for studies analyzing the distribution of brain metastases (BM) from any primary systematic cancer published January 1990-July 2020 was conducted using PRISMA guidelines. Results Two authors independently reviewed 1,957 abstracts, 46 of which underwent full-text analysis. A third author arbitrated both lists; 13 studies met inclusion/exclusion criteria. All were retrospective single- or multi-institution database reviews analyzing over 8,227 BMs from 2,599 patients with breast (8 studies), lung (7 studies), melanoma (5 studies), gastrointestinal (4 studies), renal (3 studies), and prostate (1 study) cancers. Breast, lung, and colorectal tended to metastasize to more posterior/caudal topographic and vascular neuroanatomical regions, particularly the cerebellum, with notable differences based on subtype and receptor expression. HER-2 positive breast cancers were less likely to arise in the frontal lobes or subcortical region, while ER-positive and PR-positive breast metastases were less likely to arise in the occipital lobe or cerebellum. BM from lung adenocarcinoma tended to arise in the frontal lobes, and squamous cell carcinoma in the cerebellum. Melanoma metastasized more to the frontal and temporal lobes. Conclusion The observed topographical distribution of BM likely develops based on primary cancer type, molecular subtype, and genetic profile. Further studies analyzing this association and relationships to vascular distribution are merited to potentially improve patient treatment and outcomes.

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O04 * DIFFUSION WEIGHTED MRI DISCRIMINATES PRIMARY CANCER TYPE AND OUTCOME IN BRAIN METASTASES

Neuro-Oncology ◽

10.1093/neuonc/nou250.4 ◽

2014 ◽

Vol 16 (suppl 6) ◽

pp. vi13-vi13

Author(s):

R. Zakaria ◽

M. Radon ◽

M. Bhojak ◽

V. Sluming ◽

K. Das ◽

...

Keyword(s):

Brain Metastases ◽

Cancer Type ◽

Primary Cancer ◽

Diffusion Weighted Mri ◽

Diffusion Weighted

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Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification

npj Precision Oncology ◽

10.1038/s41698-021-00187-y ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Robert L. Hollis ◽

Barbara Stanley ◽

John P. Thomson ◽

Michael Churchman ◽

Ian Croy ◽

...

Keyword(s):

High Risk ◽

Ovarian Carcinoma ◽

Expression Patterns ◽

Parp Inhibitors ◽

Receptor Expression ◽

Cancer Type ◽

Sequencing Data ◽

Molecular Features ◽

Endometrioid Ovarian Carcinoma ◽

Molecular Landscape

AbstractEndometrioid ovarian carcinoma (EnOC) is an under-investigated ovarian cancer type. Recent studies have described disease subtypes defined by genomics and hormone receptor expression patterns; here, we determine the relationship between these subtyping layers to define the molecular landscape of EnOC with high granularity and identify therapeutic vulnerabilities in high-risk cases. Whole exome sequencing data were integrated with progesterone and oestrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathological assessment, revealing dominant clinical and molecular features in the resulting integrated subtypes. We demonstrate significant correlation between subtyping approaches: PR-high (PR + /ER + , PR + /ER−) cases were predominantly CTNNB1-mutant (73.2% vs 18.4%, P < 0.001), while PR-low (PR−/ER + , PR−/ER−) cases displayed higher TP53 mutation frequency (38.8% vs 7.3%, P = 0.001), greater genomic complexity (P = 0.007) and more frequent copy number alterations (P = 0.001). PR-high EnOC patients experience favourable disease-specific survival independent of clinicopathological and genomic features (HR = 0.16, 95% CI 0.04–0.71). TP53 mutation further delineates the outcome of patients with PR-low tumours (HR = 2.56, 95% CI 1.14–5.75). A simple, routinely applicable, classification algorithm utilising immunohistochemistry for PR and p53 recapitulated these subtypes and their survival profiles. The genomic profile of high-risk EnOC subtypes suggests that inhibitors of the MAPK and PI3K-AKT pathways, alongside PARP inhibitors, represent promising candidate agents for improving patient survival. Patients with PR-low TP53-mutant EnOC have the greatest unmet clinical need, while PR-high tumours—which are typically CTNNB1-mutant and TP53 wild-type—experience excellent survival and may represent candidates for trials investigating de-escalation of adjuvant chemotherapy to agents such as endocrine therapy.

