bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictive value of co-existing genetic alterations and tumor mutation burden for patients with completely resected non-small cell lung cancer harboring EGFR mutation: Biomarker analysis of phase III IMPACT study.
Authors: Ikeda Satoshi , Tsuboi Masahiro , Sakai Kazuko , Misumi Toshihiro , Akamatsu Hiroaki , Iwamoto Yasuo , Sakakura Noriaki , Nakamura Atsushi , Ohde Yasuhisa , Hayashi Hidetoshi , Okishio Kyoichi , Okada Morihito , Yoshino Ichiro , Okami Jiro , Takahashi Kazuhisa , Ikeda Norihiko , Mitsudomi Tetsuya , Tada Hirohito , Nakagawa Kazuhiko , Nishio Kazuto
Published: June 2023

8524

Background: Although osimertinib has recently become an option for adjuvant therapy in many countries, biomarkers predicting the efficacy of adjuvant EGFR-TKI and the risk of postoperative recurrence in completely resected NSCLC harboring EGFR mutations have not been fully investigated. Methods: This IMPACT-TR study is an exploratory biomarker study for completely resected, EGFR-mutated NSCLC patients who received gefitinib or cisplatin plus vinorelbine (cis/vin) in a phase III IMPACT study (Trial registration number: UMIN000044738. Funding: AstraZeneca K.K.). Surgically resected lung cancer tissue specimens were analyzed for co-existing somatic mutations and tumor mutation burden (TMB) determined by Oncomine Tumor Mutation Load, and these data were matched with disease free survival (DFS) and overall survival (OS) data. Results: Of the 234 patients in the IMPACT study, 211 patients were enrolled, and 202 patients in the Per Protocol Set were analyzed. The most frequent co-existing somatic mutation was TP53 (58.4%), followed by CSMD3 (11.8%), NOTCH1 (9.9%) and SYNE1 (9.9%). The median TMB was 6.67 mutations/Mb, and only 15.2% had ≥10 mutations/Mb. EGFR mutation subtypes, TP53 co-mutation and TMB were not associated with DFS or OS in either the gefitinib or cis/vin groups. In the gefitinib group, patients with NOTCH1 mutation had significantly shorter OS (hazard ratio [HR] 4.18, 95%CI 1.65-10.61, p=0.003) and tended to have shorter DFS (HR 1.44, 95%CI 0.62-3.37, p=0.399) than those without NOTCH1 mutation. In the cis/vin group, patients with CREBBP mutation had significantly shorter DFS (HR 2.70, 95%CI 1.05-6.97, p=0.040) and tended to have shorter OS (HR 3.05, 95%CI 0.90-10.37, p=0.074) than those without CREBBP mutation. Conclusions: This study suggested that NOTCH1 mutation may be a biomarker to predict poor response to adjuvant gefitinib and CREBBP mutation to predict poor response to cis/vin in patients with completely resected, EGFR-mutated NSCLC. Clinical trial information: UMIN000044738 .
Dynamic ctDNA to inform the precise management of resected NSCLC: LUNGCA-2 study.
Authors: Xia Liang , Pu Qiang , Kang Ran , Mei Jiandong , Li Lu , Yang Ying , Deng Senyi , Feng Gang , Ma Lin , Lin Feng , Liao Hu , Liu Chengwu , Zhu Yunke , Li Qingyun , Zhang Xiaolong , Liu Lunxu
Published: June 2023

8528

Background: Circulating tumor DNA (ctDNA) has been reported to be valuable for minimal residual disease (MRD) detection, but there is a lack of studies comprehensively assessing whether dynamic ctDNA monitoring can inform whole-course precise postoperative cancer management. In the present study (LUNGCA-2), we analyzed data obtained from longitudinal ctDNA monitoring of stage I-III NSCLC patients in the LUNGCA cohort, and sought to assess the use of dynamic ctDNA monitoring for precise whole-course postoperative management of NSCLC patients. Methods: All eligible NSCLC patients underwent curative-intent surgery and subsequently received adjuvant therapies when indicated by clinical practice guidelines for NSCLC. The clinical follow-up was scheduled to be every 3-6 months mainly involving CT and/or MRI. Fresh frozen or paraffin-embedded tissues of primary tumors were collected intraoperatively for baseline somatic mutation profiling. Blood samples were collected before surgery, at 3 days and 1 month after surgery, and then every 3-6 months at clinical visits up to 3 years postoperatively. 233 patients with a total of 2123 plasma samples were ultimately included in the longitudinal ctDNA analysis in the current study. NGS assays were performed with a custom-designed panel that covered 769 cancer-related genes via the MinerVA platform (Genecast Biotechnology Co., Ltd). Results: Among the cohort, 166 patients harboring targetable mutations in the primary tumor tissue, 15 were preadjuvant ctDNA positive, and among them, only 25% patients treated with adjuvant TKI therapy experienced relapse during follow-up, and patients received ACT or no adjuvant therapy had a relapse rate of 100%. TKI treatment tended to improve RFS compared with no treatment (HR 0.1, P = 0.025), but ACT failed to improve RFS (HR 1.1, P = 0.834). Among all 82 patients receiving adjuvant therapy, the pre- and post-adjuvant therapy postoperative ctDNA status with a negative-negative or positive-negative pattern had similar and favorable RFS ( P = 0.545) but that patients with a positive-positive or negative-positive pattern had significantly inferior RFS than those with a negative-negative pattern (both P < 0.001). For recurrence monitoring, posttreatment ctDNA MRD status had a positive predictive value of 100% and a negative predictive value of 91.8%, and the sensitivity of MRD detection was affected by the organ of relapse. Among positive ctDNA MRD patients, faster increase of ctDNA concentration correlated with more imminent clinical relapse. The median lead time from ctDNA detection to radiological relapse was 273 days. Moreover, ctDNA negativity after relapse was associated with favorable survival. Conclusions: These findings highlight the clinical significance of ctDNA dynamics for the precise whole-course postsurgical management of NSCLC patients.
Differential expression analysis of circRUNX1 in patients with early resected EGFR-mutant NSCLC.
Authors: Pedraz Carlos , Ito Masaoki , Giménez-Capitán Ana , Giannoukakos Stavros , Molina Vila Miguel Angel , Rosell Rafael
Published: June 2023

