bluuebunny/crossref_metadata_2025 huggingface dataset:
Marvelous objective response of low dose radiotherapy plus ICIs for extended stage small cell lung cancer.
Authors: Zhou Lin , Yu Min , Chen Lin , Zhang Yan , Jiang Zhu , Liu Yongmei , Gong Youling , Xu Yong , Xue Jianxin , Li Yanying , Huang Meijuan , Lu You
Published: May 2020

e21097

Background: Immune checkpoint inhibitors (ICIs) has limited efficacy with unsatisfactory objective response for extensive stage small cell lung cancer (ES-SCLC). In this respective study, efficacy and toxicities of low dose radiotherapy (LDRT) plus ICIs for pretreated failure ES-SCLC has been evaluated, and marvelous objective response has been observed. Methods: From March 2018 to Dec 2019, ten pretreated failure ES-SCLC patients received LDRT (8-20Gy/2-10f, BED10 9.5-24Gy) for lesions located in lung or other sites plus ICIs (Nivolumab, Pembrolizumab, Ipilimumab, Durvalumab, and Sintilimab) were enrolled. Two patients received concurrent chemotherapy of etoposide plus cisplatin or albumin-bound paclitaxel monotherapy. ICIs were given within 7 days after LDRT. Efficacy, toxicities, and lung cancer symptom scale (LCSS) scores were evaluated. Results: Thirteen lesions (ten located in lungs, and the others located in adrenal gland, axillary lymph node, and abdomen) received LDRT. The gross tumor volume and planning target volume were 32.56 cc-430.19cc and 73.74 cc-771.41 cc, respectively. Eleven lesions did not receive radiotherapy. The objective response rate (ORR) of whole patients was 90% (9/10). The ORR and disease control rate (DCR) of radiated lesions were 92.3% (12/13) and 100% (13/13), compared to 9.1% (1/11) and 18.2% (2/11) for no radiated lesions. Volume shrinkage rates (VSRs) of radiated lesions were 35.16% to 95.91% (13.75cc-277.02cc), and 61.5% (8/13) of radiated lesions reduced more than 80%. VSRs for radiated lesions with volume > 100cc were 63.07% to 95.91% (122.38cc-277.02cc). LCSS improved significantly after treatment (465±13.02 vs. 380±17.8, p= 0.0013). Lymphocyte declined initially and then recovered in patients with disease not progressed, on the contrary, it declined continuously in patients with disease progressed. The most popular toxicities were lymphopenia (70%) and anemia (60%). Grade 3-4 toxicities included lymphopenia (40%), thrombocytopenia (20%), anemia (20%), and granulocytopenia (10%). Conclusions: LDRT might enhance the effectiveness of ICIs greatly for tumor lesions, and radiotherapy should be considered to be given initially for ES-SCLC received ICIs treatment.
The role of surgery in stage I small-cell lung cancer: A national VA database analysis.
Authors: Azar Ibrahim , Austin Adam , Kim Seongho , Jang Hyejeong , Chopra Amit , Mehdi Syed Arzoo , Mamdani Hirva
Published: May 2020

e21109

Background: Historically, limited stage Small Cell Lung Cancer (SCLC) has been treated with concurrent chemoradiation (CRT). While current NCCN guidelines recommend consideration of lobectomy in node-negative cT1-T2 SCLC, real world data regarding the role of surgery in very limited SCLC is lacking. To our knowledge, only one retrospective study has evaluated the role of surgery in stage I SCLC. Methods: Data from the National VA Cancer Cube were compiled. A total of 1,028 patients with pathologically confirmed Stage I SCLC were studied. Only 661 patients that either received surgery or CRT were included. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median overall survival (OS) and hazard ratio (HR), respectively. Two survival curves were compared by a Wald test. Subset analysis was performed based on the location of the tumor in the upper vs lower lobe as delineated by ICD-10 codes C34.1 and C34.3. Results: Four-hundred and forty-two patients received concurrent CRT; while 219 underwent treatment that contained surgery (92 surgery only, 84 surgery/chemo, 39 surgery/chemo/radiation and 4 surgery/radiation). The median OS for the surgery-inclusive treatment was 3.87 years (95% CI 3.25-4.60) while median OS for the CRT cohort was 2.43 years (95% CI 2.15-2.72). HR of death for surgery-inclusive treatment when compared to CRT was 0.65 (95% CI 0.54-0.79; p < 0.001). Subset analysis based on the location of the tumor in upper lobe and lower lobe showed improved survival with surgery as compared to CRT regardless of the location. HR for upper lobe was 0.61 (95% CI 0.48-0.78; p < 0.001) and lower lobe 0.60 (95% CI 0.41-0.87; p = 0.007). Multivariable regression analysis accounting for age and ECOG-PS shows a HR 0.60 (95% CI 0.42-0.85; p = 0.004) favoring surgery. Conclusions: Surgery was used in less than a third of patients with stage I SCLC who received treatment. Surgery-inclusive multimodality treatment was associated with a longer overall survival as compared to chemoradiation, independent of age, performance status or tumor location. Our study supports a more expansive role for surgery in stage I SCLC.
PIOS ratio: predicting the best response of non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors.
Authors: Dimitrakopoulos Foteinos-Ioannis D. , Nikolakopoulos Achilleas , Kottorou Anastasia E , Liolis Elias , Frantzi Theodora , Pyrousis Ioannis , Kalofonou Foteini , Koutras Angelos , Makatsoris Thomas , Kalofonos Haralabos
Published: May 2020

