bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of tumor treating fields (TTFields) therapy-related skin adverse events in pleural mesothelioma: A single center experience of TTFields therapy concomitant with chemotherapy.
Authors: Grosso Federica , Delfanti Sara , Gallizzi Giulia , Marengo Francesca , Megna Iacopo , Bertolina Carlotta , Ceresoli Giovanni Luca
Published: June 2023

e20542

Background: Tumor Treating Fields (TTFields) therapy is a noninvasive, locoregional modality comprised of electric fields which disrupt critical cellular processes necessary for cancer cell viability and tumor progression. TTFields therapy is FDA approved and CE-marked for glioblastoma, and pleural mesothelioma. Approval for the latter was based on results from the phase 2 STELLAR study (EF-23, NCT02397928), in which the median OS was 18.2 months (95% CI 12.1–25.8) and median PFS was 7.6 months (95% CI 6.7–8.6). As the electrical fields are delivered non-invasively via skin-adhered arrays, the most common adverse events (AEs) are mild-moderate skin reactions which can be effectively managed with appropriate prophylaxis and timely intervention. Here we report a single-center experience of treating and managing TTFields therapy-related AEs in the STELLAR study, based on a center-specific protocol. Methods: The STELLAR study was a multicenter, single-arm, non-randomized, phase 2 study, whereby patients received TTFields therapy (150 kHz, 18 h/day) concomitant with pemetrexed (500 mg/m2) and platinum-based chemotherapy (75 mg/m2). TTFields-therapy AEs were managed and treated using a center-specific protocol (Table). Results: In this single center, 23 patients were treated using the predefined protocol to prevent skin AEs; all were included in the safety analysis. n = 15 (65%) reported a mild-moderate skin AE (n = 12 [52%] medical device site reaction [skin AE], n = 1 [4%] had mild-moderate rash, rash erythematous and skin irritation) in the single center, vs n = 54 (68%) in the overall STELLAR population. n = 2 (9%) in the single site had a severe medical device site reaction, which was comparable with the overall STELLAR study population. Conclusions: A predefined multidisciplinary approach was successful to help prevent mild-moderate skin AEs. Timely and appropriate management of mild/moderate skin AEs can prevent exacerbations. Skin management may support usage, thus optimizing outcomes for patients. Guidelines on preventing skin AEs when using TTFields therapy are available and should be incorporated in a clinical setting. Clinical trial information: NCT02397928 . [Table: see text]
Characteristics and trends of globally registered malignant pleural mesothelioma clinical trials in the past 27 years.
Authors: Guo Chenguang , Li Congsen , Shen Guoping , Zhou HaiYu
Published: June 2023

e20544

Background: Malignant pleural mesothelioma (MPM), arising from the serosal lining of the thoracic cavity, is a rare malignancy with limited treatment options and very poor prognosis. Recent progress in immunotherapy and innovative devices have advanced treatment fields of MPM. To help investigators understand the landscape of MPM clinical research, characteristic and trends of globally registered trials in the past decades were analyzed in our study. Methods: This is a cross-sectional analysis of MPM trials registered on ClinicalTrials.gov between January 1996 and December 2022. Characteristics pertaining to trail phase, enrollment number, study design, type, funding source, age of population, trial purpose, and participating country were extracted, and chronological shifts were analyzed. Clinical trial variables were enumerated using descriptive statistics and categorical data were presented as frequencies and percentages. Chi-square trend analysis (Cochran–Armitage trend test) was used to evaluate the trend of MPM trials. Results: 267 registered MPM trials were analyzed involving 40 participating countries among which the United States, the United Kingdom, and Italy were top 3. 8.2% trials were phase 3 and 18.7% were randomized. 74 trials had publications by the December 2022. The trial purposes concerning surgery, radiotherapy, chemotherapy, target therapy, immunotherapy, photodynamic therapy, cryotherapy, tumor treating fields （TTF）and non-anticancer research accounted for 2.6%, 5.2%, 20.2%, 25.5%, 31.1%, 1.1%, 0.7%, 0.7% and 12.7% respectively. In the past 27 years, the numbers of chemotherapy and targeted therapy trials declined while immunotherapy trails steadily escalated (all above ptrend < 0.05). There are no significant changes for the trends of each trial phase. 205 drug therapy trials involved 26 cytotoxic drugs, 44 targeted drugs and 11 immune checkpoint inhibitors and 34 other drugs. Pemetrexed-cisplatin with TTF and ipilimumab-nivolumab have changed the frontline treatment space while improvement for regulatory approvals has been far slower in salvage treatment, with the median overall survival all less than 11 months in phase 3 trials. There are no definitive trials that justify the use of predictive biomarkers for systemic therapy in MPM. Conclusions: Immunotherapy and TTF have reshaped the standard of care landscape over the past 27 years. With the enhanced understanding of molecular characteristics and mechanism of MPM, it is anticipated that ongoing immunotherapy combined with target therapy, chemotherapy or other novel treatment can improve the frontline and post-line therapeutic effect.
Association of neutrophil-lymphocyte ratio with survival in peripheral early-stage non–small-cell lung cancer after stereotactic body radiation therapy.
Authors: Huang Karen , Prasad Sharan , Ma Sung Jun , Yu Han , Iovoli Austin , Farrugia Mark , Dexter Elisabeth , Demmy Todd L. , Malik Nadia Karen , Singh Anurag K.
Published: June 2023