8529

Background: In the ADAURA study, patients with stage IB-IIIA of resected EGFR mutated lung adenocarcinoma receiving adjuvant osimertinib had a 2-year survival of 89% versus 52% in the placebo group (p<0.001), however, predictive markers of response and recurrence are still needed. Circular RNA (circRNA) is a type of RNA which forms a covalently closed continuous loop. Some circRNAs have been reported as essential for tumor cell proliferation through functions distinct from the canonical linear RNA. In this project, we studied circRNA expression levels in formalin-fixed paraffin-embedded (FFPE) lung tumor samples in order to explore potential biomarkers that could predict the benefit of adjuvant EGFR TKIs in EGFR-mutant NSCLC patients. Methods: FFPE tumor samples from patients with EGFR-mutant, stage I-IIIB NSCLC (n=79) were collected. RNA was purified using the High Pure FFPET RNA Isolation Kit (Qiagen) and quantified by Nanodrop 2000 (Thermo Scientific). A total of 250 ng of RNA were subjected to overnight hybridization and downstream nCounter processing (NanoString) following manufacturer’s instructions for our circRNA custom panel. Differential expression analysis was performed using Excel (Microsoft) and Prism GraphPad (Dotmatics) software. Results: Analysis of the 79 samples included in the study shown a cluster of 3 circRNAs significantly upregulated (p<0.05 and >2 fold-change) in EGFR mutation-positive NSCLC relapsing withing the 36 months after resection, including circRUNX1, circFUT8 and circAASDH. Disease-free survival (DFS) was significantly shorter for the subgroup of patients with high versus low circRUNX1 expression. Additional multivariate analysis identified circRUNX1 expression and tumor stage as the only statically significant prognostic factors (circRUNX1 hazard ratio = 4.480, confidence interval = 2.172-9.239, P < 0.001; pathological stage hazard ratio = 2.237, confidence interval = 1.183- 4.231, P = 0.008). Conclusions: CircRUNX1 could be a novel biomarker to predict the benefit of adjuvant EGFR TKIs with regards to DFS in EGFR-mutant resected NSCLC patients.
Examining ultrafine particle pollution and lung cancer risk in a large, diverse cohort.
Authors: Bookstein Arthur , Po Justine , Cheng Iona , Wu Anna H. , Larson Timothy V. , Park Lani , Wu Jun , Shariff-Marco Salma , Inamdar Pushkar , Setiawan Veronica Wendy , DeRouen Mindy , Gomez Scarlett L. , Le Marchand Loic , Stram Daniel , Samet Jonathan , Ritz Beate , Fruin Scott A.
Published: June 2023

8532

Background: Health effects associated with particles less than 2.5 μm in diameter (PM2.5) have been well studied, leading to the establishment of air quality standards and routine monitoring. Additionally, there is growing experimental evidence that ultrafine particles (UFPs), defined as particles less than 0.1µm in diameter, may adversely affect lung health, eliciting greater injury than larger particles due to deeper penetration into airways and longer retention in the lung parenchyma. Only two epidemiological studies have investigated this topic, finding no associations between ambient UFPs and respiratory mortality or overall lung cancer incidence respectively. Given the limited epidemiologic investigation of UFPs and lung cancer, we examined the association between airport-related UFPs and lung cancer incidence in a large, racially and ethnically diverse cohort. Methods: We estimated airport-related UFP exposure for 71,387 participants of the Multiethnic Cohort, who lived within a 53 km×43 km grid area around the Los Angeles International Airport (LAX) from date of cohort entry (1993-1996) through December 31, 2013. Cox proportional hazards regression was used, with calendar month/year as the time variable, to examine associations between UFP exposure and lung cancer risk adjusting for demographics, lifetime smoking, neighborhood socioeconomic status, occupation and lifestyle factors. Subgroup analyses were conducted by racial and ethnic groups, lung cancer histology, and smoking status. Co-pollutant models were run to mutually adjust for other traffic-related air pollutants. Results: A per unit increase in the interquartile range (IQR) of airport-related UFP exposure was not associated with lung cancer risk overall [HR = 1.01, 95% CI: 0.97-1.05] or by race and ethnicity. UFP exposure was suggestive of a positive association with risk of lung squamous cell carcinoma (SCC) [HR per IQR = 1.08, 95% CI: 1.00-1.17]. No associations were observed for other histologies [Phet for histology = .05]. UFP exposure was associated with an increased SCC risk among current smokers [HR = 1.11, 95% CI: 1.01-1.22] but not among never or past smokers [Phet for smoking = 0.51]. Conclusions: This study suggests a possible association between airport-related UFP exposure and risk of SCC. These results may be explained by previous studies finding that UFPs activate genes involved in oxidative damage, TNF-α signaling via NF-κB, and secretion of inflammatory and cardiopulmonary disease biomarkers. These findings warrant further investigation in large epidemiologic cohorts.
Clinical validation of an activity-based enzyme assay for early stage lung cancer.
Authors: Dempsey Paul W. , Aparicio Cristina-Mihaela Sandu , Gonzalezirias Ricardo , Hantula Spencer , Kagawa Mari , Bossmann Stefan H. , Covarrubias-Zambrano Obdulia , Nagji Alykhan S. , Veeramachaneni Nirmal K , Ermerak Nezih O. , Kocakaya Derya , Lacin Tunc , Yildizeli Bedrettin , Witting Christensen Wen Sara , Nederby Line , Hansen Torben , Hilberg Ole
Published: June 2023