e21507

Background: With the exception of programmed death ligand 1 (PD-L1) expression and Tumour Mutational Burden (TMB), which have entered clinical practice, no other clinically useful predictive biomarker for immune checkpoint inhibitors (ICIs) has been established in the daily practice. The purpose of this study was to develop a novel, non-interventional and clinically useful predictive score for NSCLC patients with advanced disease treated with ICIs. Methods: Eighty-nine patients with advanced and histologically confirmed NSCLC (stages III and IV), treated with immunotherapy (nivolumab, pembrolizumab, atezolizumab), were enrolled in the current study. Clinicopathological data as well response rates and clinical outcome data were collected. Based on this data and using a regression model, we developed a predictive score (Patras Immunotherapy Score-PIOS) with regard to the best response to ICIs. Best overall responses (BOR) were based on the immune-based therapeutics (iRECIST) criteria. Results: Four of the studied parameters -Performance Status (PS), Body Mass Index (BMI), age and lines of treatment (LOT)- were incorporated in our formula (PS *BMI/ LOT*age) giving rise to PIOS. This score was strongly associated with BOR, with patients of a good response (SD, PR or CR) having higher PIOS compared to patients with progression disease (PD) (p<0.001). The association remained significant when we used a four-tier model (PD, SD, PR and CR) for BOR (p<0.001). PIOS predictive significance also persisted using a binary logistic regression analysis (p=0.001). Conclusions: This study suggests that PIOS, which combines 4 baseline clinical parameters, may help to identify NSCLC patients with increased probability to be benefitted from ICIs treatment. Further evaluation and possibly combination with other factors may multiply its clinical significance.
Survival differences between smokers and nonsmokers with EGFR mutated non-small cell lung cancer.
Authors: Macari David , Ibironke Oluwatoyin , Jinna Sruthi , Stender Michael J. , Jaiyesimi Ishmael A.
Published: May 2020

e21509

Background: Patients with epidermal growth factor receptor (EGFR) mutated lung cancer have an excellent prognosis compared to other non-small cell lung cancer (NSCLC) with no driver mutation, however, there is a wide range of survival between even a cohort with an EGFR driver mutation. Given that many patients with EGFR mutations are never smokers, it is possible that those with a smoking history have tumors with other oncogenic mutations and therefore as their tumors are less dependent on the EGFR driver, they may derive less benefit from targeted therapy. Methods: Pathology specimens of NSCLC sent for EGFR testing between January 1 2012 and December 31 2016 at Beaumont Hospital, Michigan were reviewed. If a tumor harbored a targetable EGFR mutation, the chart was queried. Inclusion criteria were EGFR exon 19 or 21 mutations, stage IV disease, at least 2 time points of follow up. Exclusion criteria included small cell histology, negative EGFR test, or inadequate information in the chart. The primary endpoint of the study was median survival. Results: Out of 329 cases identified, 40 were positive for EGFR exon 19 or 21 mutations. Of the 40 positive cases, 26 fit all inclusion criteria. Median duration of follow up was 14 months (range 0-80). Smokers represented 13/26 (50%) of cases. Death occurred in 9/13 (69%) of smokers vs 7/13 (54%) in non-smokers. Median survival was 8 mo (0-26) vs 20 mo (1-80) respectively for smokers vs non-smokers. Conclusions: This data suggests there may be a clinically relevant difference in the survival between smokers and nonsmokers who have NSCLC with an EGFR driver mutation. This may be due to the relatively low burden of alternative driver oncogene mutations in the nonsmoker’s tumors resulting in a lower likelihood of an escape mechanism for the tumor to survive. Further analysis of larger datasets with complete molecular analysis of the tumors would be informative in exploring this hypothesis. This would aid in risk stratifying patients more effectively for future clinical trials targeting the EGFR mutation and refining the prognosis in this otherwise good prognosis group.
Characterization of MET exon 14 skipping in Chinese non-small cell lung cancer (NSCLC) patients.
Authors: Zhang Baihua , Xia Yu , Zhang Jiujin , Yu Jin , Chen Min , Yao Wei , Zhao Juan , He Jiqiang , Mok Tony S. K. , Wang Kai
Published: May 2020

e21525

Background: MET exon 14 skipping ( METex14) has been identified as a precise biomarker for MET-targeted therapy. Most METex14 alterations occur in patients (pts) with non-small cell lung cancer (NSCLC). Here, we present the clinical, pathological, and genomic characteristics of Chinese NSCLC pts harboring METex14. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor and matched blood samples from 3433 pts were collected from December 2017 to January 2019 for a 450 cancer gene targeted next-generation sequencing (NGS) panel. Genomic alterations (GAs) including single nucleotide variations, short and long insertions/deletions (Indels), copy number variations, and gene rearrangements were assessed. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: A total of 35 (1.0%) pts harbored the GAs predicted to cause METex14, which was lower than that of the Western population (3%), and comparable to data in previously reported Chinese NSCLC pts. METex14 mutation rates were 10.5% in sarcomatoid carcinoma, 1.5% in adenosquamous carcinoma and 1.0% in adenocarcinoma. The median age of pts with METex14 was 65 years (range 46-85) and 46% were female. Compared with wild-type (WT) pts, those harboring METex14 were significantly associated with older age (median age: 65 vs. 60 years, respectively, p = 0.005) and earlier stage (stage I & II ratio: 67.7% vs 42.0%, respectively, p < 0.0001). METex14 alterations included 17 samples (48.6%) that were base substitutions located on the non-coding adjacent splice acceptor (1), donors (7), and other splice acceptors (9), and 18 (48.6%) Indels located on the non-coding adjacent splice acceptors (8), donor (1), other splice acceptor (1), and exon/intron junctions (7). MDM2, FRS2, and CDK4 amplification was observed in 22.9%, 20.0%, and 17.1%, respectively, of pts with METex14, which was significantly higher than in WT pts (P < 0.001). Concurrent EGFR mutations were rarely observed with METex14 compared with WT pts (8.6% vs. 51.7%, respectively, p < 0.0001). Concurrent MET amplification was identified in 3 samples with METex14, and no other driver genes were found. Conclusions: METex14 occurred in 1.0% of Chinese NSCLC pts and showed a significantly higher prevalence in sarcomatoid carcinoma. METex14 observed in pts with NSCLC were associated with increased concurrent MDM2, FRS2, and CDK4 amplification and decreased EGFR mutation, suggesting that METex14 acts as a driving oncogenic factor in NSCLC.
Evaluation of blood-based proteomic biomarkers associated with response to anti-PD-1 treatment in NSCLC.
Authors: Dupuis Nicholas , Lopez-Lastra Silvia , Dumont Clement , Dozio Vito , Beeler Kristina , Sklodowski Kamil , Romano Emanuela
Published: May 2020

