bluuebunny/crossref_metadata_2025 huggingface dataset:
Importance of DICER1 pathogenic variants in non-small cell lung cancer.
Authors: Wu Samuel , Evans Mark Gordon , Chong Anne-Laure , Thorner Paul , Fiset Pierre-Olivier , Butt Yasmeen M. , Oberley Matthew James , Gatalica Zoran , Foulkes William D.
Published: June 2023

e20602

Background: DICER1 encodes a miRNA processing enzyme involved in regulation of cell proliferation and differentiation. The role of DICER1 pathogenic variants (PVs) in non-small cell lung cancer (NSCLC) is relatively unknown. Germline and/or somatic PVs have been reported in pleuropulmonary blastoma, pulmonary blastoma (PB), and low-grade/well-differentiated fetal adenocarcinoma (WDFLAC), with clustering of somatic PVs at specific metal ion binding residues referred to as hotspot alterations. PVs in CTNNB1, resulting in constitutive activation of the WNT signaling pathway, have also been implicated in PB and WDFLAC. This study seeks to establish the frequency of somatic DICER1 hotspot PVs that occur in all NSCLCs, their co-occurrence with other PVs in DICER1 and with alterations of CTNNB1/WNT signaling, and their histologic correlates. Methods: Molecular sequencing data collected from 12,146 NSCLCs at Caris Life Sciences were queried for cases featuring somatic DICER1 variants. For those tumors harboring hotspot PVs, sequencing for CTNNB1 and APC mutations was performed, as well as histological review, including examination of beta-catenin immunohistochemical (IHC) staining. Results: Of the 12,146 NSCLCs analyzed, 235 (1.9%) were found to have one or more DICER1 PVs. Of these 235, 225 cases demonstrated one variant, while 10 tumors featured two. Gene analysis revealed that 8 of the observed PVs cases contained hotspot alterations: 2 in the single variant cases and 6 in the double variant cases. The remaining 4 double variant cases harbored a combination of truncating, non-hotspot missense, or splice variants. No significant differences were observed for age or smoking status between DICER1 hotspot-positive and hotspot-negative groups. All but one tumor were considered to be in histologic spectrum of PB/WDFLAC. Of the 8 DICER1 hotspot-positive cases, 1 had a PV in APC, 4 had a CTNNB1 PV, 1 had a PV in both APC and CTNNB1, and 2 had neither. Beta-catenin IHC showed nuclear positivity in 5 tumors that had a PV in either CTNNB1 and/or APC.. Conclusions: This study demonstrates that DICER1 somatic hotspots select for morphologic features of tumor types such as PB and WDFLAC, but are not implicated in the most common forms of NSCLC. Furthermore, DICER1 hotspot-positive NSCLCs frequently harbor CTNNB1 and/or APC alterations, with many cases exhibiting nuclear staining by beta-catenin IHC, suggesting a possible synergistic relationship between DICER1 hotspot PVs and activation of the WNT signaling pathway in the formation of pulmonary tumors. These findings emphasize the importance of molecular testing in clinical practice such that detecting somatic DICER1 hotspot alterations aids in the diagnosis of rare lung cancers, which ultimately require special consideration with respect to disease severity and treatment.
Demographics of the tumor formerly known as bronchiolo-alveolar carcinoma.
Authors: Luker Andrew , Hsia Beau , Wu Xinxin , Silberstein Peter T. , Keirns Darby
Published: June 2023

e20604

Background: Bronchiolo-alveolar carcinoma (BAC) is a rare subtype of non-small cell lung cancer of the lung periphery, often characterized by lepidic growth. Although BAC has undergone various reclassifications in recent years, International Classification of Disease codes still classifies these subtypes using the same codes that previously belonged to BAC. Changing diagnostic criteria and other factors cause BAC to be among the most overdiagnosed forms of lung cancer and thus a demographic study could provide insight into trends. Methods: A retrospective cohort analysis utilizing the National Cancer Database (NCDB) from 2004 – 2020 included patients with malignant forms of BAC (Invasive mucinous adenocarcinoma, mixed invasive mucinous, and nonmucinous adenocarcinoma) confirmed through histology. Demographic factors such as sex, age, race, Hispanic status, median household income, insurance status, facility type, county population, distance from facility, and Charlson Deyo score were analyzed by descriptive statistics and incidence trends. Results: In total, 12,607 patients were identified in the database with a confirmed diagnosis of BAC between 2004 – 2020. The number of cases per year remained steady (mean = 565.4) until 2018. From 2018 to 2020, the average number of diagnoses per year was 1575.0. The average age of diagnosis was 69.3 years (SD = 10.7, range = 10 to > 90 years). 58.1% of the cases were female patients. The top primary sites were the lower and upper lobes (46.2% and 39.9% respectively). The majority (59.2%) had Charlson-Deyo comorbidity scores of 0. Most cases occurred in Non-Hispanic White persons (86.8%). More patients were in the top quartile of income earners (34.0%) compared to those in lower quartiles. Medicare was the insurance provider for most patients (65.0%). More patients were diagnosed in counties with a population over 1 million (52.4%). More patients were treated in comprehensive community cancer programs (38.1%) followed closely by academic cancer programs (35.2%). Patients lived an average of 31.6 miles (SD = 113.0, range = 0.1 – 2390.7) from the treatment facility. Conclusions: This is the first NCDB analysis on the demographics of BAC. The sudden rise in cases per year in 2018 aligns with the changing pathologic and histologic definitions for BAC. A 2006 review of BAC found that 50-70% of cases occur in female patients, similar to our results. The majority of BAC patients tend to be non-Hispanic and White with a primary site diagnosis in the lower lobe, followed by the upper lobe. BAC patients are more likely to be in the top income quartile, live in densely-populated metropolitan areas, and receive treatment in a non-academic program. Further research is needed to better understand the impact of demographic, socioeconomic, and environmental factors on the diagnosis and prognosis of BAC, especially because its diagnostic criteria have changed recently.
Spread through air spaces in non-small cell lung cancer: Experience of a tertiary hospital.
Authors: Calvo Virginia , Garitaonaindia Yago , Martinez Cutillas Marta , TRASEIRA CRISTINA , Redondo Isabel , Aguado Ramon , Lorduy Ana Collazo , Campo Cañaveral Jose Luis , Martin Lopez Javier , Ospina Serrano Aylen Vanessa , Blanco Mariola , Crowley Silvana , Romero Roman Alejandra , Gil Barturen Mariana , Parejo Consuelo , Provencio-Pulla Mariano
Published: June 2023

