A biomarker exploration in small-cell lung cancer for brain metastases risk and prophylactic cranial irradiation therapy efficacy

Background: Small-cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis. Limited-stage (LS)-SCLC comprises only one-third of SCLC cases, resulting in limited molecularly targeted therapies and treatment options. Despite advances in thoracic and cranial irradiation leading to improved outcomes, a notable proportion of patients develop brain metastasis (BM), highlighting the importance of identifying high-risk patients for tailored screening and treatment strategies.

Materials and methods: We analyzed baseline tumor biopsies from 180 LS-SCLC patients who received frontline definitive chemoradiotherapy (dCRT) using a 474-gene pan-cancer panel. The cumulative incidence of BM was calculated with death scored as a competing risk. Independent prognostic factors for BM risk were identified using the Fine-Gray model.

Results: Alterations in the cell cycle pathway, particularly RB1 mutations, were more common in patients with BM, while FLT4 mutations were more frequent in those without BM (P=0.002 and P=0.021, respectively). Significant risk factors for BM include smoking (subdistribution hazard ratio [SHR]: 1.73; 95 % confidence interval [CI]: 1.11-2.70; P=0.016), RB1 mutations (SHR: 2.19; 95 % CI: 1.27-3.81; P=0.005), and BCL3 amplification (SHR: 2.27; 95 % CI: 1.09-4.71; P=0.028). Conversely, prophylactic cranial irradiation (PCI) (SHR: 0.39; 95 % CI: 0.25-1.60; P<0.001), FLT4 mutations (SHR: 0.26; 95 % CI: 0.07-0.98; P=0.047), and NOTCH pathway alterations (SHR: 0.65; 95 % CI: 0.43-1.00; P=0.049) were associated with a lower incidence of BM in LS-SCLC. Notably, consolidation PCI therapy did not reduce the BM risk in patients with baseline RB1 mutations, with BM occurrence probabilities of 34.7 % at 20 months and 62.6 % at 40 months.

Conclusion: Our study yields valuable insights into the genetic characteristics of LS-SCLC patients with and without BM, aiding the development of personalized treatment strategies. Identifying risk factors associated with the incidence and timing of BM, within the standard regimen of dCRT followed by PCI, may help optimize clinical decision-making for LS-SCLC.