e21531

Background: Immune checkpoint inhibitors have remarkably improved the natural history of patients with non-small cell lung cancer (NSCLC), with improved clinical responses and overall survival compared to standard therapy. However, most unselected NSCLC patients do not respond, highlighting the need of theranostic biomarker discovery. In a cohort of NCSLC patients treated with anti-PD-1-blockade, we investigate baseline blood-based parameters with a high-throughput quantitative proteomics workflow, based on data independent acquisition mass spectrometry (DIA-MS). Quantified proteins are evaluated as potential circulating biomarkers for predicting the response to therapy. Methods: Plasma samples from 49 NSCLC subjects treated with anti-PD-1-blockade were prepared for mass spectrometry. All samples were analyzed on a Thermo Scientific Q Exactive HF-X operated in a DIA mode using capillary flow liquid chromatography with separation over a 40 min gradient. DIA data was extracted with Spectronaut to quantify expressed proteins. Results: Across all samples, 605 proteins were quantified and 17 were significantly associated (log2 fold change > 0.58 and q-value < 0.05) with Responders (SD + PR) vs Non-Responder (PD) groups. Functional mapping and unsupervised clustering of regulated proteins identifies three major subject groups based on protein expression profiles: Group A is characterized by high expression of acute phase proteins (e.g. SAA1/2, CRP), Group B has low overall protein expression, and Group C has high expression glycolysis related enzymes (ALDOA, GAPDH) and focal adhesion proteins (VCL). Consistent with previous studies the Group A, with high levels of acute phase proteins, had poor overall survival relative to the other two families (HR = 2.2 [1.2-4.2], p = 0.003). Notably, Group C is comprised largely of Non-Responders (8/12) yet had improved overall survival relative to Group A (HR = 2.5 [1.2-5.0], p = 0.004). Conclusions: Plasma proteomic profiling with capillary flow DIA-MS enables quantification protein profiles in a hypothesis free manner. Poor outcomes on anti-PD-1 therapy was confirmed for subjects with elevated acute phase proteins. However, a subgroup with high focal adhesion and glycolysis proteins had improved survival despite containing non-responder subjects, requiring further investigation.
The association between STK11/LKB1 and/or KEAP1 mutations and response to PD-1/PD-L1 inhibitors in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Miller Meagan Elizabeth , Patel Meera , Althouse Sandra K. , Hanna Nasser H. , Mamdani Hirva
Published: May 2020

e21538

Background: Advanced non-small cell lung cancer (NSCLC) patients with tumors harboring STK11/LKB1 or KEAP1 mutations have inferior treatment outcomes when treated with PD-1/PD-L1 blockade, regardless of KRAS status, PD-L1 score, or TMB score (Skoulidis et al, Cancer Discovery 2018, ASCO abstract 102, 2019). Methods: Retrospective clinical databases from Indiana University and Karmanos Cancer Institute were queried to identify patients from 2008-2019 with advanced NSCLC treated with PD-1/PD-L1 monotherapy (group A) or concurrent chemotherapy + PD-1/PD-L1 inhibitors (group B) whose tumors harbored STK11/LKB1 and/or KEAP1 mutations. Patients were characterized by best response, progression of disease (PD) or non-PD (complete response (CR) + partial response (PR) + stable disease (SD)). Patient and disease characteristics, response, and duration of response (> vs. < 6 months) were recorded. Results: A total of 77 patients met the above criteria (55 in group A, 22 in group B). 52 of 55 patients in group A received prior chemo. Patient and disease characteristics and outcomes are summarized in the table. Conclusions: STK11/LKB1 and/or KEAP1 mutations are independent of PD-L1/TMB status, although most patients had PD-L1 of <1%. Nearly ½ of patients with STK11/LKB1 and/or KEAP1 mutations achieve at least SD with PD-1/PD-L1 inhibitor monotherapy and more than 50% of those with non-PD maintain that response status for > 6 mos. The frequency and duration of non-PD in this population is higher in patients receiving chemotherapy + PD-1/PD-L1 concomitantly. [Table: see text]
KEAP1/NFE2L2 as a prognostic biomarker on immunotherapy and correlation with immune infiltrates in non-small cell lung cancer (NSCLC).
Authors: Zhu Hongyuan , Yu Yunfang , Zheng Yating , Xu Bin , Zheng Shaopeng , Zeng Fanjun , Xie Wenzhuan , Huang Luyu , Li Fasheng , Lin Weihuan , Liao Guoqing , Wu Shaowei , Liu Xinyi , Huang Mengli , Zhou Haiyu
Published: May 2020

