Translational lung cancer research最新文献

Background: Based on current technology, the accuracy of detecting malignancy in solitary pulmonary nodules (SPNs) is limited. This study aimed to establish a malignant risk prediction model for SPNs 5-15 mm in diameter.

Methods: We collected clinical characteristics and imaging features from 317 patients with SPNs 5-15 mm in diameter from the 900th Hospital of the Joint Logistic Support Force as a training cohort and 100 patients with SPNs 5-15 mm in diameter as a validation cohort. Univariate logistic regression analysis, least absolute shrinkage and selection operator (LASSO), and binary logistic regression analysis were used to screen for the independent influencing factors of benign and malignant SPN and to establish a prediction model for benign and malignant SPN with a diameter of 5-15 mm. The model in this study was compared with the Mayo model, Veterans Affairs (VA) model, Brock model, and Peking University People's Hospital (PKUPH) model. Finally, the clinical application value of this model was assessed.

Results: Univariate logistic regression analysis showed that smoking history, nodule diameter, nodule location, nodule density, margin, calcification, lobulation sign, spiculation sign, and vascular cluster sign were statistically significant factors. The results of LASSO and binary logistic regression analysis showed that smoking history, nodule diameter, nodule density, margin, lobulation sign, and vascular cluster sign were independent influencing factors of SPNs. The prediction model was successfully constructed and demonstrated a good predictive performance, with an area under the curve (AUC) value of 0.814 [95% confidence interval (CI): 0.768-0.861; P<0.001] in the training cohort and 0.864 (95% CI: 0.794-0.934; P<0.001) in the validation cohort. This model was shown to be highly accurate in predicting malignant SPNs and thus has a high clinical application value. Compared with previously described prediction models, including the Mayo model, VA model, Brock model, and PKUPH model, the proposed model demonstrated a significantly superior predictive ability.

Conclusions: The prediction model developed in this study can be used as an early screening method for SPNs 5-15 mm in diameter.

Background: Many patients with non-small cell lung cancer (NSCLC) lack access to highly effective approved targeted therapeutics due to multiple gaps in biomarker testing. Challenges in comprehensive molecular testing include complexities associated with the need to assess the presence of multiple variants, costs of running multiple sequential assays per sample, high assay quality control (QC) failure rates, clinical need for rapid turn-around time (TAT) to initiate therapy, and insufficient tissue samples. The ASPYRE-Lung NSCLC assay addresses gaps in multiplexed testing by simultaneously analyzing DNA and RNA, detecting 114 actionable genomic variants across 11 genes, consistent with current NSCLC treatment guidelines. This study was to assess the ease of adoption and performance of ASPYRE-Lung in third-party laboratories, comparing concordance across sites and with orthogonal methods.

Methods: ASPYRE-Lung was established at two academic centers with multiple operators per site. Assay concordance was evaluated across three sites using 77 patient samples [61 derived from formalin-fixed paraffin-embedded (FFPE) tissue and 16 from cytology specimens].

Results: Reproducibility for all 77 samples yielded a positive percent agreement (PPA) of 100% and negative percent agreement (NPA) of 99.99%. Concordance with next-generation sequencing (NGS)-based methods across all three sites was high with PPA of 97.2% and NPA of 99.96%.

Conclusions: ASPYRE-Lung assay is a cost-effective, easy to adopt testing method requiring no specialized expertise or complicated bioinformatics, with the potential to inform genomic data on small tissue samples, thus enabling all patients with NSCLC to undergo biomarker testing in a timely manner and benefit from appropriate targeted therapies.

Background: Pleural invasion (PI) is considered to be an adverse prognostic factor in non-small cell lung cancer (NSCLC). However, the prognostic roles of PI in pathologic (p)T3-4N0M0 NSCLC remain controversial. Therefore, this study aimed to evaluate the predictive value of PI in patients with pT3-4N0M0 NSCLC.

Methods: This study selected 9,185 patients with resected pT3-4N0M0 NSCLC from 2010 to 2019 from the Surveillance, Epidemiology, and End Results (SEER) database. PL0 was defined as lack of PI; PL1 and PL2 as invasion of the elastic layer and of the surface of the visceral pleural invasion (VPI), respectively; and PL3 as the parietal pleura invasion (PPI). Patients were divided into six groups according to PI status and T categories. This study used propensity score matching (PSM) to reduce baseline differences. The risk factors were statistically analyzed using the Cox proportional hazard model. Overall survival (OS) was assessed with the Kaplan-Meier method and log-rank test.

Results: Kaplan-Meier analysis stratified by T category showed worse OS in patients with PI (P<0.001). In multivariable Cox analysis of OS, patients with T3 and VPI had a significantly worse prognosis than did those with T3 but not PI (after PSM: P=0.001). There was no difference between those with T3 and VPI and those with T3 and PPI (after PSM: P=0.12) or between those with T3 PI and those with T4 but not PI (after PSM: P=0.30).

