bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of synthetic lethal mutations for the immune response: Exploratory studies of two non-small cell lung cancer cohorts and two pan-cancer cohorts.
Authors: Wang Jun , Liu Miao , Zhang Ding
Published: June 2023

e21137

Background: Synthetic lethality (SL) is a phenomenon in which mutations in either of two genes do not affect cell survival, but abnormalities in both genes lead to cell death. However, it is little known whether synthetic lethality affects the response of immunotherapy. Methods: Synthetic lethal gene pairs come from the SynLethDB database, which provides a webserver to calculate the confidence scores for each SL pair by integrating individual scores derived from different evidence sources. The analysis included two immunotherapy cohorts of non-small cell lung cancer (Chan, 2015 and Hellmann, 2018) and two solid tumor cohorts (Morris, 2019 and Berger, 2020) in the published literature. Synthetic lethal gene pairs were defined as genes with a score > 0.5. The patients with synthetic lethal gene pairs were divided into one subgroup (SL group), and the other patients were divided into another subgroup (non-SL group). Kaplan-Meier analysis was used to determine progression-free (PFS) and overall survival (OS). Results: Overall, four public cohorts with 12271 patients were included in the analysis. In the cohort of Chan 2015, a total of 34 patients with non-small cell lung cancer (NSCLC) received immunotherapy. Among them, 21 patients were in the SL group and 13 were in the non-SL group, with the former having a significantly longer PFS (p = 0.0345). In the other cohort of immunotherapy (Hellmann, 2018), 90 (37.5%) patients with NSCLC were in SL group. PFS for patients with SL group was significantly longer than those in non-SL group (p = 0.0261). In cohorts with pan-cancer, patients in Morris 2019 cohort (n = 1661) received immunotherapy and patients in Berger 2020 cohort (n = 10336) received other kinds of treatment. A better prognosis was observed in patients with the immunotherapy in SL group than non-SL group (p < 0.0001). In contrast, patients with other kinds of treatment had a significantly worse prognosis in SL group than non-SL group (p < 0.0001). Conclusions: Our results suggested that synthetic lethal gene pairs containing scores greater than 0.5 may be associated with higher progression-free survival in patients with various types of tumors. The specific reasons for the impact still need to be further explored.
Pyrotinib plus antiangiogenic agents for HER2-altered advanced non-small cell lung cancer: A retrospective real-world study.
Authors: Yang Yaning , Yang Guangjian , Wang Yan
Published: June 2023

e21141

Background: Although some targeted therapies have been shown to be effective in treating HER2-altered non-small cell lung cancer (NSCLC), the survival demands have not yet been met due to the high cost and limited availability. This study aimed to assess the effectiveness and safety of pyrotinib plus antiangiogenic agents, including apatinib, anlotinib, and bevacizumab in previously treated patients with HER2-altered advanced NSCLC. Methods: In this retrospective real-world study, patients with HER2-altered NSCLC who received pyrotinib plus antiangiogenic agents as second or later-line treatment between November 2015 and January 2022 were reviewed. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety profiles of patients were analyzed. Results: A total of 107 patients were included in the analysis. Fifty-nine patients (55.1%) have received at least two lines of prior chemotherapy or HER2-targeted regimens. Most of them (87.9%) were identified as HER2 exon 20 insertions. At the data cutoff date (May 13, 2022), the ORR, DCR, median PFS, and median OS were 19.6% (21/107), 94.4% (101/107), 7.13 months (95% confidence interval [CI]: 6.26-8.01), and 19.50 months (95%CI: 12.83-26.17), respectively. There was no difference in the PFS between patients receiving apatinib or anlotinib/bevacizumab (median PFS, 7.13 months vs. 6.27 months, hazard ratio [HR] = 1.49, 95%CI: 0.87-2.54, P = 0.15). The most frequent grade 3 or higher treatment-related adverse events was diarrhoea (17.6%), followed by hypertension (11.0%) and nausea (3.3%). No treatment-related death occurred. Conclusions: Pyrotinib plus antiangiogenic agents demonstrated promising antitumor activity and a manageable safety profile in HER2-altered NSCLC patients.
First-line pembrolizumab plus platinum-pemetrexed in metastatic non-small cell lung cancer: Clinical experience in a Spanish tertiary hospital.
Authors: Lombardero Lara , De Elejoste Ibone , Casas Raquel , Azcuna Josune , Ortega Berezi , Mohamed Lamin Failah , Jiménez Labaig Pablo , Rubio Itziar , Munoz Llarena Alberto , Azkona Eider
Published: June 2023