e20547

Background: Prior studies have demonstrated that neutrophil-lymphocyte ratio (NLR) can predict overall survival in patients undergoing stereotactic body radiation therapy (SBRT) for multiple types of cancer. The role of neutrophil-lymphocyte ratio (NLR) as a predictor for survival in single fraction SBRT-treated non-small cell lung cancer (NSCLC) patients remains unclear. Methods: A single-institution database of peripheral early-stage NSCLC patients treated with SBRT from February 2007 to May 2022 was queried. Consecutive patients with peripheral early-stage NSCLC (T1-2N0M0) and a complete blood count within six months of the start of SBRT treatment were included. Patients treated with SBRT regimens of more than 3 fractions were excluded as these regimens were reserved for patients with centrally located lesions with higher risk of toxicity which could affect survival. Optimal threshold of neutrophil-lymphocyte ratio (NLR) was defined based on maximally selected rank statistics. Cox multivariable analysis (MVA), Kaplan-Meier, and propensity score matching were performed to evaluate outcomes. Results: A total of 286 patients (164 female [57.3%]; median [IQR] age 76 [69-81] years) were included for analysis with median follow up of 19.7 months. The median NLR was 3.06 ([IQR] 2.21-4.33). There were 15 local failures, 27 nodal failures, and 50 distant failures. On Cox multivariate analysis, as a continuous variable, NLR was shown to be an independent predictor of OS (adjusted hazards ratio [aHR] 1.06, 95% CI 1.02-1.10, p = 0.005; Figure 1) and PFS (aHR 1.05, 95% CI 1.01-1.09, p = 0.013; Figure 1). In addition, NLR was associated with DF (aHR 1.11, 95% CI 1.05-1.18, p < 0.001; Figure 1). Maximally selected rank statistics determined 3.28 as the cutoff point of high NLR versus low NLR. These findings were confirmed upon propensity matching. Conclusions: Pretreatment NLR is an independent predictor for survival outcomes of peripheral early-stage NSCLC patients after SBRT. High NLR is associated with worse overall survival, progression-free survival, and distant metastasis. Pretreatment NLR levels should be tracked on trials for early-stage NSCLC patients.
Blood-based DNA methylation panel for the early diagnosis of lung cancer.
Authors: Yang Rongxi , Di Feifei , Li Mengxia , Yang Yining , Yuan Hongli , Jin Jialie
Published: June 2023

e20551

Background: Early detection of lung cancer (LC) is vital for reducing of LC-related mortality. Although the screening of persons at high risk for LC by low-dose computed tomographic (LDCT) has showed an inspiring 20.0% decrease in mortality, it also comes along with a dramatically high false positive rate for distinguishing the malignant nodules from the benign nodules. Thus, it is necessary to develop a diagnostic tool with high discriminant ability for identifying malignant nodules. Methods: The methylation levels of five candidate genes were quantitatively measured via mass spectrometry. A diagnostic model was developed by blood-based methylation levels in training cohort (650 LC cases vs. 114 benign lung nodules), and further validated the performance in validation cohort (195 LC cases vs. 39 benign lung nodules) by binary logistic regression. Notably, 91.8% LC cases were collected at Stage I. Results: The methylation model of 35 CpG sites was developed and validated for LC diagnosis. This model achieved a sensitivity of 85.4% and a specificity of 92.5% in training cohort [Area Under the Curve (AUC): 0.945], and a sensitivity of 84.1% and a specificity of 97.2% in validation cohort (AUC: 0.932). The performance was well maintained in (a) Stage I subgroup (n = 447), with a sensitivity of 82.6% and a specificity of 81.6%; (b) nodule diameter ≤ 1 cm (n = 113), with a sensitivity of 80.6% and a specificity of 81.6% in validation cohort. Conclusions: This study suggests that the blood-based DNA methylation panel may provide the potential utility for early diagnosis of LC cases, which would promote early diagnosis and benefit more LC patients.
ctDNA for clonal evolution surveillance and therapeutic efficacy prediction in unresectable locally advanced non-small cell lung cancer under radiotherapy.
Authors: Bi Nan , Yang Yufan , Wang Jianyang , Wang Jingbo , Zhao Xiaotian , Yang Yin , Zhu Minyi , Wang Luhua
Published: June 2023

e20555

Background: Therapeutic efficacy differs across unresectable locally advanced non-small cell lung cancer (LA-NSCLC) patients receiving definitive radiotherapy/chemoradiotherapy (RT/CRT), but the underlying resistance mechanism, clonal evolution and molecular prognostic factors remain poorly understood. Methods: Unresectable LA-NSCLC patients treated with definitive RT/CRT were consecutively enrolled between May 2018 and November 2020. Next-generation sequencing covering 474 cancer-relevant genes was performed on plasma ctDNA collected at pre-treatment (TP0), 4-week post-RT (TP1), 1-month post-RT (TP2), 3-month post-RT (TP3), and progression (TP4). Main study endpoints included disease progression, progression-free survival (PFS), death from any cause, overall survival (OS), distant metastasis and distant metastasis free survival. Fisher’s exact test and two-sample t-tests were performed to compare the frequencies and means of independent groups, respectively. The median follow-up time was estimated using the reverse Kaplan-Meier method. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated by Cox proportional hazards models. Results: A total of 46 patients were included (median age: 63 [range: 40–80], males: 87%, clinical stage IIIB: 52%, squamous cell carcinoma: 54%, TP0 ctDNA shedding: 63%, consolidation immunotherapy: 33%). Twenty-nine (63%) patients developed disease progression by the end of follow-up (median follow-up: 23.7 months), with median PFS and OS being 15.5 and 25.4 months, respectively. The polymerase epsilon ( POLE) mutational signature at TP0 indicated inferior PFS (HR: 5.32, 95% CI: 1.83–15.45) and worse OS (HR: 20.68, 95% CI: 3.94–108.62). Notably, newly-discovered/lost mutations were rarely observed at TP4 when compared to TP0. Patients with a high ratio of mean over max variant allele frequency (m/mVAF) in TP0 samples, indicative of a clonal predominant tumor with a low subclone fraction ( P< 0.01), had relatively poor OS, compared to patients with low m/mVAF (HR: 2.92, 95% CI: 0.82–10.46) or undetectable ctDNA (HR: 3.39, 95% CI: 0.98–11.75). The prognostic value was validated in an independent publicly available dataset of 431 LA-NSCLC patients receiving definitive RT/CRT, showing patients with high m/mVAF demonstrated worse OS than those with low m/mVAF (HR: 1.43, 95% CI: 1.08–1.89). Additionally, increased m/mVAF between TP0 and TP1 indicated an elevated risk for disease progression ( vs. non-increase, HR: 3.49, 95% CI: 1.20–10.16), especially for distant metastasis ( vs. non-increase, HR: 2.85, 95% CI: 0.84–9.69). Conclusions: Our findings demonstrated the clinical value of plasma ctDNA and its derived molecular features in delineating clonal evolution, monitoring therapeutic resistance, and predicting prognosis of LA-NSCLC under definitive RT.
Neoadjuvant sintilimab combined with chemotherapy in resectable locally advanced non-small cell lung cancer: A retrospective study.
Authors: Yin Cunli , Liu Bin , Ge Jun , Hu Bin , Yang Xi , Kou Lingna , Tian Bo , Wang Chenghao , Li Siru
Published: June 2023

