A Comprehensive Meta-Analysis of Association between EGFR Mutation Status and Brain Metastases in NSCLC

Tan, Li Tee; Wu, Yinying; Ma, Xiaowei; Yan, Yanli; Shao, Shuai; Liu, Jiaxin; Ma, Hailin; Li, Rui; Chai, Linyan; Ren, Juan

doi:10.1007/s12253-019-00598-0

Cited by 13 publications

(7 citation statements)

References 54 publications

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“…10 Hotpot KRAS mutations are known to activate EGFR signalling pathways, which in-turn is associated with an increased risk of brain metastases in non-small cell lung cancer. 11 Transgenic mouse models have established that oncogenic Kras can induce naevi and be a founder event in melanomagenesis. 12 In one study, a Kras G12D allele was combined with alleles of p53 or Lkb1 and with a melanocyte-specific Cre driver to generate a model that developed melanoma with a penetrance of 100%.…”

Section: Discussionmentioning

confidence: 99%

The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence

et al. 2020

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Brain metastases are a major cause of melanoma-related mortality and morbidity. We undertook whole-exome sequencing of 50 tumours from patients undergoing surgical resection of brain metastases presenting as the first site of visceral disease spread and validated our findings in an independent dataset of 18 patients. Brain metastases had a similar driver mutational landscape to cutaneous melanomas in TCGA. However, KRAS was the most significantly enriched driver gene, with 4/50 (8%) of brain metastases harbouring non-synonymous mutations. Hotspot KRAS mutations were mutually exclusive from BRAFV600, NRAS and HRAS mutations and were associated with a reduced overall survival from the resection of brain metastases (HR 10.01, p = 0.001). Mutations in KRAS were clonal and concordant with extracranial disease, suggesting that these mutations are likely present within the primary. Our analyses suggest that KRAS mutations could help identify patients with primary melanoma at higher risk of brain metastases who may benefit from more intensive, protracted surveillance.

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Section: Discussionmentioning

confidence: 99%

The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence

et al. 2020

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“…10 In the same way the PI3K/AKT pathway has been mechanistically linked with the development of brain metastases 11 , and analyses of patient-matched pairs of brain and extracranial metastases have revealed that brain metastases have higher levels of activated AKT and lower expression of PTEN , a finding also observed using immunohistochemistry. 12 Hotpot KRAS mutations are known to activate EGFR signaling pathways, which in-turn is associated with an increased risk of brain metastases in non-small cell lung cancer (NSCLC) 13 . One human sequencing study has further shown a direct association between KRAS -mutations and NSCLC brain metastases 14 , although further functional validation will be required.…”

Section: Discussionmentioning

confidence: 99%

HotspotKRASmutations in brain metastases at the first metastatic recurrence of cutaneous melanoma

Rabbie

Ferguson

Wong

et al. 2020

Preprint

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IMPORTANCEBrain metastases occur in 60% of patients with advanced melanoma and are a major cause of melanoma-related mortality and morbidity. Although our understanding of the molecular alterations associated with melanoma progression is improving, there are currently no validated biomarkers which might help identify those patients at highest risk of developing brain metastases.OBJECTIVETo examine the somatic mutational and copy-number landscape of brain metastases that develop as the isolated first visceral site of recurrence – “early brain-metastasis” compared to extracranial melanoma metastases.DESIGN, SETTING AND PARTICIPANTSWhole-exome sequencing of 50 tumors from patients undergoing surgical resection of one or more brain metastasis occurring as the first site of visceral relapse were identified from prospectively maintained databases in Sydney, Wellington, New York and Cambridge. Whole exome sequencing analyses allowed mutational profiles to be compared to cutaneous melanomas in The Cancer Genome Atlas (SKCM-TCGA; n=358) and the Memorial Sloan Kettering (SKCM-MSK-IMPACT; n=186) datasets. An external dataset comprising a further 18 patients with surgically resected early brain metastasis from two additional academic centers served as an independent validation cohort.MAIN OUTCOMES AND MEASURESTo assess the frequency of driver mutations in early brain metastasis and their influence on survival.RESULTSIn concordance with the landmark melanoma sequencing studies, we identified mutations in BRAF (21/50, 42%), NRAS (14/50, 28%) and NF1 (11/50, 22%) as the most frequently mutated melanoma driver genes. When compared to the mutational landscape of cutaneous melanomas in TCGA (SKCM-TCGA), KRAS was the most significantly enriched driver gene, with 5/50 (10%) of brain metastases harboring non-synonymous mutations, of which 4/5 (80%) were in the hotspot positions of codons 12 and 61. This was significantly higher than the corresponding frequency of KRAS-mutations within the entire SKCM-TCGA (2% (7/358), p=0.009, Fisher’s Exact Test) as well as the SKCM-MSK-IMPACT cohort (1.6% (3/186), p=0.016). Variants in KRAS were mutually exclusive from BRAFV600, NRAS and HRAS mutations and were associated with a significantly reduced overall survival from resection of brain metastasis (relative to KRAS-wild type brain metastases) in multivariate Cox proportional hazard models (HR 1.80, 95% CI 1.46-24.89, p=0.013). Mutations in KRAS were also clonal and concordant with extracranial disease, which suggests these mutations are present within the primary tumorCONCLUSIONS AND RELEVANCEOur analysis, the largest to date, suggests that early metastases to the brain (presenting as the first site of visceral relapse) are characterized by significant enrichment of hotspot KRAS mutations, potentially implicating constitutive RAS-driven cellular programs in neurotropic metastatic behavior in these cases. Based on these data, we suggest that screening for KRAS mutations might help identify those patients with primary melanoma at higher risk of brain metastases or poor survival, and could help inform future surveillance strategies.Key PointsQuestionWhat is the frequency of driver mutations in early melanoma brain metastases?FindingsIn this study of 50 patients with melanoma metastasizing first to the brain, KRAS mutations were the most significantly enriched driver gene (n=5, 10% of patients) when compared to landmark cutaneous melanoma studies. The high KRAS mutation frequency was also observed in an external validation cohort of 18 patients with early brain metastases. Mutations in KRAS were mutually exclusive from mutations in the key RAS signaling genes and conferred a worse overall survival from resection of brain metastasis.MeaningHotspot KRAS mutations could help identify those patients with primary melanoma at higher risk of brain metastases that may benefit from more intensive, protracted surveillance as well as earlier use of adjuvant therapy.

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“…Renaud and colleagues reported a higher risk of liver and brain metastases in NSCLC patients with EGFR mutation, and patients with KRAS G12C and G12V developed significantly more bone and pleuro-pericardial metastases, respectively (14). Despite some discordances between reports, multiple studies have suggested a higher risk of brain recurrence in NSCLCs with EGFR mutation after pulmonary resection (14,15), which is also supported by the higher incidence of brain metastases in clinical stage IV NSCLCs with EGFR mutation (16).…”

Section: Prognostic Biomarkers Specific For Nsclcs With Egfr Mutationmentioning

confidence: 97%

Personalized post-surgical care?—possible strategies for NSCLCs with EGFR mutation

Suda¹

2020

Transl Lung Cancer Res

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A Comprehensive Meta-Analysis of Association between EGFR Mutation Status and Brain Metastases in NSCLC

Cited by 13 publications

References 54 publications

The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence

The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence

HotspotKRASmutations in brain metastases at the first metastatic recurrence of cutaneous melanoma

Personalized post-surgical care?—possible strategies for NSCLCs with EGFR mutation

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