e21551

Background: Molecular characterization studies revealed recurrent KEAP1/ NFE2L2 alterations in non-small cell lung cancer (NSCLC). Previous studies have confirmed that KEAP1/NFE2L2 mutations are a poor prognostic factor for chemotherapy in patients with NSCLC. Nevertheless, it is unclear whether KEAP1/NFE2L2 mutations (MUT) of liquid biopsy can predict the efficacy of immunotherapy in NSCLC. Methods: Two independent cohorts (the OAK and POPLAR study cohort) with data from approximately 853 patients with advanced NSCLC were used to analyze the prognostic effect of KEAP1/NFE2L2 on immunotherapy. In addition, based on a deconvolution algorithm (known as CIBERSORT), we comprehensively analyzed the tumor-infiltrating immune cells present in NSCLC. The fraction of 22 immune cells subpopulations was evaluated to determine the associations between each cell type and KEAP1/NFE2L2 mutation status utilizing data from 1268 patients by lung adenocarcinoma (LUAD) and squamous cell lung carcinoma (LUSC) in TCGA pan-cancer cohort. Results: The OAK and POPLAR study cohort of NSCLC patients showed that KEAP1/NFE2L2 MUT was associated with poorer overall survival (OS), and progression-free survival (PFS) (OS: HR = 1.7, P < 0.001; PFS:HR = 1.4, P < 0.001) on immunotherapy, even after EGFR and ALK mutations were excluded, significant difference can also be gained (OS:HR = 1.8, P < 0.001; PFS:HR = 1.5, P < 0.001). Then, the NSCLC patients were subdivided into LUAD and LUSC, the OS and PFS of patients with KEAP1/NFE2L2 MUT is lower than wild-type (WT) (OS:HR = 1.8, P < 0.001; PFS:HR = 1.4, P = 0.0014) in LUAD, significant differences were obtained even when EGFR and ALK mutations were excluded (OS:HR = 1.9, P < 0.001;PFS:HR = 1.6, P < 0.001). In LUSC, patients with KEAP1/NFE2L2 MUT have lower OS (HR = 1.4, P = 0.0473),and there was no difference on PFS (HR = 1.2, P = 0.1588) between KEAP1/NFE2L2 MUT and WT, when EGFR and ALK mutations were excluded, the survival results did not change significantly. In addition, KEAP1/NFE2L2 MUT was positively correlated with infiltrating levels of plasma cells, T cells CD4 memory activated, T cells follicular helper, and Macrophages M1, but negatively correlated with infiltrating levels of T cells CD4 memory resting, monocytes, Dendritic cells activated, Mast cells resting, and Neutrophils in NSCLC. The immunoinfiltration of LUAD was significantly different from that of LUSC. Conclusions: These findings suggest that KEAP1/NFE2L2 can be used as a poorer biomarker for determining prognosis on immunotherapy and immune infiltration in NSCLC.
Gender disparities in hormone positive lung cancer.
Authors: Xia Bing , Feldman Rebecca , Cozen Wendy , Kang Irene , Raez Luis E. , Borghaei Hossein , Kim Chul , Nagasaka Misako , Mamdani Hirva , Vanderwalde Ari M. , Pai Sachin Gopalkrishna , Lopes Gilberto , Socinski Mark A. , Wozniak Antoinette J. , Kim Edward S. , Spira Alexander I. , Liu Stephen V. , Nieva Jorge J.
Published: May 2020

e21552

Background: Lung cancer has not declined in U.S. women as much as it has in men over the past 20 years despite similar rates of smoking cessation among the genders. We explored whether differences in hormone receptor status could contribute to the reason for the observation. Methods: A total of 3,256 non-small lung cancer (NSCLC) tumor samples submitted for molecular profiling between 2013-2018 were retrospectively identified for having hormone receptor (HR) expression results. HR-positive (HR+) status was defined as ≥ 1+ and 1% nuclear staining of Estrogen Receptor alpha (SP1, Ventana) and/or Progesterone Receptor (IE2, Ventana) by immunohistochemistry. DNA sequencing by NGS included cases sequenced by the Illumina MiSeq hot spot 47 gene panel (n = 2753) and Illumina NextSeq 592 gene panel (n = 503). Tumor mutation burden (TMB) was measured by counting somatic non- synonymous missense mutations on the 592 gene panel and ≥ 10 mutations/Megabase (mut/Mb) was considered high. Fisher’s Exact, Chi- square and likelihood ratio (LR) tests were utilized for statistical analyses. Results: Hormone receptor positivity (HR+) was identified in 318 women and 186 men, 504/3256 or 15% of NSCLC. EGFR mutation subtypes observed were Exon19del (46%), L858R (28%), uncommon non-classical (17%), G719X|S768I|L861Q (5%). HR+ occurred more commonly in women compared to men (20% vs 11%, p < 0.001). HR+ NSCLC had the same age distribution as HR-negative (HR-) cancers (range: 16-94 and 18-93, respectively). Compared to patients (pts) who were HR-, pts with HR+ NSCLC were more likely to harbor activating EGFR mutations in men and women (LR 1.39, p = 0.0017), and less likely to have mutations in TP53 (LR 0.83, p = 0.0076), K-RAS (LR 0.66, p < 0.0001), or translocations in ALK (LR 0.46 p = 0.0190). No differences in the incidence of ERBB2 or BRAF mutations were identified. The median tumor mutational burden was equivalent in HR+ vs. HR- pts, both 9 mut/MB. Conclusions: The disparity in the prevalence of hormone receptors in lung cancers affecting men and women deserves further exploration. The presence of hormone receptors in NSCLC is increased in women and in tumors bearing EGFR mutations. Further elucidation of the mechanism and dual targeting of EGFR and ER in patients with HR+ NSCLC deserves exploration.
Histopathological prognostic markers in metastatic lung adenocarcinoma, validation of stromal fibrosis and immunoscore as easy to interpret findings and their correlation with survival.
Authors: Rojas Puentes Luis Leonardo , Ruiz-Patiño Alejandro , Mayorga Diana Carolina , Rodríguez July Katherine , Ávila Coy Jenny Mireya , Bravo Espinosa Melissa Andrea , Arrieta Oscar , Zatarain-Barron Zyanya Lucía , Barron Feliciano Barron , Carranza Hernan , Otero Jorge M. , Vargas Carlos Alberto , Archila Pilar , Sotelo Rodríguez Diana Carolina , Martin Claudio , Recondo Gonzalo , Pino Luis , Rolfo Christian Diego , Rosell Rafael , Cardona Zorrilla Andres Felipe
Published: May 2020