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BSCI-20. THERAPEUTIC TARGETING OF HLA-G IN BRAIN METASTASES

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.018 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i5-i5

Author(s):

Sheila Singh ◽

Blessing Bassey-Archibong ◽

Nikoo Aghaei ◽

Agata Kieliszek ◽

Chitra Venugopal ◽

...

Keyword(s):

Brain Metastases ◽

Systemic Disease ◽

Human Leukocyte ◽

Genetic Profile ◽

Whole Brain Radiation ◽

Metastatic Cells ◽

Metastatic Process ◽

Xenograft Models ◽

Sphere Formation ◽

The Brain

Abstract Brain metastases (BM) are the most common brain tumor in adults, with an incidence ten times greater than that of primary brain tumors. The most common sources of BM in adult cancer patients include cancers of the lung, breast and melanoma, which together account for almost 80% of all BM. Current clinical modalities for BM include surgery, whole brain radiation therapy and stereotactic radiosurgery but these therapies still offer limited efficacy and reduced survival of only months in treated patients, emphasizing the need for novel BM research approaches and better therapeutic strategies. Our laboratory recently discovered that stem-like cells exist in patient-derived BM from lung, breast and melanoma cancers, which we termed “brain metastasis-initiating cells” or BMICs. Through clinically relevant human-mouse xenograft models established with these patient-derived BMICs, we captured lung, breast and melanoma BMICs at pre-metastasis – a key stage where circulating metastatic cells extravasate and initially seed the brain, prior to organization into micro-metastatic foci. Transcriptome analysis of pre-metastatic BMICs revealed a unique genetic profile and several genes commonly up-regulated among lung, breast and melanoma BM, including the non-classical human leukocyte class I antigen-G (HLA-G). Loss of HLA-G in lung, breast and melanoma BMICs using two HLA-G specific shRNAs attenuated sphere formation, migratory and tumor initiating abilities of lung, breast and melanoma BMICs compared to control BMICs. HLA-G knockdown also resulted in reduced phospho(p)-STAT3 expression in patient-derived BMICs suggesting a potential cooperative role between HLA-G and pSTAT3 in BM. Since HLA-G is highly expressed at the cell surface in control tumors, ongoing experiments are focused on developing HLA-G specific chimeric antigen receptor -T cells (CAR-Ts) and determining their efficacy in targeting lung-, breast- and melanoma-BM as blocking the brain metastatic process will markedly extend patient survival and ultimately transform a fatal systemic disease into a more treatable one.

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Survival of patients with synchronous brain metastases: an epidemiological study in southeastern Michigan

Neurosurgical FOCUS ◽

10.3171/foc.2000.9.2.2 ◽

2000 ◽

Vol 9 (2) ◽

pp. 1-5 ◽

Cited By ~ 2

Author(s):

Ajith J. Thomas ◽

Jack P. Rock ◽

Christine C. Johnson ◽

Linda Weiss ◽

Gordon Jacobsen ◽

...