e21142

Background: In the phase III trial KEYNOTE-189 first-line pembrolizumab (pembro) plus platinum-pemetrexed (pem) significantly improved OS and PFS in metastatic nonsquamous non-small cell lung cancer (NSCLC) without EGFR/ALK alterations. We report outcomes of real-world patients (pts) treated with first line pembro plus platinum-pem in our hospital. Methods: We have done a descriptive, retrospective, single center study developed in a Spanish tertiary hospital where patients with metastatic nonsquamous NSCLC treated with first-line pembro plus platinum-pem have been included. SPSS v23 software has been used to analyze clinical data for OS and PFS using the Kaplan-Meier method. PFS-2, defined as time from first treatment to objective tumor progression on next-line treatment or death from any cause, whichever occurred first, was also recorded using the Kaplan-Meier method. Adverse events (AEs) were graded according to CTCAE v5.0. Results: From December 2019 to May 2022, 79 pts (67.1% M, 26% W; 64y median age, ECOG 0, 1, 2: 5.1%; 88.6% and 6.3%; PD-L1 < 1% 36 [45.6%], PD-L1 1-49% 37 [36.8%], PD-L1 50% 3 [3.8%]; unknown PD-L1 3 [3.8%]; 95% adenocarcinoma) were assessed. After a median follow-up of 19 months, OS was 17 months (5.3-28.7). Stratified by PD-L1 expression, mOS was 9 months (6.3 -11.7) in PD-L1 < 1%; 25 months in PD-L1 1-49%, NR in the rest. Median PFS was 9 months (5.8-12.2). According to PD-L1 expression, mPFS was 6 months (4.6 - 7.4) in PD-L1 < 1%; 19 months (8.7 - 29.2) PD-L1 1-49% and 7 months (0.6 - 13.4) in PD-L1 50%. PFS-2 was 17 months (10.7 - 23.3). At the time of the cut off 66 pts (83.5%) had discontinued treatment: 35 (53%) due to progression, 23 (34.8%) due to toxicity; 2 (3%) due to both, and 6 (9.1%) due to other reasons. Grade 3-5 AEs were observed in 35/79 pts (44.3%). 15.2% pts needed dose-reduction and 32.6% glucocorticoids. Conclusions: First-line treatment with pembro plus platinum-pem has demonstrated benefit in terms of OS, PFS and PFS-2 with tolerable adverse effects. The results obtained in our hospital, taken together, are consistent with those published in KEYNOTE-189 trial. However, the survival of our pts with PD-L1 < 1% seems to be poorer. This finding could be explained by the short median follow-up, low number of patients and differences in baseline demographic characteristics.
Eosinophil count and immune-related adverse events (irAEs) as predictive biomarkers of survival in patients with NSCLC treated with ICIs.
Authors: Giommoni Elisa , Pillozzi Serena , Ottanelli Carlotta , Cosso Federica , Caliman Enrico , Mazzoni Francesca , Fancelli Sara , Lavacchi Daniele , Brugia Marco , Pellegrini Elisa , Vannini Agnese , Napolitano Brunella , Fuccio Sanzà Roberta , Shabani Sonia , Zepponi Francesca , Pasqui Adriano , Zenoni Andrea , Antonuzzo Lorenzo
Published: June 2023

