bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemo or chemo-free regimens in heavily pretreated multiple myeloma? Role of bendamustine-bortezomib-dexamethasone (BVD) in NOVEL agents' era.
Authors: Cerchione Claudio , Catalano Lucio , Nappi Davide , Ronconi Sonia , Cangini Delia , Ceccolini Michela , Musuraca Gerardo , Martinelli Giovanni
Published: June 2022

e20010

Background: The treatment of heavily pretreated Multiple Myeloma continues to be considered as an important unmet clinical need. Bendamustine is an old bi-functional alkylating agent which has proved to be effective in relapsed, refractory and in new diagnosed Multiple Myeloma (MM). Thus, aiming to provide further insights in this field, also in novel agents’era, we present here a retrospective, real-life analysis of patients with relapsed/refractory MM (rrMM), who had received salvage therapy with bendamustine in combination with bortezomib and dexamethasone (BVD). Methods: 81 patients (44 M/37 F), with rrMM, median age at diagnosis 59.4 years (r. 36-82), median age at start of treatment 63.6 years (r.37-86) treated with several lines of treatments (median 6, r. 2-11), every refractory to all the drugs previously received (also Bortezomib), received BVD (B 90 mg/sqm days 1,2; V 1.3 mg/sqm days 1,4,8,11, D 20 mg days 1,2,4,5,8,9,11,12, Pegfilgrastim day +4) every 28 days, until progression. All patients had previously received bortezomib-based and IMIDs-based treatments, and 32% (26/81) had also received radiotherapy. 69% (56/81) had undergone single or double autologous and three (2%) allogeneic stem cell transplant. All patients were relapsed and refractory to last therapies received before BVD. Results: Bendamustine was well tolerated, with grade 3-4 transfusion-dependent anemia in 56% (46/81) of patients, and 43% (35/81) grade 3-4 neutropenia (no ospedalization was required, no septic shocks were observed). No severe extrahematologic toxicity was observed, only grade 1 gastrointestinal side effect (nausea), treated by common antiemetic drugs. According to IMWG, ORR was 63% (51/81: 7 CR, 18 VGPR, 15 PR, 11 MR) with 11 PD and 19 patients in SD, which can be considered as an impressive result in this subset of rrMM patients. In particular, for 11 patients, BVD was, after having achieved at least a PR, a bridge to second auSCT, and for two patients a bridge to alloSCT. Eight patients have surprisingly achieved a notable PR after failure of novel agents (i.e. Carfilzomib, Daratumumab and Pomalidomide). Median time to response was 1.3 months (r.1-3), median OS from diagnosis was 67.3 months (r.6-151), median OS from start of Bendamustine was 9.6 months (r.2-36). Conclusions: The triplet Bendamustine-Bortezomib-Dexamethasone has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, and, in particular cases, it could be considered as a bridge to a second autologous or allogenic SCT, also after failure of novel agents. Clinical trial information: A101.
Responses to salvage therapy in AL amyloidosis after progression on daratumumab.
Authors: Mann Hashim , Salei Yana , Fogaren Teresa , Toskic Denis , Scalia Stephanie , Ma Xun , Zhou Ping , Comenzo Ray
Published: June 2022

e20030

Background: Daratumumab (Dara)-based therapy is the standard for upfront treatment in systemic light-chain (AL) amyloidosis and is preferred in the relapsed setting. However, outcomes of patients who relapse on dara remain unclear. In such circumstances, optimal sequencing of subsequent drugs is also not well-established. Here, we describe outcomes of AL patients who progressed on dara-based treatments. Methods: We conducted a retrospective review of AL patients treated at our center from 2015 to 2022. Patients were eligible if they progressed on dara at any time during disease course. We recorded all standard metrics, including serologic and biomarker data. Patients with incomplete follow-up or missing data were excluded. Descriptive statistics were performed with Prism 5.0 (GraphPad; San Diego, CA). Results: A total of 11 patients were identified. Median age was 73. Nine were male, and 8 had AL, λ-type (2–κ, 1–heavy chain). Median iFLC at baseline was 342 mg/L (55.6–9780) and NT-proBNP was 1166 pg/mL (147–5000). Cardiac involvement was most common (82%); 64% had ≥2 organs involved. Six had t(11;14) by FISH and/or cyclin D1 overexpression by IHC, 3 had gain 1q, 2 had del 17p, and 4 had complex cytogenetics. Five patients received ≥2 prior lines of therapy, including 3 ASCT. Three (27%) received dara in induction, whereas the most common indications for later use were hematologic/organ progression (45%), suboptimal response (18%), and refractory disease (9%). At a median follow-up of 82 weeks, all patients had progressed. Median time to next therapy was 15 weeks (7–151). Six (55%) continued dara at salvage, while other agents used were bortezomib (n=5), ixazomib (n=6), pomalidomide (n=5), cyclophosphamide (n=4), bendamustine (n=4), and belantamab mafodotin (n=3). All patients with t(11;14) or cyclin D1 overexpression received venetoclax, of whom 4 also received HMG-CoA reductase inhibitors (statins). ORR was 100%. Hematologic VGPR and CR rates were each 36%, PR 18%, and 1 patient had low dFLC PR. Rate of VGPR or better was higher in patients with t(11;14) and/or cyclin D1 overexpression (83% vs 60%; P=0.55). Of the 4 patients who received venetoclax and statins for t(11;14) disease, 3 had CR and 1 had VGPR. One renal and 3 cardiac responses were observed. At last follow-up, 2 patients with VGPR had died while the rest had ongoing responses. Conclusions: In our study, most patients had t(11;14) and progressed on dara within 20 weeks. Salvage therapy incorporating novel agents yielded impressive responses. The combination of venetoclax and statins was effective in overcoming the negative impact of t(11;14) although further studies are needed for validation.[Table: see text]
Prevalence of monoclonal gammopathy of undetermined significance in black South African men.
Authors: Cicero Kara Ilene , Joffe Maureen , Patel Moosa , Pentz Audrey , Ruff Paul , Lentzsch Suzanne , Leng Siyang , Chiuzan Codruta , Jacobson Judith , Rebbeck Timothy , Neugut Alfred I.
Published: June 2022