Keyword(s):

Brain Metastases ◽

Median Survival ◽

Cancer Diagnosis ◽

Systemic Disease ◽

Primary Source ◽

Primary Site ◽

Unknown Primary ◽

Primary Cancer ◽

Significant Difference ◽

Frequent Site

Object It has been suggested that synchronous brain metastases (that is, those occurring within 2 months of primary cancer diagnosis) are associated with a shorter survival time compared with metachronous lesions (those occurring greater than 2 months after primary cancer diagnosis). In this study the authors used data obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program to determine the incidence of synchronous brain metastases and length of survival of patients in a defined population of southeastern Michigan residents. Methods Data obtained in 2682 patients with synchronous brain metastases treated from 1973 to 1995 were reviewed. Study criteria included patients in whom at least one brain metastasis was diagnosed within 2 months of the diagnosis of primary cancer and those with an unknown primary source. The incidence per 100,000 increased fivefold, from 0.69 in 1973 to 3.83 in 1995. The most frequent site for the primary cancer was the lung (75.4%). The second largest group (10.7%) consisted of patients in whom the primary site was unknown. The median survival length was 3.3 months. There was no significant difference in the median survival in patients with primary lung/bronchus and those with an unknown primary site (3.2 months and 3.4 months, respectively). Conclusions Patients who present with synchronous lesions have a poor prognosis, and the predominant cause of death, in greater than 90% of cases, is related to systemic disease; however, despite poor median survival lengths, certain patients will experience prolonged survival.

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Breast cancer brain metastases: Molecular subtype, treatment and survival

Breast Disease ◽

10.3233/bd-160237 ◽

2016 ◽

Vol 36 (4) ◽

pp. 133-141 ◽

Cited By ~ 2

Author(s):

Jennifer A. Crozier ◽

Lauren F. Cornell ◽

Bhupendra Rawal ◽

Edith A. Perez

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Molecular Subtype ◽

Breast Cancer Brain Metastases

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RADT-05. PROSPECTIVE LONG-TERM EVALUATION OF MRI- AND CLINICAL CHANGES FOLLOWING STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES – IS REPEAT SRS A CONSEQUENCE, OR ALSO A CAUSE OF LONG-TERM SURVIVAL?

Neuro-Oncology ◽

10.1093/neuonc/noab196.163 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi41-vi42

Author(s):

Bente Skeie ◽

Per Øyvind Enger ◽

Geir Olve Skeie ◽

Jan Ingemann Heggdal

Keyword(s):

Brain Metastases ◽

Stereotactic Radiosurgery ◽

Whole Brain Radiotherapy ◽

Cancer Site ◽

Response Patterns ◽

Primary Cancer ◽

Term Survival ◽

Cover Ratio ◽

Primary Cancer Site

Abstract The use of stereotactic radiosurgery (SRS) for brain metastases are increasing. Response assessment is challenging and the clinical significance of radiological response and retreatments are poorly defined. Ninety-seven patients with a total of 406 brain metastases were followed prospectively for 10 years or until death. Volume changes over time and clinical outcome in response to first time SRS and SRS retreatments were analyzed. Tumors grew significantly before (p = 0.004), but shrunk at 1 and 3 months (p = 0.001) following SRS. Four response-patterns of were observed; tumors either continuously reduced in size (A, 62%), pseudo-progressed (PP, B, 13%), temporarily reduced in size (C, 24%), or grew continuously (D, 2%); corresponding to 75% local control (LC) at initial SRS. Predictors for LC were primary cancer site (p = 0.001), tumor volume (p = 0.002) and target cover ratio (p = 0.005). Subsequent SRS for new lesions resulted in 94% LC (87% A) and repeat-SRS for local failures in 80% LC (57% B), predicted by higher prescribed dose, p = 0.001 and p = 0.042, respectively. Overall survival was only 4.5 months if A-response for all lesions, 13.3 months if at least one B-response, 17.1 months if retreated C- or D-response (p < 0.001), (7.5 and 4.7 months if untreated). Quality of life (p = 0.003), steroid use (p = 0.019) and prior whole brain radiotherapy (p = 0.026) were predictors for survival. There are 4 response patterns to SRS predicted by tumor size, primary cancer site, target cover ratio and prescribed dose. Long-term survivors experienced a higher incidence of PP and were more often retreated for new lesions and local failures. The immune response induced by PP seems beneficial but further studies are needed.

