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. 2021 Nov 27;13(23):5973. doi: 10.3390/cancers13235973

Table 2.

Summary of studies investigating candidate markers for the detection of IMD specific to NSCLC, breast cancer, and melanoma skin cancer.

Study Participant Numbers Biomarkers of Interest (Sample Type) Findings
NSCLC Saad et al. [84] IMD: 21, no IMD: 33 Ki-67, caspase-3, VEGF-A, VEGF-C, E-cadherin, EGFR
(tissue)

  • Significantly increased risk of developing IMD associated with: high Ki-67, low caspase-3, high VEGF-C, low E-cadherin

  • No significant risk associated with: VEGF-A and EGFR
Gomez-Roca et al. [85] IMD: 9, no IMD: 40 EGFR, ERCC1, VEGFR, Ki-67
(tissue)

  • Significantly increased expression in IMD samples compared to samples from the primary site: ERCC1

  • Decreased levels of EGFR expression in metastases, but no significant difference in different metastatic sites

  • No significant differences: VEGFR, Ki-67
Grinberg-Rashi et al. [86] IMD: 25, no IMD: 82 KIFC1, KIFC2, KIG14, CCNB2, SIL, TNPO1, LMNB1; CDH2, SGNE1, FALZ, ADAM8, SPP1
(tissue)

  • Positive predictive effect: CDH2, KIFC1

  • Negative predictive effect: FALZ

  • No significant effect observed for any of the other genes

  • Generated predictive score based on expression of: CDH2, KIFC1, FALZ
Chen et al. [87] NSCLC+ IMD: 100, NSCLC no IMD: 50, CVD: 50 S100B protein
S100B antibody
(serum)

  • S100B significantly elevated in patients with IMD compared with patients without IMD or CVD

  • No significant differences between patients without IMD and CVD

  • No significant difference in levels of S100B antibody

  • Patients with IMD and high levels of S100B had significantly shorted OS and PFS compared to patients with IMD and low levels of S100B

  • S100B sensitivity: 94%, specificity: 93% (cut-off: 0.014 ng/mL)
Choi et al. [88] IMD: 18, no IMD: 110 S100B protein
S100B antibody
(serum)

  • S100B protein sensitivity: 89%, specificity: 43%, accuracy: 51%, (cut-off: 0.058 ng/mL)

  • S100B protein + autoantibody - sensitivity: 89%, specificity: 58%, accuracy: 62.5% (antibody threshold: < 2.00 absorbance units)

Pang et al. [89] IMD: 15, no IMD: 15 S100B protein
(serum)

  • S100B significantly higher in IMD group

  • Infection of cells with full-length S100B expression vectors significantly promoted cell proliferation and inhibited apoptosis
Kondrup et al. [90] IMD: 22, no IMD: 50 S100B protein (serum)

  • No significant difference in S100B

Breast cancer Siravegna et al. [91] Single patient ctDNA
(plasma and CSF)

  • Comparison of pre-treatment and post-treatment samples: reduction in plasma ERBB2, tp53, and PIK3CA consistent with extra-cranial disease control but not CSF-derived tp53 and PIK3CA consistent with non-response

  • Plasma ERBB2 amplification, tp53 and PIK3CA mutations were detected at the time of CNS progression

Sato et al. [53] IMD: 51, no IMD: 28 miRNA
(serum)

  • miR-4428 and miR-4480 could distinguish IMD from non-IMD (greater than 2-fold change between the groups, p<0.001)

  • miR-4428 sensitivity: 82.4%, specificity: 64.3%

  • miR-4480 sensitivity: 76.5%, specificity: 71.4%

Melanoma skin cancer Hoon et al. [92] total: 37 MAGE, MART-1, tyrosinase
(CSF)

  • MART-1 and/or MAGE-3 were positive predictive markers for the development of IMD

  • RT-PCR could detect approximately 50% of patients who developed IMD during a 4-year follow up period based on only a single time point
Lok et al. [93] IMD: 22, healthy control: 5 Cytokines and chemokines
(CSF)

  • Cluster analysis revealed that suppression of IL1α, IL4, IL5, and CCL22, with concomitant elevation of CXCL10, CCL4, and CCL17 correlated with more aggressive IMD (time to IMD and survival outcomes)

CCNB2: cyclin B2; CDH2: N-cadherin; CSF: cerebrospinal fluid; CVD: cerebrovascular disease; EGFR: epidermal growth factor receptor; ERCC1: excision repair cross-complementing; FALZ: fetal Alzheimer antigen; IMD: intracranial metastatic disease; KIFC1: kinesin family member C1; LMNB1: lamin B1; NSCLC: non-small cell lung cancer; OS: overall survival; PFS: progression free survival; SIL: SCL-TAL1 interrupting locus; SGNE1: secretogranin V; TNPO1: transportin 1; VEGFR: vascular endothelial growth factor receptor.