8533

Background: The USPSTF guidelines recommend annual LDCT scans for 15.5 million adults with a heavy smoking history. While LDCT can reduce deaths by 20%, screening compliance remains low. A blood test with clinically useful, cost effective performance could improve compliance and access when integrated with the standard of care. We describe here a lyophilized nanosensor system for detecting protease enzyme activity in sera with clinically useful diagnostic activity in early stage lung cancer. We evaluated the performance of the assay by examination of prospectively collected sera for detection of cancer in high risk patients. Methods: Sera were obtained in multiple independent studies to include pathologically confirmed, treatment naive lung cancer patients and LDCT confirmed negative individuals. Protease activity was measured on 18 different nanosensors built with protease targets mainly selective for members of the Matrix Metalloproteinase and Cathepsin families. Lyophilized plates were incubated with serum and enzyme activity was measured indirectly as a continuous variable by a fluorescent plate reader. A machine learning modeling tool (Emerge) was used to detect signal associated with a cancer “fingerprint” of protease activity. The analysis stratified allocation into training and testing sets of 250 samples each and reserved a third out of sample validation set (250 samples) for reporting. Results: 750 clinical samples included 30% lung cancers, 63% males, 91% smokers, and an average age of 63 years (SD=9). Cancer cases were distributed across stages I (41%), II (17%), III (20%) and IV (20%) with 5% unknown. Histological classification included 59% adenocarcinoma, 31% squamous cell and 11% other subtypes. Using an Emerge model with only nanosensor activity and gender as inputs, we evolved a balanced algorithm. The algorithm can be further modified to favor sensitivity or specificity depending on the application by applying model weighting factors. We report the performance observed in the 250 out of sample validation set at three points on this spectrum (Table). Among Stage I cancer samples, the balanced algorithm had an accuracy of 90% (26/29). Conclusions: Current LDCT tools show low compliance. We demonstrate clinical validity of a cost effective tool to detect lung cancer in support of LDCT screening. Based on a simple blood sample, the current test may predict early stage lung cancer with an accuracy of 90%. The performance suggests applications in LDCT compliance, post LDCT management, and eventually screening. A clinically validated version of this technology is being evaluated as a triage tool for LDCT screening. [Table: see text]
Validation of recurrence prediction using circulating tumor DNA in patients with curatively treated early stage non-small cell lung cancer.
Authors: Schuurbiers Milou , Smith Christopher Gareth , Hartemink Koen , Rintoul Robert , Monkhorst Kim , van den Broek Daan , Rosenfeld Nitzan , Heuvel Michel van den
Published: June 2023

8535

Background: Stage II-III non-small cell lung cancer (NSCLC) patients receive adjuvant chemotherapy after surgery as standard-of-care treatment, despite an absolute 5-year disease free survival benefit of only 5.8%. Stage I patients do not receive adjuvant treatment but may benefit. Identification of residual disease by circulating tumor DNA (ctDNA) after curative intent therapy may allow more accurate decisions. Methods: Tumor tissue and serial plasma samples were collected from stage I-III NSCLC patients enrolled in the LEMA trial (NCT02894853). Somatic mutations identified by tumor exome sequencing were used to design patient-specific RaDaR assays, targeting up to 48 variants per patient, to analyze ctDNA in serial plasma samples. Results were compared and combined with an independent dataset (LUCID; Gale et al, Annals Oncol 2022). Results: In LEMA, 129 patients (53% stage I, 18% stage II and 29% stage III) were treated with curative intent by surgery (n=117), chemoradiation (n=8) or stereotactic radiotherapy (n=4) and followed for a median of 3.4 years. The LUCID dataset included 88 patients (49%/28%/23% in stage I/II/III). Results in the two cohorts were highly concordant (Table) and were assessed in the combined dataset of 808 serial plasma samples. Before treatment, ctDNA was detected in 22%, 72% and 90% of patients with stage I, II and III disease. ctDNA was detected post-treatment (at least one positive samples ≥14 days after the end of therapy) in 41/65 (63%) of patients who developed radiographic recurrence of their primary cancer, and preceded recurrence by a median of 204 days. For recurrence prediction by ctDNA detection post-treatment, the sensitivity, specificity, positive and negative predictive value (PPV and NPV) in stage I patients were 53%, 99%, 91% and 90%. In stage II-III patients, sensitivity was higher but specificity and NPV were lower (67%, 93%, 91% and 74%, respectively). ctDNA detection after treatment was associated with shorter recurrence-free survival (hazard ratio (HR) 11.5, P=1.8x10-32) and overall survival (HR 8.1, P=1.2x10-17). Conclusions: ctDNA detection by RaDaR assays predicted recurrence in two independent cohorts, confirming the potential to identify patients for adjuvant treatment. In stage I patients with positive ctDNA, adjuvant treatment could be offered with confidence due to high specificity of 99% and PPV of 91%. In stage II-III patients, the primary cancer recurred in a quarter of patients with no ctDNA detected post-treatment (NPV 74%). Our results help identify the potential role for ctDNA analysis as a decision support tool for adjuvant therapy in NSCLC. [Table: see text]
EGFR assessment using next generation sequencing as a reflex testing on surgically resected non-squamous non-small cell lung carcinoma.
Authors: Goffinet Samantha , Hofman Veronique , Bontoux Christophe , Benzaquen Jonathan , Cohen Charlotte , Marquette Charles-Hugo , Berthet Jean-Philippe , Ilie Marius , Hofman Paul
Published: June 2023