e21566

Background: Several histopathological markers have been associated with immune system activity and its relationship with clinical outcomes in lung cancer. Determination of tumor infiltrating lymphocytes as well as specific subpopulations could reveal cytotoxic potential. Additionally, changes in stromal composition and fibrosis could also reflect potential cellular interactions with the tumor lesions. In this study we validate these two findings as potential prognostic factors. Methods: A retrospective cohort analysis of patients with advanced lung adenocarcinoma treated in a reference center in Bogota, Colombia was conducted. Demographic as well as treatment variables were collected between January 2018 and December 2019. In addition to clinical outcomes, the percentage of stromal fibrosis and immunoscore were estimated for all biopsy samples by a trained oncological pathologist. Results: A total of 133 patients were included. Male predominance (51.1%) with Karnofsky performance scores (KPS) greater than 80 and 19% of prior cigarette exposure (26 patients) was identified in the cohort. Median overall survival of the cohort was 27.1 months (95%CI 22.1-NA) and progression free survival of 19.4 months (95%CI 18-24.5 months). Percentage of fibrous stroma and immunoscore were associated with a benefit in both OS and PFS. For patients who presented with a low stromal fibrosis, defined as harboring less than 10%, OS reached a median of 25.1 months (95%CI 21.5- 40.5 months) compared to 38.7 months for patients with high fibrosis (95%CI 27.7 months – NA), (p = 0.02). In terms of immunoscore, values under 40% were associated with a longer median OS (38.7 months, [95%CI 31.3- 58.6 months] vs 22.1 months [95%CI19.8- 42.3 months], p < 0.001). Immunoscore and stromal fibrosis were not codependent variables (p < 0.001), suggesting that these markers offer independent prognostic value with regards to OS. Conclusions: Stromal fibrosis and immunoscore serve as prognostic factors that could be easily interpreted and evaluated in order to offer prognostic classification of patients with metastatic adenocarcinoma of the lung.
Age and gender specific lung cancer incidence and mortality in Hungary: Trends from 2011 through 2016.
Authors: Galffy Gabriella , Kiss Zoltan , Bogos Krisztina , Moldvay Judit , Bittner Nora , Vastag Aladar , NAGY-ERDEI ZSOFIA MARIA , Rokszin Gyorgy , Ostoros Gyula , Dr Szabone Dr Muller Veronika Judit , Sarosi Veronika , Polanyi Zoltan , Nagy Balazs , Horvath Krisztian , Abonyi-Toth Zsolt , Voko Zoltan , Tamási Lilla
Published: May 2020

e21572

Background: No assessment was conducted describing the age and gender specific epidemiology of lung cancer (LC) prior to 2018 in Hungary, thus the objective of this study was to appraise the detailed epidemiology of lung cancer (ICD-10 C34) in Hungary based on a retrospective analysis of the National Health Insurance Fund database. Methods: This longitudinal study included patients aged ≥20 years with LC diagnosis (ICD-10 C34) between 1st January 2011 and 31th December 2016. Patients with different cancer-related codes 6 months before or 12 months after LC diagnosis or having any anti-cancer treatment different from lung cancer protocols were excluded. Results: In 2011, 4,522 new male lung cancer cases were registered in the NHIF database, while we found 4,176 incident patients in 2016. The number of female patients increased from 2,636 to 2,828 during the same period. The mean age at diagnosis was 64.51 years for men (SD±9.85) and 64.93 years for women (SD±11.19) in 2011, increasing steadily to 65.80 years (SD±9.41) and 65.99 years (SD±10.45), respectively. Lung cancer incidence and mortality increases with age, peaking in the 70–79 age group (375.0/100,000 person-years) among males, while at 60–69 age group for females (148.1/100,000 person-years). The male-to-female incidence rate ratio reached 2.46 to 3.01 (p < 0.0001) among the 70–79 age group. We found 2-11% decrease in male incidence rate at most age groups, while a significant 1-3% increase was observed in older females ( > 60) annually during the study period. Conclusions: This nationwide epidemiology study demonstrated that LC incidence and mortality in Hungary is decreasing in younger male and female population, however we found significant increase of incidence in older female population, similar to international trends. Incidence rates peaked in younger age-groups compared to Western countries, most likely due to higher smoking prevalence in these cohorts, while lower age LC incidence could be attributed to higher competing cardiovascular risk resulting in earlier mortality in smoking population.
Management of lung cancer in elderly population: A mono-centric retrospective study at University Hospital of Caen, Normandy, France.
Authors: Oulkhouir Youssef , Bergot Emmanuel , Madelaine Jeannick , Stchepinsky Boris
Published: May 2020

e21573

Background: Lung cancer is one of the leading causes of death worldwide and its incidence is increasing in the elderly patient population. Management of these population is not as well codified as that of younger patients due to their under-representation in clinical trials. The objective of this study is to assess the clinical characteristics, diagnostics and treatments in our population at the University Hospital of Caen (CHU). Methods: It was a retrospective monocentric study including all patients over 75 years old who were diagnosed with a lung cancer between January 1, 2014 and December 31, 2017 in our center of Caen. We analyzed epidemiological, clinical and therapeutic criteria. We evaluated the overall survival and according to the type of treatment used, the identification of factors of poor prognosis. Adverse events in that specific population of patients were analyzed. We also looked at the correlation between length of hospitalization and survival data. Results: 132 patients aged 75 to 95 years were included, with a large predominance of men. Almost 90% of our patients had comorbidities. The median survival of the entire population was 7 months. Factors identified as significantly influencing survival are the initiation of a specific cancer treatment, performans status, undernutrition, presence of comorbidities, age, stage of disease, and hospitalization at diagnosis. 58.9% of our patients received treatment including 60% chemotherapy and 17.7% surgery. 52% of patients treated with chemotherapy had Grade 3-4 toxicities. None of the patients treated with targeted therapy had any major side effects. 67.4% of our patients were hospitalized for diagnosis. The percentage of survival time spent in hospital is also significantly higher in the best supportive care group with a rate of 69% versus 25%. 14 patients had a diagnosis of early stage lung cancer. Surgery and radiotherapy were performed and were well tolerated. Conclusions: The elderly population with lung cancer managed in our center is highly diagnosed at an advanced stage and has many associated comorbidities affecting survival. Performans status, nutritional condition and inaugural hospitalization are factors of poor prognosis leading to exclusive palliative care. However, in early stages disease radical treatment good be performed and be well tolerated.
PD-1 inhibitor plus chemotherapy as 2nd/subsequent line therapy had similar clinical outcome with PD-1/PD-L1 inhibitor monotherapy in advanced NSCLC.
Authors: Zhai Xiaoyang , Tian Yaru , Yan Weiwei , An Ning , Zhu Hui
Published: May 2020

