Preliminary analysis of distinct clinical and biologic features of bone metastases in melanoma

Abstract

Melanoma disseminates to the skeletal system where it is then difficult to treat. Yet, there remains limited research investigating metastatic bone disease (MBD) in melanoma. Here, we evaluate whether there are distinct clinicopathologic variables at the time of primary melanoma diagnosis that predispose metastases to engraft bone, and we test the hypothesis that patients with MBD have different responses to treatment. Cutaneous melanoma patients enrolled in a prospective database were studied. Individuals with metastatic melanoma and bone metastases (M-Bone) were compared to those with metastatic disease but no M-Bone. Of the 463 (42.7%) patients, 198 with unresectable metastatic melanoma had M-Bone and 98 developed bone metastasis (bone mets) as first site. Progression-free survival and overall survival were significantly worse in patients with M-Bone compared to those without M-Bone (P < 0.001) independent of treatment modalities, and in patients whose melanoma spread to bone first, compared to those who developed first mets elsewhere (P < 0.001). Interestingly, patients with bone mets presented with primary tumors that had more tumor infiltrating lymphocytes (P < 0.001) and less often a nodular histologic subtype compared to patients without M-Bone (P < 0.001). Our data suggest that melanoma bone metastasis is a distinct clinical and biological entity that cannot be explained by generalized metastatic phenotype in all patients. The observed dichotomy between more favorable primary histopathologic characteristics and a grave overall prognosis requires more studies to elucidate the molecular processes by which melanomas infiltrate bone and to build a mechanistic understanding of how melanoma bone metastases yield such detrimental outcomes.

Figure 1.

Patients with melanoma that metastasizes to bone first have worse survival compare to those whose disease first metastasizes to non-bone sites. PFS since (A) systemic treatment initiation (P=3e-05), (B) immunotherapy initiation (P=0.1), and (C) targeted therapy initiation (P=0.11). OS since (D) systemic treatment initiation (P= 8.7e-09), (E) immunotherapy initiation (P=0.003), and (F) targeted therapy initiation (P=0.041).

Figure 2.

Patients with melanoma and M-Bone had worse survival outcomes than patients without M-Bone, independent of treatment type. PFS since (A) systemic treatment initiation (P=0.0079), (B) immunotherapy initiation (P=0.85), and (C) targeted therapy initiation (P=0.13). OS since (D) systemic treatment initiation (P= 6.4e-07), (E) immunotherapy initiation (P=0.066), and (F) targeted therapy initiation (P=0.029). Bone – patients with bone metastases. Control – patients without bone metastases.

Figure 3.

Bone directed therapy did not improve PFS. Bone specific PFS since treatment initiation (P=0.138).