e21144

Background: Immune Checkpoint Inhibitors (ICIs) changed the algorithm of treatment for Non-Small Cell Lung Cancer (NSCLC). Consequently, an increased incidence of specific immune-related adverse events (irAEs) were reported, although a clear relationship between toxicity and response to ICIs was not identified. To date no strong predictive factor of response to ICIs are univocally recognized in NSCLC. Methods: This is an observational, retro-prospective, monocentric study aimed to evaluate, in patients (pts) with NSCLC treated with ICIs, the predictive impact of selected blood biomarkers and the occurrence of irAEs on survival. Differential cells count, and specifically the Absolute Eosinophil Count (AEC, N°/μL), were registered at baseline to evaluate their impact on response to ICIs. Patients were divided in two groups: those with high AEC ( > 190/µL, group A), and those with low basal AEC ( < 190/µL, group B). Results: We enrolled 48 pts, median age was 70 years. All pts were treated with an ICI as single-agent: 5 (10%) with Nivolumab (N), 37 (77%) with Pembrolizumab (P), and 5 pts received Atezolizumab (A). Thirty-seven pts were treated in first-line setting, 9 pts in second-line, and 2 pts in successive lines. Of total, 63% pts (30/48) developed at least one irAE: an endocrine event occurred in 11 pts (23%), gastrointestinal toxicity in 10 pts (21%), dermatological events in 19 pts (40%), while a pulmonary irAE in 6 pts (13%). Progression free survival (PFS) was higher in group A than in group B (16 vs 9.5, p = 0.041) with a trend for a superior median Overall Survival (mOS) (median not reached vs 23 months, p = 0.07, respectively). At a median follow-up of 18 months (mos), pts who developed at least one irAE had a significant benefit in PFS (15mos vs 8mos, p = 0.027), reporting a trend for better PFS for pts with endocrine toxicities (p = 0.057) and GI- toxicities (p = 0.051) vs no toxicities. Pulmonary irAEs are significantly related to a better PFS: median not reached vs 12 mos, p = 0.025. Conclusions: In this real-life experience we observed that baseline AEC values correlates with PFS in pts with NSCLC treated with ICIs. Additional analyses are ongoing to identify appropriate cut-offs of AEC to better stratify patients. Moreover, our study underlines that the development of toxicities, in particular pulmonary ones, could be considered as a predictive indicator of response to ICIs in NSCLC. With all the limitations of being a small analysis, our real-life experience is innovative and explored prospectively the potential role of differential cell count and irAEs as predictive biomarkers of survival in NSCLC patients treated with ICIs.
Effect of immunotherapy cessation without disease progression on outcomes in patients with metastatic non-small cell lung cancer.
Authors: McKinley Blake , Li Shenduo , Wiest Nathaniel , Butts Emily , Pai Tanmayi , Wang Jing , Mosalem Osama M , Sacchi de Camargo Correia Guilherme , Patel Jaydeepbhai , Koshiya Hiren , Inampudi Jyothik Varun , Zhao Yujie , Manochakian Rami , Lou Yanyan
Published: June 2023

