Osteoblastosis and activating epidermal growth factor receptor mutations: a relationship?

In this issue of the journal, there are two reports concerning the rare situation of osteoblastic bone metastases occurring either initially or during tyrosine kinase inhibitor (TKI) therapy in patients with advanced nonsmall cell lung cancer (NSCLC). 1,2 Almost all (34 of 38, 89%) were in patients with adenocarcinomas. One is a retrospective study of 36 patients with such metastases, the other, a brief report of two patients. Of the total of 38, only three (8%) were active smokers. Majority (22 of 38, 58%) were women. The majority in one study (13 of 25, 54%) had epidermal growth factor receptor (EGFR) tyrosine kinase mutations. Combining both the studies, mutations were found more often in exon 19 (11 patients, 73%) than exon 21 (4 patients, 27%). In this regard, recent reports have shown that patients with exon 19 deletions have a better outcome compared with the exon 21 L858R point mutation in patients receiving erlotinib.3 In both the studies, the authors comment on the fact that the apparent progression of and to osteoblastic transformation should not be considered prima facie evidence of progressive disease. In fact, it may well represent excellent disease response to the TKI, either erlotinib or gefitinib. In addition, such patients seem to have a better survival than those without osteoblastic disease. In fact, in the larger study, those presenting with osteoblastic disease (23 patients) had a remarkable 2-year survival rate of 31% and an overall disease-control rate of 61% (14 of 23). In addition, the initial presence of osteoblastic disease strongly suggested excellent disease control of extraosseous sites (20 of 23, 87%). Being rare, however, it is not known whether such patients have a better survival because of the natural history of osteoblastic disease, because they received a TKI, or both. Also, because only the common mutations, exons 19 and 21, were tested and that just in the larger study, it is possible that the mutation rate of 54% (13 of 25) could be larger if other, less common, EGFR mutations were also examined. (Ten of the 36 tumors were not tested.) These studies raise the question of why the finding of or transformation to osteoblastic disease is associated with a favorable outcome. Development of bone metastases is a complex phenomenon that involves initial activation of osteoclasts that are responsible of bone resorption and eventually of osteoblasts that synthesize the bone matrix. The osteolytic or osteoblastic nature of the bone metastases will depend on the prevalence of the osteoclastic or osteoblastic activity. One of us (N.N.) has previously demonstrated that EGFR regulates bone marrow-derived mesenchymal stem cells (MSC) secretion of cytokines, such as receptor activator of NF-kappaB ligand and M-colonystimulating factor, which activate osteoclasts.4 In addition, EGFR signaling has been shown to prevent the differentiation of MSC into osteoblasts.5 We (N.N.) have also shown that NSCLC cells secrete EGF-like peptides that can activate EGFR in MSC within the bone metastases microenvironment, thus leading to activation of osteoclasts and inhibition of osteoblastic differentiation.6 Interestingly, it has been recently shown that tumors derived from NSCLC cells carrying activating mutations of EGFR express higher levels