Bone metastases in non-small cell lung cancer: a narrative review

Abstract

Background and objective: Bone metastases are common in patients with non-small cell lung cancer (NSCLC) and remain a significant source of morbidity, mortality, and diminished quality of life, despite the considerable progress made in the overall management of patients with metastatic NSCLC over the last decade. Understanding the molecular pathogenesis of bone metastases is critical to improving survival, preserving function, and managing symptoms in this patient population. The objective of our review is to provide a comprehensive review of the pathophysiology, clinical presentation, management, and factors predicting the development and prognosis of patients with NSCLC with bone metastases.

Methods: An online electronic search was performed on PubMed and Google Scholar of all English-language literature using combinations of the following keywords: bone metastases, non-small cell lung cancer, pathophysiology, skeletal related events, response to therapy, predictive factors, and immunotherapy. Bibliographies of identified papers were reviewed for additional articles of interest. Observational cohort, retrospective studies, randomized controlled trials (RCTs), meta-analyses, and review articles were examined for this review.

Key content and findings: Bone metastases in lung cancer patients remain a common occurrence, impacting morbidity, mortality, and quality of life. Patients with skeletal related events (SREs) have worse prognosis. There is data supporting use of bisphosphonates and/or denosumab, and these should be considered in all patients with bone metastases. Novel studies comparing the genomic alterations of skeletal metastases and primary tumors are needed. As therapy for patients with advanced disease evolves, more studies are needed to evaluate the interplay between immunotherapy and bone metastases, and in determining the response to treatment in bone.

Conclusions: Predicting development and progression of bone metastases could allow earlier and targeted therapy in patients with bone metastases. Predicting and evaluating response to conventional chemotherapy and immune checkpoint inhibitors in NSCLC patients with bone metastases remains an unmet need and merits further study.

Keywords: Bone metastases; non-small cell lung cancer (NSCLC); skeletal related events (SREs); treatment response.

Figure 1

Invasion of tumor cells into bone. The initial steps through which bone metastases are established are likely similar to that of metastatic colonization of other distant sites. First, there is tumor invasion of the surrounding normal tissue and new vessel formation, followed by tumor invasion into the blood vessel. Once in the blood vessel, tumor cells can travel to distant sites (10,11). Chemokines, especially CXCL12 and its receptor CXCR4, serve a vital role in tumor cells via honing from circulation to bone. NSCLC cells express CXCR4 and undergo chemotaxis in response to CXCL12, which is expressed in the bone marrow stroma (12,13). BSP is expressed by NSCLC cells and interacts with integrins in the bone marrow stroma (14-17); PDGFR-β is also expressed in the stroma (18,19). Both BSP and PDGFR-β are associated with increased tumor invasiveness. DDR1, expressed on cancer cells, interacts with collagen in the stroma and bone marrow matrix and has also been associated with cell migration, homing, and colonization in bone (20,21). CXCR4, C-X-C chemokine receptor 4; BSP, bone sialoprotein; DDR1, discoidin domain receptor-1; CXCL12, C-X-C motif chemokine 12; ECM, extracellular matrix; PDGFR-β, platelet derived growth factor receptor beta; NSCLC, non-small cell lung cancer.

Figure 2

Simplified schema of osteolytic and osteoblastic metastases. On the left, the RANK and RANK-L interaction is described. RANK is expressed by osteoclasts, osteoclast precursor cells, and some tumor cells. RANK-L is expressed by bone marrow stromal cells, osteocytes, and T-lymphocytes. Binding of RANK to RANK-L stimulates osteoclast differentiation and activity and may increase metastatic potential of tumor cells; RANK-L expression is increased by PTHrP and ILs, among other cytokines and chemokines (11,22-25). OPG is produced by osteoblasts and osteocytes and prevents binding of RANK-L to RANK (26,27). On the right is a depiction of osteoblastic metastases, focused on TGF-β. TGF-β is a cytokine, expressed by cancer and stromal cells, that controls expression of MMPs, ILs, VEGF, and PTHrP, all of which increase bone metastases (9,28-34). TGF-β has also been implicated in inhibiting immune cell infiltration, allowing tumor growth (33,34). TGF-β induces production of VEGF and PDGF from immune cells, such as neutrophils and macrophages which increase bone metastases (29). Lung cancer cells also express PTHrP, which increases both osteoblastic and osteolytic metastases (35,36). TGF-β stimulates cancer cells to produce PTHrP, and also stimulates stromal cells to release other bone activating cytokines (such as MMPs, IGFs, FGFs, and BMPs), leading to a vicious cycle of bone osteolysis and bone formation (28,33,37,38). Most bone metastases lie on a spectrum of bone formation and bone resorption. RANK, receptor activator of nuclear factor kappa-beta; RANK-L, RANK-ligand; PTHrP, parathyroid hormone-related peptide; ILs, interleukins; OPG, osteoprotegerin; TGF-β, transforming growth factor-beta; MMPs, matrix metalloproteinases; IGFs, insulin like-growth factors; FGFs, fibroblast growth factors; BMPs, bone morphogenic proteins; VEGF, vascular endothelial growth factor; PDGF, platelet derived growth factor.