e21156

Background: Immunotherapy (IO) is one of the major treatments for patients with metastatic non-small cell lung cancer (mNSCLC). IO may be discontinued in patients for many reasons, the most common being progression of disease (POD). For those patients who discontinued IO for reasons other than POD, such as immune-related adverse event (irAE), there is limited data that compare progression-free survival (PFS) and overall survival (OS) when IO is continued vs. stopped. Methods: We conducted a retrospective study of all patients with mNSCLC (stage IV) treated with IO at our institution from 2011 to 2022. Patients who discontinued IO due to POD were excluded from the analysis. The clinical outcomes, including PFS, OS, and irAE were investigated among patients with no POD who stopped IO prior to 6 or 12 months (m) vs. those that continued IO > 6 or 12m. Results: The analysis at the 6m timepoint included 92 patients, 82.6% were white, 50% were male, 67.4% had adenocarcinoma, and 82.6% used tobacco. The most common site of metastasis was bone (28.3%), followed by CNS (20.7%). 51.2% of patients had received IO as the first line systemic therapy and 32.6% received it as their second. Pembrolizumab was the most used IO (84.78%). Among these patients, 25 discontinued IO before 6m, and 67 patients continued IO beyond 6m. irAE, of any grade, occurred in 44.0% vs 37.3% when comparing IO discontinued with IO continued group at 6m. Patients who continued treatment beyond 6m had a longer duration of PFS (22.8m vs 11.8m, p = 1.14E-04) with a significant increase in OS (34.5m vs 14.0m, p = 1.34E-07). The analysis at the 12m timepoint included 71 patients, 87.3% were white, 46.5% were male, 78.9% had adenocarcinoma, and 80.3% used tobacco. The most common site of metastasis was bone (29.9%), followed by CNS (22.5%). 62.0% of patients had received IO as the first line systemic therapy and 28.7% received it as their second. Pembrolizumab was the most used IO (87.3%). Among these patients, 30 discontinued IO before 12m, and 41 patients continued IO beyond 12m. irAE, of any grade, occurred in 36.7% vs 41.5% when comparing IO discontinued with IO continued group at 12m. Similarly, patients who continued treatment beyond 12m had a longer duration of PFS (28.4m vs 14.2m, p = 1.91E-06) with a significant increase in OS (39.9m vs 17.6m, p = 3.45E-09). Conclusions: We observed that patients with mNSCLC and no POD, who continued IO beyond 6m and 12m, experienced a significant increase in PFS and OS than those who discontinued IO, with more significant increases in those who continued IO past 12m. These findings need to be verified in a larger cohort.
Immunologic constant of rejection as a predictive biomarker of immune checkpoint inhibitors efficacy in non-small cell lung cancer.
Authors: Mogenet Alice , Greillier Laurent , Denicolai Emilie , Barlesi Fabrice , Bertucci Francois , Finetti Pascal , Tomasini Pascale
Published: June 2023

e21162

Background: Immune checkpoint inhibitors (ICI) transformed non-small cell lung cancer (NSCLC) prognosis but response rate remains disappointing. Besides PDL1 expression, tumor mutational burden, quantification of tumor infiltrating lymphocytes or methylation profile failed to confirm their predictive role. The ICR (Immunologic Constant of Rejection) signature is defined as an immune phenotype quantifying the expression of 20 genes all involved in cancer immunity. Our first objective was the assessment of ICR signature predictive value and our secondary objectives were to compare ICR signature with other published immune signatures and to assess the prognostic value of ICR signature. Methods: Our series included 77 paraffin-embedded (FFPE) tumors derived from NSCLC patients treated with ICI as a single agent in at least the second line setting. We also collected clinical and biological data from 4 public data sets to expand and confront our local data. Transcriptomic analysis was performed using nCountertechnology Dx analysis by Nanostring based on microscopic imaging counting relative abundance of hundreds of transcripts using the “nCounter PanCancer Immune Profiling Panel” including the 20 ICR genes. Results: We applied the ICR classification to a series of 44 local tumor samples enhanced with 118 samples from public datasets. Hierarchical clustering on both local cohort and public datasets allowed us to distinguish the four ICR classes, from ICR 1 (“cold” tumors) to ICR 4 (“hot” tumors). Among the 5 datasets, we did not observe any significant difference between ICR groups for age, sex and smoking status. We observed a relative homogeneity in Durable Clinical Benefit (DCB) rate among ICR groups 2 to 4 (median DCB above 20%) unlike ICR group 1 (median DCB under 10%) leading us to consider ICR as a binary signature (ICR 1 vs ICR 2-4). ICR signature indeed showed a significant association with DCB among the 5 pooled datasets (OR = 4.40 [95% Confidence Interval 1.44-13.45] p = 0.950) with uniform distribution between them. Then, we conducted a logistic regression univariate analysis of DCB among various previously published immune signatures and ICR signature was the only one to show a significant association with DCB in this analysis ( p = 0.007). Conclusions: We identified a feasible transcriptomic signature with a promising signal of ICI efficacy prediction in the so far disappointing immune biomarkers field. In a near future, predict ICI efficacy will be a major challenge with three pivotal questions. When, balanced with the new data on ICI use in early-stage lung cancer or widely pretreated patients. How, assessing various techniques to develop composite signatures to better consider every driver of immune response. What, considering the amount of potential new therapeutic targets, starting by the 20 genes of ICR signature.
Safety, tolerability, and quality of life (QoL) of single-agent plinabulin (Plin) for the prevention of docetaxel (Doc) chemotherapy (chemo)-induced neutropenia (CIN) in non-small cell lung cancer (NSCLC) patients (pts) from two randomized trials.
Authors: Blayney Douglas W. , Legaspi Gabrielle , Duprez Stephen , Huang Lan , Mohanlal Ramon W.
Published: June 2023

