Lung Cancer最新文献

Objectives: Evaluating invasion in non-mucinous adenocarcinoma (NMA) of the lung is crucial for accurate pT-staging. This study compares the World Health Organization (WHO) with a recently modified NMA classification.

Materials and methods: A retrospective case-control study was conducted on small NMA pT1N0M0 cases with a 5-year follow-up. Seventy cases were reviewed by 42 pulmonary pathologists first according to the WHO classification and after tutorial according to a modified classification. A third round was conducted based on feedback from 41 peers of previous rounds. Additionally, orthogonal biomarker analysis was performed.

Results: In the first two rounds, 42 pathologists from 13 countries assessed all 70 cases, while 36 pathologists evaluated 41 non-unanimous cases in the third round. Kappa values for invasiveness increased in rounds 1, 2, and 3 to 0.27, 0.45 and 0.62, respectively. In contrast to low variation in total tumor size measurements (6 %), a marked increase in invasive tumor size variation was observed (42 %), which was associated with high uncertainty. In the third round 10 cases were non-invasive, all without recurrence. The modified classification showed in the 3rd round marked reduction of the variation in pT staging compared to the current WHO classification. Proliferation rate, tumor mutational burden, and transcriptomic profiles supported the distinction between invasive cases and non-invasive cases of the modified classification.

Conclusion: The modified classification demonstrates essentially higher reproducibility compared to the current WHO classification in NMA. The modified classification proves valuable in identifying low-risk lesions that are entirely non-invasive, and is supported by biomarker analysis.

Background: Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs). This study investigates the relationship between CT-assessed sarcopenia and irAEs in patients with lung cancer who are receiving ICIs.

Methods: Patients were enrolled if they had lung cancer treated with ICIs at the University Medical Center Groningen (2015-2021) and had undergone low-dose CT scans that included the third lumbar vertebral level (L3). CT-assessed sarcopenia was defined based on reported L3 skeletal muscle mass index (L3SMI) thresholds. Patients were categorized into no, any-grade, and severe irAE groups. The association between CT-assessed sarcopenia and irAEs was assessed by competing risk time-to-event analysis, accounting for the risk of death. Sub-distribution hazard ratios (_SDHR) were calculated using Fine-Gray regression models adjusted for relevant confounders. The association between CT-assessed sarcopenia and overall survival (OS) was evaluated through survival analyses.

Results: We included 363 patients; most were male (60.9 %), had favorable Eastern Cooperative Oncology Group (ECOG) performance statuses (0-1; 90.1 %), had stage IV disease (92.8 %), and received ICI monotherapy (82.9 %). Of these, 45.6 % developed any-grade irAEs and 21 % developed severe irAEs. Endocrine disorders were the most common mild irAEs (24.8 %), while respiratory disorders were the most common severe irAEs (24.7 %). CT-assessed sarcopenia was more prevalent in the no irAE group (87 %) compared with the any-grade (77 %) and severe (79 %) irAE groups. Presence of CT-assessed sarcopenia was associated with a lower risk of developing any irAEs (_SDHR = 0.62 [95 % CI: 0.41-0.92]). No significant association was found between CT-assessed sarcopenia and severe irAEs (fully adjusted model, _SDHR = 0.74 [95 % CI: 0.39-1.4]), or between CT-assessed sarcopenia and OS.

Conclusion: CT-assessed sarcopenia is associated with a reduced risk of any irAEs in patients with lung cancer receiving ICIs, possibly because higher muscle mass enhances the host response to immunological stimulation. Recognizing sarcopenia as a predictive factor for irAEs is relevant for personalizing treatments.

Background: Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare subtype of non-small-cell lung cancer. This study aims to compare the efficacy and safety of perioperative PD-1/PD-L1 inhibitor plus chemotherapy versus chemotherapy alone in stage II-IIIB PLELC patients.

Patients and methods: This retrospective study included stage II-IIIB PLELC patients. Patients received either perioperative immuno-chemotherapy (IO-Chemo) or chemotherapy alone (Chemo). Data on patient characteristics, treatments, efficacy, toxicities, and pathology were collected. Primary endpoints were major pathological response (MPR) and event-free survival (EFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), and adverse events (AEs).