e20032

Background: Monoclonal gammopathy of undetermined significance (MGUS) is the precursor to multiple myeloma (MM). MM disproportionately affects black individuals, but the cumulative risk of progression from MGUS to malignancy does not differ by race. Hence, the racial disparities in MM incidence appear to arise from differences in the occurrence of MGUS. Nonetheless, MGUS has been studied mainly in white populations; the study that first described the natural history of MGUS was conducted by Kyle, et al. (2006) in 97.3% white Olmsted County, Minnesota. Methods: We determined the prevalence of MGUS among black South African men >30 years of age at the Chris Hani Baragwanath Academic Hospital in Johannesburg. We conducted serum protein electrophoresis (SPEP) and free light chain (FLC) quantification and used the same criteria for MGUS as the Olmsted County studies: a monoclonal protein on SPEP or an abnormal FLC-ratio plus elevation in the appropriate FLC. We also investigated the association between MGUS and various clinical and behavioral factors. Results: The prevalence of MGUS in our cohort (n=386) was 8.03% (95%CI 5.32-10.74), nearly 1.6-fold higher than in Olmsted County males. In a univariable logistic regression model, MGUS was associated with HIV status (odds ratio (OR) 2.39, 95%CI 0.95-5.51), but in the adjusted model that also included body mass index (BMI) and cigarette use, the magnitude of the association decreased to an OR of 2.17 and was not statistically significant. MGUS was associated with current (vs. never) cigarette smoking in both univariable (OR 5.2, 95%CI 1.53-24.0) and multivariable (OR 4.11, 95%CI 1.08-20.4) models. Conclusions: Not only did we find the prevalence of MGUS in black South African men to be substantially higher than in white populations, but we also report that MGUS cases are associated with potentially modifiable risk factors. Building on this pilot study, a larger study is currently underway powered to confirm the relationship between MGUS and HIV, as well as between MGUS and cigarette smoking, in a black African population inclusive of both genders. Future studies designed to evaluate genetic and matched-environmental contributions may elucidate racial disparities and facilitate the development of strategies to prevent plasma cell malignancies.[Table: see text]
Real-world treatment patterns and clinical outcomes in early stage non-small cell lung cancer (eNSCLC) in Canada.
Authors: O'Sullivan Dylan E , Boyne Devon J , Ford-Sahibzada Chelsea , Inskip Jessica A , Smith Christopher J , Sripada Kaushik , Brenner Darren R , Cheung Winson Y
Published: June 2022

e20504

Background: The prognosis of eNSCLC remains uniformly poor. An understanding of current therapies and outcomes can provide insights into how novel therapies can be integrated into our management paradigm. Methods: We conducted a large, retrospective, population-based cohort study of de novo eNSCLC patients (stages IB, IIA, IIB, and IIIA) diagnosed in Alberta, Canada between 2010-2019 using electronic medical records and administrative claims data. The primary objectives were to describe treatment patterns and survival outcomes among eNSCLC patients. In addition, we examined the association between systemic therapy (ST) and overall survival (OS) using multivariable Cox proportional hazards models. Results: A total of 5,126 eNSCLC patients were included. The stage distributions were: 31.0% IB, 13.4% IIA, 17.7% IIB, and 37.9% IIIA. The mean (SD) age was 71.3 (10.3) years and 52.5% were female. 45.3% of patients were referred to a medical oncologist, ranging from 23.7% in stage IB and 58.3% of IIIA. Among stage IB and II patients, 59.2% and 58.1% received surgery, respectively, while 25.7% of stage IIIA patients underwent surgery. 23.6% of patients initiated ST, ranging from 3.5% in stage IB to 38.5% in IIIA. ST use increased over the study period by 9.3% and 19.5% in stage IIB and IIIA disease, respectively. Median follow-up for the cohort was 21.86 months; median OS was 28.18 months (95% CI: 26.56-29.69). Median OS for stage IB, IIA, IIB, and IIIA were 49.01 (95% CI: 45.00-54.15), 36.56 (95% CI: 32.94-42.25), 29.23 (95% CI: 25.32-33.11), and 16.50 (95% CI: 15.39-17.59). Findings from the Cox analyses are tabulated (see Table). For stage IIB and IIIA individuals who received surgery, adjuvant ST was also associated with a decreased likelihood of death [hazard ratios (HR) of 0.77 (95% CI: 0.56-1.07) and 0.69 (95% CI: 0.54-0.89), respectively]. Conclusions: In a Canadian real-world setting, stage IIB and IIIA patients who received adjuvant ST tended to have better survival than patients who did not. However, a considerable proportion of patients are not referred to a medical oncologist to be considered for ST. Improving referral pathways appears to be an essential step to ensure that emerging novel therapies are implemented effectively in the real world so that potential survival gains from new drugs can be realized.[Table: see text]
Physician referral patterns and use of adjuvant therapy among stage IB-IIIA non-small cell lung cancer (NSCLC) patients (2010-2017).
Authors: Kale Hrishikesh , Wang Wei-Jhih , Chirikov Viktor , Shah Anne , Apple Jon
Published: June 2022

