Incidence and Prognostic Nomogram for Resected Non-small Cell Neuroendocrine Tumor: A Population-Based Respective Study in China and the SEER Database

Background: Pulmonary neuroendocrine tumors, including small cell lung cancer (SCLC) and non-small cell neuroendocrine tumor (NSCLC-NET), have obvious heterogeneity. The comparison between SCLC and NSCLC-NET, and prognostic nomogram of resected NSCLC-NET have not been performed.Methods: We retrieved patients’ information with pulmonary neuroendocrine tumors from SEER database. Age-adjusted incidence and prognostic impacts of histological subtypes, surgery strategies and smoking were compared between SCLC and NSCLC-NET. Independent prognostic factors, screened by Cox regression, were enrolled for prognostic nomogram of resected NSCLC-NET. The nomogram were evaluated and compared to the 8th AJCC TNM staging system. A Chinese cohort was used for external validation.Results: Age-adjusted incidence of SCLC declined after 1991 but the incidence of NSCLC-NET continuously rose. Patients with typical carcinoid had the best prognosis in both overall survival and lung cancer specific survival after operation. Sleeve and segmental resection were more recommended in NSCLC-NET and SCLC, respectively. High-smoking index was associated with worse prognosis in both SCLC and NSCLC-NET. Histological subtype, age, surgery type, N, M stage and chemotherapy were independent prognostic factors and used to construct prognostic nomogram of resected NSCLC-NET. The nomogram performed well with good discrimination, calibration and clinical usefulness, which was validated by Chinese cohort (1, 3, 5-year AUC: SEER cohort 0.873, 0.901, 0.875; Chinese cohort 0.867, 0.892, 0.874). Compared to 8th staging system, the nomogram had higher C-index (0.87 vs 0.728, P < 0.001), clinical usefulness, increasing AUC value over time and improved 68%. The online server can be accessed at https://nsclc-net-prognostic-prediction.shinyapps.io/DynNomapp/. Conclusion: NSCLC-NET had increasing incidence over the past decades. The nomogram had high discrimination, calibration and clinical usefulness and performed better than 8th staging system. It may have certain value in risk stratification and survival prediction of patients with resected NSCLC-NET and help clinicians to take measures for high-risk patients in advance.

Dynamic recurrence risk and adjuvant chemotherapy benefit prediction by ctDNA in resected NSCLC

Accurately evaluating minimal residual disease (MRD) could facilitate early intervention and personalized adjuvant therapies. Here, using ultradeep targeted next-generation sequencing (NGS), we evaluate the clinical utility of circulating tumor DNA (ctDNA) for dynamic recurrence risk and adjuvant chemotherapy (ACT) benefit prediction in resected non-small cell lung cancer (NSCLC). Both postsurgical and post-ACT ctDNA positivity are significantly associated with worse recurrence-free survival. In stage II-III patients, the postsurgical ctDNA positive group benefit from ACT, while ctDNA negative patients have a low risk of relapse regardless of whether or not ACT is administered. During disease surveillance, ctDNA positivity precedes radiological recurrence by a median of 88 days. Using joint modeling of longitudinal ctDNA analysis and time-to-recurrence, we accurately predict patients’ postsurgical 12-month and 15-month recurrence status. Our findings reveal longitudinal ctDNA analysis as a promising tool to detect MRD in NSCLC, and we show pioneering work of using postsurgical ctDNA status to guide ACT and applying joint modeling to dynamically predict recurrence risk, although the results need to be further confirmed in future studies.