e21600

Background: PD-1/PD-L1 inhibitor monotherapy has been approved as second line therapy in advanced non-small-cell lung cancer (NSCLC). The study aims to compare clinical outcome of PD-1 inhibitor plus chemotherapy with PD-1/PD-L1 inhibitor monotherapy as 2nd/subsequent line therapy in advanced NSCLC. Methods: The clinical data of NSCLC patients who received PD-1/PD-L1 inhibitor as 2nd/subsequent line therapy were retrospectively collected in our study. According to the therapy modality, patients were assigned to PD-1/PD-L1 inhibitor monotherapy group and PD-1 inhibitor plus chemotherapy group. Disease control rates (DCRs), progression free survival (PFS) and overall survival (OS) were evaluated between the 2 groups. The prognostic role of derived neutrophils-to-lymphocyte ratio (dNLR) on the outcomes was also evaluated at the same time. Results: From April 2017 to October 2019, a total of 84 patients were enrolled in the current study. Twenty-six patients were allocated to the PD-1/PD-L1 inhibitor monotherapy group and fifty-eight patients were allocated to PD-1 inhibitor plus chemotherapy group. Chemotherapy regimens were detailed as follow: liposome paclitaxel (n = 15), nab-paclitaxel(n = 12), docetaxel(n = 9), pemetrexed(n = 6), and others(n = 16). Disease control rates (DCRs) and overall survival (OS) were not significantly different between the two groups. Progression free survival (PFS) in the PD-1/PD-L1 inhibitor monotherapy was longer(median PFS: NR vs 4.4 months, p = 0.02). Univariate and multivariate analyses suggested that derived neutrophils-to-lymphocyte ratio (dNLR) was independent prognostic factor of OS and gender was independent prognostic factor of PFS. In the second-line therapy subgroup of 38 patients, OS and PFS were not significantly different in the two groups. In the subgroup of 46 patients of over 2nd line, PD-1/PD-L1 inhibitor monotherapy group had longer PFS (median PFS: NR vs 4.0 months, p = 0.01).The incidence of any grade adverse events (AEs) was no significant difference in the two groups. One patient in the PD-1 inhibitor plus chemotherapy group died of immune-related pneumonitis. Conclusions: The addition of chemotherapy to PD-1 inhibitor as 2nd/subsequent line therapy had similar clinical outcomes compared with PD-1/PD-L1 inhibitor monotherapy of advanced NSCLC patients.
Efficacy and safety of immunotherapy in non-small cell lung cancer patients with poor performance status.
Authors: Lobefaro Riccardo , Viscardi Giuseppe , Di Liello Raimondo , Massa Giacomo , Iacovino Maria Lucia , Sparano Francesca , Ferrara Roberto , Signorelli Diego , Proto Claudia , Prelaj Arsela , Galli Giulia , De Toma Alessandro , Brambilla Marta , Ganzinelli Monica , Trevisan Benedetta , Bottiglieri Achille , De Braud Filippo G. , Morgillo Floriana , Garassino Marina Chiara , Lo Russo Giuseppe
Published: May 2020

e21601

Background: The introduction of Immunotherapy (IO) has dramatically improved the prognosis of patients (pts) with advanced Non-Small Cell Lung Cancer (NSCLC). However, data regarding the role of IO in ECOG Performance Status (PS) 2 pts are generally limited in randomized trials, and real-world evidences could support clinical decision-making. Methods: We retrospectively analyzed data about pts with stage IV NSCLC treated with IO between April 2013 and December 2019 in two Italian Centers. The aim of our study was to assess the impact of PS status (0-1 vs 2) on disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Response was classified according to RECIST v1.1 criteria. PFS and OS were estimated by the Kaplan-Meier method. Chi-square test was used to compare clinical-pathological variables: gender, age ( < 70, 70-79, ≥80 years-old), smoking status, histology (squamous, non-squamous), PDL1 expression ( < 1%, ≥1%), IO line (1°, ≥2°), number (N) of metastatic sites (1, ≥2), presence of liver and/or brain metastasis. Their impact on survival was evaluated through Cox proportional hazard models. Results: Four-hundred-one pts (35.7% female) with median age of 65.4 years (range 27-88) were studied. Baseline PS was 0 in 134 pts (33.4%), 1 in 209 pts (52.1%) and 2 in 58 pts (14.5%). 312 pts had non-squamous NSCLC, 89 squamous NSCLC. Clinical-pathological variables were uniformly distributed across PS groups except for a higher rate of liver metastasis in PS2 pts ( p= 0.046). Response evaluation was available for 386 pts. DCR was 49.7% in PS0-1 pts and 25.9% in PS2 pts ( p= 0.006). At a median follow-up of 29 months (mos), median PFS was 3.0 mos (95% CI 2.63-4.00) and 2.04 mos (95% CI 1.84-3.00) in pts with PS0-1 and 2 ( p< 0.0001). Median OS was 13.2 mos (95% CI 11.18-15.78) and 4.0 mos (95% CI 2.66-5.62) in pts with PS 0-1 and 2 respectively ( p< 0.0001). Univariate analysis showed significant correlation of PS2 status, negative PDL1, IO line ≥2, N of metastatic sites ≥2 and liver metastasis, for both PFS and OS. Multivariate analysis confirmed an independent association of PS ( p= 0.0013 for PFS, p< 0.0001 for OS), PDL1 ( p= 0.0002 for PFS, p= 0.02 for OS) and liver metastasis ( p= 0.017 for PFS, p= 0.02 for OS). The incidence of Grade 3/4 adverse events was 10.5% in PS 0-1 pts and 13.7% in PS 2 pts ( p= 0.41). Conclusions: Our data confirm reduced efficacy of IO in pts with poor PS, regardless of the N of prior therapy lines or PDL1 expression. Despite IO appears to be safe and tolerable its role remains uncertain in PS2 pts based on worse survival outcomes.
Molecular subtyping reveals stage-specific mutational landscape and prognostic predicting factors of stage IV NSCLC.
Authors: Huang Yuqing , Yang Yingshun , Yao Jianfei , Liu Qiang , Wang Bingzhi , Min Xianjun , Pei Guotian , Wang Shuai , Wang Xiaoyu , Liu Jun , Dang Shiying , Huang Tanxiao , Xu Mingyan , Song Lele
Published: May 2020

