Genomic Profiling of Circulating Tumor DNA From Cerebrospinal Fluid to Guide Clinical Decision Making for Patients With Primary and Metastatic Brain Tumors

Ramkissoon, Lori; Pegram, Worthy; Haberberger, James; Danziger, Natalie; Lesser, Glenn J.; Strowd, Roy; Dahiya, Sonika; Cummings, Thomas J.; Bi, Wenya Linda; Abedalthagafi, Malak; Sathyan, Pratheesh; McGregor, Kimberly; Reddy, Prasanth; Severson, Eric Allan; Williams, Erik; Lin, Douglas I.; Edgerly, Claire; Huang, Richard S.P.; Hemmerich, Amanda; Creeden, James; Brown, Charlotte A.; Venstrom, Jeffrey M.; Hegde, Priti S.; Ross, Jeffrey S.; Alexander, Brian M.; Elvin, Julia A.; Ramkissoon, Shakti

doi:10.3389/fneur.2020.544680

Cited by 18 publications

(13 citation statements)

References 42 publications

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“…Of note, while the CGP results of blood liquid biopsy has shown considerable concordance with tissue biopsies and has shown clinical utility in many metastatic diseases, several studies have demonstrated that the blood-brain barrier (BBB) may limit the quantity of ctDNA that is shed into the circulating blood plasma, rendering blood liquid biopsy limited in its ability to detect the genomic profile of the NSCLC-BM. 36 …”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic and Genomic Landscape of Non-Small Cell Lung Cancer Brain Metastases

Huang¹,

Harries²,

Decker³

et al. 2022

The Oncologist

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Background In patients with non-small cell lung cancer (NSCLC), 10%-40% will eventually develop brain metastases. We present the clinicopathologic, genomic, and biomarker landscape of a large cohort of NSCLC brain metastases (NSCLC-BM) samples. Materials and Methods We retrospectively analyzed 3035 NSCLC-BM tested with comprehensive genomic profiling (CGP) during routine clinical care. In addition, we compared the NSCLC-BM to a separate cohort of 7277 primary NSCLC (pNSCLC) specimens. Finally, we present data on 67 paired patients with NSCLC-BM and pNSCLC. Results Comprehensive genomic profiling analysis of the 3035 NSCLC-BMs found that the most frequent genomic alterations (GAs) were in the TP53, KRAS, CDKN2A, STK11, CDKN2B, EGFR, NKX2-1, RB1, MYC, and KEAP1 genes. In the NSCLC-BM cohort, there were significantly higher rates of several targetable GAs compared with pNSCLC, including ALK fusions, KRAS G12C mutations, and MET amplifications; and decreased frequency of MET exon14 skipping mutations (all P < .05). In the subset of NSCLC-BM (n = 1063) where concurrent PD-L1 immunohistochemistry (IHC) was performed, 54.7% of the patients with NSCLC-BM were eligible for pembrolizumab based on PD-L1 IHC (TPS ≥ 1), and 56.9% were eligible for pembrolizumab based on TMB-High status. In addition, in a series 67 paired pNSCLC and NSCLC-BM samples, 85.1% (57/67) had at least one additional GA discovered in the NSCLC-BM sample when compared with the pNSCLC sample. Conclusions Herein, we defined the clinicopathologic, genomic, and biomarker landscape of a large cohort of patients with NSCLC-BM which can help inform study design of future clinical studies for patients with NSCLC with BM. In certain clinical situations, metastatic NSCLC brain tissue or cerebral spinal fluid specimens may be needed to fully optimize personalized treatment.

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Section: Discussionmentioning

confidence: 99%

Clinicopathologic and Genomic Landscape of Non-Small Cell Lung Cancer Brain Metastases

Huang¹,

Harries²,

Decker³

et al. 2022

The Oncologist

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“…We found a higher prevalence of clinically relevant GAs in patients with BCBM, which suggests that metastatic tissue to the brain or cerebrospinal fluid specimen should be considered as specimens for CGP testing [36]. In addition, we saw a higher frequency of immunotherapy biomarker A B Figure 3.…”

Section: Discussionmentioning

confidence: 78%

“…In the confirmed TNBC cohort, the number of GAs per sample was also increased in the brain metastasis cohort, and in many cases it was different from the primary BCs. Because of these differences, for patients with breast carcinoma that has metastasized to the brain, the metastatic tissue in the brain or cerebrospinal fluid specimen, when safely available, should be considered as specimens for CGP testing [36,37].…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic and Genomic Landscape of Breast Carcinoma Brain Metastases