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MET-01 INDICATION AND OUTCOME OF SALVAGE SURGERY FOR LOCAL PROGRESSION OF BRAIN METASTASIS PREVIOUSLY TREATED WITH STEREOTACTIC IRRADIATION

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.157 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii35-ii35

Author(s):

Koichi Mitsuya ◽

Shoichi Deguchi ◽

Yoko Nakasu ◽

Nakamasa Hayashi

Keyword(s):

Overall Survival ◽

Prognostic Factors ◽

Brain Metastasis ◽

Brain Metastases ◽

Salvage Surgery ◽

Primary Cancer ◽

Stereotactic Irradiation ◽

Meaningful Improvement ◽

Local Progression ◽

Clinical Records

Abstract PURPOSE To determine treatment outcome following salvage surgery (SS) for local progression of brain metastasis treated by stereotactic irradiation (STI). METHODS The clinical records of patients who underwent SS of local progression of brain metastases after STI at our institute between October 2002 and July 2019 were retrospectively reviewed. Kaplan-Meier curves were used for the assessment of overall survival (OS). The decision to perform SS was based on findings of magnetic resonance imaging and/or clinical evidence of local progression of the brain metastases and status of systemic disease. Prognostic factors for survival were analyzed; age, sex, primary cancer, RPA classification at surgery, extent of resection, radiotherapy after salvage surgery, and pre-surgical neutrophil-to-lymphocyte ratio (NLR). RESULTS Fifty-four SS of 48 patients were performed. The median age of the patients was 63 years (range 36–79). The median interval from STI to SS was 12 months. The median overall survival was 20.2 months from SS. Primary cancer were lung 34, breast 10, and other 10. Fourteen of 54 lesions (26%) developed local recurrence. Leptomeningeal dissemination occurred after the SS in 3 patients (5.7%). RPA classification (1 vs 3, HR:0.16, 95%CI: 0.03–0.59) (2 vs 3, HR:0.44, 95%CI:0.19–0.97) and primary cancer (breast vs lung, HR:0.21, 95%CI:0.05–0.64) (breast vs others, HR:0.08, 95%CI:0.015–0.32) (lung vs others, HR:0.38, 95%CI:0.16–0.94)) were identified as good prognostic factors of overall survival in multivariate analysis. The optimum NLR threshold value was identified as 3.65 for 1-year survival from SS (AUC0.62, sensitivity:71%). CONCLUSIONS Salvage surgery for local progression of brain metastases after STI in selected cases leads to a meaningful improvement in survival.

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BMET-15. FREQUENCY OF SYNCHRONOUS BRAIN METASTASES AT TIME OF PRIMARY CANCER DIAGNOSIS IN THE US, 2010-2013

Neuro-Oncology ◽

10.1093/neuonc/now212.115 ◽

2016 ◽

Vol 18 (suppl_6) ◽

pp. vi29-vi29

Author(s):

Courtney Kromer ◽

Jordan Xu ◽

Quinn Ostrom ◽

Carol Kruchko ◽

Jill Barnholtz-Sloan

Keyword(s):

Brain Metastases ◽

Cancer Diagnosis ◽

Primary Cancer ◽

The Us

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Highlights of the 2019 Society for Neuro-Oncology Inaugural Brain Metastases Conference: establishing a dedicated meeting to address an unmet need in the field

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa036 ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Jeffrey A Zuccato ◽

Ayal A Aizer ◽

Eudocia Quant Lee ◽

Manmeet S Ahluwalia ◽

Philip J O’Halloran ◽

...