Conclusions: PI is a factor of poor prognosis in patients with pT3-4N0M0 NSCLC. Our results recommend future studies exploring the prognostic value of various T3-4 subcategories to allow PI to be separated from other T descriptors and confounders.

Background: The precision of segmentectomy/subsegmentectomy for ground glass opacity (GGO)-dominant cT1a-bN0 non-small cell lung cancer (NSCLC), including mono-segmentectomy, mono-subsegmentectomy, combined subsegmentectomies, and single segmentectomy with adjacent subsegmentectomy, has improved. The aim of this study is to investigate their positional indications by focusing on the three-dimensional location of lesions, utilizing three-dimensional computed tomography bronchography and angiography (3D-CTBA).

Methods: We retrospectively analyzed 195 patients with GGO-dominant cT1a-bN0 NSCLC who underwent segmentectomy/subsegmentectomy between August 2015 and November 2020. We included 173 patients: mono-segmentectomy (71, 41.04%), mono-subsegmentectomy (37, 21.39%), combined subsegmentectomies (42, 24.28%), and single segmentectomy with adjacent subsegmentectomy (23,13.29%). Patient demographics and perioperative outcomes were compared among groups to identify positional indications.

Results: Significant differences were observed among the four groups in terms of lobe location of the lesions and their relationships with adjacent intersegmental veins (P<0.001), but not in their diameter and depth (P=0.33; P=0.79). All groups showed similar surgical margins (P=0.77) despite differences in the number of subsegments resected (P<0.001). No perioperative deaths or postoperative recurrences were reported. For lesions located in the middle region, located inter-segmentally, or with a diameter >1 cm, a greater number of subsegments were resected (P=0.02; P<0.001; P=0.003), while the surgical margins were not inferior to those located in the outer region, located intra-segmentally, or with a diameter ≤1 cm (P=0.29; P=0.77; P=0.46).

Conclusions: It is the specific lobe in which lesions are located and their relationship with adjacent intersegmental veins that determine the specific surgical procedure of segmentectomy/subsegmentectomy for GGO-dominant cT1a-bN0 NSCLC, rather than their diameter and depth.

Background: The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is widely used as a first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC). However, there is no established treatment for osimertinib resistance, so second-generation afatinib is an alternative treatment option. The purpose of this study was to elucidate gene alterations associated with afatinib efficacy and resistance by analyzing cell-free DNA (cfDNA) obtained from patients with EGFR-mutated NSCLC.

Methods: This study was conducted as a prospective clinical trial in patients with EGFR-mutated NSCLC at multiple institutions. We analyzed plasma cfDNA from the patients treated with afatinib as the first-line therapy.

Results: Paired specimens were obtained before and at the time of resistance to afatinib treatment, and specimens only at afatinib resistance were obtained from 22 and 18 patients, respectively. In plasma cfDNA from the 22 cases, driver EGFR mutations were detected in 13 cases (59.1%), and the compound V834L mutation was detected in two cases in cis with EGFR-L858R mutation. The median progression-free survival (mPFS) was remarkably shorter in patients with V834L than in all 22 cases (4.2 vs. 9.2 months). Moreover, we detected V834L and T790M combined with EGFR-L858R in the cfDNA from one patient resistant to afatinib. Preclinical experiments using EGFR-L858R, with or without V834L, in Ba/F3 cells revealed that V834L with L858R conferred resistance to low concentrations of EGFR-TKIs, including afatinib and osimertinib. In three cases of EGFR-L858R+V834L, other co-mutations, including TP53, CTNNB1, and RB1, were detected either before or after afatinib resistance.

Conclusions: These results suggested that V834L cooperates with other coexisting mutations to influence the therapeutic efficacy of EGFR-TKIs.

Background: Apart from ALK fusions and the common EGFR mutations, targetable molecular alterations are irrelevant for adjuvant treatment decision making in early-stage non-small cell lung cancer (NSCLC). This retrospective analysis aimed to investigate if there is a difference in recurrence-free survival in stage I-III NSCLC harboring druggable molecular alterations compared to subtypes without targetable molecular alterations.

Methods: All consecutive patients who underwent surgery with curative intent for NSCLC (stage I-III) with targetable mutations between January 2015 and December 2020 at three Austrian institutions were identified and compared with tumors without targetable molecular alterations. Tumors with the EGFR-mutated subtype were excluded due to already existing results from prospective trials.