e20509

Background: As the treatment landscape for early-stage NSCLC continues to evolve with the recent approvals of targeted and immunotherapy agents in the adjuvant setting, it is important to understand physician referral patterns and predictors of adjuvant therapy (AT). This study examined physician referral patterns at key treatment phases and assessed predictors of receiving AT in stages IB-IIIA NSCLC patients. Methods: A retrospective study using the linked SEER-Medicare database (01/01/2010-12/31/2017) included patients newly diagnosed with stages IB-IIIA NSCLC who received surgical resection. Specialties were identified by linking NSCLC claims to the AMA Physician Masterfile. AT was defined as the use of systemic chemotherapy or radiation therapy within 4 months of surgery. Multivariable logistic regression was conducted to assess predictors of receiving AT. Results: A total of 7,108 patients met the study criteria (53% IB; 9% IIA; 19% IIB; 20% IIIA). Primary care physicians (PCP) (71%), surgical oncologists (29%), and medical oncologists (36%) were the most frequently visited first specialists during pre-diagnosis, diagnosis to surgery, and post-surgery phases, respectively. The median time from diagnosis to surgery was 44 days. After surgery, 74% patients visited a medical oncologist (62% IB; 87% IIA; 83% IIB; 88% IIIA). About 41% received AT (21% IB; 64% IIA; 56% IIB; 69% IIIA). Of those, the median time from surgery to adjuvant therapy was 46 days. In the adjusted analysis, later stage at diagnosis and shorter referral time to medical oncologist had the highest odds of receiving AT (Table). Conclusions: The strongest predictors of receiving adjuvant therapy were time to medical oncologist post-surgery and stage at diagnosis. Future studies in the era of targeted therapies can use these results as a benchmark to optimize management and outcomes as well as assess changes in referral patterns in IB-IIIA NSCLC patients.[Table: see text]
The clinical implications of TMB and the relationship between TMB and EGFR mutations in non-small cell lung cancer of Xuanwei, China.
Authors: Peng Hao , Zhang Hushan , Zhang Libin , Xu Zheyuan , Wang Yang , Wang Han
Published: June 2022

e20512

Background: Xuanwei lung cancer is a type of non-small cell lung cancer that occurs in Xuanwei, southwest China. It is different from non-Xuanwei non-small cell lung cancer in many aspects. The key is that Xuanwei lung cancer does not currently have a recognized prognostic biomarker. The significant molecular difference between Xuanwei lung cancer and non-Xuanwei lung cancer is the mutation type and mutation ratio of EGFR. Are different mutations of EGFR related to the prognosis of Xuanwei lung cancer? What are the reasons for the difference between Xuanwei lung cancer and non-Xuanwei lung cancer? These are clinical issues that we are very interested in. In addition, tumor mutation burden (TMB) has been shown to be an effective biomarker for predicting the clinical outcome of multiple cancer types. However, its prognostic value in Xuanwei lung cancer remains unknown. Methods: The Formalin-Fixed Paraffin-Embedded (FFPE) tissues samples from 172 primary NSCLC patients who have underwent next-generation sequencing (NGS) in a laboratory accredited by the College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendment (CLIA) (3D Medicines Inc., Shanghai, China) from June 2015 to October 2020 were analyzed. The written informed consent was obtained from all included patients. The postoperative follow-up data of all these NSCLC patients were collected. Results: The prognosis of Xuanwei lung cancer is better than that of non-Xuanwei (p < 0.05). Xuanwei is superior to non-Xuanwei mainly in EGFR-positive patients (p < 0.05). Among patients without EGFR mutations, there is no difference in the prognosis of Xuanwei lung cancer and non-Xuanwei lung cancer. Further analysis revealed that there is a difference in TMB levels between Xuanwei lung cancer and non-Xuanwei lung cancer. The TMB level in Xuanwei lung cancer is significantly higher than that in non-Xuanwei lung cancer (p < 0.05). EGFR mutations can be used as prognostic markers for Xuanwei lung cancer, and this is related to patients with EGFR mutations having higher TMB levels. Our research results indicate that EGFR mutation may help combine traditional clinicopathological risk factors to optimize risk stratification and guide treatment decisions. Conclusions: Xuanwei lung cancer is a special subtype of NSCLC with different molecular features and prognosis. Analysis of data in this area will lead to the development of precision treatment options for Xuanwei lung cancer.
EGFR mutations in lung carcinomas: Mutation profile and survival analysis.
Authors: Warrier Narayanankutty Edavalath , Vallathol Dilip Harindran , Sankar Uma V , Salahuddin Sameer , P. S. Sreedharan , Parameswaran Prasanth V. , K V Sajeevan
Published: June 2022

e20518

Background: Epidermal growth factor receptor (EGFR) mutation have been demonstrated to be both predictive and prognostic for patients with metastatic lung cancer. The administration of EGFR tyrosine kinase inhibitors (TKIs) has improved survival in this group of patients. Several generations of EGFR TKIs are currently available. The EGFR mutations have been divided into common and rare. The common mutations include Exon 19 deletion and Exon 21 L858R mutations and rest are grouped as rare. The presence of visceral metastasis in the brain and liver are usually portends a poor prognosis. Methods: We conducted a retrospective analysis of lung cancer patients who attended our hospital outpatient department from 2017 to 2021. The prevalence, demographics and clinical profile of EGFR common and rare mutations were studied using descriptive statistics. Survival of EGFR mutated patients was plotted using Kaplan Meier plots. SPSS was used for statistical analysis. Results: The prevalence of EGFR mutation among metastatic lung cancer was 14.10% (161/1148). The median age of the group was 60 years (23- 104 years). Smokers with EGFR mutations were 11.8% (n = 19). Male to Female ratios was 76:85 (47.2% and 52.8%). Three patients with squamous cell carcinoma exhibited EGFR mutation. Most common EGFR TKI used was Gefitnib. Osimertinib was used in 13 patients (1.4%). The percentage of common mutations were 85.75% (N = 132) and rare mutations were 14.3% (n = 22). The type of mutations could not be identified in 10 patients. The percentage of patients with exon 19 deletion were 63% (n = 97) and L858R were 24.7% (n = 38). Visceral metastasis (brain and liver) was seen in 47 patients (n = 29.2%). Brain progression was seen in 32 patients (n = 19.9%). The survival of patients with EGFR exon 19 deletion and L858R mutation was 16.36 + 8.97 months and 15.97+ 10.93 months, Survival among patients with common mutation was 16.20 + 9.57 months and among rare mutation was 13.43 + 12.19 months. Median Survival period of patients with visceral metastasis was 12 months (0 to 38 months). Conclusions: In our retrospective study, there was no significant difference between survival among common and rare EGFR mutations.
Discordant genomic correlates of PD-L1 expression in lung adenocarcinoma among multiple cohorts using dissimilar PD-L1 testing techniques.
Authors: Wang Lijie , Liu Siyao
Published: June 2022