e21607

Background: The mutational profile of non-small cell lung cancer (NSCLC) has been widely studied. However, the correlation between mutational profile and the prognosis of various molecular subtypes of NSCLC has not been fully investigated. Methods: We established the mutational landscape from 244 stage I-IV NSCLC patients using a 605-gene next generation sequencing panel. Molecular subtyping was performance based on the mutational status of EGFR, TP53, KRAS and STK11 genes according to reported methods. Sequencing data were analyzed with R packages and statistics analysis was performed with Graphpad PRISM 5.0 software. P ≤ 0.05 was regarded as statistically significant. Results: Differential SNV/INDEL mutation frequency across stage I-IV was found in EGFR, TP53, ATM, CDKN2A and NF1 (P < 0.05), differential CNV frequency was found in EGFR, RB1, PIK3CA, TERT, KRAS, FGFR1 and ERBB2 (P < 0.05), and differential SV frequency was found in ROS1 (P < 0.05). TMB of stage III-IV patients was higher than those of stage I (P < 0.05). TMB was higher in patients with TP53 but without EGFR mutations (P < 0.05). The association between prognosis and mutational status was further investigated in stage IV NSCLC. Patients with EGFR SNV/INDEL mutations exhibited better PFS and OS time, while patients with KRAS and/or STK11 SNV/INDEL mutations, or without mutations in EGFR, TP53, KRAS and STK11 exhibited worse PFS and OS time. However, no significant difference was observed in PFS and OS between patients with or without TP53 SNV/INDEL, EGFR CNV, ERBB2 CNV or TERT CNV variations. Further analysis showed that male or age≥62 exhibited worse OS time (P < 0.05), while smoking history, palliative surgery and palliative radiotherapy did not affect the PFS and OS time of stage IV patients. Conclusions: We found differential frequency in SNV/INDEL, CNV and SV variations across stage I-IV NSCLC. EGFR SNV/INDEL, KRAS SNV/INDEL, STK11 SNV/INDEL mutation, gender and age were found to be prognostic predicting factors for stage IV NSCLC.
Real-world evidence: Molecular subtype and its prognostic implications of Lung-molGPA in EGFR-mutated adenocarcinoma.
Authors: Kuan Feng-Che , Shi Chung-Sheng , Yang Wei-Hsun , Lai Hung-Yi , Huang Chun-Chieh , Yang Cheng-Ta
Published: May 2020

e21621

Background: EGFR mutations are heterogenous but all carry the same weight in the Lung-molGPA. The aim of this study was to elucidate the different prognostic implications of molecular subtypes and frontline TKIs in EGFR-mutated lung adenocarcinoma with synchronous brain metastases (BM) using the Lung-molGPA. Methods: Medical records were searched in hospital databases from 2011 to 2015. Patients with EGFR-mutated adenocarcinoma and brain metastases who received TKIs were included. The Kaplan-Meier method was used to estimate survival, and multivariate Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results: A total of 256 patients were included with a median overall survival (OS) of 17.2months. Patients with Lung-molGPA scores of 1, 1.5-2.0, 2.5-3.0, and 3.5-4.0 had median OS of 5.9,11.5, 17.2, and 23.4months, respectively (p < 0.001). In multivariate analysis of OS, only age (³70 versus < 70 years, HR:1.71, 95% CI:1.25-2.35, p < 0.001), KPS ( < 70 versus ³70, HR:1.71, 95% CI:1.26-2.31, p < 0.001), and rare mutations (other versus exon 19 deletions, HR:1.78, 95% CI:1.04-3.05, p = 0.037) remained statistically significant. In patients with a Lung-molGPA score £2.5, EGFR molecular subtypes had different median OS (exon 19 deletions versus Leu858Arg versus other, 18.9vs 12.8vs 4.5months, p = 0.021) and prognostic implications (Leu858Arg versus exon 19 deletions, HR: 1.85, 95% CI: 1.20-2.84, p = 0.005; other versus exon 19 deletions, HR:2.18, 95% CI:1.11-4.26, p = 0.023). Conclusions: Different molecular subtypes treated with frontline TKIs have different prognostic implications in the Lung-molGPA. Further prospective studies are warranted to validate these findings.
Advanced Lung Cancer Inflammation Index: Prognostic value in a retrospective lung cancer cohort.
Authors: Syrigos Konstantinos N. , Patsilinakou Stavroula , Grapsa Dimitra , Chrysanthopoulou Evangelia , Gkiozos Ioannis , Kavantzas Nikolaos , Politi Ekaterini
Published: May 2020

