Table 3.
Current studies on signaling markers.
| Marker | Reference | Sample location | Sample size (N) | Finding |
|---|---|---|---|---|
| EGFR/KRAS/ALK | Fujimoto et al. (72) | Tumor tissue | 276 | The EGFR-mutated group had significantly more metastatic lesions in the brain and bone than the wild-type group. EGFR mutations were significantly more frequent in patients with multiple lung metastases than those with a single lung metastasis. |
| Hendriks et al. (74) | Tumor tissue | 189 | The incidence of brain and bone metastases was not different between EGFR+, KRAS+, and wild-type patients. Post-metastatic bone disease survival was significantly longer in EGFR+ patients. | |
| Renaud et al. (100) | Tumor tissue | 481 | After thoracic surgery for NSCLC, patients with KRAS G12C developed significantly more bone metastases compared with the remainder of the cohort (59% vs. 16%, respectively; p<0.0001). More patients with mEGFR developed liver and brain metastases (30% vs. 10%, respectively; p=0.006; 59% vs. 1%, p<0.0001, respectively). Patients with KRAS G12V developed significantly more pleuro-pericardial metastases (94% vs. 12%, respectively; p<0.0001). | |
| Kuijpers et al. (73) | Tumor tissue | 1,994 | Compared with triple-negative tumors, EGFR+ tumors had more metastases to the bone (31.5% vs. 53.8%, respectively) and pleura (24.1% vs. 37.5%, respectively). At diagnosis, KRAS+ and ALK+ tumors had metastasized more frequently to the lungs (20.3% vs. 26.7%, respectively) and liver (13.1% vs. 23.8%, respectively). | |
| Zang et al. (118) | Tumor tissue | 176 | In patients with NSCLC spinal metastasis, survival was associated with the EGFR status and many other factors. | |
| Amelot et al. (76) | Tumor tissue | 210 | In patients with NSCLC spinal metastasis, ALK gene rearrangement (p<0.0001) and mEGFR (p<0.0001) were associated with longer survival. | |
| Dormieux et al. (75) | Tumor tissue | 550 | EGFR-mutated tumors preferentially spread to the pleura and less commonly to the adrenals. ALK-rearrangement tumors usually spread to the brain and the lungs, whereas BRAF-mutated tumors are unlikely to spread to bones (21% vs. 42%, respectively; p=0.011). | |
| Yao et al. (104) | Tumor tissue | 75 | With F-FDG PET/CT, low bmSUVmax is more frequently observed in EGFR mutations, rendering it an independent predictor of these mutations. | |
| Terpos et al. (43) | Serum | 79 | Patients with bone metastasis showed an increase in RANKL and OPG. An unusually low TRACP-5b/RANKL ratio was observed in patients who had or later developed metastasis. | |
| Santini et al. (119) | Tumor tissue | 74 | 66 patients (89%) with bone metastases were RANK-positive, and 40 patients (59.5%) showed >50% positive tumor cells. There was no significant difference between primary tumors and metastases. | |
| Ibrahim et al. (120) | Serum | 49 | RANKL was the most accurate marker, with an area under the curve of 0.74 (95% confidence interval: 0.54–0.93). | |
| CXCL12/CXCR4 | Zhou et al. (62) | Tumor tissue | 150 | The molecular model for predicting bone metastasis was logit (P) = −2.538 + 2.808 CXCR4 + 1.629 BSP + 0.846 OPN − 2.939 BMP4 |
| Li et al. (121) | Tumor tissue | 65 | Univariate analysis suggested that high expression of CXCR4 was significantly correlated with bone metastasis (p=0.004). In addition, it was marginally correlated with brain metastasis (p=0.068) and lymph node metastasis (p=0.085), as well as worse OS (p=0.004) and PFS (p=0.005). | |
| Liao et al. (122) | Tumor tissue | 32 | CXCR4 was highly expressed in the bone destruction area of metastatic NSCLC samples. Also, it was related to poor survival in NSCLC patients with bone metastasis, with an increase in VCAM1 and a decrease in ADAM17. | |
| C5A (CD88)/C5AR | Ajona et al. (107) | Tumor tissue | 95 | Patients with high levels of C5AR1 had significantly shorter RFS and OS (p<0.001). They found significantly higher C5AR1 levels in primary NSCLC tumors from patients who developed bone metastases during disease progression compared with those from patients who developed metastases to other non-skeletal sites. |
ADAM17, ADAM metallopeptidase domain 17; ALK, anaplastic lymphoma kinase; bmSUVmax, maximum standardized uptake value in bone metastasis; C5A, complement component 5a; C5AR, complement component 5a receptor; CXCL12, C-X-C motif chemokine ligand 12; CXCR4, C-X-C motif chemokine receptor 4; EGFR, epidermal growth factor receptor; F-FDG PET/CT, fluorodeoxyglucose positron emission tomography/computed tomography; KRAS, Kirsten rat sarcoma; mEGFR, EGFR mutation; NSCLC, non-small-cell lung cancer; OPG, osteoprotegerin; OS, overall survival; PFS, progression-free survival; RFS, recurrence-free survival; TRACP-5b, tartrate-resistant acid phosphatase isoform-5b; RANK, receptor activator of nuclear factor κB; RANKL, receptor activator of nuclear factor κB ligand; VCAM1, vascular cell adhesion molecule 1.