Osteoblastic bone reaction in non-small cell lung cancer harboring epidermal growth factor receptor mutation treated with osimertinib

The bone is one of the most common metastatic sites of non-small cell lung cancer (NSCLC), and bone metastasis is found in 30–40% of patients with advanced NSCLC [1]. Bone metastasis often induces pain, impaired mobility, or pathologic fracture, which negatively affects the quality of life of the patients [2, 3]. Moreover, bone metastasis is reportedly associated with poor survival in patients with NSCLC [4, 5]. Bone metastases are classified into sclerotic, lytic, and mixed types according to their radiographic or pathological appearance [6]. In various cancers, such as breast or multiple myeloma, tumor cells usually promote osteoclast differentiation rather than osteoblast differentiation. Hence, bone resorption exceeds bone formation, and osteolytic lesions are formed. However, in prostate cancer, tumor cells release substances that stimulate the osteoblast lineage, resulting in the formation of osteosclerotic lesions. Nevertheless, these processes can coexist, forming mixed lesions [6, 7]. While most bone metastases of NSCLC present as lytic or mixed types, a previous study reported that the presence of sclerotic metastatic lesions was associated with a good prognosis compared to other types of metastases in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma [8, 9]. However, studies on the types of bone metastases in NSCLC are limited.

An osteoblastic bone reaction (OBR) refers to an increase in bone density at the site of bone metastasis or the appearance of new sclerotic bone lesions after anticancer treatment [10, 11]. Although the mechanism underlying OBR has not been completely elucidated, it represents the healing process of new bone formation after treatment [12, 13]. OBR was first reported in the 1970s in patients with prostate cancer and has been widely documented in patients with prostate or breast cancer treated with hormones or chemotherapeutics [14‐16]. OBR has also been reported in patients with NSCLC and small-cell lung cancer treated with chemotherapy or molecular targeting therapy regimens since the 2000s [3, 10, 11, 17‐20]. In particular, many cases of OBR have been reported in patients with EGFR-mutant NSCLC treated with EGFR-thyroxine kinase inhibitors (TKIs) [13, 18, 19, 21]. The third-generation EGFR-TKI, osimertinib, was shown to be superior to the first-generation TKIs, gefitinib and erlotinib, in terms of progression-free survival (PFS) and overall survival (OS); therefore, it is now widely recommended as a first-line treatment for patients with NSCLC harboring EGFR mutations [22‐25]. Nevertheless, previous studies investigating OBR in EGFR-mutant NSCLC targeted only patients receiving first-generation TKIs; therefore, it is unknown whether OBR develops in patients treated with osimertinib. Recognizing OBR in this population is important to avoid misunderstanding this phenomenon as a progressive disease and changing treatments unnecessarily [11, 17].

In this study, OBR developed in 82% of patients with EGFR-mutant NSCLC with bone metastasis. Anticancer therapy may alter the balance of bone metabolism into a dominant bone formation process by reducing tumor cells and suppressing the increased bone metabolism caused by tumor cells. In fact, previous studies have shown that OBR is associated with good treatment responses [3, 20]. The proportion of OBR in our study was relatively higher than those in previous studies—OBR in patients with advanced lung cancer ranged from19.7% to 26.8%, wherein it varied from 67.8% to 71.4% in those with bone metastasis [3, 10, 11, 17‐20]. The higher frequency of OBR in our study than that in previous studies in which chemotherapy or first-generation EGFR-TKIs were administered could be explained by the differences in treatment regimens. Based on the clinical effectiveness of osimertinib [22], it is conceivable that osimertinib has a greater impact on reducing the tumor burden at bone metastasis than other anticancer therapeutic agents. Furthermore, EGFR-TKIs inhibit the recruitment of osteoclasts during bone metastasis by preventing their differentiation and activation in the bone marrow [28, 29]. Together, these findings suggest that the increased incidence of OBR in patients with EGFR-mutant NSCLC with bone metastases treated with osimertinib should not be misunderstood as disease progression.

This study provided three additional findings regarding bone metastasis and OBR. First, sclerotic bone metastasis was found in 38% of patients with bone metastasis, although mixed metastasis was the most frequent type. To the best of our knowledge, only one study has investigated the types of bone metastases in patients with NSCLC harboring EGFR mutations, and the percentage of each type was similar to that in our study [9]. Because most bone metastases of NSCLC are present as lytic or mixed types [8], sclerotic metastasis may be a clinical indicator of positive EGFR mutations. Second, OBR can develop from lytic or mixed bone metastasis as well as sclerotic metastasis. This indicates that osimertinib treatment can change bone metabolism into bone formation in any bone metastasis type. Furthermore, in 40% of patients, OBR developed even in lesions that could not be recognized on CT but on PET-CT at baseline, which could be because of the low sensitivity of CT scans for some bone metastases (72.9%) [30]. In these patients, bone metastases became apparent on CT after OBR. Third, OBR can develop at various sites of bone metastasis, including the vertebra, ribs, and pelvis. Although vertebral metastasis is the most common site of metastasis and causes spinal cord injury [31], metastasis to the ribs or pelvis also causes pain, fractures, or impaired mobility. Therefore, it is important to correctly assess whether bone metastasis deteriorates and to recognize that OBR can develop at any site in all such lesions.

Although OBR has been reported to be associated with good treatment response or long PFS in patients with NSCLC in previous studies [3, 13, 20], no study has investigated the association between OBR and indices related to SRE. The use of zoledronic has been reported to be associated with an increased density of bone metastasis [32, 33]. Although there have been no reports on the association between denosumab administration and bone density on radiological examinations, considering that denosumab binds to the receptor activator of nuclear factor kappa-B ligand (RANKL) and inhibits osteoclast function, it is reasonable to assume that denosumab administration increases bone density. Furthermore, clinicians would tend to prescribe denosumab as a priority for patients with massive or multiple bone metastases in clinical practice, and these patients appear to have a higher risk of SRE or death. Therefore, we conducted a Cox regression analysis of OBR and denosumab administration. The multivariate analysis including denosumab administration, showed OBR was associated with SRE-FS. Considering these result, we inferred that OBR may represent not only increased density on CT scans but also increased practical bone intensity. Conversely, the findings suggest we should be more alert to SRE onset or poor survival when OBR is not detected at the first CT scan evaluation after osimertinib initiation.

The present study had several limitations. First, this was a single-center retrospective study. Second, although a radiologist and an oncologist reviewed the CT scans, the quantitative index was not used, which may have caused bias. Third, our sample size was small and only two variables were considered in the multivariate analysis. Finally, the observation period was short. A longer observation period may be required to precisely evaluate PFS and SRE-FS.

In conclusion, OBR developed in most patients with bone metastasis who received osimertinib. This phenomenon should be considered to avoid misunderstanding OBR as a disease progression.