8539

Background: EGFR status assessment is mandatory in early stage (IB-IIIA) non-squamous non-small cell lung carcinoma (NS-NSCLC), but whether NGS methods should be used as reflex testing for this evaluation in daily practice is controversial. However, co-occuring mutations, notably TP53 mutations, may have an impact on tumor behavior and prognosis, and so, on future adjuvant therapeutic strategies. Methods: EGFR mutations were assessed prospectively using NGS (Oncomine Precision Assay genes panel) in 720 NS-NSCLC surgically resected between January 2021 and September 2022 in a single institution (LPCE, Nice, France). PD-L1 expression was evaluated in all tumors. Disease free survival (DFS) analysis was available in 675/720 (94%) patients. Results: EGFR mutations were detected in 83/720 (11.5%) cases. A common non-compound EGFR mutation (L858R or del19) was observed in 62/83 (75%) cases. 12/83 (14%) and 9/83 (11%) tumors had a rare non-compound and compound EGFR mutations, respectively. 40/83 (48%) has a co-occuring mutation, including a TP53 (30/40; 75%) mutation, mainly in exon 5, 7 or 8. EGFR/TP53 mutated tumors were significantly associated with higher PD-L1 expression compared to EGFR mutated tumors. A significant correlation was noted between worse DFS and the detection of a mutation in EGFR exon 18 mutation, as well as the detection of a co-mutation in TP53 exon 7 and in MET exon 14. Conclusions: Genomic alteration should be systematically evaluated using an NGS reflex testing in surgically resected NS-NSCLC, since future adjuvant therapeutic decision making may consider the presence of compound EGFR mutations as well as co-occuring mutations in other genes, especially in TP53.
Association of nuclear shape in the tumor epithelium with response to atezolizumab in NSCLC.
Authors: Leo Patrick , Patil Namrata Srivastava , Ruderman Daniel , Giltnane Jennifer M. , Fuentes Eloisa , Schedlbauer Amber , Nabet Barzin , Kozlowski Cleopatra
Published: June 2023

8543

Background: Anti-PD-(L)1 treatment is the standard of care for advanced non-small cell lung cancer (NSCLC). However, additional biomarkers are needed to identify patients who will benefit from these therapies. In this study, we demonstrate the atezolizumab response score (ARS), which uses digital pathology features of the shape and size of nuclei in the tumor epithelium to predict response to the anti-PD-L1 antibody atezolizumab in NSCLC. Methods: Patients were drawn from two trials comparing atezolizumab to docetaxel in second-line advanced NSCLC. A single digitized slide stained for the epithelial cell marker pan-cytokeratin (CK) and CD8 was selected for each patient. OAK, a phase III trial, had 819 patients with images available and was used for training the ARS model. POPLAR, the phase II trial preceding OAK, had 168 evaluable patient images for validating ARS. Color deconvolution was used to identify the CK-positive regions in each image. Nuclei were segmented using the hematoxylin channel. The area, perimeter, eccentricity, solidity, and minor/major axis lengths were extracted from each nucleus in the CK-positive compartment of the pathologist-annotated tumor lesion, excluding necrosis and artifacts. Each measure’s mean, median, standard deviation, skewness, and kurtosis across the slide was calculated, for a total of 30 features. Features with an interaction p< 0.35 with trial arm in a Cox model were used to fit an elastic-net regularized Cox model on the atezolizumab-treated training set patients, producing ARS. The ARS threshold maximizing atezolizumab overall survival (OS) benefit in the ARS-high group was identified in OAK and applied to POPLAR (the validation set). ARS performance was assessed in the validation set by OS concordance index (c-index) and by atezolizumab benefit in the high- vs. low-ARS groups by hazard ratio (HR) [95% confidence interval]. Results: ARS employs five features. Lower nuclear median and standard deviation of major axis length, higher perimeter mean and standard deviation, and higher area were associated with better atezolizumab response. In the validation set, high-ARS (prevalence = 42%) patients had longer OS on atezolizumab vs. docetaxel (HR = 0.42 [0.24-0.72]) while low-ARS patients did not (HR = 0.95 [0.62-1.47]). ARS was positively associated with OS in the validation set atezolizumab arm (c-index = 0.60 [0.54-0.66]), but not the docetaxel arm (c-index = 0.47 [0.41-0.54]). Conclusions: We validated a nuclear morphology-based biomarker for atezolizumab response in advanced NSCLC. This demonstrates the utility of digital pathology for biomarker development and motivates study into the identified responder phenotype. Combination of ARS with additional markers, such as PD-L1 expression, might further improve stratification.
A systematic comparison of whole genome sequencing and targeted panel sequencing for precision oncology.
Authors: Park Ji-Hyung , Connolly-Strong Erin , Kim Young Tae , Ju Young Seok
Published: June 2023