e20606

Background: Tumor spread through air space (STAS) is a novel pattern of invasion related to poor prognosis in non-small cell cancer (NSCLC). In 2015, Kyuichi Kadota first described spread through air spaces (STAS) as a novel histologic pattern of invasion related to poor prognosis NSCLC. The objective of this study is to describe the incidence of STAS in a surgical series of NSCLC patients resected in Hospital Universitario Puerta de Hierro-Majadahonda and identify the association of STAS with clinicopathological characteristics. Methods: Observational retrospective cohort study was performed from 2015 to 2021. Inclusion criteria were: age more than 18 years, histologically confirmed diagnosis of NSCLC, clinical stage I-IV and radical treatment with surgery. Descriptive analysis was performed. Results: 178 patients were included. 69.1% (123) were male, median age was 68.0 years. In relation to histological subtypes: 65.2% were adenocarcinoma, 22.5% squamous-cell carcinoma and 12.3% other histologies. Patients were classified by pathological stage: 71.9% were in stage I, 11.4% in stage II, 15.6% in stage III and 1.1% in stage IV. STAS was observed in the surgical specimen in 62 cases (34.8%). In Table-1 the association of STAS with clinicopathological characteristics is shown. Conclusions: In our study, we found statistically significant association between STAS and histological subtype and presence of lympho-vascular invasion. STAS were present more frequently in adenocarcinoma and were associated with more incidence of lympho-vascular invasion, as reported in other studies. More analysis are required for further description of this dissemination pattern and its implication in the prognosis of the patients. [Table: see text]
Survival for patients of stage III non-small cell lung cancer after radiotherapy in different periods.
Authors: Wang Zhuofan , Liu Qi , Wang Yuxiang , Qi Zhan , Zhang Zhimen , Shi Jian , Chen Xinyuan , Zhang Jian , Wang Yuan , Jia Zhongfei , Song Meng , Zhao Yan
Published: June 2023

e20611

Background: Concurrent chemoradiotherapy (CCRT) is the main treatment for patients of unresectable stage Ⅲ non-small cell lung cancer (NSCLC).To retrospectively analyze prognosis and its related factors for patients of unresectable stage III NSCLC after radiotherapy in different periods. Methods: From 2000 to 2010 and from 2015 to 2019, patients of stage III NSCLC which received radiotherapy in the Fourth Hospital of Hebei Medical University were enrolled. Statistical analysis was used with the SPSS 21.0 software.The Kaplan-Meier method, log-rank test and Cox model were used for survival analysis, univariate analysis, and multivariate analysis, respectively. Results: A total of 808 patients of stage III NSCLC were enrolled. There were 674 males and 134 females. The median age was 63 years old( 29-86 years old ) . Radiotherapy (RT) were performed in 474 patients between 2000 to 2010 and in 334 patients between 2015 to 2019. There were 240 cases received with RT alone, 449 cases with sequential chemoradiotherapy (Seq-CRT) and 119 cases with CCRT. 55 were treated with 3-dimensional radiotherapy (2DRT) plus 3-dimensional conformal radiotherapy (3DCRT)，386 with 3DCRT，and 367 with intensity-modulated radiotherapy（IMRT)， respectively. The median doses was 60 Gy (range 36-77Gy). The median overall survival (OS) was 21.0 months (19.4-22.6 months), and the 1-, 3- and 5-year OS rates were 69.8%, 30.7% and 21.3%, respectively. Under univariate analysis, gender, age, radiotherapy technology，period of treatment and whether combined chemotherapy were significantly associated with OS ( P< 0.05). The median OS was 18.0 months in group of 2000-2010 and 26.1 months in group of 2015-2019, respectively. The median OS for groups of2DRT+3DCRT, 3DCRT and IMRT were 10.0, 21.0, 23.4 months, respectively. The median OS for RT alone, Seq-CRT and CCRT was 17.0, 21.0, 30.3 months, respectively. Under multivariate analysis, sex, age, times of RT and combined chemotherapy were independent prognostic factors for OS ( P< 0.05). Conclusions: From 2DRT to 3DCRT or IMRT, the OS in patients of stage Ⅲ NSCLC was gradually increased; the OS was more higher in patients treated between 2015-2019 also. In addition, the OS was significantly longer in patients with CCRT than with Seq-CRT or RT alone.
Surgery with adjuvant chemotherapy versus chemoradiation for early-stage large cell neuroendocrine cancer (LCNEC) of the lung: A SEER plus based analysis.
Authors: Shah Anish , Potluri Lakshmi Bhavani , Budhathoki Pravash , Gaire Suman , Uprety Dipesh
Published: June 2023