e20526

Background: Programmed death-ligand 1 (PD-L1) is a crucial biomarker predicting efficacious treatment of immune checkpoint inhibitors (ICIs). Previous studies identified distinct staining utility among multiple PD-L1 antibodies, however, whether the genomic correlate of stained PD-L1 is also impacted by different testing assays is largely unknown. Methods: Here, we analyzed 873 lung adenocarcinoma (LUAD) samples by the FDA-approved SP263 and 22C3 antibodies, and discovered that TP53, KRAS, MET, and ALK alterations associated with high SP263/22C3-PD-L1 expression, while EGFR and ERBB2 aberrations linked to SP263/22C3-PD-L1 negativity. Results: We retrieved the data of 873 LUAD patients whose PD-L1 (SP263/22C3) and mutational data. The SP263/22C3-PD-L1 expression was significantly correlated with tumor mutational burden and was greater in metastatic lymph node than lung lesion and distal metastasis. Furthermore, TP53, MET, ALK, KRAS alterations were associated with higher SP263/22C3-PD-L1 expression, while EGFR and ERBB2 alterations were linked to SP263/22C3-PD-L1 negativity. In the TCGA database lacking fusion data except for ALK and using reverse phase protein arrays (RPPA) for quantifying PD-L1 expression, STK11 mutation exhibited negative correlation with PD-L1 mRNA (p < 0.001), but not the RPPA-PD-L1 protein-level expression (p > 0.10), while samples with ALK fusion showed a tendency of higher RPPA-PD-L1 (p = 0.088). Moreover, in the OAK trial providing data of single nucleotide variation and using SP142 (Ventana, Tucson, AZ) assay evaluating both tumor and immune cells, weak correlation between STK11 mutation and SP142-PD-L1 negativity was observed (p = 0.076). Conclusions: Identical usage of staining antibody is the fundament of further comparisons and deeper investigations. The FDA-approved SP263 and 22C3 assays with fixed reagent, machine and protocol may perform more effective and repeatable than LDTs such as the E1L3N method. In addition to the different staining utility among PD-L1 antibodies indicated by previous studies, we further provide insights into the dissimilar genomic correlates of stained PD-L1 by using different PD-L1 quantifying techniques.
Predicting patient treatment response and resistance via single-cell transcriptomics of their tumors.
Authors: SInha Sanju , Vegesna Rahulsimham , Dhruba Saugato Rahman , Wu Wei , Kerr D. Lucas , Stroganov Oleg V. , Grishagin Ivan , Aldape Kenneth D. , Blakely Collin M. , Jiang Peng , Thomas Craig J , Bivona Trever G. , Schaffer Alejandro , Ruppin Eytan
Published: June 2022

e20540

Background: Tailoring the best treatments to cancer patients is an important open challenge. Here, we build a precision oncology data science and software framework for PERsonalized single-Cell Expression-based Planning for Treatments In Oncology (PERCEPTION). Methods: Our approach capitalizes on recently published matched bulk and single-cell transcriptome profiles of large-scale cell-line drug screens to build treatment response models from patients’ single-cell (SC) tumor transcriptomics. Our approach is a two-step process: first, the prediction models are trained on large-scale bulk-expression profiles of cancer cell lines and then, in a second step, the models’ performance is further optimized by training on SC-expression profiles of cancer cell lines. Results: First, we show that PERCEPTION successfully predicts the response to monotherapy and combination treatments in screens performed in cancer and patient-tumor-derived primary cells based on SC-expression profiles. Second, it successfully stratifies responders to combination therapy based on the patients’ tumor’s SC-expression in two very recent multiple myeloma and breast cancer clinical trials. Thirdly, it captures the development of clinical resistance to five standard tyrosine kinase inhibitors using tumor SC-expression profiles obtained during treatment in a lung cancer patients’ cohort. Notably, PERCEPTION outperforms state-of-the-art bulk expression-based predictors in all three clinical cohorts. Conclusions: In sum, this study provides a first-of-its-kind conceptual and computational method that is predictive of response to therapy in patients, based on the clonal SC gene expression of their tumors.
Blockade of STAT3/IL-4 overcomes EGFR T790M-cis-L792F-induced resistance to osimertinib via promoting M2 macrophages polarization.
Authors: Sun Yiting , Ma Yuanyuan , Tian Zhihua , Liu Xijuan , Yan Xiang , Zhao Wei , Wang Jie , Wang Zhijie
Published: June 2022