8546

Background: The analysis of the cancer genome provides clinically meaningful information such as actionable cancer driver mutations. Whole genome sequencing (WGS) provides a complete mutational landscape at an affordable cost thereby having increase clinical utility compared to the usual approach of targeted panel sequencing (TPS). To understand the capabilities of WGS in oncology, we conducted a study in lung adenocarcinomas. Methods: We produced WGS (surgically resected tumor tissues and matched blood; mean coverage 42x) and TPS (tumor only; SNUH panel encompassing 75 cancer genes; mean coverage 904x) through the Illumina sequencing platform and conducted comprehensive bioinformatic analyses. Oncogenic driver events, including single base substitution (SBS), insertion or deletion (INDEL), complex deletion-insertion, and fusion oncogene, were investigated in both datasets. Lastly, we compared the pattern-based mutational features, such as tumor mutational burden (TMB), mutational signatures, and copy number changes which is associated with genomic instability. Results: In 60 lung adenocarcinomas, the TPS method identified 120 driver mutations from the 75 targeted genes. Of these, 114 mutations were also detected by the WGS method, showing 95.0% sensitivity of WGS in detection of core driver mutations. In uncovered genomic regions by TPS, WGS captured 9 additional driver mutations (such as loss-of-function mutations in PIK3R2, ARID2, and APC) and 37 copy number variations (such as amplification of LMO and SMO, deletion of PIK3R1 and APC) in the cancer genes. TMB calculation is straightforward in WGS however, sophisticated considerations were necessary in TPS for TMB, to remove false positives and germline mutations. TPS showed a good capability for identifying hypermutator tumor samples, but a quantitative estimation was not always feasible due to the substantial background fluctuation, particularly for INDELs. Mutational signatures are unique combinations of mutation types in a given sample, which can give important clues to the mechanism underlying mutations. TPS showed adequate mutational signatures (cosine similarity > 0.7), but was not constantly satisfactory in tumors with high TMB ( > 20,000 genome wide SBS and INDELs). In TPS, approximately 30% of high TMB tumors represented marginal cosine similarity (0.5-0.7), and tobacco smoking related signature (SBS 4) found in WGS was captured only in 50% of the associated cases (9 out of 18). For DNA copy number changes and loss-of-heterozygosity analyses, WGS showed a much higher resolution. Conclusions: Our study demonstrates that WGS has comparable capabilities for the detection of driver mutations in core oncogenes and tumor suppressor genes. WGS was superior for pattern-based features, such as TMB, mutational signatures, and copy number changes. WGS is a medically necessary more comprehensive approach to precision oncology.
Prospective dynamic sampling and molecular residual disease monitoring to predict clinical outcomes for patients with unresectable, locally advanced non-small cell lung cancer undergoing radical radiotherapy.
Authors: Zhang Jia-Tao , Pan Yi , Gao Xuan , Chen Zhi-yong , Yan Bingfa , Tan Pei-Xin , Yang Xiao-Rong , Lin Hui , Yan Hong-Hong , Dong Song , Wang Bin-Chao , Yang Jin-Ji , Tu Hai-Yan , Yang Xue-Ning , Zhong Wenzhao , Xia Xuefeng , Yi Xin , Zhou Qing , Wu Yi-Long
Published: June 2023

8549

Background: The role of molecular residual disease (MRD) detection in non-small cell lung cancer (NSCLC) patients after definitive resection has been progressively elaborated. However, the dynamic patterns of circulating tumor DNA (ctDNA) during and after radical radiotherapy (RT) remain unclear but are critical for detecting MRD in this context. Methods: We enrolled 139 patients with locally advanced NSCLC treated with radical RT in this prospective study. And 761 blood samples were successfully detected by ctDNA-MRD assay at different preset timepoints before, during and after RT. Results: There was a declining trend in ctDNA concentrations of “during RT” time point (RT reached 40 Gy) relative to those after RT. Patients with negative ctDNA of “during RT” and “after RT” time points may indicate an early response to RT, and had better progression-free survival (PFS) than those with late response to RT(ctDNA clearance only at “after RT” time point, HR = 0.30, 95%CI: 0.12-0.75, p = 0.004). Moreover, patients with both negative ctDNA of “during RT” and “after RT” time points could not benefit from consolidation therapy (HR = 0.72, 95%CI: 0.29-1.78, p = 0.478), while patients with any positive ctDNA of them could (HR = 0.59, 95%CI: 0.38-0.93, p = 0.023).The sensitivity of longitudinal MRD was 97.8% and only two patients with local progression were overlooked. The 2-year cancer-specific PFS of patients with longitudinal undetectable MRD was 88.4%, which corresponds to the potentially cured population. For patients with only blood-informed MRD detection, the sensitivity and median lead time of longitudinal MRD were 97.7% and 3.9 months, respectively, which indicating the feasibility and efficacy of blood-informed MRD detection strategy. Conclusions: These data shed new light on the ctDNA-MRD detection for localized NSCLC patients who received radical RT.
Assessing the efficacy and safety of DEB-BACE combined with intravenous chemotherapy for the treatment of intermediate to advanced lung adenocarcinoma after progression of targeted drug resistance.
Authors: Lai Lingqiang , Tu Jianfei , Zhang Dengke , Ying Xihui , Wu Jiahao , Chen Jie , Chen Li
Published: June 2023

8555

Background: To compare the efficacy and safety of drug-eluting bead bronchial arterial chemoembolization (DEB-BACE) combined with intravenous chemotherapy versus systemic intravenous chemotherapy for intermediate to advanced lung adenocarcinoma with positive driver genes after progression of targeted therapy. Methods: A total of 131 patients with intermediate to advanced lung adenocarcinoma were retrospectively recruited from 2018-2022 and divided into Group A (standard chemotherapy regimen, N=62) and Group B (DEB-BACE and intravenous chemotherapy, N=69). The short-term efficacy, hemoptysis remission rate, dyspnea remission rate, and incidence of adverse effects were compared between the two groups using the χ2 test. Survival estimates were performed by Kaplan-Meier, and a Log-rank test was performed to examine survival differences between groups. Results: The three-month disease control rate (DCR: 82.6% vs 58.1%) and objective remission rate (ORR: 60.9% vs 38.7%) were better in group B than in group A (both P<0.05). Median progression-free survival (PFS, 10.0 vs 7.9 months) and median overall survival (OS, 33.0 vs 18.0 months) were better in group B than in group A (both P < 0.05). The PFS rates at 6, 12, and 24 months were 67.3%, 40.8%, and 0.0% and 54.1%, 23.2%, and 0.0% in groups B and A, respectively; and the OS rates at 6, 12, and 24 months were 100%, 95.7%, 72%, 88.6%, 66.1%, and 21.8% in group B and group A, respectively, with statistically significant differences (P < 0.05). Within one month after treatment, group B had better hemoptysis relief (83.3% vs. 20.0%) and dyspnea relief (57.5% vs. 30.0%) than group A (both P < 0.05). During the follow-up period, the incidence of adverse reactions was significantly lower in group B than in group A (P < 0.05). Conclusions: For patients with intermediate to advanced lung adenocarcinoma who have failed to progress on targeted therapy, DEB-BACE combined with intravenous chemotherapy has shown superior efficacy and survival benefit and lower adverse effects, while significantly improving patients' symptoms of hemoptysis and dyspnea, with important application prospects.
Development and validation of a prediction model for the recurrence of stage 1 EGFR mutation positive NSCLC in patients using machine learning with WES-based gene sets.
Authors: Tateishi Akiko , Horinouchi Hidehito , Takasawa Ken , Kouno Nobuji , Mizuno Takaaki , Okubo Yu , Yoshida Yukihiro , Watanabe Shun-ichi , Miyake Mototaka , Kusumoto Masahiko , Inaba Koji , Igaki Hiroshi , Yatabe Yasushi , Mukai Masami , Tanaka Katsuya , Mihara Naoki , Shiraishi Kouya , Kohno Takashi , Ohe Yuichiro , Hamamoto Ryuji
Published: June 2023