e21168

Background: Plin, is a novel, non-G-CSF, small molecule agent with comparable CIN-preventive effects vs pegfilgrastim. In contrast to pegfilgrastim, Plin is given on the same day of chemo (30 mins after chemo), and does not cause bone pain, nor thrombopenia. In the two randomized controlled (placebo (Plac)/no treatment) cancer trials, Phase (Ph) 2 Study 101 and Ph3 Study 103, single-agent (SA) Plin reduced estimated Doc-induced mean duration of severe neutropenia by > 1 Day vs Plac. We conducted a post hoc analysis of safety, tolerability, and QoL in NSCLC pts from these trials. Methods: NSCLC pts in 2nd/3rd line, with at least 1 NCCN FN risk factor, were randomized to Doc (75 mg/m2) + Plin (n = 116; at the CIN dose of 20 mg/m2 or its pharmacokinetic equivalent), or Doc + Plac (n = 296) in trials 101 (NCT00630110) and 103 (NCT02504489). Doc was given on day (D) 1, and Plin was given twice per cycle, on D1 and D8 (Plin D1 and D8 dosing is supratherapeutic for CIN but facilitated a more robust safety/tolerability evaluation [the CIN Plin dose is D1 only]). Safety blood draws and AE collection on D1 and D8; tolerability; and QoL (pre-dose and D8) were evaluated over 4 cycles. All pts received dexamethasone premedication. QoL scores were obtained in study 103 only, with Plin (n = 80) and Plac (n = 234), by validated questionnaires (EORTC QLQ C30, to evaluate global health status/QoL; the combined symptom scales/items, and the lung cancer-specific QoL questionnaire QLQ-LC13). Results: QoL scores over 4 cycles between Plin and Plac were similar, indicating Plin was well-tolerated. Grade (Gr) 3/4 AEs of interest for Plin (+Doc) and Plac (+Doc) are summarized in the table. With Plin, AE frequency of diarrhea was slightly higher (5.2% vs 1%; 1 Gr4 case with Plin), but was manageable, and so was hypertension (11.2% vs 1.7%; all Gr3 cases) vs Plac. Hypertension occurred around the time of infusion and was short-lasting (~2-4 hours) and typically self-limiting. Plin had less AEs of neutropenia (16.4% vs 50.3%) and leukopenia (15.5% vs 38.5%) vs Plac. Conclusions: Plin is an effective agent for CIN, has a favorable safety, tolerability, and QoL profile, and has the advantage of dosing on the same day of chemo. Clinical trial information: NCT02504489 . [Table: see text]
Update on real-world efficacy of anlotinib in non-small cell lung cancer.
Authors: Gao Junzhen , Xu Yan , Liu Yonggang , Liang Li , Yu Yan , Zhao Dahai , Jin Jiahui , Wang Mengzhao
Published: June 2023