e20552

Background: Missense alteration at EGFR L792F emerges after osimertinib resistance in patients with non-small cell lung cancer (NSCLC). However, its mechanism has not been sufficiently clarified. We aimed to explore the critical molecular events and coping strategies in osimertinib resistance due to acquired L792F mutation. Methods: Circulating tumor DNA-based sequencing data of 1382 patients with osimertinib resistance were collected to illustrate the prevalence of L792F mutation. Sensitivity to osimertinib was tested with constructed 19Del/T790M-cis-L792F mutations and control cell lines in vitro and in vivo. The correlation and linked pathways between M2 macrophage polarization and EGFR 19Del/T790M-cis-L792F-induced osimertinib resistance were investigated. Also, possible interventions to suppress osimertinib resistance by targeting IL-4 or STAT3 were explored. Results: The concomitant EGFR L792 was identified as an independent mutation following the acquisition of T790M after osimertinib resistance, in that 5 of the 946 patients with osimertinib resistance harbored EGFR L792F- cis mutation. Transfected EGFR 19Del/T790M-cis-L792F in cell lines had decreased sensitivity to osimertinib and enhanced infiltrating macrophage with M2 polarization. Silico analyses confirmed the role of M2 polarization in osimertinib resistance induced by EGFR T790M-cis-L792F mutations. The upregulated phosphorylation of STAT3 Tyr705 and downstream expression and secretion of IL-4 induced M2 polarization. Furthermore, blockade of STAT3/IL-4 (SH-4-54 or dupilumab) suppressed M2 macrophage polarization and regressed tumor sensitivity to osimertinib and delayed tumor growth. Conclusions: Our results provided solid evidence of EGFR T790M-cis-L792F mutation as a factor inducing osimertinib resistance. Targeting EGFR T790M-cis-L792F/STAT3 Tyr705/IL-4 pathway could be a potential strategy to suppress osimertinib resistance in NSCLC.
Tumor necrosis or cavity on baseline CT scan as a negative predictive biomarker for immune checkpoint inhibitors in advanced lung squamous cell carcinoma.
Authors: Long Feng , Lin Gen , Zheng Xinlong , Jiang Kan , Miao Qian
Published: June 2022

e20556

Background: Current predictive biomarker for immune checkpoint inhibitors (ICIs) does not distinct according to histologic subtype. We hypothesize that necrosis or cavity on baseline CT scan in lung squamous cell carcinoma (LSCC) is predictive of treatment for ICIs. Methods: This was a multicenter retrospective analysis of patients with advanced LSCC. All eligible patients must had received either first-line chemotherapy only (chemotherapy group), or ICIs as monotherapy or combined with chemotherapy (ICIs group). Radiotherapy to thorax was not allowed. Baseline contrast-enhanced CT were reviewed by independent radiologist in each center. Radiologic finding was correlated with outcomes. Results: Total of 538 patients were eligible with 270 patients in the chemotherapy group and 268 patients in ICIs group. Baseline characteristics were well balanced. Tumor necrosis or cavity was identified in 111 (41.1%) in chemotherapy group and 99 (36.9%) in ICIs group. In chemotherapy group, there was no difference in PFS between patients with or without necrosis or cavity (5.33 vs 4.97 months, Hazard Ratio (HR) 1.05, 95% confidence interval (CI), 0.81-1.36, p= 0.726). In contrast, there was significant difference in PFS in ICIs group favoring patients without tumor necrosis or cavity (8.7 vs 6.5 months, HR 0.67, 95% CI 0.42–0.63, p< 0.001). Multivariate Cox analysis confirmed necrosis or cavity as an independent unfavorable predictive factor for PFS (HR 0.68; 95% CI, 0.51-0.9; p= 0.007). Conclusions: Tumor necrosis or cavity on baseline chest CT scan is a promising predictive biomarker for ICIs in LSCC, and this observation warrant further investigation.
The impact of EGFR Exon 20 mutation subtypes on lung cancer prognosis.
Authors: Xu Ming , Li Yingmei , Liu Danni , Mu Tianhao , Cheng Nitao
Published: June 2022

e20557

Background: Many lung cancer patients with epidermal growth factor receptor (EGFR) mutations benefit from tyrosine kinase inhibitors (TKIs). However, patients with EGFR exon 20 mutations usually have worse response rates than other types of EGFR mutations. Here we investigated how different mutation subtypes of EGFR exon 20 affected the prognosis. Methods: Clinical and genomic data from 3 studies (MSKCC2020, MSKCC2021, and OncoSG) of patients with lung adenocarcinoma (LUAD) were reviewed (n = 1,001). Four hundred and seventeen patients harbored EGFR mutations and 52 of them had EGFR exon 20 mutations. The correlation of mutation subtypes with OS data was analyzed using R package. Results: In lung cancer patients with EGFR mutations (n = 417), 52 of them (12.5%) had a total of 64 EGFR exon 20 mutations, and could be categorized into 16 different subtypes, with top 5 subtypes being T790M (n = 28), S768I (n = 8), C797S (n = 7), A767_V769dup (n = 6) and S768_D770dup (n = 3). Patients with S768I (p = 0.0038) and A767_V769dup (p = 0.03) were found to have significantly worse OS than patients without these mutations by log-rank test. EGFR T790M, which was the most prevalent exon 20 mutation in these patients, did not present significant correlation in survival analysis. Conclusions: Although patients with EGFR exon 20 mutations accounted for only about 5% LUAD patients, and had worse response rates in general, certain subtypes had significantly different prognoses compared with other subtypes.
Neoadjuvant chemo-immunotherapy increases tumor immune lymphocytes infiltration in resectable NSCLC.
Authors: Li Ziming , Chen Tianxiang , Wen Fengcai , Zhang Ding , Chen Yanan , Zhao Xiaochen
Published: June 2022