e21624

Background: As shown in recent studies, inflammation plays a key role in lung cancer (LC) pathogenesis and evolution, while the potential prognostic and predictive value of various inflammation markers in different disease stages is being extensively studied. We herein aimed to further evaluate the potential prognostic value of a new inflammation marker (ALI, Advanced Lung Cancer Inflammation Index = BMI x Alb / NLR), which combines previous markers of systematic inflammation with markers of nutrition or cachexia at the time of LC diagnosis. Methods: The medical records of 67 patients, diagnosed with LC in Sismanoglio Athens General hospital, within a two-year period (January 2016-January 2017) were retrospectively studied. Demographic, clinicopathological and laboratory features of patients, including pre-treatment ALI, were recorded and correlated with prognosis (overall survival, OS). Results: A total of 67 patients were included with a mean age of 60 (± 8) years. The majority of cases were men (39/67,58.2 %), with positive smoking history (62/67, 92.5%), performance status (PS) 1-2 (43/67, 64.2%) and disease stage IV (54/67, 80.6%). Adenocarcinoma was the commonest histological type observed (19/67, 28.5%). Values of ALI ranged from 7.8 to 37.2 (mean: 21±6). The cut-off point of ALI was 19 (based on ROC curve analysis) and patients were divided into two groups: those with ALI < 19 and those with ALI ≥ 19. In univariate analysis, PS and the presence of metastatic disease, as well as ALI values < 19, were all correlated with reduced survival (p = 0.002, p = 0.028 and p = 0.018, respectively). In multivariate analysis, PS was the only parameter that retained its statistically significant correlation with an adverse prognosis (p = 0.048), although its prognostic significance was increased when combined with ALI. Conclusions: Although failing to confirm an independent prognostic value for ALI, the results of our study suggest that combination of ALI with standard prognostic predictors such as PS may improve prediction of patients’ survival. Additional prospective studies are warranted to validate the prognostic significance of this promising biomarker and expand its use in routine practice.
Association of baseline characteristics and survival in patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (CPIs): Real-world evidence.
Authors: Crawley Danielle , Beckmann Kerri , Ravindra Saranya , Josephs Debra Hannah , Spicer James F. , Montes Ana , Karapanagiotou Eleni , Ghosh Sharmistha
Published: May 2020

e21625

Background: CPIs including antibodies to programmed death-1 (PD-1) and its ligand anti PD-L1 are associated with superior overall survival (OS) in NSCLC. PDL1 is an imperfect predictive biomarker. We have examined real world data to identify additional factors associated with clinical benefit. Methods: 96 consecutive NSCLC patients (pts) were treated with CPIs at our institution. Multivariate cox proportional hazard regression models were used to examine the associations between OS and baseline characteristics including age, sex, histology, PDL1 status, performance status (PS), steroid use and brain metastases. Results: 93% (89/96) of pts received pembroluzimab, 6 (6%) nivolumab, and 1 (1%) atezoluzimab. All pts had metastatic disease (68% adenocarcinoma). 15% had PS 0, and 70% PS1. 11 of the 96 pts had brain metastases prior to CPI, 4 (37%) had whole brain radiotherapy, 2 (18%) targeted radiotherapy, 2 (18%) resection with radiotherapy and 3 (27%) had no definitive treatment for brain metastases. After multivariate analysis those with PS 1-2 had an increased risk of death (PS = 1 HR 2.74, 95% CI 1.11-6.72; PS = 2 3.61, 95% CI 1.28-10.15) compared with PS 0. Outcomes for pts receiving corticosteroids at the time of initiation of CPI were also inferior (HR 2.29, 95% CI 1.10-4.74) compared to those who were not. Conversely those who had brain metastasis diagnosed prior to commencing CPI had superior OS (HR 0.29 95% CI: 0.11-0.76). No statistically significant association was seen with age, gender, histology, stage at diagnosis, smoking or mutational status. PDL < 50% compared to > 50% was associated with an increased risk of death (HR 1.53 95% CI: 0.90-2.60) though it was not statistically significant. Conclusions: Here we show, using real world data, that PS and use at baseline of oral corticosteroids are associated with inferior OS with CPI treatment for NSCLC, in line with reports from large clinical trials. We show that baseline brain metastases are associated with improved outcomes. This may be explained by survivor bias, in that those who are successfully treated for brain disease, remain PS ≤2 and are able to commence CPI represent a highly selected group.
Exploratory analysis of factors associated with hyperprogression in advanced non-small cell lung cancer (NSCLC) treated with PD1/PDL1 inhibitors.
Authors: Decatris Marios P. , Thomas Joy A , Hayes Mark , Ryan Philip , Phillips Aled , ElBatrawy Sherouk , Bowden Caitlin , Du Rand Ingrid
Published: May 2020

e21634

Background: Hyperprogressive disease(HPD) is a recently recognized type of accelerated tumor progression with immune checkpoint inhibitor(ICI) therapy. A recent meta-analysis identified serum lactate dehydrogenase(LDH) above upper limit of normal(ULN), liver metastases and > 2 metastatic sites to be associated with increased likelihood of HPD. Methods: We performed a single-center retrospective analysis of NSCLC patients treated with ICI from 2/2017-1/2020. We defined HPD using combined criteria of failure to complete > 4 cycles of ICI and radiological progression with development of new lesions or marked clinical progression where restaging was not achievable because of rapid decline in performance status. Treatment discontinuation/interruption because of toxicity alone, was not designated as HPD. Results: HPD was seen in 9/41(22%) patients treated with at least 1 cycle of ICI. In 6/9 there was marked radiological progression (new lesions/significant progression of existing lesions); in the remaining 3 restaging was not possible because of rapid decline which mandated treatment cessation. Patients with HPD were more likely to have a raised LDH, liver metastases or > 2 metastatic sites but these differences were not statistically significant. 9/9 versus 5/32 patients in the HPD/non-HPD cohorts respectively progressed within 10 weeks of treatment (p < 0.001) and 7/9 versus 12/32 respectively did not survive beyond 6months (p = 0.057). Conclusions: This small study has shown a non-statistically significant trend for association between HPD, raised LDH, liver metastases and presence of > 2 metastatic sites. A better understanding of risk/predictive factors for HPD is essential for improved patient selection for treatment with ICI. [Table: see text]