8563

Background: Predicting the risk of postoperative recurrence is becoming increasingly important in EGFR mutation positive ( EGFR-m) non-small cell lung cancer (NSCLC). Only a few reports conducted whole exome sequencing (WES) for genomic profiling in large scale EGFR-m NSCLC cases. Methods: We conducted WES and analyzed the clinical course of patients (pts) with NSCLC who underwent surgery between 1985 and 2019 in the PRISM project of our institute. We evaluated the EGFR-m patients’ characteristics, recurrence-free survival (RFS), and developed a prediction model using machine learning, Overlapping Group LASSO to predict whether the EGFR-m patients will recur within 5 years or not as "high-risk" and "low-risk". To develop and validate the prediction model, we divided the data from 2006 as the training cohort data set and the data before 2006 as the validation cohort data set. After the development of the prediction model, we performed a stratified Cox proportional hazards model to compare the RFS between the predicted groups. Results: A total of 585/1351(43.3%) pts were EGFR-m included in the PRISM project. Of all pts, stage I, EGFR-m were 205 pts. The median RFS of the stage I, EGFR-m 123.1 months (m). In the training cohort, the model detected 43 pts for high-risk and 88 pts for low-risk. In the validation cohort, the model predicted 29 pts for high-risk and 45 pts for low-risk. Median RFS of high-risk vs. low-risk were 52.2 m vs. 105 m (HR 2.43, p=0.01). The 1-year RFS rate, 2-year RFS rate, and 5-year RFS rates for high-risk and low-risk pts were 100% vs. 98.5%, 66.7% vs. 89.2%, and 41.7% vs. 66.1%, respectively. Twenty-eight gene set coefficients were non-zero in the prediction model. The gene sets with large positive coefficients that were considered important for prediction as "high risk" were the gene sets affected by KRAS gene overexpression and p53 gene knockdown. In contrast, gene sets repressed by mTOR inhibition and genes repressed by TBK1 gene knockdown and KRAS gene overexpression had large negative coefficients. Conclusions: We developed and validated the prediction model whether the EGFR-m patients will recur within 5 years or not. EGFR-m NSCLC recurrence appears to be high risk with pathways associated with KRAS and p53 genes, and low risk with mutations in the gene sets suppressed by the mTOR pathway and TBK1 gene. [Table: see text]
Association of immune-related adverse events and efficacy outcomes in phase II trial of consolidation nivolumab plus ipilimumab or nivolumab alone after chemoradiation in patients with unresectable stage III non–small-cell lung cancer (NSCLC).
Authors: Wei Cynthia , Althouse Sandra K. , Mamdani Hirva , Hanna Nasser H. , Durm Greg Andrew
Published: June 2023

8565

Background: Immunotherapy has been widely incorporated into the treatment of patients with non-small-cell lung cancer. Many of these patients will experience immune-related adverse events (irAEs) that may lead to early discontinuation of therapy. Previous studies have reported that patients with Stage III and metastatic NSCLC who experienced irAEs receive fewer cycles of immunotherapy without decreased efficacy. Here we report a retrospective analysis of the association between irAEs and efficacy outcomes from the BTCRC LUN 16-081 randomized phase 2 trial of consolidation immunotherapy with nivolumab (N) plus ipilimumab (IPI) vs N alone following concurrent chemoradiotherapy in patients with unresectable Stage IIIA/IIIB NSCLC. Methods: A total of 105 eligible patients were enrolled from 9/2017 to 4/2021. Demographics, disease characteristics, and number of immunotherapy cycles received were reported in patients with and without irAEs in the two arms. Chi-square test was used for comparisons for categorical variables and Wilcoxon test for continuous variables. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). A log-rank test was used to compare groups. Results: In treatment arm A (N alone), any grade irAEs occurred in 64.8% of patients. At a follow up of 48 months, there was no significant difference in number of N cycles started (6 vs 6, p = 0.238), progression free survival (29.4 vs 31.9 mo, p = 0.897), or overall survival (NE vs. 31.9 mo, p = 0.798) in patients with and without irAEs. Patients who discontinued N because of irAEs (n = 8 or 14.8% of patients) received significantly fewer cycles of N (2 vs 6, p = < .0001) and had a shorter PFS (8.2 vs. 31.9 months, p = < .0001) and OS (12.3 months vs. NE, p < .0001). In treatment arm B (IPI+N), any grade irAEs occurred in 84.3% of patients. At follow up of 48 months, there was no significant difference in number of IPI+N started (4 vs. 4, p = 0.260) or overall survival (NE vs. NE, p = 0.576), but there was a significantly longer PFS in those who experienced irAEs (30.9 months vs. 6.8 months, p = 0.0083). Patients who discontinued IPI+N because of irAEs (n = 18 or 35.3% of patients) received significantly fewer cycles of IPI+N (2 vs 4, p = < .0001) without a significant difference in PFS (28.1 vs. 25.3 mo, p = 0.830) or OS (NE vs NE, p = 0.755). Conclusions: The occurrence of irAEs alone in both arms, regardless of number, was not associated with decreased efficacy outcomes in this exploratory analysis. However, if irAEs resulted in the discontinuation of therapy, these patients did have a shorter PFS and OS in the N alone arm. This difference was not observed in the IPI+N arm and those who experienced any irAEs in the IPI+N arm had an improved PFS.
Optimal number of lymph node stations associated with improved survival among patients with non-small cell lung cancer (NSCLC).
Authors: Ray Meredith , Matthews Anberitha T , Akinbobola Olawale , Smeltzer Matthew , Fehnel Carrie , Faris Nicholas R , Saulsberry Andrea , Dortch Kourtney , Muhit Samuel , Osarogiagbon Raymond U.
Published: June 2023