e20573

Background: NCIT (neoadjuvant Chemo-immunotherapy treatment) has revolutionized the treatment of resectable NSCLC due to its better MPR (major pathologic response) rate and pCR (pathologic complete response) rate over neoadjuvant chemotherapy or immunotherapy. However, the intrinsic mechanism underlying this treatment remains unclear. In recent years, the immune microenvironment has attracted considerable attention in the field of immunotherapy. In this study, we explored the relationship between tumor immune lymphocytes (TILs), tertiary lymphoid structures (TLS), and response to NCIT in resectable NSCLC and the change in TILs before and after NCIT. Methods: Twenty-five patients with stage IIA-IIIC NSCLC who underwent surgery after NCIT were enrolled in this retrospective study. Multiplex immunofluorescence (mIF) staining and image analysis assays were performed on the samples collected before and after NCIT for each patient. Results: Among the enrolled patients, 10 achieved MPR or pCR which were defined as response group, whereas 15 did not respond well to NCIT which were defined as non-response group. The results of the mIF assays revealed that NCIT was associated with an increase in immune lymphocytes, including CD3+ (tumor, p = 0.23; stroma, p < 0.01), CD4+ (tumor, p = 0.011; stroma, p < 0.001), CD4+Foxp3+ (tumor, p = 0.63; stroma, p < 0.001), CD8+ (tumor, p = 0.00031; stroma, p < 0.001), CD8+PD-1+ (tumor, p = 0.13; stroma, p = 0.022), PD-L1+CD68+ (tumor, p = 0.85; stroma, p = 0.041), and TLS (tertiary lymphoid structures, p = 0.00027). The comparison of TIL between response group and non-response group revealed that CD3, FOXP3+, and CD8+PD-1+ may serve as predictors of the response to neoadjuvant immunotherapy. Conclusions: To our knowledge, this is the first study to explore the relationship between TILs, TLS, and response to NCIT and TIL changes during NCIT in resectable Chinese NSCLC. In resectable NSCLC, the infiltration of immune cells before NCIT was correlated with the pathologic complete response, which enhanced the TILs as a promising predictor for selecting patients who were more likely to benefit from NCIT.
Automated imaging-based prognostication (IPRO) for stage I non-small cell lung cancer using deep learning applied to computed tomography.
Authors: Torres Felipe Soares , Akbar Shazia , Raman Srinivas , Yasufuku Kazuhiro , Hannessy Thomas Jay , Baldauf-Lenschen Felix , Leighl Natasha B.
Published: June 2022

e20575

Background: Computed tomography (CT) imaging is used to inform staging and treatment decisions for stage I non-small cell lung cancer (NSCLC) patients. We have previously used deep learning applied to pretreatment CTs to generate an imaging-based prognostication (IPRO) score that automatically quantifies mortality risk and stratifies patients beyond tumor, node, metastasis (TNM) substages. Here we present validation data of its prognostic impact. Methods: We developed a fully automated deep learning model, IPRO, designed to process a CT scan, localize the 36cm3 space centered on the lungs, and learn prognostic imaging features to predict mortality risk. IPRO was trained on pretreatment CTs acquired from 1,696 patients treated for NSCLC at a tertiary care center between 2004 and 2018. We withheld 20% of the cases for validation, including 162 patients that were diagnosed with stage I NSCLC by clinical staging. We evaluated IPRO’s ability to stratify stage I NSCLC patients into mortality risk quintiles using the Cox proportional hazards model and assessed differences in median overall survival (mOS). Results: Of the 162 stage I NSCLC patients in the validation set, the mOS was 68.5 months (95% CI 66.7-69.6), 85 (52.5%) were male, and 125 (77.2%) were diagnosed with stage IA. Of these, 111 patients received surgery, 40 received radiotherapy (RT), 9 received surgery + adjuvant systemic therapy (ST), and 2 patients received surgery + ST + RT. According to IPRO, the patients predicted to have the highest risk had significantly increased 5-year mortality compared to those predicted to have the lowest risk (OR 8.4, 95% CI 2.4-29.2, p < 0.01); median survival 48.0 months and 69.5 months, respectively. Conclusions: Deep learning applied to pretreatment CTs provides personalized prognostic insights for stage I NSCLC beyond current TNM staging. [Table: see text]
Efficacy and safety of second-line (2L) therapy in patients with relapsed small cell lung cancer (SCLC): A systematic literature review (SLR).
Authors: Nair Abhishek A. , Kwon Christina S. , Harricharan Sharada , Zhang Xinke
Published: June 2022

e20576

Background: Although SCLC is sensitive to first-line chemotherapy, most patients experience relapse, and options for 2L therapy are limited. Patients with relapsed SCLC have a poor prognosis, particularly those with resistant disease. To better understand the clinical unmet need of relapsed SCLC, we conducted a SLR of the efficacy and safety of currently approved 2L treatments for SCLC. Methods: EMBASE, MEDLINE, Cochrane databases (01/1990-11/2021), and congress abstracts (2020-21) were queried in accordance with the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using Population, Intervention & Comparators, Outcomes and Study Design (PICOS) criteria to identify interventional studies involving 2L SCLC treatments. Efficacy and safety data were extracted in overall populations (O), as well as platinum-sensitive (S) and resistant (R) subgroups. Efficacy data including overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and duration of response (DoR) were summarized for currently approved treatments including topotecan (T), amrubicin (A), and lurbinectedin (L) monotherapies. Results: Of the 4,329 records identified, 130 studies were selected, of which 35 studies investigated T (22 studies), A (15 studies) and L (1 study) monotherapies (3 studies comparing A vs T) and outcomes by these treatments are presented (Table). Median OS ranged from 5.0 to 12.0 months in O, 3.4 to 11.0 in R, and 5.0 to 14.4 months in S. Median PFS was up to 4 months in O and R. ORR ranged widely by treatments. Median DoR was 3.1 to 5.3 months in O, less than 5 months in R, and 10 months in S. Among studies reporting overall safety, grade 3+ adverse events (AEs) were observed in 72%-96% and 74%-93% of patients with T (n = 308 from 3 studies) and A (n = 526 from 3 studies), respectively. The most common grade 3+ AEs in patients with L (n = 105) were neutropenia (46%) followed by leucopenia (29%). Conclusions: Relapsed SCLC patients treated with currently approved treatments have poor survival outcomes, especially those with resistant disease. A significant unmet need exists for treatment options extending survival and durability.[Table: see text]
Treatment patterns and outcomes associated with small cell lung cancer by platinum sensitivity status in a U.S. Medicare population.
Authors: Cockrum Paul , MacEwan Joanna P. , Ramirez Robert A.
Published: June 2022