Huang¹,

Haberberger²,

McGregor³

et al. 2021

The Oncologist

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Background. Among breast carcinoma patients with metastatic disease, 15-30% will eventually develop brain metastases. We examined the genomic landscape of a large cohort of breast carcinoma brain metastases (BCBMs) and compared them to a cohort of primary breast carcinomas (BCs). Material and Methods. We retrospectively analyzed 733 BCBMs tested with comprehensive genomic profiling (CGP) and compared them to 10,772 primary breast carcinomas (not-paired) specimens. For a subset of 16 triplenegative breast carcinoma (TNBC)-brain metastasis (BM) samples, PD-L1 immunohistochemistry was performed concurrently. Results. A total of 733 consecutive BCBMs were analyzed. Compared to primary BCs, BCBMs were enriched for genomic alterations in TP53 (72.0%, 528/733), ERBB2 (25.6%. 188/733), RAD21 (14.1%, 103/733), NF1 (9.0%, 66/733), BRCA1 (7.8%, 57/733), and ESR1 (6.3%,46/733) (p < 0.05 for all comparisons). Immune checkpoint inhibitor (ICPI) biomarkers such as tumor mutational burden (TMB)-High (16.2%, 119/733), microsatellite instability (MSI)-High (1.9%, 14/733), CD274 amplification (3.6%, 27/733), and APOBEC mutational signature (5.9%, 43/733) were significantly higher in the BCBM cohort compared to the primary BC cohort (p < 0.05 for all comparisons). When using both CGP and PD-L1 IHC, 37.5% (6/16) of the TNBC brain metastasis patients were eligible for atezolizumab based on PD-L1 IHC, and 18.8% (3/16) were eligible for pembrolizumab based on TMB-High status. Conclusion. We found a high prevalence of clinically relevant genomic alterations in BCBM patients, suggesting that tissue acquisition (surgery) and or cerebrospinal fluid (CSF) for CGP in addition to CGP of the primary tumor may be clinically warranted. The Oncologist 2021;9999:• •

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“…In most cancers, blood is a good source of circulating tumour DNA and can be used to obtain a molecular profile of the tumour in a minimally invasive way. However, in patients with CNS tumours the ability to detect ctDNA in the blood is much more limited compared to other solid tumours ( 6 , 17 ). In the paediatric setting, most studies have been limited by small patient numbers and even though they were focused on using highly sensitive methods (mainly ddPCR) that allow detection of variants at very low levels (VAF of 0.01%–0.1%), the ability to detect pathogenic variants in cfDNA from plasma of patients with brain tumours has been low, with 0%–10% of patients having detectable ctDNA alterations in patients with glioma and up to 40% detectability in patients with medulloblastoma ( 6 , 14 , 16 ).…”

Section: Detection Of Ctdna In Blood Lacks Sufficient Sensitivity In ...mentioning

confidence: 99%

Liquid biopsy for children with central nervous system tumours: Clinical integration and technical considerations

et al. 2022

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Circulating cell-free DNA (cfDNA) analysis has the potential to revolutionise the care of patients with cancer and is already moving towards standard of care in some adult malignancies. Evidence for the utility of cfDNA analysis in paediatric cancer patients is also accumulating. In this review we discuss the limitations of blood-based assays in patients with brain tumours and describe the evidence supporting cerebrospinal fluid (CSF) cfDNA analysis. We make recommendations for CSF cfDNA processing to aid the standardisation and technical validation of future assays. We discuss the considerations for interpretation of cfDNA analysis and highlight promising future directions. Overall, cfDNA profiling shows great potential as an adjunct to the analysis of biopsy tissue in paediatric cancer patients, with the potential to provide a genetic molecular profile of the tumour when tissue biopsy is not feasible. However, to fully realise the potential of cfDNA analysis for children with brain tumours larger prospective studies incorporating serial CSF sampling are required.

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Genomic Profiling of Circulating Tumor DNA From Cerebrospinal Fluid to Guide Clinical Decision Making for Patients With Primary and Metastatic Brain Tumors

Cited by 18 publications

References 42 publications

Clinicopathologic and Genomic Landscape of Non-Small Cell Lung Cancer Brain Metastases

Clinicopathologic and Genomic Landscape of Non-Small Cell Lung Cancer Brain Metastases

Clinicopathologic and Genomic Landscape of Breast Carcinoma Brain Metastases

Liquid biopsy for children with central nervous system tumours: Clinical integration and technical considerations

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