e20556

Background: In recent years, neoadjuvant immunotherapy with chemotherapy has shown increasing promise for locally advanced non-small cell lung cancer (NSCLC). However, more real-world clinical outcomes are needed. In this study, we aimed to evaluate the safety and efficacy of sintilimab combined with chemotherapy as neoadjuvant therapy in patients with potential resectable NSCLC. Methods: We retrospectively reviewed thirteen patients with previously treated NSCLC receiving neoadjuvant chemoimmunotherapy in Sichuan Cancer Hospital between February 2021 and February 2023. Sintilimab injection (intravenously,200mg, iv, d1, q3w) and platinum-based chemotherapy were administered intravenously every 3 weeks, with surgery planned approximately 4-11 weeks after the last dose. The primary endpoint of the study was pathologic complete response (pCR). The secondary endpoints were objective response rate (ORR), and safety. Results: All patients received sintilimab combined with platinum-based chemotherapy for two to four cycles before. None of them needed a reduced initial dose or delay due to intolerable adverse events. A total of nine patients (69.2%) achieved pCR. Nine patients experienced neoadjuvant treatment-related adverse events (TRAEs). Only one patient (7.6%) experienced grade 4 neoadjuvant TRAE. Conclusions: Neoadjuvant sintilimab plus platinum-based chemotherapy was feasible and safe for patients with resectable stage IIB-IIIB non-small-cell-lung-cancer.
Clinical and molecular characteristics of multiple primaries identified by whole-exome sequencing-based genetic divergence in non-small-cell lung cancer.
Authors: Liu Ning , Wang Yongsheng , Li Xue , Jiang Lili , Wang Weiya , Ma Qizhi , Tang Jie , Zhu Daxing , Mei Jiandong , Zhang Benxia , Shu Pei , Chen Yue , Qin Diyuan , Guo Fuchun
Published: June 2023

e20558

Background: With the recommendation of high-resolution chest computed tomography scan in lung cancer screening, multiple primary lung cancers (MPLC) is gaining more attention. Identifying MPLC from intrapulmonary metastases (IPM) is crucial to the clinical management. The current guidelines for the identification are always based on expert consensus rather than clinical evidence. We aim to develop a reliable identification method and further figure out the clinical and genetic features of MPLC. Methods: We retrospectively screened 305 lung lesions from 131 patients who underwent radical resection for multiple lung carcinomas. To minimize the effect of therapeutic intervention on prognostic outcomes, patients with each single tumor size smaller than 4cm, free of nodal or systemic metastases, and had high-quality whole-exon sequencing (WES) data were included. We selected 11 patients with confirmed intrapulmonary metastases for training. All patients’ follow-up information was collected until disease recurrence or metastases. A WES genetic divergence method for identifying MPLC from IPM was developed. The disease-free survival (DFS) was used as a validation tool for identification reliability. Results: A total of 61 eligible multi-lesion patients with 128 resected non-small cell lung cancer (NSCLC) lesions were finally analyzed. Based on WES genetic divergence identification, 51 MPLC patients were identified, whose DFS was significantly prolonged (HR, 0.27; 95% CI, 0.08 to 0.91; P = 0.02), while other recommended methods for identifying MPLC patients failed to show a DFS advantage. Among MPLC patients, 43.1% (22/51) had a first-degree relatives cancer family history, of whom 54.5% (12/22) had a lung cancer family history. EGFR was still the most common mutation gene (72.5%, 37/51); however, TP53 mutations was less frequent in MPLC (21% vs. 48%, P < 0.05), and tumor mutation burden (TMB) was lower (median, 0.73 muts/Mb vs. 1.15 muts/Mb, P < 0.01). Notably, despite the lack of shared alterations, unique germline variants in cancer-predisposing genes, particularly nonsynonymous SNV in solute carrier gene (SLC) family, were observed in most MPLC patients, rarely overlapping with IPM patients. Conclusions: WES-based genetic divergence clearly distinguishes independent primary tumors from IPM in NSCLC patients. MPLC patients represent a unique population which deserves further study.
A real-world analysis of nonmetastatic non–small-cell lung cancer in Italy.
Authors: Esposito Immacolata , Ronconi Giulia , Dondi Letizia , Calabria Silvia , Piccinni Carlo , Pedrini Antonella , Dondi Leonardo , Dell'anno Irene , Addesi Alice , Martini Nello
Published: June 2023