e21173

Background: Anlotinib is a novel oral small molecule TKI with anti-tumor vascular generation and growth inhibition effects, targeting VEGFR, PDGFR, FGFR, and c-kit. It has been shown to be highly effective and low toxicity in the ALTER 0303 study and was approved by NMPA in 2018 for the treatment of NSCLC(non-small cell lung cancer)as third-line and above. Previous studies have shown that anlotinib can benefit patients with advanced NSCLC, especially those in the front-line(first-/second-line). This real-world study aims to update the efficacy of anlotinib in treating NSCLC and to screen the advantage population for anlotinib treatment from front-line/back-line (third-/above-line) treatment, pathological subtype, metastasis site, gene mutation, to provide more effective anlotinib treatment strategies. Methods: This is a multicenter, retrospective, real-world study. Patients with NSCLC who have received anlotinib are included, and subgroup analysis is performed based on pathological subtypes, clinical stages, gene mutations (EGFR mutant/wildtype), front-line/back-line treatments, exploring the impact of different factors on the PFS and OS of NSCLC patients using anlotinib. Results: As of September 2022, a total of 478 patients diagnosed with NSCLC were enrolled in the study, of which 434 were evaluable, with a median age of 63 years, 263 (60.6%) were male, adenocarcinoma in 292 (67.3%), squamous cell carcinoma in 75 (17.3%). At baseline, 59 patients (13.6%) had brain metastasis, 39 (9.0%) had liver metastasis, 127 (29.3%) had bone metastasis, 194 cases (44.7%) had genetic mutations, including 135 cases (31.1%) carrying EGFR mutations. 198 patients (45.6%) received anlotinib as front-line treatment, and 236 patients (54.4%) as back-line treatment. The median follow-up time was 5.09 months (95% Cl, 2.86-7.16), with a mPFS of 4.37 months (95% Cl: 3.78-5.45) in the overall population and a mOS of 20.34 months (95% Cl: 14.88-NA). Among the 138 patients who were evaluable for efficacy, 0 cases achieved complete response (CR), 6 cases partial response (PR), and 57 cases stable disease (SD). ORR was 4.3%, and DCR was 44.9%. The mPFS of front-line was longer than the back-line (5.45 vs 3.52 months), and front-line group had a longer mOS than back-line (NR vs 16.03 months). Subgroup analysis did not find any correlations between pathological subtype or EGFR mutations and patient PFS and OS. However, it was found that the presence of liver and bone metastasis at baseline was related to a shorter OS with anlotinib in the back-line (8.28 vs 16.23 months, p = 0.0253; 7.89 months vs NR, p < 0.001). Conclusions: Anlotinib shows well efficacy in NSCLC patients, prolonging progression-free survival (PFS) and overall survival (OS), especially for front-line patients, suggesting that these patients may be a preferred population for using anlotinib, providing effective evidence for the use of anlotinib treatment for NSCLC patients.
Correlation of drug susceptibility testing on short term cultures of CTCs positively with clinical outcomes in non-small cell lung cancer.
Authors: Kumar Prashant , Limaye Sewanti Atul , Kanakasetty Govind Babu , Balakrishnan Ajay , Joshi Asim , Govindan Sindhu , Venkataramanan R , Kuriakose Moni
Published: June 2023