e20617

Background: Platinum-based chemotherapy plus irinotecan or etoposide is the standard of care for first line (1L) treatment of small cell lung cancer (SCLC). Sensitivity to platinum-based chemotherapy has implications for regimen choice in subsequent lines of treatment. The goal of this study was to examine differences in patient characteristics, treatment patterns, and survival associated with the management of SCLC in a Medicare population by platinum sensitivity status, i.e., platinum sensitive (PS) or platinum refractory (PR). Methods: A retrospective analysis was conducted using the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data. Patients were included if they had a record with a diagnosis of SCLC in the database from 1/1/2007 – 12/31/2017 and were ≥65 years of age at diagnosis. Patients also had continuous enrollment for ≥180 days pre-SCLC diagnosis and platinum-based 1L treatment. Patient characteristics, treatment patterns, and outcomes were stratified by PS status, which was defined as initiating 2L therapy more than 6 months after the last administration of platinum-based chemotherapy in 1L. Median overall survival (OS) was estimated using the Kaplan Meier method. Results: 7,208 patients met the study criteria and one in three (33.6%, N = 2,424) SCLC patients were PS. The PS population was majority female (64.4% vs 35.6% males), younger on average (aged 72.4 yrs vs 72.9 yrs), and more likely to be diagnosed at stage I-III than the PR patient population (50.6% vs 21.1%). Among PS patients, mean time from diagnosis to 1L treatment was 6.1 weeks versus 5.7 weeks among PR patients. Only 29.7% of PS patients initiating 1L went on to second line (2L) versus 40.4% of PR patients. 68.6% of PR patients received monotherapy in 2L, with topotecan (31.7%), paclitaxel (12.1%), and irinotecan (9.9%) being the most common monotherapy regimens. 51.7% of PS patients were retreated with platinum-based chemotherapy in 2L. Median OS from initiation of 1L was 20.2 months (95%CI: 19.3-21.1 months) among PS patients versus 6.4 months (95%CI: 6.2-6.6 months) among PR patients. 5-year survival was 20.0% among PS patients and 1.5% among PR patients. Conclusions: Approximately two-thirds of SCLC patients are refractory to platinum-based chemotherapy. These patients have fewer treatment options and shorter OS than PS patients, underscoring the ongoing need for effective therapies for SCLC.
Impact of cachexia on the efficacy of first-line immunotherapy in extensive-stage small-cell lung cancer patients.
Authors: Fan Xinyu , Li Butuo , Wang Linlin
Published: June 2022

e20620

Background: This study was to investigate the association between cachexia and prognosis in extensive-stage small-cell lung cancer(ES-SCLC) patients who received first-line immunotherapy. And the prognostic values of some systematic inflammatory and nutritional indexes were also evaluated. Methods: Data of 123 ES-SCLC patients receiving immunotherapy as first-line treatment in one single center from June 2019 to February 2021 were analyzed. Development of cachexia after the initiation of immunotherapy was defined as patients with more than 5% weight loss over past 6 months, or more than 2% weight loss with body mass index (BMI) less than 20 kg/m2. Endpoints included response rate, progression-free survival (PFS) and overall survival (OS). Univariate and multivariate survival analysis were performed to identify the factors correlated with PFS and OS. Results: At evaluation after 6 months of initial treatment, cachexia was presented in 51 patients(41.5%). The treatment response and survival of patients with cachexia were worse than those without. The overall median overall survival (OS) was 14.4 months (95% CI 13.3–15.6). The overall median progression-free survival (PFS) was 8.1 months (95% CI 7.0–9.2). The median PFS was significantly longer in patients without bone metastases at diagnosis(HR = 2.362,95%CI:1.452-3.842;p = 0.001), without cachexia(HR = 1.802,95% CI: 1.121-2.895; p = 0.015), and with lower change of total protein(HR = 1.799,95% CI: 1.084–2.984; p = 0.023). The median OS was significantly shorter in patients with poor ECOG PS (HR = 1.904, 95% CI: 1.017-3.564; p = 0.044), higher baseline SII (HR = 2.135,95% CI: 1.117–4.080; p = 0.022), with cachexia(HR = 2.020,95% CI: 1.075-3.795; p = 0.029), advance M stage(HR = 3.111,95% CI:1.545–6.262; p = 0.001) and higher post-treatment SIRI (HR = 2.135,95% CI: 1.281–4.697; p = 0.007). Conclusions: ES-SCLC patients who develop cachexia after first-line immunotherapy have a poor prognosis. our study also confirms that baseline SII and SIRI at 6 weeks after treatment appears to be promising predictors for OS of ES-SCLC who treated with first-line immunotherapy.
Shift of tumor-infiltrating immune cells after adding immune checkpoint inhibitors to neoadjuvant chemotherapy against NSCLC.
Authors: Ren Yulin , Hui Zhenzhen , Zheng Liuqing , Wang QI , Wang Tao , Xiao Shanshan , Wang Hao , Liu Shaochuan , Ren Xiubao
Published: June 2022