e20616

Background: LCNEC of the lung is a rare and highly aggressive tumor with neuroendocrine differentiation. Given its rare occurrence and lack of data from large randomized trials, treatment recommendations are based on the extrapolation of data, primarily from small-cell lung cancer studies. We conducted this study to evaluate the survival difference among patients with LCNEC with an N1 disease between those who received surgery and adjuvant chemotherapy versus definitive chemotherapy and radiotherapy. Methods: We utilized Surveillance, Epidemiology, and End Results (SEER) plus 18 registries database to identify patients diagnosed with LCNEC with tumor stage of T1, T2, or T3 and nodal stage of N1. The study population included patients, 18 years and above, who underwent surgical resection followed by adjuvant chemotherapy and patients who received definitive chemo-radiotherapy for early stage LCNEC. Kaplan-Meier and log rank test were used to compare overall survival (OS) and Cancer specific survival (CSS). Multivariate survival analysis was done using the cox proportional hazards regression model. Results: A total of 178 patients were included, 57.3% (n = 102) were < 65-year-old, 50.56% (n = 90) were male, mostly Caucasian 87.08% (n = 155) and identified as non-Hispanic 93.26% (n = 166). Out of them, 70.22% (n = 125) underwent surgery plus adjuvant chemotherapy and 29.78% (n = 53) underwent chemoradiation. Patients who underwent surgery with adjuvant chemotherapy had higher overall survival (OS) than chemoradiation (37 vs. 11 months respectively). 3-year (49.9% vs. 15.7%) and 5-year OS rates (36.7% vs. 10.4%) were also higher in the earlier group. On multivariate analysis after adjusting for age, gender, race and origin, patients who received chemoradiation had higher hazards as compared to those who received surgery and adjuvant chemotherapy (Hazard ratio: 2.91, 95% Confidence interval (CI):1.93,4.37, P value < 0.001). When examining the cancer specific survival (CSS), similar results were observed with higher CSS in the surgery with adjuvant chemotherapy group (18 vs. 8 months) reaching a statistical significance of P < 0.001 and higher hazards in chemoradiation group (Hazard ratio: 3.33, 95% Confidence interval (CI):2.09,5.28, P value < 0.001). 3-year survival (26.47% vs. 2.7 %) and 5-year CSS rates (11.76% vs. not reached) were also pronounced in the patients treated with surgery with adjuvant chemotherapy. Conclusions: Our study demonstrates that patients with early stage LCNEC (T1-3 N1) disease treated with surgery and adjuvant chemotherapy had statistically significant overall and cancer specific survival rates compared to those treated with chemoradiation.
Real-world analysis of ICI efficacy in ES-SCLC patients with and without brain metastases: A call for inclusion in clinical trials.
Authors: Cao Yuanzhen , Afzal Muhammad Zubair , Lu Ziyao , Sharma Aditya , Pirruccello Jonathan P. , Shirai Keisuke
Published: June 2023

e20621

Background: Immune checkpoint inhibitors (ICIs) have proven successful in treating extensive stage small-cell lung cancer (ES-SCLC). Atezolizumab, a PD-L1 inhibitor, is approved as first-line therapy for ES-SCLC in combination with chemotherapy. SCLC has a high incidence to spread to the brain with more than 50% of patients developing brain metastases (BM) during their clinical course. However, patients with BM have frequently been excluded from clinical trials due to their perceived poor prognosis. This study aimed to assess the efficacy of ICI in achieving disease response and managing intracranial disease in patients with ES-SCLC. Methods: We conducted a retrospective study on patients with biopsy-confirmed ES-SCLC treated with at least one cycle of atezolizumab/carboplatin/etoposide combination from 2015 to 2022. Overall survival (OS), progression-free survival (PFS) and radiographic response were noted in patients with and without BM. Intracranial (IC) response was documented in patients with radiographic evidence of BM who had at least one follow-up brain imaging after the start of ICI. Results: A total of 83 patients were included, 39.3% (n = 33) of which had BM. Median follow-up was 8 (95%CI: 4.5-11.6) months. Baseline characteristics were summarized in the table below. Disease progression occurred in 90.9% patients with BM and death in 51.5%. Among 21 patients who fulfilled IC response assessment criteria, one (4.8%) had complete response, four (19.0%) had partial response, two (9.5%) had stable disease and fourteen (66.7%) had disease progression. Median duration of IC response was 5.3 (95%CI: 0.00-20.35) months; IC objective response rate was 23.8%. No difference was found in OS (10 vs. 30 months, P = 0.3) or PFS (6 vs. 7 months, P = 0.18) in patients with and without BM respectively. Patients with > 3 BM (n = 16) had inferior OS (7 vs. 21 months, P = 0.01) and PFS (5 vs. 6 months, P = 0.002) compared to those with ≤3 BM. Conclusions: This study demonstrated that ICI achieved similar outcomes in patients with and without BM and produced meaningful intracranial response in patients with BM. Therefore, further clinical trials on ES-SCLC should encompass patients with BM, especially those with ≤3 BM. Future research on a larger, more diverse patient population is warranted. [Table: see text]
Correlations between overall response rate, progression-free survival and overall survival in refractory small cell lung cancer treated with lurbinectedin.
Authors: Wasifuddin Mustafa , Ilerhunmwuwa Nosakhare Paul , Hakobyan Narek , Tahir Muhammad , Abowali Hesham , Avezbakiyev Boris
Published: June 2023

e20623

Background: Lurbinectedin is a novel second-line option for refractory small-cell lung cancer. It is a synthetic alkaloid that functions by covalently binding to DNA and generates double-strand breaks, and disrupts DNA-protein interactions and RNA transcription. It is yet to be well established in the literature if the overall response rate (ORR) can predict progression-free survival (PFS) and/or overall survival (OS). This study aims to investigate the correlations between PFS, ORR, and OS in refractory small-cell lung cancer treated with lurbinectedin. Methods: PubMed, Google Scholar, and Clinicaltrials.gov databases were queried for randomized, phase 3 clinical trials, phase 2 trials, phase 1 trials with expansion cohorts, and retrospective and prospective studies. The criteria for eligibility included a clinical diagnosis of treatment-refractory small cell lung cancer, at least one prior line of therapy, articles in English, and lurbinectedin treatment. ORR, OS, and PFS data were extracted manually from the selected studies, and correlation analyses with Spearman’s rank correlation were performed. Results: Seventy-one articles and trials were identified. Seven articles, including 849 patients, met our criteria and were included for further analyses. OS and PFS were strongly correlated (rs = 0.9196, p-value = 0.02), whereas the correlation between OS and ORR was not statistically significant (rs = 0.6696, p-value = 0.20). Also, the correlation between ORR and PFS was not statistically significant (rS = 0.6785, p-value = 0.05419). Conclusions: There was a strong correlation between OS and PFS in studies investigating lurbinectedin use in patients with refractory small-cell lung cancer. There were no significant correlations between ORR and PFS/OS. We propose that PFS can be used as a surrogate for OS in studies involving lurbinectedin-treated refractory small-cell lung cancer, especially when the time to reach OS is protracted.
Outcome of immune checkpoint inhibitors in patients with extensive-stage small-cell lung cancer and brain metastases.
Authors: Wang Chunyu , Jing Fangfang , Zhang Fan , Tao Haitao , Ma Junxun , Hu Yi , Wang Lijie
Published: June 2023