Results: A total of 72 patients were included in this retrospective study. The ORR was 75.0 % in the IO-Chemo group and 58.3 % in the Chemo group (odds ratio [OR] 0.47 [95 % CI 0.15-1.42]; P = 0.200). The percentage of patients achieving major pathological response (MPR) was 54.2 % in the IO-Chemo group and 12.5 % in the Chemo group (OR 1.91 [95 % CI 1.22-2.99]; P < 0.001). Pathological complete response (pCR) was achieved by 33.3 % of patients in the IO-Chemo group compared to 4.2 % in the Chemo group (OR 1.44 [95 % CI 1.08-1.92]; P = 0.002). The median EFS was not reached in the IO-Chemo group, whereas it was 35.0 months in the Chemo group (95 % CI 14.2-55.8; hazard ratio [HR] 0.42 [95 % CI 0.19-0.93]; P = 0.031). Median overall survival (OS) was not reached after a median follow-up of 47.0 months. Multivariate analysis indicated that the PD-1/PD-L1 inhibitor combination was independently associated with longer EFS (HR = 0.32 [95 % CI 0.11-0.95]; P = 0.043). AEs of any grade occurred in 91.7 % of the patients in the IO-Chemo group versus 89.6 % in the Chemo group.

Conclusions: In patients with resectable PLELC, perioperative PD-1/PD-L1 inhibitor plus chemotherapy resulted in significantly longer EFS and a higher percentage of patients achieving MPR and pCR than chemotherapy alone, with a tolerable safety profile.

Objectives: To study the prognostic significance of tumour budding (TB) compared with the grading of lung adenocarcinoma (LAC).

Materials and methods: The postoperative haematoxylin and eosin-stained histological slices of 207 surgically treated LAC patients were retrospectively reviewed by a lung pathologist. Two groups were formed from the cohort: the high-grade TB group (≥10 buds) and low-grade TB group (0-9 buds). The prognostic significance of high-grade TB for the 5-year progression-free survival (PFS) and overall survival (OS) of patients was studied using the Kaplan-Meier method and Cox regression models. A novel four-tier grading system for LACs was developed by combining the World Health Organization (WHO) grading system and high-grade TB. The computed tomography (CT) imaging features of the tumours were assessed semiquantitatively by two chest radiologists.

Results: There were 166 patients with low-grade TB and 41 LAC patients with high-grade TB. Most of the tumours with high-grade TB were Grade 3 tumours. The median follow-up time was 60 months. The 5-year PFS was lower in the high-grade TB group than in the low-grade TB group (37.6 vs. 50.9 months, p < 0.001). High-grade TB remained an independent prognostic factor for poor PFS (clinical model: hazard ratio [HR] = 2.07, adj. p = 0.012, histopathological model: adj. HR = 2.09, adj. p = 0.010). Compared with the WHO Grade 3 group, the Novel Grade 4 group had a shorter mean PFS (36.7 vs. 45.3 months), and according to the PFS analysis, the novel four-tier grading system was superior to the WHO grading system (AIC = 591.9 vs. AIC = 596.6, ΔAIC > 2). On CT, tumours with higher TBs are usually smooth or spiculated.

Conclusion: This is the first study to show that high-grade TB is associated with a higher LAC grade. The incorporation of TB into the WHO grading scheme may improve the prognostic significance of LAC grading.

Introduction: Several prognostic scores were developed for non-small-cell lung cancer (NSCLC) patients with brain metastases (BM), though limited data reported for the KRAS-mutated subgroup. KRAS-targeted therapies have improved extracranial and intracranial response, highlighting the need for reliable prognostic biomarkers.

Methods: A retrospective cohort (2010-2020) comprising 220 patients with BM KRAS-mutated NSCLC from two large academic Thoracic Oncology centers (Karolinska and Heidelberg) was analyzed. Clinicopathological parameters were collected from electronic health records. Prognostic factors of overall survival from BM diagnosis (BM-OS) were identified using Cox regression models.

Results: The median age at diagnosis was 65 years, with a female predominance (55.9 %). Adenocarcinoma was the dominant histological subtype, performance status (PS) was 0-2 in 91 % of the patients and one-third had > 4 BMs. Variables independently correlated with BM-OS included the presence of primary BM disease, PS, age, symptomatic CNS disease, extracranial metastases and number of BM, and were used to design a new KRAS-Brain Prognostic Index (KRAS-BPI). Patients with high-index score showed significantly longer BM-OS, compared to intermediate/low-index groups (median BM-OS = 30.0 vs 9.0 vs 2.0 months, respectively).

Conclusions: In the largest real-word data study of KRAS-mutated NSCLC patients with BM, we developed a novel prognostic tool for improved patient stratification.