Results: One hundred and sixty subjects had tumors with molecular alterations and 355 subjects served as control cohort. There was a higher prevalence of female sex (P<0.001) and never-smokers (P=0.01) among patients with tumors harboring oncogenic driver mutations. The three most common alterations were the KRAS G12C mutation (n=92), ALK fusions (n=21), and the BRAF V600E mutation (n=15). The 1-, 3- and 5-year cumulative incidence of recurrence estimates were 16%, 38% and 46% in patients without molecular alterations and 16%, 38% and 48% in patients with the KRAS G12C mutation and 12%, 33% and 55% in patients with other molecular alterations, respectively (P=0.89). Univariable predictors of an increased recurrence risk were higher tumor stage (P<0.001), receipt of neoadjuvant treatment (P<0.001) and receipt of adjuvant treatment (P=0.03). The lack of association between molecular alteration status and recurrence risk prevailed after multivariable adjustment for tumor stage and perioperative treatment (P=0.82 for KRAS G12C mutation and P=0.43 for any other molecular alteration).

Conclusions: NSCLC patients with resected tumors that harbor molecular alterations have the same recurrence risk as patients with tumors without molecular alterations if treated with surgery plus chemotherapy when indicated.

Background: Approximately 30% of the non-small cell lung cancer (NSCLC) patients which harbor no recognizable oncogenic driver mutation are not eligible for targeted therapy. Functional drug screening of tumor cells helps to identify susceptible drug targets not recognized by gene panels for targeted mutation analysis. The aim of this study is to characterize the BH1406 cell line carrying an activating SOS1 mutation and to check its sensitivity to cognate inhibitors.

Methods: The NSCLC cell line BH1406 was established from a pleural effusion and found to be sensitive to the SOS1 inhibitor BAY-293 in initial viability screenings. Since in a limited next-generation sequencing (NGS) lung cancer mutation panel no driver could be detected, the patient underwent chemotherapy with poor outcome. This cell line was further characterized by exome sequencing, SOS1 Western blotting, comparison of two-dimensional (2D) and three-dimensional (3D) chemosensitivity assays and phosphoprotein arrays.

Results: In whole-exome sequencing (WES) the SOS1 mutation P481delinsLFFL, positioned near the known P478L activating mutation was detected. Besides BAY-293, BH1406 cells proved to be sensitive to the SOS1 inhibitors MRTX0902 and BI-3406. The sensitivity of BH1406 cells to BI-3406 was increased under 3D conditions compared to 2D cultures. Western blot phosphoprotein arrays revealed reduced phosphorylation of CREB, GSK3, CHK-2 and STAT3 in BH1406 by BAY-293 treatment in 2D culture. In 3D conditions, cells switched from GSK3α to elevated ERK1/2 signaling, again blocked by the SOS1 inhibitor BAY-293. Similar results were obtained for the SOS1 inhibitors MRTX0902 and BI3406. Additionally, the PI3K inhibitor dactolisib, the GSK-3 inhibitor BI-5521 as well as the bromodomain protein-directed PROTAC ARV-771 inhibited the growth of BH1406 cells significantly and showed synergistic interaction with BAY-293. Furthermore, Western blots demonstrated reduced expression of SOS1 and MYC proteins in response to BAY-293 treatment.

Conclusions: The rare SOS1 P481delinsLFFL mutation in lung cancer may be targetable with corresponding inhibitors, alone or in combination with GSK3/PI3K/BET inhibitors. BH1406 cells represent a novel cellular model suitable for the molecular characterization of SOS1 druggability. Such rare oncogenic driver genes are not included in standard NGS panels and need to be detected by expanded assays like WES.

Background: Delineating gross tumor volume (GTV) using computed tomography (CT) imaging is the standard for lung cancer contouring, but discrepancies among observers compromise accuracy and reliability. Magnetic resonance imaging (MRI) provides superior soft-tissue resolution compared to CT, thus, we design this retrospective study to compare the treatment outcomes of magnetic resonance-based (MR-based) and CT-based tumor delineation in locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with hypo-fractionated concurrent chemoradiotherapy (hypo-CCRT).

Methods: A total of 293 LA-NSCLC patients treated with hypo-CCRT from three trials between October 2015 and October 2020 were screened. Ninety patients with each MR-based delineation and CT-based delineation of the primary tumor were selected for analysis. In the MR-based delineation group, T1-enhanced MR images was rigidly registered with 10 respiratory phases of planning CT images, respectively. The primary tumors were contoured on each respiratory phase based on co-registered MRI. The locoregional progression-free survival (LPFS), progression-free survival (PFS), overall survival (OS) and toxicities in both groups were analyzed.