e20625

Background: Brain metastases (BMs) are common in extensive-stage small-cell lung cancer (SCLC) and are underrepresented in pivotal clinical trials that demonstrate the efficacy of immune checkpoint inhibitors (ICIs). We conducted a retrospective analysis to assess the role of ICIs in BM lesions in less selected patients. Methods: Patients with histologically confirmed extensive-stage SCLC who were treated with ICIs were included in this study. Objective response rates (ORRs) were compared between the with-BM and without-BM groups. Kaplan‒Meier analysis and the log-rank test were used to evaluate and compare progression-free survival (PFS). The intracranial progression rate was estimated using the Fine-Gray competing risks model. Results: A total of 133 patients were included, 45 of whom started ICI treatment with BMs. In the whole cohort, the overall ORR was not significantly different for patients with and without BMs (p = 0.856). The median progression-free survival for patients with and without BMs was 6.43 months (95% CI: 4.70-8.17) and 4.37 months (95% CI: 3.71-5.04), respectively (p = 0.054). In multivariate analysis, BM status was not associated with poorer PFS (p = 0.101). Our data showed that different failure patterns occurred between groups, with 7 patients (8.0%) without BM and 7 patients (15.6%) with BM having intracranial-only failure as the first site progression. The cumulative incidences of brain metastases at 6 and 12 months were 15.0% and 32.9% in the without-BM group and 46.2% and 59.0% in the BM group, respectively (Gray’s p < 0.0001). Conclusions: Although patients with BMs had a higher intracranial progression rate than patients without BMs, the presence of BMs was not significantly associated with a poorer ORR and PFS with ICI treatment in multivariate analysis.
Anlotinib plus irinotecan or docetaxel in small-cell lung cancer (SCLC) relapsed within six months: Updated results from a single-arm, phase Ⅱ study.
Authors: Zhang Minna , Chen Xueqin , Jiang Hong , Wang Jiaoli , Ye Jian , Ma Shenglin , Xia Bing
Published: June 2023

e20629

Background: There is still no unsatisfactory treatment strategy for patients (pts) with advanced SCLC relapsed within six months after first-line treatment, although chemotherapy alone is the standard treatment. Anlotinib, an oral multitarget tyrosine kinase inhibitor, effectively inhibits angiogenesis and enhances tumor cell response to chemotherapy. In the ALTER 1202 trial, anlotinib had significantly improved progression-free survival (PFS) and overall survival (OS) of advanced SCLC pts who received at least two lines chemotherapy. Therefore, we presented the updated efficacy and safety of anlotinib plus irinotecan or docetaxel in SCLC relapsed within six months after first-line treatment. Methods: Eligible pts with advanced SCLC who have relapsed within six months after first-line platinum-based treatment received anlotinib (12mg, QD from day 1 to 14 of a 21-day cycle, the dose could be adjusted to 10mg or 8mg according to the patient's tolerance) and irinotecan (65mg/m2, day1,8, q3w, up to 4 cycles) or docetaxel (60mg/m2, q3w, up to 4 cycles) until progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). Secondary endpoints included PFS, the disease control rate (DCR), OS and safety. Results: As of Jan 31, 2023, we recruited 39 pts, among which 36 pts (median age: 63.2 years, male: 86.1%, ECOG PS 1: 80.6%, brain metastasis: 58.3%, liver metastasis: 36.1%) were eligible for efficacy analysis. Median follow-up time was 17.2 months (95% Cl, 8.27 -26.13 ). Of 36 evaluable pts, 1 pts had complete response (CR) , 20 pts reached partial response (PR) and 11 pts had stable disease(SD). The ORR was 58% (21/36) and the DCR was 89% (32/36), respectively. The median PFS was 4.4 months (95%Cl: 3.73- 5.08). The median OS was 7.9 months (95%Cl: 5.28-10.52). The Progression-free survival and overall survival in patients with recurrence > 3 months and ≤ 6 months (PFS 6.5 m and OS 11.9 m) after first-line therapy improved more significantly than in patients with recurrence ≤ 3 months (PFS 4.1 m and OS 5.9 m). Most common grade 1-2 treatment-related adverse events (TRAEs) included weakness(58.3%), anorexia(38.9%), anemia(25%), hypertension (15.6%), Oral mucositis (13.9%) and leucopenia (11.1%). 3 pts (8.3%) suffered from grade 3 AEs, which were thrombocytopenia, leukopenia, and anemia. Conclusions: Anlotinib combined with irinotecan or docetaxel as second-line treatment for non-sensitive recurrent SCLC (i.e., extensive-stage disease time to relapse: 0-6 months) showed superior efficacy and safety compared with standard chemotherapy. It may become a novel therapeutic strategy for the population. Clinical trial information: NCT04757779 .
Racial disparities in the prevalence of extrathoracic metastases in lung cancer patients and survival: A SEER database study (2010–2019).
Authors: Al Armashi Abdul Rahman , Alkrekshi Akram , Al Zubaidi Anas , Hammad Faris , Elantably Dina , Truong Vien , Ngo Tam N.M. , Bruno Debora S.
Published: June 2023