e20566

Background: The majority of all lung cancer cases are represented by non-small cell lung cancer (NSCLC), for which the standard of care is surgical resection. Chemotherapy, radiotherapy and immunotherapy are the most important perioperative systemic treatments. This study aimed to identify newly NSCLC diagnosed, non-metastatic (i.e., stages I-III) and resected patients, and characterize them from the perspective of the Italian National Health Service (INHS). Methods: From the Fondazione ReS (Ricerca e Salute) database (~5 million inhabitants/year), in 2017 (accrual period), patients with a new in-hospital diagnosis of NSCLC (i.e., excluding those diagnosed back up to 2013), at stage I-III (i.e., excluding those with distant metastases at the first diagnosis and/or within 60 following days), and resected (i.e., with ≥1 in-hospital surgery within 6 months from the first diagnosis), were identified. The cohort was characterized by age, sex and comorbidities. The dispensation of neoadjuvant therapy (≥1 radio and/or chemotherapy session) between the first diagnosis and surgery was analyzed. Within 2 years after surgery, overall survival-OS and progression free survival-PFS (Kaplan Meier analyses), and healthcare integrated costs charged to the INHS (pharmaceuticals, hospitalizations, specialist/outpatient services) were described. Results: In 2017, of 2440 (incidence 52.1 x100,000) newly NSCLC diagnosed patients, 1605 were defined with stage I-III. Of these, 467 (29.1%) underwent surgery. They were mainly males (74.3%) and on average aged 69±10. Arterial hypertension (64.7%), chronic lung diseases (46.7%) and dyslipidaemia (36.0%) were the most frequent comorbidities. Lung lobectomy (highest mean length of in-hospital stay: 11 days) was the most common surgery (296/467; 63.4%). Before surgery, 48/467 patients (10.3%) received neoadjuvant therapy. During the 2nd year after surgery, 418/467 patients (89.5%) were analysable. At 2 years after surgery, OS was 81.6% and increased with age, while PFS was 59.8%. On average: within 1 year, the INHS spent € 20,942 per capita (hospitalizations – including first hospitalization - accounted for 56.3%, and pharmaceuticals for 35% of the total cost); within the 2nd year, the INHS expenditure was € 9,851 per capita (pharmaceuticals weighed 65.8% of the overall cost, and hospitalizations 19.8%). Conclusions: Italian administrative healthcare data can identify and describe newly NSCLC diagnosed patients with stage I-III and resected, quantify their burden on the INHS and show a substantial survival benefit.
Association of lymph node examination during resection with overall survival (OS) and healthcare costs in patients with early non–small-cell lung cancer (eNSCLC).
Authors: Lee Jay M. , To Tu My , Lin Chia-Wei , Wang Shu , Johnson Ann , Lee Janet
Published: June 2023

e20567

Background: To evaluate the effect of LN examination status on OS and healthcare costs in patients (pts) with eNSCLC. Methods: Retrospective observational study of pts with resected stage IA-IIIB NSCLC (AJCC 7th ed) from SEER data linked with Medicare claims. Eligible pts were ≥65 years at diagnosis (Jan 2010-Dec 2017), had surgery ≤1 month before or 12 months after diagnosis and were continuously enrolled in Medicare Parts A and B for ≥6 months before diagnosis and in Parts A, B and D up to 6 months post-surgery or date of death. Pts were analyzed by LN examination status: no examination (pNX), examination and no LN metastasis (pN0) and examination with N1 (pN1) or N2 (pN2) metastasis. Extended Cox proportional hazards models presented OS hazard ratios (HRs) for specific time periods. Total healthcare costs per patient per month (PPPM) were analyzed using a gamma-log regression model. Results: A total of 9448 pts were included: 996 pNX (11%), 6457 pN0 (68%), 1003 pN1 (11%) and 992 pN2 (10%). pNX pts were slightly older with lower median income, more comorbidities and more baseline smoking history vs other LN examination status cohorts. Stage distribution in pNX and pN0 pts appeared similar. Grade 3/4 tumors were less prevalent in pNX (n = 301, 30%) and pN0 (n = 1934, 30%) pts relative to pN1 (n = 482, 48%) and pN2 pts (n = 424, 43%; P< 0.001). Unadjusted OS was worse for pN1 and pN2 vs pN0 pts and was similar between pNX and pN2 pts. Adjusted OS showed higher risk of death for pN1 and pN2 vs pN0 pts; this risk decreased over time. pNX pts also had higher risk of death vs pN0 pts. Adjusted marginal mean follow-up costs were lowest for pN0 and highest for pN2 pts (All P < 0.001). Costs were higher, but not statistically significant ( P= 0.591) in pNX vs pN0 pts. The majority of total healthcare costs (62-65%) were due to inpatient services. Conclusions: Stage distribution in pNX pts was more similar to that of pN0 than pN1/2 pts, likely due to understaging from lack of LN examination. However, prognosis in pNX pts was nearly identical to that of pN2 pts, suggesting missed LN metastasis diagnosis in a substantial proportion of pNX pts. Despite worse OS in pNX vs pN0 pts, healthcare costs in pNX pts were not significantly higher, which may reflect underutilization of systemic therapy in pts with resected eNSCLC. [Table: see text]
Surgical outcomes and patient-reported outcomes of unresectable stage III non-small cell lung cancer patients who underwent PD-1 inhibitor plus chemo as induction therapy.
Authors: Wang Xin , Liu Guixian , He Jintao , Zhuang Xiang
Published: June 2023