Results: The 2-year LPFS rate was 69.2% [95% confidence interval (CI): 59.6-80.2%] in the MR-based delineation group and 61.0% (95% CI: 50.9-73.0%) in the CT-based delineation group (P=0.37). There was no significant difference in median PFS (P=0.45) or OS (P=0.69) between the two groups. The MR-based delineation group had smaller planning target volume (186.1 vs. 315.3 cm³, P<0.001), lower incidences of ≥G2 pneumonitis (10% vs. 24.4%, P=0.001) and ≥G3 esophagitis (2.2% vs. 15.6%, P<0.001). In evaluating the patterns of recurrence, in-field recurrences were the dominant type in both groups (21 out of 27 patients in MR-based delineation group, 24 out of 32 patients in CT-based delineation group).

Conclusions: MR-based delineation in hypo-CCRT was feasible and achieved similar treatment efficacy to CT-based delineation. The use of MR imaging to reduce the target volume resulted in promising local control and lower incidence of radiation-induced toxicities.

Background: Non-small cell lung cancer (NSCLC), the most prevalent lung cancer subtype, presents significant treatment challenges. Cisplatin (CP)-based regimens are central to the treatment of multiple solid tumors, but its use is restricted due to its dose-related renal toxicity. We previously found that fluorofenidone {1-[3-fluorophenyl]-5-methyl-2-[(1H)]-pyridone (AKF-PD)} effectively reverses CP-induced acute kidney injury (AKI). However, it remains unclear whether AKF-PD can synergistically ameliorate NSCLC when used together with CP. Thus, this study sought to investigate the effect of AKF-PD on NSCLC and examined its combinatory use with CP for cancer treatment.

Methods: We conducted cell viability assays, 5-ethynyl-2'-deoxyuridine (EdU) experiments, colony-forming assays, wound-healing tests, and Transwell experiments in A549 and H1299 cells to explore the effects of AKF-PD on NSCLC. We then detected the epithelial-mesenchymal transition (EMT) markers [i.e., epithelial cadherin (E-cadherin), matrix metallopeptidase 9 (MMP9), vimentin, and snail family transcriptional repressor 1 (SNAIL)], phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK), to identify the potential mechanisms of AKF-PD. Further, via the combined use of AKF-PD and CP, we found that AKF-PD enhanced the antitumor effect of CP, and we suggest that this may be due to its inhibitory effect on EMT. We also examined the effect of combining AKF-PD and CP in other cancer cell lines, including Hela, SiHA, MDA-MB-231, 5-8F, and UM-UC-3 cells.

Results: AKF-PD significantly inhibited the proliferation and invasion of NSCLC cells (A549 and H1299), suppressed the activation of the MAPK and PI3K/AKT/mTOR pathways, and inhibited the EMT of the tumor cells. When AKF-PD was used in combination with CP, these effects were further enhanced. We also found that AKF-PD enhanced the anti-cancer effect of CP in a variety of cancer cell lines, including cervical cancer (Hela cells and SiHA cells), nasopharyngeal cancer (5-8F cells), triple-negative breast cancer (MDA-MB-231 cells), and bladder cancer (UM-UC-3 cells).

Conclusions: AKF-PD not only mitigates CP-induced AKI but also enhances the anti-cancer efficacy of CP. Our findings provide valuable insights into the treatment of NSCLC and may have clinical applications.

Background: The introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has revolutionized advanced non-small cell lung cancer (NSCLC) treatment. However, their efficacy can be compromised by concurrent use of gastric acid suppressants (GASs), such as proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs). This study aimed to update the evidence on the impact of GASs on the overall survival (OS) and progression-free survival (PFS) in patients on EGFR-TKI treatment.

Methods: A systematic review and meta-analysis were conducted using data from PubMed, Embase, Cochrane Library, Web of Science, Scopus, KoreaMed, and preprint repositories. Data from 13 retrospective studies, involving 10,814 patients, were analyzed.

Results: Overall, 34.6% of the patients used GASs, with most being Asian females and non-smokers. Most patients had EGFR-mutated adenocarcinoma, reflecting typical EGFR-TKI usage scenarios. Concurrent use of GASs was significantly associated with reduced OS [hazard ratio (HR) =1.34, 95% confidence interval (CI): 1.26-1.42], and PFS (HR =1.52, 95% CI: 1.25-1.86). In subgroup analysis, PPIs had a more negative impact on OS (HR =1.64, 95% CI: 1.51-1.79) than did H2RAs (HR =1.11, 95% CI: 0.95-1.31). Longer overlap times of GASs correlated with a higher trend in HRs for OS. However, the results for PFS were not significant in both subgroup analyses.

Conclusions: Concurrent use of GASs with EGFR-TKIs is linked to poorer OS and PFS in patients with advanced NSCLC. Careful consideration is advised when prescribing GASs, including adjusting administration timing, minimizing overlap duration, or opting for H2RAs over PPIs. Further research is needed to optimize treatment protocols, specifically addressing the duration of overlap time, to improve patient outcomes.