e20630

Background: Metastatic disease at the time of lung cancer diagnosis influences therapy choice and prognosis. Metastasis to the brain, bones, and liver may lead to higher morbidity. Differences in the prevalence of metastatic sites among patients (pts) of White (W) and Black (B) race and their association with overall survival need further elucidation. Methods: Utilizing the SEER database from 2010-2019, we identified W and B pts with metastatic small cell (SCLC), squamous cell (SQ-NSCLC), and adenocarcinoma (AD-NSCLC). Only pts with bone, brain, or liver metastasis (mets) at diagnosis were included. Metastatic site prevalence rates were determined. Cox proportional hazard ratios for survival were calculated while controlling for gender, ethnicity, other metastatic sites, chemotherapy, and radiation. Results: Total of 338,411 pts, 11.4% of B race. In SCLC, B pts had a higher prevalence of brain mets, while W pts demonstrated a higher prevalence of bone and liver mets. Survival between W and B pts with SCLC was comparable except for modest superior survival in B pts with liver mets. In SQ-NSCLC, metastatic disease for the 3 sites of interest was more prevalent in B pts, most notably in brain. However, survival did not differ. In AD-NSCLC, B pts were more likely to present with brain and liver mets. B pts with bone mets had inferior survival. Conclusions: Significant differences in patterns of mets at the time of lung cancer diagnosis between W and B pts exist. B pts with SCLC and liver mets had longer survival. Interestingly, B pts with bone mets and SQ-NSCLC had better survival while those with AD-NSCLC fared worse. Multiple factors, including socioeconomic, environmental/smoking patterns and access to healthcare, may have contributed. Further studies are needed. [Table: see text]
The changing landscape of small-cell lung cancer.
Authors: Cittolin Santos Giordano Fabricio , Knapp Brendan , Ganesh Bharath , Gao Feng , Stinchcombe Tom , Govindan Ramaswamy , Morgensztern Daniel
Published: June 2023

e20634

Background: Small-cell lung cancer (SCLC) is an aggressive histologic subtype of lung cancer with distinct biology and clinical course. The aim of this study is to investigate the trends in demographics and outcomes. Methods: We queried the Surveillance, Epidemiology, and End Results (SEER) database to assess the incidence, demographics, and survival for SCLC using SEER 8 (8 registries), which include data from 1975 to 2019. The pattern of metastases was evaluated using SEER 17 from 2010 to 2019. Jointpoint analysis was used to calculate the trends in annual percentage change according to year of diagnosis. Results: There were 530,198 patients with lung cancer, including 73,362 (13.8%) patients with SCLC in the SEER 8. The percentage of SCLC among all lung tumors progressively increased from 13.3% in 1975 to a peak of 17.5% in 1986, followed by steadily decrease since 1990, reaching 11.1% in 2019. The incidence per 100,000 population increased from 9.5 in 1975 to 15.3 in 1986 followed by a gradual decline to 6.5 in 2019. Among patients with SCLC included in SEER 8, demographic changes from 1975-1979 to 2015-2019 included increased median age at diagnosis from 63 years to 69 and increased percentage of women from 31.4% to 51.2%. The percentage of patients with stage IV increased from 56.9% to 63.8% from 1995-1999 to 2000-2004, and to 69.5% in 2010-2014 without further increase. Among the 55,035 patients with SCLC in SEER 17 from 2010 to 2019, the most common sites of metastasis at diagnosis were mediastinal lymph nodes (69.9%) liver (30.5%), bone (22.8%), and brain (15.8%). The median, 1-year, and 5-year overall survival increased from 6 months, 23%, and 3.6% respectively in 1975-1979 to 7 months, 30.8%, and 6.8% respectively in 2010-2019 (P < 001). Conclusions: The incidence of SCLC in the United States reached a peak in 1985 to 1989 followed by a gradual decline. Demographic changes included an increased median age at diagnosis and the percentage of women, which surpassed men in the last study period. There was also an increase in the percentage of stage IV. The improvement in 5-year OS has been statistically significant but clinically modest.
A study on oligo-progression after durvalumab plus platinum-etoposide for ES-SCLC.
Authors: Watanabe Kageaki , Misawa Kazuhito , Uematsu Mao , Hashimoto Kana , Hosomi Yukio
Published: June 2023

e20642

Background: Chemotherapy plus immune-checkpoint inhibitor(ICI) therapy is the standard of care for untreated extensive-stage small cell lung cancer(ES-SCLC), but the pattern of progression has not been fully investigated. It is known that a certain percentage of patients with ES-SCLC have Oligo-Progression, and ICI treatment can be continued with the addition of local therapy. This is great significance in the current situation where post-treatment is limited. Methods: We performed a retrospective analysis of patients with ES-SCLC treated with durvalumab plus platinum–etoposide regimen from September 2020 to January 2023 in our institution. Results: Forty patients were included, median age was 68 years (range 45-89), 32 (80%) patients were male and 8 (20%) patients were female, ECOG-PS was 0 or 1 in 25 (63%) patients, 2 or 3 in 15 (38%) patients, 38 (95%) patients had a smoking history, 39 (98%) patients were Stage IV, and the regimens were durvalumab plus cisplatin–etoposide in 15 (38%) patients and durvalumab plus carboplatin–etoposide in 25 (63%) patients. The median PFS was 5.9 months (95% CI: 3.8-8.0) and the median OS was 25.4 months (95% CI: 6.0-44.8). 14(35%) patients were still on treatment. Of the 17 (43%) patients with confirmed RECIST-PD, 4 patients had Oligo-Progression. All of them continued ICI treatment with additional radiation therapy. Two patients are continuing ICI treatment. Two patients with second recurrence, and the time from RECIST-PD to second recurrence was 5 months and 18 months, respectively. Conclusions: Among patients with RECIST-PD after durvalumab plus Platinum–Etoposide for ES-SCLC, Oligo-Progression was observed in 24%, and the strategy of continued ICI treatment in addition to local therapy may be promising.
Carcinoid tumor of the bronchus and lung: A nationwide cross-sectional study.
Authors: Perez Esmirna , Guevara Nehemias , Portillo Shellsea , Francis-Morel Garry
Published: June 2023