e20570

Background: For locally advanced unresectable NSCLC, studies of PD-1 inhibitor plus chemo as induction therapy and its roles on subsequent surgical resection are still limited. In this study, a consecutive series of unresectable stage III NSCLC patients were collected to investigate the surgical outcome and postoperative symptom changes in locally advanced patients who received adjuvant chemotherapy combined with immunotherapy. Methods: 92 locally advanced NSCLC patients received 2-4 cycles of chemotherapy combined with immunotherapy. Surgical rates, major pathologic remissions(MPR), pathologic complete remissions(PCR), postoperative complications, and immune-related adverse reactions(irAEs) were assesd. The follow-up of symptoms was performed during treatment and within 3 months postoperatively, and symptom changes were described based on patient-reported outcomes. Results: 26.09% of patients developed irAEs, the most common was skin toxicity, followed by thyroid dysfunction. 71.74% of patients underwent surgical resection. 63.64% (42/66) achieved MPR and PCR, of which 37.87% (25/66) were PCR. Most of these patients have clinical symptoms at the time of presentation, mainly cough (90%), and after treatment, cough is significantly reduced compared with before treatment. After treatment, the cough was significantly reduced compared with before treatment , nausea and vomiting , loss of appetite , dry mouth , and diarrhea were increased or aggravated. The most common symptoms on the first day after operation included pain (90%), shortness of breath (62.5%), fatigue (45%), cough (42.5%), and dry mouth (37.5%). On the third day after surgery, the incidence and severity of each symptom changed significantly, pain and dry mouth decreased significantly compared with before, cough, shortness of breath, and fatigue worsened and the incidence increased. Pain remains the most severe symptom in the early postoperative period, with the most severe on the first day after operation and then reduced, returning to preoperative levels 1.5 months after surgery. Cough was the main symptom at the time of presentation, which was significantly reduced after preoperative treatment, and the incidence and severity of postoperative cough increased significantly compared with preoperative treatment and returned to the preoperative level within 1 week after surgery. Dyspnea lasts long after surgery. Two weeks after surgery, shortness of breath (dyspnea) becomes the most obvious symptom. Conclusions: Preoperative chemotherapy combined with immunotherapy provides more opportunities for radical resection in locally advanced NSCLC patients. The most common postoperative symptoms are pain, dyspnea, cough, and fatigue; dyspnea is the symptom that affects patients the most and lasts the longest after surgery.
Transcriptomic subtype, TP53 mutation status, and APOBEC mutation signature in early-stage EGFR-mutant non-small-cell lung cancer.
Authors: Jung Hyun Ae , Lim Jinyeong , Choi Yoon-La , Park Sehhoon , Sun Jong-Mu , Ahn Jin Seok , Ahn Myung-Ju , Lee Se-Hoon
Published: June 2023

e20571

Background: In a previous pilot study, we classified early-stage EGFR-mutant NSCLC according to two transcriptomic subtypes (i.e., terminal respiratory unit [TRU], which was related with the downregulation of a proliferative-related pathway; and non-TRU, which was related with the activation of a proliferative-related pathway) and the presence of a co-existing TP53 mutation. In turn, the clinical significance of the APOBEC mutation signature has not been elucidated clearly owing to the small sample size of the previous pilot study. Thus, this study aimed to validate the predictive value of transcriptomic subtype, TP53 mutation status, and APOBEC mutation signature, to expand our pilot study via the use of additional samples and a long-term follow-up. Methods: We performed whole-exome sequencing and whole-transcriptome sequencing using fresh tissue or FFPE from 101 patients with pathological stage II–IIIA non-squamous EGFR-mutant NSCLC who underwent complete resection between January 2014 and December 2020 at the Samsung Medical Center. This study evaluated the recurrence-free survival (RFS) and progression-free survival (PFS) afforded by EGFR-TKI therapy after recurrence according to transcriptomic subtype, TP53 mutation status, and APOBEC mutation signature. Results: The median duration of the follow-up period was 54.2 months (range, 11.3–107.7 months). Six patients were excluded because of failure of the initial quality control; thus, 95 patients were included in the final analysis. The median age was 61.9 years (range, 44.7–91.0 years), and 75.8% of the patients were never-smokers. Moreover, 51.6% of the patients had stage III disease. Among the 95 patients, 47 (49.5%) patients were in the non-TRU group and 44 (46.3%) patients carried a TP53 mutation. The median RFS was 25.8 months (95% CI, 17.6–34.0 months). Patients with non-TRU and/or TP53 mutation had an inferior RFS compared with patients with TRU and wild-type TP53, regardless of the pathological stage (hazard ratio, 1.9; 95% CI, 1.4–2.7). The APOBEC mutation signature was not associated with RFS ( P = 0.17). Among the 65 patients who experienced radiological recurrence, 59 patients received EGFR-TKI therapy as the first-line treatment. The median PFS of EGFR-TKI therapy was 20.7 months (95% CI, 13.6–26.6 months). However, among these patients, those with the APOBEC mutation signature had a shorter PFS than those without this mutation signature (8.2 vs. 23.5 months, P < 0.05). Conclusions: This study showed consistently that the transcriptomic subtype and TP53 mutation status were predictive factors of RFS, regardless of the pathological stage, in patients with early-stage EGFR-mutant NSCLC. Additionally, the APOBEC mutation signature may be present at the initial diagnosis of early-stage EGFR-mutant NSCLC and was associated with a poor PFS after EGFR-TKI therapy.
Comparison of clinical outcomes in patients with advanced pulmonary sarcomatoid carcinoma treated with immunotherapy-based regimen or chemotherapy: A study based on the SEER database and multicentric real-world settings.
Authors: Peng Duanyang , Xiong Le , Luo Yuxi , Liu Anwen , Wang Xia , Zeng Zhimin
Published: June 2023