Impact of Genetic Polymorphisms on the Metabolic Pathway of Vitamin D and Survival in Non-Small Cell Lung Cancer

Vitamin D has been associated with risk, development, and progression of cancer. However, the genes involved in its metabolism are highly polymorphic, compromising its activity. The aim of this study is to evaluate the association between the gene polymorphisms involved in the metabolic pathway of vitamin D and survival in patients with non-small-cell lung cancer (NSCLC). The study was designed as an observational cohort which included 194 Caucasians patients from southern Spain with NSCLC. Real-time polymerase chain reaction was used to analyze the following polymorphisms: CYP27B1 rs4646536, rs3782130, and rs10877012; CYP24A1 rs6068816 and rs4809957; GC rs7041; CYP2R1 rs10741657; VDR rs1544410 (BsmI), rs11568820 (Cdx-2), rs2228570 (FokI), rs7975232 (ApaI), and rs731236 (TaqI). Progression-free survival (PFS) and overall survival were assessed. Cox regression showed that rs4646536 was associated with PFS in the general population (p = 0.0233) and in the non-resected NSCLC subgroup (p = 0.0233). In the resected NSCLC subgroup, rs11568820 was associated with OS (p = 0.0129) and rs7041 with PFS (p = 0.0447). In the non-resected NSCLC subgroup, rs6068816 was associated with PFS (p = 0.0048) and OS (p = 0.0089) and rs731236 and rs7975232 were associated with OS (p = 0.0005) and PFS (p = 0.0002), respectively. The other polymorphisms showed no effect on the results. The rs4646536, rs6068816, rs7041, rs11568820, rs731236, and rs7975232 polymorphisms are associated with survival in NSCLC and may have a substantial role as prognostic markers of the disease.

Anticipating EGFR Targeting in Early Stages of Lung Cancer: Leave No Stone Unturned

Background: The current treatment landscape of early stage lung cancer is rapidly evolving, particularly in EGFR mutant non-small cell lung cancer (NSCLC), where target therapy is moving to early stages. In the current review, we collected the available data exploring the impact of EGFR targeting in both neoadjuvant and adjuvant settings, underlying lights and shadows and discussing the existing open issues. Methods: We performed a comprehensive search using PubMed and the proceedings of major international meetings to identify neoadjuvant/adjuvant trials with EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. Results: Limited data are available so far about the activity/efficacy of neoadjuvant TKIs in EGFR mutant NSCLC, with only modest downstaging and pathological complete response rates reported. Differently, the ADAURA trial already proposed osimertinib as a potential new standard of care in resected NSCLC harboring an activating EGFR mutation. Conclusion: Anticipating targeted therapy to early stage EGFR mutant NSCLC presents great opportunities but also meaningful challenges in the current therapeutic/diagnostic pathway of lung cancer care. Appropriate endpoint(s) selection for clinical trials, disease progression management, patients’ and treatment selection, as well as need to address the feasibility of molecular profiling anticipation, represent crucial issues to face before innovation can move to early stages.

Effects of postoperative radiotherapy on cardiovascular-pulmonary disease mortality in patients with stage IIIA-N2 resected NSCLC: analysis of the SEER database

Background The role of postoperative radiotherapy (PORT) in cardiovascular-pulmonary disease mortality in patients with stage IIIA-N2 resected non-small cell lung cancer (NSCLC) remains uncertain. The purpose of this population-based analysis was to explore the effect of PORT on cardiovascular-pulmonary disease mortality in these patients. Methods Patients aged ≥ 18 years with stage IIIA-N2 resected NSCLC were identified in the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2015 and were grouped according to the use of PORT. Propensity score matching (PSM) was used to account for differences in baseline characteristics between the Non-PORT and PORT groups. The cumulative risk for cardiovascular-pulmonary disease death was estimated using the cumulative incidence curve. Competing risk regression was used to run univariate and multivariate analyses to evaluate risk factors. Results A total of 3981 patients were included in the study population. Among them, 1446 patients received PORT, and 2535 did not. A total of 1380 patients remained in each group after PSM, and the baseline characteristics were not significantly different between the two groups. The cumulative incidence of cardiovascular-pulmonary mortality was 10.93% in the Non-PORT group compared with 9.85% in the PORT group. There was no significant difference in the cumulative risk between the two groups (HR 1.07, 95% CI 0.77–1.48, p = 0.703). Multivariate analysis indicated that PORT had no significant impact on increased risk, with an HR of 1.18 (p = 0.377). Conclusions No significant differences between the PORT and Non-PORT groups were found in cardiovascular-pulmonary-specific modalities in this study. Further studies are required to validate these results. This study highlights the importance of long-term surveillance for NSCLC patients.