Background: HER2 mutations are critical drivers of non-small cell lung cancer (NSCLC), affecting 2 %-3 % of patients and often leads to poor prognosis and limited response to conventional therapies. This study investigates the genomic characteristics and prognostic relevance of dynamic circulating tumor DNA (ctDNA) monitoring in advanced NSCLC patients with HER2 mutations treated with pyrotinib and apatinib.

Methods: The PATHER2 study included 33 advanced NSCLC patients harboring HER2 mutations or amplification, who received combination therapy of pyrotinib and apatinib. Among them, 27 patients had baseline blood samples available for analysis. Baseline blood samples (n = 27), follow-up samples after one treatment cycle (n = 13), and samples upon disease progression (n = 18) were collected. ctDNA was extracted and sequenced using a 556-gene panel.

Results: At baseline, HER2 mutations were detected in 21 of 27 patients through ctDNA, and 19 showed consistent results between tissue and blood sample testing. Patients with TP53 and DNMT3A alterations at baseline had significantly shorter progression-free survival (PFS). Dynamic ctDNA monitoring revealed that patients without detectable HER2 mutations after one treatment cycle had longer PFS and a trend toward longer overall survival (OS) compared to those with persistent HER2 mutations. The newly emerged mutations after resistance were infrequently found in HER2, instead primarily enriched in the chromatin remodeling pathway.

Conclusion: ctDNA holds significant value in guiding the treatment of patients with HER2 mutations. Baseline TP53 and DNMT3A alterations, along with persistent HER2 mutations after initial treatment, are associated with poorer prognosis. The primary mechanism of resistance to pyrotinib and apatinib in these patients may be attributed to chromatin remodeling rather than on-target alterations.

Background: Despite the advancements in early lung cancer detection attributed to the widespread use of low-dose computed tomography (LDCT), this technology has also led to an increasing number of pulmonary nodules (PNs) of indeterminate significance being identified. Therefore, this study was aimed to develop a model that leverages plasma methylation biomarkers and clinical characteristics to distinguish between malignant and benign PNs.

Methods: In a training cohort of 210 patients with PNs, we evaluated plasma circulating tumor DNA (ctDNA) for the presence of three lung cancer-specific methylation markers: SHOX2, SCT, and HOXA7. Subsequently, we constructed a combined model utilizing methylated SHOX2/SCT/HOXA7 (mSHOX2/SCT/HOXA7) ctDNA levels, the largest nodule size measured by LDCT, and age, employing the binary logistic regression algorithm. Furthermore, we compared the diagnostic performances of the combined model with the Mayo Clinic model and the single mSHOX2/SCT/HOXA7 model by analyzing the area under the receiver operating characteristic curve (AUC) for each.

Results: The combined model demonstrated an impressive AUC of 0.87 and an accuracy of 0.75 in the training cohort, using pathologic diagnoses as the gold standard. This performance was significantly superior to that of the single mSHOX2/SCT/HOXA7 panel (AUC = 0.81, P < 0.0001) and the Mayo model (AUC = 0.65, P = 0.0005). Further validation in a cohort of 82 patients with PNs confirmed the diagnostic value of the combined model. Additionally, we observed that as the size of the nodule increased, the diagnostic accuracy of the combined model also improved.

Conclusions: A combined model incorporating the ctDNA-based methylation status of SHOX2/SCT/HOXA7 genes, the largest nodule size measured by LDCT, and age can serve as a supplementary approach to LDCT for lung cancer. This model enhances the precision in identifying high-risk individuals and optimizes the clinical management strategies for PNs detected by CT.

Purpose: The therapeutic advantage of postoperative radiation therapy (PORT) for non-small cell lung cancer (NSCLC) has not been shown to benefit overall survival (OS) according to two randomized controlled trials (RCTs), albeit an enhancement in locoregional-free survival was observed. We aimed to evaluate the relative influence of locoregional recurrence (LR) and distant metastasis (DM) on OS for patients with NSCLC after surgery.

Methods: This was a secondary analysis of PORT-C RCT. Patients with pN2 NSCLC undergoing complete resection followed by chemotherapy were included. A dynamic prediction model was developed to evaluate the impact of LR and DM on OS. The endpoint was OS. Age, sex, smoking history, histology, Karnofsky Performance Status, tumor side, T stage, and positive lymph node were baseline factors, whereas LR and DM status were time-dependent covariates.