e20573

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare pulmonary cancer characterised by early metastasis and invasion, predominantly diagnosed with locally advanced or metastasis, hindering the possibility of surgical intervention. However, a standardised treatment strategy for advanced PSC is yet to be established. Herein, we aimed to evaluate the effects of immunotherapy-based strategies or chemotherapy on patients with advanced PSC. Methods: We conducted a retrospective study to compare the clinical outcomes of immunotherapy-based regimens and chemotherapy in patients with advanced PSC using the Surveillance, Epidemiology, and End Results (SEER) database and data from three cancer centres. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier method. Univariate and multivariate analyses were performed to identify prognostic factors. Results: In total, 202 patients with stage IV PSC were identified from the SEER database. The median OS was 5 months. The median follow-up time of PSC patients from three cancer centres was 27.5 months Considering all three cancer centres, first-line treatment with a first-line immunotherapy-based regimen and chemotherapy were administered to 12 and 16 patients, respectively. The median PFS was 2.1 (95% confidence interval [CI] [2.1, 4.1]) and 7.2 (95% CI [6.8, 7.6]) months for the chemotherapy- and immune-based groups, respectively (p < 0.001). The median OS was 3.6 (95% CI [1.6, 5.6]) and 13.7 (95% CI [5.1, 22.3]) months for the chemotherapy and immune-based groups, respectively (p = 0.003). Multivariate analysis revealed that the immunotherapy-based regimen was an independent prognostic factor for PFS and OS (p < 0.01, hazard ratio [HR] = 0.22, 95% CI [0.07,0.67] and p < 0.01 HR = 0.27 95% CI [0.11,0.68], respectively). Conclusions: Conventional chemotherapy has limited benefits in patients with stage IV PSC. However, patients with advanced PSC who received first-line immunotherapy-based regimens exhibited a remarkable response. The immunotherapy-based regimen was an independent prognostic factor for PFS and OS.
Pathological response and tumor immune microenvironment remodeling of neoadjuvant ALK-TKIs in NSCLC with ALK.
Authors: Li Li , Zheng Nan , Zhang Yi Min , Zhang Ruiguang , He Yong , Wu Fang
Published: June 2023

e20574

Background: Anaplastic lymphoma kinase–tyrosine kinase inhibitor (ALK-TKI; ALKi) has shown potent antitumor activity in metastatic non–small-cell lung cancer (NSCLC) with ALK rearrangement (ALK+). However, its efficacy in neoadjuvant settings for patients with ALK+ resectable NSCLC has been poorly explored. Given this, the present study aimed to examine the clinical activity and tumor immune microenvironment (TIME) remodeling of neoadjuvant ALKi therapy. Methods: In this retrospective study, ALK+ NSCLC patients treated with neoadjuvant ALKi therapy at three hospitals in China were enrolled between February 2018 and April 2022.Data on clinical features, radiographic responses, and pathological responses were collected and evaluated. Multiplex immunofluorescence was performed on pre-treatment biopsy specimens and surgically resected specimens to investigate the impact of ALKi on TIME. Two panels (Panel 1: CD8, PD1, GB, CK, 4′,6-diamidino-2-phenylindole [DAPI]; Panel 2: CD4, FOXP3, CD68, CD163, CK, DAPI) were used to identify multiple immune cell types. Results: A total of 12 patients with stage IIA to IIIB NSCLC who received neoadjuvant ALKi therapy and R0 resection were enrolled; the median age was 54.0 years, and 66.7% (8/12) were female. The median duration of neoadjuvant ALKi was 5.5 months. The objective response rate was 91.7% (11/12). All patients successfully underwent R0 resection. The major pathological response (MPR) rate was 75.0% (9/12), with 58.3% (7/12) achieving a pathological complete response (pCR). After neoadjuvant ALKi therapy, we observed asignificant increase in immune infiltration of total CD8+ (histochemistry score: median, 10.51 vs 24.01, P= 0.028; density: median, 128.38 vs 694.09 cells/mm2, P= 0.028; percentage: median, 3.53% vs 15.92%, P= 0.028) and total CD4+ (density: median, 275.56 vs 651.82 cells/mm2, P= 0.028; percentage: median, 5.98% vs 10.46%, P= 0.028). Similar results were found for CD4+FOXP3+, CD8+PD1+, CD8+PD1-, CD8+GB+, and CD8+GB-. However,macrophages, including CD68+CD163- M1 and CD68+CD163+ M2 macrophages, showed little change after neoadjuvant ALKi therapy. When comparing TIME between neoadjuvant ALKi and PD1 inhibitors in resected specimens from patients with pCR, neoadjuvant ALKi therapy presented higher levels of CD8+PD1+ but lower levels of CD8+GB+. Conclusions: Neoadjuvant ALKi therapy achieved an encouraging MPR rate of 75% and enhanced immune infiltration, suggesting its safety and feasibility for ALK+ resectable NSCLC. This study advances our understanding of TIME remodeling by neoadjuvant ALKi therapy and merits further investigation in the neoadjuvant setting for patients with ALK+ resectable NSCLC.
A robust and accurate method to detect MET Exon 14–skipping mutation in pan-cancer samples using an NGS-based RNAseq approach.
Authors: Wang Yongjie , HengDa Ren , Zhang Yiqun , Pei Zhihua , Wang Dongliang , Zhou Qiming , Wang Jing
Published: June 2023