e20645

Background: Carcinoid tumor of the lung is a rare neuroendocrine tumor (NET), little is known of the in-hospital characteristics of this tumor. This study aims to describe the characteristics of patients hospitalized with NET of the bronchus and lung. Methods: This is a retrospective descriptive study of patients with lung carcinoid tumors admitted to acute care from 2016 to 2020. Data is derived from the National Inpatient Sample (NIS). The patients were divided into two groups: malignant and benign carcinoid tumors of the bronchus and lung. Patients' characteristics were described, including demographics, hospital length of stay (Los), and total cost. Mortality and common comorbidities were included. Hypothesis testing for categorical variables were tested with Chi-Square. Continuous variables were tested with a Student t-test. Statistical significance was defined as a two-tailed P value of < 0.05. Results: A total of 13,335 admissions were identified over a period of 5 years, but only 1,810 of them met inclusion criteria. The elderly population was the most affected group, with a mean age of 60 years (Malignant 61 versus Benign 52; p 0.001). There was a trend of female predominance, representing 57% vs 42% of males ( p 0.727). White patients constituted the majority of the population (72%), followed by Black (13%) and Hispanics (10%), with a minority of Native Americans and Asian/ Pacific Islanders ( p 0.016). Medicare was the most frequent primary payer (50%, p 0.015). No difference in household distribution ( p 0.138), hospital teaching status ( p 0.743) hospital region ( p 357) or hospital bed size (0.273) were noted. However, the majority of the admissions were to private-non-profit facilities, accounting for 78% ( p 0.003). Mean LoS was 7.4 days ( p 0.021). On subgroup analysis, the malignant carcinoid tumor of the lung was predominant, with 1,490 malignant carcinoid tumors of the lung and bronchus compared to 329 benign carcinoid tumors of the bronchus and lung. Affection by comorbidities like CAD and COPD was significantly associated with a carcinoid tumor of the lung (17% malignant carcinoid tumor of the lung and bronchus and 5% benign carcinoid tumor of the lung and bronchus p 0.003 and 24% malignant carcinoid tumor of the lung and bronchus and 11% benign carcinoid tumor of the lung and bronchus, p 0.008 respectively). All deaths (n = 90) were observed in the malignant carcinoid lung tumor group. Conclusions: In this cross-sectional study of patients with NET of the bronchus and lung admitted to acute care, we found that patients over the age of 50 and Whites were the most affected, with patients with malignant tumors being older. As expected, Medicare was the most frequent primary payer. In addition, COPD and CAD were not uncommon among both groups.
Effect of SARS-CoV-2 mRNA vaccine booster in serologically negative patients with thymic epithelial tumors.
Authors: Pietroluongo Erica , De Placido Pietro , Morra Rocco , Buonaiuto Roberto , Tafuro Margherita , Longobardi Alessandra , Caltavituro Aldo , Tortora Marianna , Marretta Antonella Lucia , Del Deo Vitoantonio , Malfitano Anna Maria , Gelzo Monica , Daniele Bruno , Ottaviano Margaret , Formisano Pietro , Castaldo Giuseppe , Veneziani Bianca Maria , Palmieri Giovannella , De Placido Sabino , Giuliano Mario
Published: June 2023

e20651

Background: Thymic epithelial tumors (TETs) are rare malignancies associated with humoral and cell-mediated immunity dysregulations. Anti-syndrome coronavirus type 2 (SARS-CoV-2) vaccine is effective at preventing COVID-19 morbidity and mortality. We have previously shown an impaired seroconversion after 1st and 2nd anti-SARS-CoV-2 vaccine doses in TETs patients. The aim of this study was to evaluate the seroconversion rate after the third vaccine dose (booster) in TET patients who remained serologically negative after full vaccination. Methods: Starting from November 2021 to March 2022, consecutive TET patients found to be serologically negative after two SARS-Cov-2 mRNA vaccine (BNT162b2 by Pfizer-BioNTech) doses were enrolled. SARS-CoV-2 spike-binding IgG antibody serological levels were centrally analyzed by chemiluminescent immunoassay (CLIA) at two different time-points: T0 and T1 (before and one month after booster, respectively). Cut-off for Ab titers positivity was > 25 AU/mL. Results: Among the 23 enrolled patients, 10 (43.5%) were female and 13 (56.5%) males; 6 (26%) pts had thymic carcinoma and 17 (74%) had thymoma. Autoimmune disorders were detected in 20 patients (86.9%), of whom 3 (15%) suffered from Myasthenia Gravis, 8 (40%) from Good’s Syndrome, 7 (35%) from both diseases, and 2 (10%) from other autoimmune disorders. By the time of booster administration 2 pts were lost to follow up, 2 pts died, 5 pts suffered from SARS-CoV-2 infection and seroconverted. Of the remaining 14 pts, only 7 (50%) achieved seroconversion. Among these patients, 2 had active cancer disease, whereas the remaining were disease-free. On the other hand, among the 7 patients who did not achieve seroconversion after booster, 6 had active cancer disease. Moreover, 6 of these patients suffered from Good’s Syndrome. Conclusions: Our results suggest that the anti-SARS-CoV-2 third dose could contribute to improved seroconversion of TET patients who did respond to the first two doses. It remains to be investigated why half of the patients are still not achieving seroconversion after the booster and whether this is determined by the presence of active disease or by alterations in humoral and/or cell-mediated immune response. These data may have important clinical implications because they could help to better identify fragile patients who could benefit from improved vaccine protocols or from alternative prophylaxis strategies, such as the use of monoclonal antibodies.
Characterization of URST1 as a prognostic marker and therapeutic target for lung cancer.
Authors: Takano Atsushi , Miyagi Yohei , Daigo Yataro
Published: June 2023