Results: In total, 364 patients were eligible, including 214 and 150 in the non-PORT and PORT groups, respectively. DM significantly decreased OS in both the non-PORT (odds ratio [OR], 4.74; 95 % CI, 2.70-8.30; P < 0.01) and PORT (OR, 5.43; 95 % CI, 2.56-11.48; P < 0.01) groups. LR also significantly impacted OS in the non-PORT (OR, 2.09; 95 % CI, 1.12-3.93; P = 0.02) and the PORT (OR, 3.44; 95 % CI, 1.53-7.75; P < 0.01) groups. Multivariate Cox analysis identified the pT stage, positive lymph nodes, and histology as variables correlated with DM. A nomogram was developed to estimate the risk of DM. PORT did not significantly enhance OS in either the low (HR, 1.42; 95 % CI, 0.63-3.19, P = 0.40) or high-risk (HR, 0.62; 95 % CI, 0.35-1.09, P = 0.10) subgroup but in the medium-risk subgroup (HR, 0.20; 95 % CI, 0.05-0.86, P = 0.02).

Conclusion: DM and LR significantly impacted OS in patients with NSCLC after surgery. DM emerged as the dominant failure pattern, emphasizing more effective control of DM. PORT was beneficial for patients with a medium risk of DM.

Background: As for squamous (Sq)-NSCLC, Checkmate-017 trial showed a significant overall survival (OS) improvement in favor of Nivolumab (Nivo) over Docetaxel in 2nd-line. We hypothesized that anticipating Nivo use, as early switch maintenance after 1st-line chemotherapy (CHT), might have improved survival as compared to delayed 2nd-line treatment.

Methods: EDEN was an open-label, 2-arm, phase III study which randomized (1:1) stage IIIB/IV Sq-NSCLC pts non-progressive after 1st-line platinum-based CHT, to receive early Nivo as switch maintenance (Arm A) or standard best supportive care followed by 2nd-line Nivo at disease progression (Arm B). In both arms, Nivo was administered at the dose of 240 mg i.v. every 2 weeks until progressive disease, intolerable toxicity, or for a maximum of 2 years. The primary endpoint was OS.

Results: From Sep 2017 to Aug 2020 125 patients (62 Arm A vs 63 Arm B) were randomized from 32 Italian centers. Accrual was stopped early, before the planned sample size (388 pts) was reached, because of registration of ICPIs in 1st-line. Most patients were male (79.2 %), current/former smokers (93.6 %), had stage IV (74.4 %), performance status 0-1 (98.4 %). mOS (95 % CI) was 14.9 (10.4-18.6) months in arm A vs 18.8 (14.4-21.1) months in arm B (HR 1.09, 95 %CI 0.74-1.62, p = 0.659).

Conclusions: In advanced Sq-NSCLC, the use of Nivo as switch maintenance after 1st-line CHT, does not improve OS compared to its use as 2nd-line. Although the optimal use of ICPIs remains in 1st-line, its role as maintenance has to be better investigated.

Clinicaltrials: gov: registration number: NCT03542461.

Introduction: The EORTC-Lung Cancer Group initiated a Delphi consensus process to establish a consensual definition of resectable stage III non-small cell lung cancer (NSCLC) for the use in clinical trials, including a systematic review, survey, and review of clinical cases. Here, the survey results are presented, aimed to identify areas of controversy.

Methods: A survey was distributed among the members of six international organizations related to lung cancer. Respondents were interrogated on the resectability (not limited to the technical resectability) of all stage III NSCLC TNM-subsets (8th edition). Additionally, four N2-subdivisions were used. The threshold for agreement was 75%. Answers with "yes" were considered upfront resectable. "Yes" and "maybe" were grouped together and considered potentially resectable. Answers with "no" were considered unresectable.

Results: 558 responses were collected from thoracic surgeons (38%), radiation oncologists (27%), medical oncologists (17%), pulmonologists (14%), and others (4%). Most worked in a specialized center (80%), had >5 years of experience (80%), were European (76%), male (73%), and treated >20 patients with stage III NSCLC annually (77%). Agreement was found in 26 (70%) out of 37 TNM-subsets: 9 (24%) were considered (potentially) resectable, and 17 (46%) unresectable. There was no agreement for 11 (30%) TNM-subsets: smaller tumors with N2-multistation, larger tumors with N2-single station, and invasive T4-tumors with maximum N2-single station involvement.

Conclusions: This international and multidisciplinary survey showed agreement on the resectability for the majority of stage III NSCLC TNM-subsets, but also identified several TNM-subsets for which no agreement was found.