Keyword(s):

Brain Metastases ◽

Disease Control ◽

Targeted Therapies ◽

Systemic Disease ◽

Unmet Need ◽

Primary Cancer ◽

Primary Tumors ◽

Inaugural Meeting

Abstract Brain metastases comprise the majority of central nervous tumors in adults and confer poorer survival for patients with primary cancer. Systemic disease control is improving with advances in treatment for primary tumors and the complexity of brain metastases management is increasing with multimodality approaches incorporating combinations of surgery, radiotherapy, chemotherapy, targeted therapies, and immunotherapy. Accordingly, the Society for Neuro-Oncology established an annual brain metastases conference to unite colleagues from multiple disciplines with content spanning a range of timely topics relevant to improving our understanding of brain metastases and how they are optimally treated. The inaugural meeting on August 16–17, 2019 was very successful with 163 impactful presentations being delivered to a large multidisciplinary audience on current research advances in the field of neuro-oncology. This review summarizes the major themes of the meeting and highlights the main findings presented.

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Brain metastases in patients diagnosed with a solid primary cancer during childhood: experience from a single referral cancer center

Journal of Neurosurgery Pediatrics ◽

10.3171/2014.7.peds13318 ◽

2014 ◽

Vol 14 (4) ◽

pp. 372-385 ◽

Cited By ~ 15

Author(s):

Dima Suki ◽

Rami Khoury Abdulla ◽

Minming Ding ◽

Soumen Khatua ◽

Raymond Sawaya

Keyword(s):

Brain Metastasis ◽

Brain Metastases ◽

Primary Tumor ◽

Lung Metastases ◽

Cancer Center ◽

Leptomeningeal Disease ◽

Tumor Type ◽

Primary Cancer ◽

Extracranial Metastases ◽

The Brain

Object Metastasis to the brain is frequent in adult cancer patients but rare among children. Advances in primary tumor treatment and the associated prolonged survival are said to have increased the frequency of brain metastasis in children. The authors present a series of cases of brain metastases in children diagnosed with a solid primary cancer, evaluate brain metastasis trends, and describe tumor type, patterns of occurrence, and prognosis. Methods Patients with brain metastases whose primary cancer was diagnosed during childhood were identified in the 1990–2012 Tumor Registry at The University of Texas M.D. Anderson Cancer Center. A review of their hospital records provided demographic data, history, and clinical data, including primary cancer sites, number and location of brain metastases, sites of extracranial metastases, treatments, and outcomes. Results Fifty-four pediatric patients (1.4%) had a brain metastasis from a solid primary tumor. Sarcomas were the most common (54%), followed by melanoma (15%). The patients' median ages at diagnosis of the primary cancer and the brain metastasis were 11.37 years and 15.03 years, respectively. The primary cancer was localized at diagnosis in 48% of patients and disseminated regionally in only 14%. The primary tumor and brain metastasis presented synchronously in 15% of patients, and other extracranial metastases were present when the primary cancer was diagnosed. The remaining patients were diagnosed with brain metastasis after initiation of primary cancer treatment, with a median presentation interval of 17 months after primary cancer diagnosis (range 2–77 months). At the time of diagnosis, the brain metastasis was the first site of systemic metastasis in only 4 (8%) of the 51 patients for whom data were available. Up to 70% of patients had lung metastases when brain metastases were found. Symptoms led to the brain metastasis diagnosis in 65% of cases. Brain metastases were single in 60% of cases and multiple in 35%; 6% had only leptomeningeal disease. The median Kaplan-Meier estimates of survival after diagnoses of primary cancer and brain metastasis were 29 months (95% CI 24–34 months) and 9 months (95% CI 6–11 months), respectively. Untreated patients survived for a median of 0.9 months after brain metastasis diagnosis (95% CI 0.3–1.5 months). Those receiving treatment survived for a median of 8 months after initiation of therapy (95% CI 6–11 months). Conclusions The results of this study challenge the current notion of an increased incidence of brain metastases among children with a solid primary cancer. The earlier diagnosis of the primary cancer, prior to its dissemination to distant sites (especially the brain), and initiation of presumably more effective treatments may support such an observation. However, although the actual number of cases may not be increasing, the prognosis after the diagnosis of a brain metastasis remains poor regardless of the management strategy.

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