e21002

Background: Immunotherapy, represented by immune checkpoint inhibitors (ICIs), has revolutionized the treatment strategies in multiple cancer types, including NSCLC. Anti-PD1 combined with chemotherapy was superior to chemotherapy alone, but the fundamental mechanisms underlying their synergic effect remain incompletely understood. Here, we investigated the different effects induced by neoadjuvant pembrolizumab combined with chemotherapy (NAPC) and neoadjuvant chemotherapy (NAC) on tumor immune microenvironment in patients with NSCLC. Methods: We performed single-cell RNA-sequencing (scRNA-seq) to characterize the immune cells composition in seven patients with NSCLC received NAPC or NAC and validated these findings in a large population cohort (n = 58) utilized multiplex fluorescent immunohistochemistry (mIHC). Results: The results of scRNA-seq revealed that patients with NSCLC received NAPC or NAC displayed distinct immune cell composition, with myeloid cells being the predominant cells in NAC patients, whereas T cells, B cells and NK cells were more abundant in NAPC patients. Consistent with these results, mIHC confirmed that compared to NAC, NAPC was associated with increased infiltration of CD8+ T cells, CD8+KLRG1+ effector cells, CD8+CD127+ memory cells, CD4+CD127+ memory cells, CD20+ B cells, accompanied by reduced CD66b+ neutrophils but had no effect on other immune subsets examined, including CD68+ macrophage, CD68+CD163+ M2 and mast cells. Survival analysis showed that, for both NAPC and NAC patients, CD8+ T cells, CD8+KLRG1+ effector cells, CD8+CD127+ memory cells were associated with favorable overall survival (OS), while CD66b+ neutrophils was related to inferior OS. Moreover, CD20+ B cells appear to have a more pronounced effect than CD8+ T cells on the efficacy of NAPC, but not for NAC. Conclusions: Compared to neoadjuvant chemotherapy, the addition of pembrolizumab induced a shift in tumor-infiltrating immune cells toward enhanced antitumor immunity and reduced immunosuppressive cells. In additional, post-treatment tumor-infiltrating immune cells were able to provide prognostic value.
Lung cancer patients with germline mutations have a unique fusion molecular spectrum.
Authors: Yang Zixin , Zheng Likang , Wu Yaqing , Luo Ningning , Zhang Qin , Bu Xuesong , Sun Tingting , Qi Chuang
Published: June 2022

e21009

Background: In contrast to numerous studies of somatic mutations, the researches of lung cancer germline mutations remain smaller. Some certain germline mutations are assumed to increase susceptibility to lung cancer. However, the details of such mechanism remain to be established. In this study, DNA profiles were performed by targeted next-generation sequencing (NGS). Methods: A retrospective study of 3,421 lung cancer patients with available NGS data was performed to identify germline mutations. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, germline mutations were categorized as being pathogenic (P), likely pathogenic (LP) and other significance (Non_P). Thus, the patients were divided into two groups: patients with P or LP mutation(P&LP), and patients with Non_P mutation. Results: Of 3421 patients with lung cancer, 174 (5.09%) patients were identified to carry pathogenic or likely pathogenic germline mutations, with a median age of 62.5 years old. BRCA2, ATM, MUTYH, BRCA1 and ERCC2 were the top five genes with germline alterations, and their mutation rates were 11.5, 6.90, 6.32, 5.17 and 4.60%, respectively. Homozygous mutations were identified in only two patients, one was TP53( p.Ser215Ile), and the other was TSC2(splice site alteration). No statistically significant difference in age and sex between P&LP and Non_P group. Somatic mutation data was also involved in our study. The frequency of gene fusion events was same between these two groups. Interestingly, fusion molecular spectrum of P&LP group was different. Among all the 25 fusion events of P&LP group, 20 were unique and 19 fusion events couldn't be retrieved in the PubMed database. In total, 44 genes involved in fusion events and 5 genes were located on chromosome 17. Frequency of FAT1 single nucleotide variant (SNV) mutation was significantly higher in P&LP group (9.77% vs 5.57%, p = 0.03). Most copy number variations (CNV) were amplification, and frequency of EGFR copy number amplification was higher in P&LP group (19.5% vs 12.6%, p = 0.01). Conclusions: These data implied that genomic profile of lung patients who carried germline gene mutations could be different. Associations between germline mutation and lung cancer susceptibility, treatment will be studied further.
The genomic landscape of SMARCA4 and the clinical characteristics in Chinese NSCLC patients.
Authors: Guo Renhua , Li Jun , Xu Jiali , He Yuange , Sun Wei jie
Published: June 2022

e21010

Background: The tumor suppressor gene SMARCA4 encodes a submit of SWI/SNF chromatin remodeling complexes and inactivated by mutations or other mechanisms. Previous studies have reported the genomic landscape of SMARCA4 and the clinical impact in Caucasian population, but the molecular and clinical characteristics in Chinese NSCLC patients have never reported. Herein, we explore the SMARCA4 profiles in Chinese population. Methods: A total of 740 patients of NSCLC with paired tumor-normal samples were collected into the study, all samples were detected by DNA based sequencing with a 1021 gene panel. Results: The incidence of SMARCA4 mutation in Chinese NSCLC patients was 7.16% (53/740), the top10 co-mutated genes were TP53, LRP1B, KEAP1, EGFR, KRAS, HGF, FGFR1, FAT1, CDKN2A, STK11. The SMARCA4 alterations were divided to functional or unfunctional mutations according to the OncoKB database (developed by MSKCC), then we compared the clinical characteristics among the SMARCA4-functional (S-F), SMARCA4-unfunctional (S-UNF) and SMARCA4-wide type (S-WT) patients. The results showed the S-F group tended to have more Male patients (88% vs. 64% vs. 55%, p = 0.004) and more smokers (68% vs. 46% vs. 34%, p = 0.015), meanwhile the age and histopathological subtype showed no significant difference among the three groups. We also analyzed the mutation burden characteristics, The S-F group have more somatic mutations (19.20 vs. 16.29 vs. 9.06, p < 0.0001) and higher TMB value (15.67 vs. 12.20 vs.5.61, p < 0.0001), indicating the patients may have more clinical benefits from immunotherapy. As recent studies revealed the SMARCA4 alterations associated with a very poor prognosis in NSCLC, according to our results, the immunotherapy may be an alternative strategy, and this need more clinical explorations. Conclusions: The patients with SMARCA4-functional mutations were associated with Male and smoker in Chinese population and tended to have more somatic mutations and higher TMB value, thus may benefit more from immunotherapy.