During the past two decades, the advances of EGFR-TKIs revolutionarily improved the prognosis of EGFR-mutated advanced NSCLC patients. The WJTOG3405 trial reported that the median OS of patients with EGFR-mutated advanced NSCLC was up to 30.2 months [32], which is non-inferior to the outcomes of patients with stage III disease. Our results of 157 EGFR-mutated advanced NSCLC patients without BM at initial diagnosis showed a median OS of 37.5 months and a median PFS of 13.6 months (Fig.1). Although EGFR-TKIs was reported to be more effective than chemotherapy for BM in EGFR-mutated NSCLC patients [14,15], patients with longer survival exposed to higher risk of BM [8], and patients with EGFR mutation was associated with higher incidence of developing BM [8–10]. In our study, 30 patients (30/157, 19.1%) developed secondary BM during first-generation EGFR-TKIs treatment, and 1-, 2- and 3-year risks of developing BM were 11.6%, 22.6% and 29.4% respectively (Fig.1). Therefore, the first-generation EGFR-TKIs therapy resulted in decreased risk of non-BM but had limited impact on BM.
It was well known that BM is a common reason leading to treatment failure associated with poor prognosis [33]. In our study, compared with patients without BM, patients developing secondary BM during the course of EGFR-TKIs treatment were at higher risk on OS (HR = 1.86, 95%CI:1.07–3.26). Our findings confirmed that patients with secondary BM had worse outcomes (Fig.2) on the condition that there was no difference on clinical and treatment characteristics between the two groups grouped by BM status (Table 1). Therefore, reducing risk of BM in EGFR-mutated advanced NSCLC patients becomes increasingly significant for achieving prolonged survival.
The use of PCI or first-line osimertinib treatment could reduce risk of developing secondary BM for EGFR-mutated advanced NSCLC patients. However, existing evidences suggest that PCI might just suitable for patients with a high risk of developing BM, and the high cost of osimertinib leaded to the first-line osimertinib treatment limited in most developing countries. Therefore, it is important to identify population subsets with higher risk of BM as candidates for PCI or the first-line osimertinib treatment. But there is a lack of data for EGFR-mutated advanced NSCLC in literature.
In the present study, multivariate analysis indicated that age ≤ 49 years was correlated with higher risk of secondary BM (Table. 2). Despite the difference of age cut-off, our results were consistent with previous studies [25,34]. The underlying mechanism is still to be investigated. It was partly interpreted that young people may have better performance status, which are associated with longer survival. Moreover, several studies have shown that BM is associated with the angiogenic microenvironment, and the cerebrovascular microenvironment factors of young patients may be better than those of older patients [35]. Further investigations are required to identify the specific reasons that younger patients are more likely to develop BM.
The numbers of extracranial metastases and malignant pleural effusion were also independent risk factors of secondary BM (Table. 2). The underlying mechanism was also unclear. It may be interpreted that both pleural effusion and BM is associated with the angiogenic microenvironment [35]. In addition, the numbers of extracranial metastases are reflection of tumor burden, which was positive correlated with the development of BM.
Furthermore, our results confirmed that the predictive value of gender and KPS score for secondary BM may remain controversial [36]. Previous studies reported that elevated CEA [27,31,36], NSE [24], and CA125 [24] were independent risk factors of BM. However, there is no correlation between tumor markers levels before treatment (including CEA, NSE, and CA125) and the secondary BM in our study. And the first-line treatment regimen was also not associated with secondary BM in our multivariate Cox analysis. Koo et al [37] reported that EGFR-TKIs were effective for EGFR-mutated NSCLC, regardless of treatment timing, which is consistent with our results. In addition, EGFR exon 19 or 21 mutations are now well recognized as different prognostic markers for NSCLC. A recent retrospective study [31] showed that point mutations in exon 21 were independent risk factors of BM. However, our results failed to show a statistical difference in the association between types of EGFR mutations and secondary BM.
Furthermore, the 1-year actuarial risk of developing secondary BM in patients with no risk factor (n = 101), 1 risk factor (n = 46), and 2 risk factors (n = 10) were 7.01%, 14.61%, and 43.75%, respectively (P < 0.001, Fig. 3). Obviously, patients with more risk factors had a higher risk of developing secondary BM. Our studies suggested that the patients with ≥ 1 risk factors were more likely to benefit from PCI or were candidates for the first-line osimertinib treatment. Certainly, there are several limitations in our study, this was a retrospective study in a single institution, which inevitably resulted in a selection bias. More finely devised prospective and random study is needed to confirm our results, and the mechanisms of the correlation between these risk factors and secondary BM is to be further explored.
At last, the findings of this study were as follows. First, our studies confirmed EGFR-mutated advanced NSCLC patients with secondary BM had worse outcomes. Second, the multivariate Cox analysis indicated that younger age (≤ 49 years), more extracranial metastases, and malignant pleural effusion were independent risk factors of secondary BM. Third, the patients with more risk factors are more likely to benefit from PCI or the first-line osimertinib treatment.