8571

Background: Good quality pathologic nodal evaluation is associated with improved long-term survival in NSCLC after surgical resection. However, there is no universal definition of quality. We examined the association between number of lymph node stations (NLNS) sampled and overall survival. Methods: We examined the population-based Mid-South Quality of Surgical Resection (MS-QSR) cohort, excluding patients with neoadjuvant therapy, positive margins, and secondary resections. We summarized demographic and clinical characteristics with appropriate statistics. We employed four Cox regression models: 1) including NLNS as the only predictor; 2) model 1, adjusting for age, sex, histology, clinical stage, extent of resection, and surgical technique; 3) examined the impact of pathologic staging (pStage in 3 groups: IA/IB[<4cm tumor size]; IB[>4cm]/II/IIIA[pN2-]; pN2]) by modeling interaction with pStage and NLNS; 4) model 3 plus adjustments (no clinical stage). In a cut point analysis to identify the optimal NLNS for improved survival, we dichotomized the NLNS for cut points 0 to 12. Hazard ratios (HR) were calculated (as above) and plotted for each dichotomization. Results: The 3916 eligible patients were 21% Black, 54% male, 15% on Medicaid and 49% Medicare; 84% and 85% had clinical and pathologic stage I/II, respectively; 84% had no invasive staging; 84% had a PET-CT scan. For every additional lymph node station sampled, the HR decreased by 0.94 (95% confidence interval: 0.92, 0.96). After adjustments, the HR remained significant (Table). Our pStage cohorts comprised of 2474 (64%) IA/IB[<4cm]; 1080 (28%) IB[>4cm]/II/IIIA[pN2-]; and 290 (8%) pN2+. Once stratified, HRs remained significant among those with early stage but not for pN2+ (Table). When further adjusted, only pStage IA/IB[<4cm] patients had a significant HR, 0.94 (0.91, 0.97). The cut point analysis indicated sequential survival improvement up to ≥ 7 total stations sampled, consistently across all models/adjustments. Conclusions: The number of lymph node stations examined is directly associated with survival after lung cancer resection. Examination of a total of 7 intrapulmonary, hilar and mediastinal stations seems optimal. Hazard ratios (95% confidence intervals) for modeling hazards as a function of lymph node stations sampled (model 1), further adjusted for age, sex, histology, clinical stage, extent of resection, and surgical technique (model 2), including interaction with pathologic stage with no adjustments (model 3), and interaction with pathological stage with adjustments (no clinical stage) (model 4). [Table: see text]
Analysis of tumor- and circulating-free DNA methylation to identify clinically relevant small cell lung cancer subtypes.
Authors: Heeke Simon , Gay Carl Michael , Estecio Marcos Roberto , Tran Hai T. , Morris Benjamin B. , Zhang Bingnan , Tang XiMing , Raso Maria G , Rocha Pedro , Arriola Edurne , Hofman Paul , Kopparapu Prasad , Lovly Christine M. , Concannon Kyle , Xi Yuanxin , Diao Lixia , Wang Qi , Wang Jing , Byers Lauren Averett , Heymach John
Published: June 2023

8577

Background: Small-cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, defined by the predominant expression of one of the three transcription factors ASCL1 (SCLC-A), NEUROD1 (SCLC-N) and POU2F3 (SCLC-P) as well as an inflamed subtype (SCLC-I; see Gay et al. Cancer Cell. 2021), each with potential therapeutic vulnerabilities. Implementing subtyping in the clinic has remained challenging due to limited tissue availability, particularly for longitudinal monitoring. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that there would be subtype-specific patterns of DNA methylation that could be detected in tumor or blood from SCLC patients. Methods: We included 179 patients with SCLC and performed RNA sequencing and genomic-wide reduced-representation bisulfite sequencing (RRBS). We further analyzed DNA methylation in 68 plasma samples including longitudinal samples to track SCLC subtype evolution over time. Results: Using machine learning approaches, we developed a highly accurate DNA methylation-based classifier (SCLC-DMC) that could distinguish SCLC subtypes using clinical tumor samples with 95.8% accuracy in the testing set compared to mRNA-based profiling. We further adjusted the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we could demonstrate that SCLC subtypes evolve frequently during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. Furthermore, methylation-based subtyping predicted response to a wide variety of drugs in preclinical models like CDK and AURK inhibitors, and clinical outcomes were indistinguishable in cohorts of patients subtyped using mRNA or SCLC-DMC (p = 0.95). Conclusions: These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and guide precision SCLC therapy.
Updated safety and efficacy results of SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for extensive-stage small cell lung cancer (ES-SCLC) from a phase II trial.
Authors: Chen Dawei , Gao Aiqin , Huang Wei , Shao Qian , Meng Xiangjiao , Tang Xiaoyong , Zhang Pinliang , Hu Xudong , Zhang Yan , Guo Jun , Fu Lei , Zhao Wei , Zhao Changhong , Yuan Jiajia , Yu Jinming , Wang Linlin
Published: June 2023