e21000

Background: The improved understanding of cancer-specific oncoproteins could lead to the development of novel biomarkers or therapeutic targets for lung cancers. Methods: We screened oncoproteins as follows: i) Identification of up-regulated genes in lung cancers by cDNA microarray, ii) Validation of clinicopathologic importance of their gene product by tissue microarray, iii) Examination of the growth of cancer cells after transfection of their siRNA or expression vector, iv) Screening of their signal pathways. Results: We identified up-regulated in solid tumor 1 (URST1) as a candidate. Immunohistochemical staining of URST1 showed that URST1 expression was observed in 231 (64.5%) of 358 non-small cell lung cancers (NSCLC) and 11 (84.6%) of 13 small cell lung cancers. High level of URST1 expression was associated with poor prognosis for NSCLC patients ( P = 0.0003). Multivariate analysis confirmed that strong URST1 expression was an independent prognostic factor for NSCLC patients that had undergone radical surgery. Knockdown of URST1expression by siRNAs against URST1 significantly suppressed the growth of lung cancer cells, and also inhibited the cell invasive ability. Treatment of lung cancer cells with small molecule inhibitor against URST1 suppressed the cell growth partly through G2/M arrest and cell death. In contrast, enforced expression of URST1 significantly promoted lung cancer cell growth. Microarray analysis coupled with siRNAs for URST1 suggested various URST1 related oncogenic pathways in lung cancer cells. Conclusions: URST1 could play an essential role in malignant potential of lung cancer and it might be useful as a prognostic biomarker and therapeutic target molecule for lung cancer.
Clinical analysis of the presence of comutations in patients with EGFR-mutated NSCLC.
Authors: Rubio Jaime , Santolaya Carlota , Fernandez Marina , Villalba Paula Lucia , Avedillo Mercedes , Garcia-Foncillas Jesus , Domine Manuel
Published: June 2023

e21001

Background: EGFR mutation is the most common treatable molecular alteration in non-small cell lung cancer (NSCLC), in particular in adenocarcinoma it can be found in 10-15% of our patients (spanish population). But the presence of other commutations in EGFR mutated tumors and its implications has not been well characterized. Methods: We selected patients diagnosed with EGFR mutation non-small cell lung carcinoma (NSCLC) from February 2021 to March 2022 from 4 hospitals in Madrid (most of them from Fundación Jimenez Diaz University Hospital). EGFR status and the presence of commutations was determined by using the AVENIO Tumor Tissue Targeted Kit (a Next Generation Sequencing test). PD-L1 status was determined by immunohistochemistry assay (22C3 pharmDx). Molecular and clinicopathological characteristics were collected and we performed a descriptive analysis of our population. Results: Of the 48 patients evaluated, 68.8% were women and 31.3% were men. 73% were ECOG 0 and 23% ECOG 1 and only 44% were non-smokers, being 18.8% smokers and 37% ex-smokers, most of them with low consumption. The 91.7% were adenocarcinomas and 8.3% were squamous carcinomas. 43.7% were PD-L1 negative and 10.4% were high expressors (PD-L1 > 50%). Of the stage at diagnosis, 60.4% were stage IV and 16.7% were stage III, with 22.9% being stage I and II. Of the Stage IV patients, 87.7% debuted as patients with high disease burden, with only 13.3% being oligometastatic (oligometastatic being understood as those with less than 5 metastases in 3 different organs, including the primary tumor). 40% of them had brain metastasis at the diagnosis. Of the mutational profile, 50% had an exon 19 deletion, 25% had an L858R mutation and the rest had infrequent mutations (12.5% amplification, 10.4% exon 20 insertion and 6.3% exon 18 mutations). In our cases, we evidence that 56.25% of the patients, analyzed by NGS, had another mutation. Of all of them the most frequent was p53 (seen in 55% of the commutated cases), being less frequent others, such as MET and APC amplification (4.2%) and others with a 2.1% (PI3K, BAP1, KRAS, ALKt or HER2 amplification). Finally, we analyzed the progression-free survival (PFS) and overall survival (OS) of commutated patients vs. non-commutated treated with Osimertinib as a first line treatment and, although it was statistically non-significant due to the small sample size (11 vs 9) and the short follow-up, a very positive trend was seen (log-rank test p = 0.055 and p = 0.136 respectively). Conclusions: With the development of NGS, the presence of other commutations besides EGFR have implications that are still unknown, but it appears that it may cause worse OS and PFS. This should be studied in larger cohorts with longer follow-up.
Role of HLA-DRB4 as a biomarker for endocrine toxicity and survival outcomes after immunotherapy in metastatic non-small cell lung cancer.
Authors: Jiang Cindy , Ravishankar Shashidhar , Zhao Lili , Green Michael , Towlerton Andrea , Scott Anthony , Raghavan Malini , Cusick Matthew , Warren Edus H. , Ramnath Nithya
Published: June 2023