e20575

Background: Met exon 14 skipping mutation(METex14) occurs in multiple cancer species, mainly in non-small cell lung cancer (NSCLC, 3~4%) and pulmonary sarcomatoid carcinoma (PSC, 22%). Several drugs expressed curative effect in previously treated patients who harboring METex14, such as savolitinib approved by NMPA, capmatinib and tepotinib licenced by FDA. Developing a quick and precise method which detect METex14 and help patients benefit from clinical drug treatment is a desiderative issue currently. Previous researches suggest that transcriptome-based RNA-seq method was superior to DNA-based NGS (exome, panel) and PCR method. Here We introduce a fast and accurate method to detect METex14 alternation in RNAseq data. Methods: We sequenced NGS-based Ribo-zero RNAseq (pair-end, 150bp×2) and METex14 ddPCR on 99 pan-cancer samples, of which 38 lung carcinoma (38%), 8 renal carcinoma (8%), 7 pancreatic carcinoma (7%). In 38 lung carcinoma, 35 NSCLC samples were consist by 29 lung adenocarcinoma (LUAD, 76%), 4 lung squamous carcinoma (LUSC, 10%) and 2 PSC (5%). Begin of the study, data quality control applied by Fastp and aligned to human hg19 genome by STAR subsequently. Next, MET exon14 related candidate soft-clipping reads were extracted from BAM files and translated to fastq file. Then we remapped the translated fastq file to hg19 genome with Blat using parameters ‘stepSize = 5, -repMatch = 2253, -minScore = 20, -minIdentity = 90’. Next, supporting reads were sequentially retained by: single end length longer than 18bp; block mapped reads of MET gene; the pair end reads mapped to genome if one end fall in the last 3bp of MET intron 13 and another end fall in at least initial 3bp of MET exon 15. Pair or single end support junction read, distance of junction site to reads end and site coverage were enrolled in a bayesian model to calculate METex14 confidence score (BMMETs). Threshold of our model was defined by the cut-point of max youden-index and 16 samples were validated METex14 by ddPCR. Finally, we would predict a sample with METex14 when score > = 0.752. Results: Our method reported 15 TP samples, 1 FP sample and 1 FN samples (AUC 0.97, sensitivity 0.88, specificity 0.98) while STAR-fusion detected 14 TR samples and 6 FP sample and 2 FN samples (AUC 0.715, sensitivity 0.64, specificity 0.73). BMMETs FP sample scored approximately 0.739 that close to the threshold. Conclusions: Strategy of screen reliable METex14 supporting reads and using bayesian model to calculate a METex14 confidence score could robustly and efficiently predict METex14 event in NGS-based RNAseq data.
Concurrent durvalumab plus chemoradiation therapy followed by durvalumab in Chinese patients with unresectable stage III non-small cell lung cancer: CRUISER study.
Authors: Teng Feifei , Ge Hong , Wang Buhai , Xu Yaping , Meng Xue , Wang Suzhen , Xing Ligang , Yu Jinming
Published: June 2023

e20576

Background: Concurrent chemoradiation therapy (CRT) followed by durvalumab consolidation therapy has demonstrated significant survival benefit for unresectable stage III non-small cell lung cancer (NSCLC) in PACIFIC trial. However, there are still 20%-30% patients who have disease progression (PD) or intolerable toxicity. This prospective study aimed to evaluate safety and clinical activity of concurrent durvalumab plus CRT followed by durvalumab in unresectable stage III NSCLC (NCT04982549). Methods: This is a single-arm, open-label, multicenter phase II clinical trial and planned to enroll 35 patients with unresectable stage III NSCLC of any PD-L1 expression level and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. All of patients will receive concurrent durvalumab 1500mg every 4 weeks plus SoC CRT followed by durvalumab monotherapy 1500mg every 4 weeks until PD or unacceptable toxicity. One cycle of induction durvalumab plus chemotherapy is allowed before radiotherapy upon investigator discretion. The primary endpoint is the incidence of grade ≥3 immune-mediated adverse event (AE). Here we report the preliminary clinical activity and safety of a preplanned interim analysis of this study. Results: By September 2022, 28 patients finished concurrent durvalumab plus CRT treatment and were included for analysis. 21 (75%) of 28 patients had radiographic tumor evaluation and entered the consolidation treatment stage, 7 (25%) patients discontinued treatment without radiographic tumor evaluation because of intolerable AE (5 patients) or withdrawing from the study (2 patients). 20 (71.4%) of 28 patients received one cycle induction therapy of durvalumab plus chemotherapy. The median age of these 28 patients was 64 years old, 26 (92.9%) of 28 patients with ECOG performance status of 1, and 14 (50%) of 28 patients were squamous carcinoma. Disease stage was IIIA (42.9%, 12/28), IIIB (39.3%, 11/28) and IIIC (17.9%, 5/28), with most of them (89.3%, 25/28) had N2/N3 lymphatic metastasis. 19 (90.5%) of 21 patients achieved objective response. Median interval from enrollment to the first radiological evaluation was 112 days. Grade ≥3 treatment-related adverse event (TRAEs) occurred in 13(46.4%) of 28 patients, including six (21.4%) possibly related to durvalumab. Conclusions: The interim results from CRUISER study showed promising clinical activity and manageable toxicity of durvalumab plus concurrent CRT followed by durvalumab for unresectable stage III NSCLC. The survival outcome and biomarker exploration will be analyzed upon data maturity. Phase 3 PACIFIC-2 study investigating clinical outcome of concurrent durvalumab plus CRT in unresectable NSCLC is ongoing. Clinical trial information: NCT04982549 .
Detection effectiveness of immune-related gene mutations in lung adenocarcinoma by circulating tumor DNA.
Authors: Qin Jing , Yin Fengxiang , Guo Weifeng , Zhang Guoying , Du Shasha , Liu Danni , Jing Zhang , Cheng Shaochen
Published: June 2023