8580

Background: CAPSTONE-1 study showed that SHR-1316 (PD-L1 antibody) combined with first-line chemotherapy could prolong overall survival in patients (pts) with ES-SCLC. Previous studies have shown that radiotherapy could potentially promote tumor antigen presentation and reverse immunosuppressive microenvironment in tumor. The purpose of this study was to explore the efficacy and safety of SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for ES-SCLC. Methods: Key inclusion factors were 18-75 years old, histologically or cytologically confirmed ES-SCLC, ECOG performance status 0-1, no previous systematic treatment. Pts included in this study received 4~6 cycles of SHR-1316 (20mg/kg, D1, q3w) combined with EP/EC (cisplatin, 75mg/m², D1-3, q3w or carboplatin, AUC = 5, D1, q3w and etoposide, 100mg/m2, D1-5, q3w), sequentially SHR-1316 combined with chest radiotherapy (≥3Gy*10f or ≥2Gy*25f, involved-field irradiation), and then entered the maintenance treatment stage until disease progression or intolerable side effects. The main endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Results: From October 2020 to January 2023, 63 pts with ES-SCLC were enrolled and received at least one dose of SHR-1316, 33 of them have received chest radiotherapy. The median age was 63 (range: 38-75), and most pts were male (53, 84.1%), former smokers (42, 66.7%) with an ECOG performance status 1 (60, 95.2%). At baseline, 24 (38.1%) pts were diagnosed with brain metastasis and 19 (30.2%) pts had liver metastasis. At the data cutoff date, the average number of treatment cycles was 6.9, 17 pts remained on treatment. 55 pts had at least one post-treatment tumor assessment. 41 pts achieved a confirmed partial response, and 12 pts had stable disease. The confirmed ORR and DCR were 74.5% and 96.4%, respectively. The median PFS was 7(CI: 4.3~9.7) months. Adverse events (AEs) occurred in 47 (74.6%) pts. Grade 3 or 4 AEs occurred in 35 (55.6%) pts. The most common grade 3 or 4 AEs included neutropenia (27, 42.9%), leukopenia (13, 20.6%), lymphocytopenia (5, 7.9%), pneumonia (4, 6.3%), anemia (3, 4.8%), and thrombocytopenia (2, 3.2%). Conclusions: SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety. It is worthy of further clinical exploration. Clinical trial information: NCT04562337 .
Efficacy and safety of lurbinectedin in elderly patients with relapsed SCLC.
Authors: Cousin Sophie , Paz-Ares Luis G. , Fülöp Andrea , Horvath Ildiko , Trigo Perez Jose Manuel Manuel , Zugazagoitia Jon , Bonanno Laura , Lopez-Vilariño Jose Antonio , Kahatt Carmen Maria , Fernandez Cristian Marcelo , Gomez Javier , Zeaiter Ali Hassan , Navarro Alejandro , Syrigos Kostas N. , Smit Egbert , Ciuleanu Tudor-Eliade , Chiappori Alberto , Lopez-Lopez Rafael , Besse Benjamin
Published: June 2023

8591

Background: Relapsed SCLC is a difficult-to-treat disease. A considerable number of SCLC patients are elderly with associated fragility and numerous comorbidities. Accelerated approval from the US FDA of lurbinectedin (Zepzelca) 3.2 mg/m2 q3wk as second-line therapy in metastatic small cell lung cancer (SCLC) was based on results from a phase 2 basket trial (NCT02454972) showing overall response rate of 35.2% and duration of response of 5.3 months. The ATLANTIS trial (NCT02566993) assessed the combination of lurbinectedin 2mg/m2/ doxorubicin (DOX) 40 mg/m2 as second-line treatment for SCLC vs. a control arm of topotecan/CAV. Methods: This post hoc analysis explores the efficacy and safety of lurbinectedin in relapsed SCLC patients ≥65 years included in both phase 2 basket (26 patients treated with lurbinectedin) and ATLANTIS (121 patients treated with lurbinectedin/DOX and 118 patients treated in the control arm) trials. This analysis did not include patients from the phase 2 basket trial with chemotherapy-free interval (CTFI) < 30 days, as these patients were excluded in the ATLANTIS trial. Results: Median age was similar (72.5 in lurbinectedin basket vs. 69 in ATLANTIS lurbinectedin/DOX vs. 69 in ATLANTIS control arm), most were males (65.4% vs. 57.9% vs. 60.2%), with ECOG PS 1 (65.4% vs. 68.6% vs. 68.6%) and CNS involvement (7.7% vs. 10.7% vs. 15.3%). Median CTFI (days) was also similar (105.5 vs. 123 vs. 120). Median number of cycles was 4 vs. 6 vs. 4. Main efficacy and safety results are shown in the table. Treatment-related adverse events (AEs) were reported in 92.3%, 92.6% and 94.1% of patients, respectively (grade ≥3 in 50.0%, 59.5% and 81.4%). Conclusions: In elderly patients, lurbinectedin seems to be superior to the standard of care in terms of both efficacy (higher response rate and longer duration of response and overall survival) and safety (less associated hematological AEs), which reinforces its role as a treatment option in relapsed SCLC patients ≥65 years. Clinical trial information: NCT02454972 , NCT02566993 . [Table: see text]