e21005

Background: Immune checkpoint inhibitors (ICI) have significantly improved outcomes in non-small cell lung cancer (NSCLC) but are associated with development of immune related adverse events (irAEs). Currently, the role of germline determinants on immunotherapy efficacy and toxicity is unclear. Human leukocyte antigen (HLA) is emerging as a possible predictive biomarker. Our study aimed to assess HLA class II genotypes and their correlation to irAEs and survival. Methods: We conducted a single institution, prospective study with collection of baseline blood samples in patients with metastatic NSCLC treated with ICIs. Clinical characteristics and HLA genotypes (ScisGo HLA typing kits) were obtained. Kaplan-Meier method was used to calculate progression free survival (PFS) and overall survival (OS). Cox regression model was used for multivariate analysis (MVA) and we adjusted for age, gender, race, stage, and histology. Cumulative incidence function was used for association between HLA-DRB4 and endocrine irAEs. Results: Among 98 eligible patients, 85 had complete HLA genotyping. Most patients were men (96.5%), Caucasian (75.3%), and former/active smokers (98.8%) with a median age of 72 years. Median follow up time was 42.8 months. Majority of patients received pembrolizumab (83.5%). Other ICIs included durvalumab (10.6%) and nivolumab (4.7%). Twenty patients (23.5%) experienced irAEs – 11 patients had endocrine irAEs and 9 with other irAEs. 3 patients (27.3%) with endocrine irAEs had toxicity grade 3. Presence of irAE did not improve PFS (p = 0.226, HR 0.61, 95% CI [0.268,1.365]) or OS (p = 0.219, HR 0.63, 95% CI [0.301,1.316]). HLA-DRB4 was present in 39/85 patients (45.9%) and was the predominant genotype in patients with endocrine irAE (9/11, 81.8%) (Table 1). The cumulative incidence of endocrine irAEs was higher in patients expressing HLA-DRB4 (p = 0.0139 ). HLA-DRB4 improved survival in both univariate (PFS 9.9 months, p = 0.040; OS 26.3 months, p = 0.0085) and MVA (PFS p = 0.0310, HR 0.55, 95% CI [0.31, 0.95]); OS p = 0.003, HR 0.40, 95% CI [0.21, 0.73]). Conclusions: Expression of HLA-DRB4 was associated with the development of endocrine irAEs and correlated with improved survival outcomes in metastatic NSCLC patients being treated with ICIs. Further studies are necessary to validate our findings of HLA-DRB4 as a possible predictive marker for endocrine irAEs and therapy efficacy.[Table: see text]
A differential analysis of TCR repertoire between patients with EGFR-mutant and KRAS-mutant non–small-cell lung cancer.
Authors: Xie Yuancai , Li Yingmei , Dong Linfeng , Chen Shifu , Liu Jixian
Published: June 2023

e21012

Background: T-cell receptor (TCR) repertoire could partially represent tumor micro-environment. EGFR and KRAS are common driver genes mutated and often mutually exclusive in non-small cell lung cancer (NSCLC). There’s a hypothesis that the immune system responds differently according to different mutations. Here we investigated the TCR features, including diversity, clonality, evenness and sequence similarity in EGFR and KRAS mutated NSCLC patients, to better understand the immune response in carcinogenesis. Methods: A total of 71 EGFR-mutant and 31 KRAS-mutant NSCLC tissue samples underwent multiplex PCR based TCR-β sequencing. TCR-β cdr3 amino acid sequences were obtained from the sequencing data using MiXCR and VDJtools. To compare TCR repertoires in EGFR-mutant and KRAS-mutant groups, each assemble CDR3 amino acid sequence was taken as a word, and each repertoire was taken as a document. Each repertoire was compared with every other one as a sample pair. TF-IDF (term frequency-inverse document frequency) document vectors was built for each sample and cosine similarity scores were computed for sample pairs. Results: The total cosine similarity score within EGFR-mutant group is 11.07 and average cosine similarity score is 0.0044±0.01, while in the KRAS-group, the total cosine similarity score is 13.41 and average cosine similarity score is 0.029±0.04. Between these two groups, the total cosine similarity score is 8.76 and average cosine similarity score is 0.0019±0.0009. See table for summary. The intergroup similarity score is significantly less than that within each group respectively (p < 1E10). Conclusions: Our results demonstrated that the TCR repertoire was clearly associated with cancer mutational profile. The mechanism of how mutations affect the immune system and shape the TCR repertoire is yet to be investigated. [Table: see text]
Frequency and patterns of TP53 mutations in lung cancer.
Authors: Yang Yaxian , Wang Heran , Wang Lucas , Fan WenTao , Lian Bin , Jin Ying , Luo Weiquan , Mao Jiewei , Feng Yilin , Xie Hongtao , Huang Mingjian , Zheng Liyu , Pan Zhaodong , Huang Mingming , Wang Yongsi , Wen Yunjie , Huang Jian
Published: June 2023

e21013

Background: Lung cancer (LC) is the second leading causes of cancer-related mortality and composed of diverse molecular types. Tumor suppressor gene TP53 is one of the most frequency mutation genes in cancer, however, whether there are the hot sports of TP53 mutations has always been a challenging issue. The aim of this study was to explore the spectrums and hot spots of TP53 mutation in LC. Methods: The total 1932 LC tissue samples (from same number of patients，all cases had patients' informed consent) in formalin fixed and paraffin embedded were collected from Guangzhou Huayin Health Medical Group Co.,Ltd. By targeting next generation sequencing (NGS) of 600 genes, the mutation information of TP53 and other genes was obtained. Results: Among 1932 samples, 1025(53%) were male, 1685(87.2%) were lung adenocarcinoma (LUAD), 232(12.0%) were lung squamous cell carcinoma (LSCC), 7(0.4%) were large-cell carcinoma and 8(0.4%) were small-cell carcinoma, median age was 62.82(range: 27-92). The mutated TP53 was detected in 890 (46%) samples. Other most frequently altered genes were EGFR (1114/1932, 57%), KRAS (213/1932, 11%), PIK3CA (116/1932, 6%), APC (107/1932, 6%) and ERBB2 (97/1932, 5%) . Additionally, 412 (21.3%) patients with TP53 and EGFR co-mutation, TP53 and KRAS co-mutation occurred in 81 (4.2%) patients, PIK3CA mutation co-occurred with TP53 in 53 (2.7%) patients. The total of 920 TP53 mutant sites were detected, and these sites scattered throughout the 11 exons, especially exon 5-8. 13 of these mutation sites which accounted as high frequency ( > 10), including R273C (18/920), R248W (16/920), Y220C (15/920), Y163C (14/920), R249S (13/920), R282W (13/920), H179R (12/920), R158L (12/920), R175H (11/920), G245D (11/920), R273H (10/920), Y234C (10/920), and R273L (10/902). In addition, missense mutations were the main type, and the proportion of SNP with C > T was the highest in mutation sites. Conclusions: This study characterized the mutational signatures that TP53 mutations are interspersed, and hot spots are just in small proportions in LC. This study may provide a basis for drug development for targeting TP53 mutations in the future.