e20580

Background: Lung adenocarcinomas (LUAD) is the major pathological subtype of lung cancer with a poor prognosis. Tumor development and progression are significantly influenced by immune microenvironment. However, immune-related gene alterations have not been utilized in prognostic evaluation frequently. Circulating tumor DNA (ctDNA) provides a non-invasive approach to cancer diagnosis and prognosis. It is possible to find immune-related biomarkers that may be used to predict clinical outcomes and evaluate the effectiveness of ctDNA for the detection of immune-related gene mutations in LUAD. Methods: Immunologically relevant genes were downloaded from ImmPort, including chemokines (n = 102), cytokine receptors (n = 307), cytokines (n = 456), interferons (n = 17), interleukins receptors (n = 42), interleukins (n = 47), TGF-β family (n = 33) and TNF family (n = 12). Clinical and genetic mutation data of 604 LUAD samples were obtained from cBioPortal. The Kaplan-Meier method of survival analysis was used to estimate the overall survival (OS) of the published LUAD data set. 1837 LUAD patients collected both tumor tissue and blood samples were screened from the HapLab database (HaploX, Shenzhen, China). Results: OS analysis had been processed in each immune-related gene set and gene receptively. Only patients with cytokine receptor mutations showed a poor prognosis compared with the wild-type (log-rank test, p-value = 0.027). OS did not differ statistically significantly in patients with or without alterations in any other immune-related gene sets or individual genes. Protein-coding mutations of 32 cytokine receptor genes were found in 1290 LUAD tumor tissue samples from HapLab database. 93.75% (30/32) genes were observed mutations in paired plasma ctDNA results, and the minimum variant allele frequency (VAF) was 0.04%. 243 alterations in cytokine receptor genes were only detected in 54 peripheral blood samples. The overall sensitivity and specificity were 91.09% and 40.05% in blood ctDNA assay. Conclusions: The mutational status of cytokine receptor genes in LUAD is significantly associated with long-term OS. The presence of tumor DNA in the blood showed high diagnostic accuracy for detecting cytokine receptor mutations in LUAD patients. Circulating tumor DNA-based liquid biopsy offers LUAD patients a non-invasive prognostic assessment method based on immune-related gene mutation screening. [Table: see text]
Patients’ epidemiology in stage III, unresectable non-small-cell lung carcinoma: A real-world analysis in Brazil.
Authors: Amaral Duarte Flavia , Marques dos Santos André , Santana Pamela , Dias Caique , Lopes Danilo , Denapoli Priscila
Published: June 2023

e20589

Background: Although breakthrough therapy options for NSCLC have emerged in the last few years, lung cancer is still the principal cause of cancer-related deaths in both men and women worldwide. In Brazil, lung cancer is the major cause of cancer mortality – the second most common cause of cancer-related death in females and the first cause among males. The main factors contributing to the high burden of the disease remain the late-stage diagnosis and unequal healthcare access, which are most prevalent in low- and middle-income countries. This study aimed to describe lung cancer epidemiology – patients in stage III, unresectable NSCLC that could benefit from consolidation therapy after chemoradiation (CRT) treatment - in the Brazilian public health system for evaluating the future impact of new therapies. Methods: We gathered information on lung cancer procedures performed between January 2018 and October 2022 using the Brazilian public health system database (DATASUS). Since this is a claim medical database without clinical data, assumptions were specified based on procedures performed to determine the potential number of patients in Brazil who would benefit from these new treatment strategies in stage III NSCLC. The assumptions were the following: 1. Having received systemic therapy for a malignant tumor of the bronchi and lung (ICD-10 - C34); 2. Having received a pre-defined list of chemotherapy regimens (to define which patients were NSCLC); 3. Having started systemic therapy with a Stage III tumor; 4. Having not undergone surgery between three months before and two months following the start of systemic treatment 5. Treated with chemotherapy and radiotherapy (concomitantly or sequentially - until two months later); 6. Patients who died or progressed during treatment were classified as incomplete treatment. Results: Between 2018 and 2022, we identified an average of 9,340 patients each year who started therapies for lung cancer; 75% (7,023) of them performed specific procedures for NSCLC and were classified as such. 21% (1,472) of patients started treatment for stage III NSCLC, and 98% (1,438) of these cases were unresectable. Of these, 26% (377) received chemotherapy and radiation, 92% of whom finished the course of treatment. In Brazil, 346 patients per year with stage III unresectable NSCLC could be treated with consolidation therapy after CRT in the public health system. Conclusions: The number of NSCLC patients who can benefit from consolidation therapy after CRT (346) represents 3.7% of all lung cancer patients starting systemic treatment annually. It allows a better management of the possible economic impact of the addition of this new therapy in the Brazilian health public system. Increased screening for early diagnosis and improving access to CRT would expand the patient population eligible for this therapeutic approach.
Efficacy and safety of pembrolizumab plus chemotherapy and sequential surgical resection in initial unresectable stage IIIB NSCLC.
Authors: Zhou Jianya , Li Yuekang , Zheng Jing , Ruan Kexin , Zhou Jianying
Published: June 2023

e20595

Background: Neoadjuvant immunochemotherapy has been proved effective in resectable NSCLC, while its role in unresectable stage IIIB NSCLC remains controversial. This study aims to demonstrate the efficacy and safety of neoadjuvant immunochemotherapy sequential surgical resection in initial unresectable stage IIIB NSCLC patients. Methods: This multicenter study retrospectively analyzed 59 patients with initial unresectable stage IIIB NSCLC who received induction pembrolizumab combined with chemotherapy between June 2019 and April 2022. The clinical characteristics, radiological and pathological response and survival outcomes were collected and evaluated. Results: A total of 59 initial unresectable stage IIIB NSCLC patients were identified and divided into the surgery group (n = 23) and non-surgery group (n = 36) with a median follow-up time of 15.0 months. The median PFS/DFS of surgery group was significantly longer than that of non-surgery group (not reached versus 15.5 months, p = 0.0031). The median OS was not reached in both groups, overall survival rate was 100% (23/23) in surgery group and 83.3% (30/36) in non-surgery group. Pathological analysis suggested that 13 of 23 patients (56.5%) achieved major pathological response (MPR) or pathological complete response (pCR), and more squamous cell carcinoma cases were observed in MPR group compared to non-MPR group ( p = 0.034). Of 23 patients in surgery group, all patients had a R0 resection, no surgical-related mortality was recorded, only 3 patients (13.0%) experienced any postoperative complications. Conclusions: Surgical resection after neoadjuvant immunochemotherapy is beneficial in the survival outcome of initial unresectable stage IIIB NSCLC patients, with a high MPR rate and good surgical safety.