e21177

Background: Enumeration of circulating tumor cells (CTCs) is rapidly emerging as a minimally invasive and reliable technique for monitoring disease progression and patient’s response to treatment. However, its utility beyond enumeration in clinical management of cancer remains scarcely explored. Being biologically similar to both primary and secondary tumors, CTCs may help in identification of most efficacious therapies. In this study, we propose a method for short term culture of CTCs thereby allowing to evaluate the drug susceptibility testing in individual patients. Methods: We obtained peripheral blood samples from 20 advanced stage lung cancer patients undergoing treatment at Kidwai Memorial Institute of Oncology, Bangalore, India. These blood samples were processed and cultured on ellipsoidal microwells maintained at hypoxic conditions (1% O2). The CTC clusters were seeded onto 96 well plates coated with Matrigel and treated with the same drug regimen as the respective patients. The viability of the cells was measured using CellTitre-Glo. Results: Of the 20 samples, tight cluster formation was observed in four samples and drug susceptibility testing was performed. Based on clinical treatment received, we treated CTCs with combination of pemetrexed and carboplatin at respective Cmax concentrations of 5.68 and 3.68 µg/ml. The combination drug treatment resulted in decreased viability of CTCs to 30.7%. Notably, the CT scan images demonstrated significant reduction of pleural effusion in patient following treatment with carboplatin and pemetrexed, thus correlating with our in vitro drug susceptibility finding. Conclusions: In this proof of concept study, we demonstrate the feasibility of utilizing in vitro drug susceptibility testing on CTCs as an approach to guide patient specific chemotherapeutic treatment approaches, thus opening avenues for personalized treatments.
Auranofin and the efficacy of anti-PD1 immunotherapy.
Authors: Zhang Yan
Published: June 2023

e21180

Background: Anti-PD-1 immunotherapy brings hope for the treatment of malignant tumors, but its overall response rate is low.Therefore, how to sensitize anti-PD-1 therapy to make more patients benefit from immunotherapy is an urgent clinical demand. Methods: PKCι, as a classical oncogenic gene that affects cell proliferation and differentiation, has recently been found to participate in the formation of tumor immunosuppressive microenvironment (TIME). TIME directly leads to resistance to anti-PD1 therapy, so by inhibiting the expression of PKCι to regulate the inhibitory tumor immune microenvironment and sensitize anti-PD1 therapy. Auranofin is a commonly used anti-inflammatory drug in clinic. Recently, it was found that it can inhibit the expression of PKCι and retard growth of tumor. Results: Our study found that interference with PKCι expression in tumor cells can reverse the immunosuppressive microenvironment and enhance the effect of anti-PD1 therapy. Auranofin (PKCι inhibitor) combined with anti-PD-1 immunotherapy has better anti-tumor effect than single drug therapy. Auranofin can inhibit the expression of PKCι and its downstream YAP1 and TNFα, reduce the recruitment of immunosuppressive cells such as MDSCs and Treg, promote the infiltration of effector T cells, ultimately reverse the inhibitory immune microenvironment and play a synergistic anti-tumor role. Conclusions: In summary, the combination of Auranofin and anti-PD-1 immunotherapy can reverse the TIME to sensitize the immune effect, play a synergistic anti-tumor effect, and provide a new idea and theoretical basis for immunotherapy of malignant tumors.
Long-term survival following adrenalectomy for secondary adrenal tumor (SATs): A systematic literature review and meta-analysis.
Authors: Alhajahjeh Abdulrahman Ahmad , Kong Joshua , Odisho Tanya , Maqsood Hannan Ahmad , Al-Share Bayan A , Shahait Awni , Shahait Mohammed
Published: June 2023

e21181

Background: Secondary Adrenal tumors (SATs) are uncommon forms of cancer that occur as a result of metastasis from primary tumors (PT) elsewhere. A systemic review and metanalysis was conducted to assess characteristics and survival following adrenalectomy for SATs. Methods: A systematic literature search was performed (01/1990-12/2022) using several databases (PubMed, Embase, the Cochrane Library, the ASCO library). The inclusion criteria included a known previous PT and confirmed isolated adrenal metastasis either by biopsy or serial imaging (synchronous or metachronous) in patients who underwent adrenalectomy. The primary outcome of interest was the overall survival (OS) of patients following adrenalectomy of SAT. Metanalysis of pooled survival curves for OS was completed, and KM curves were used to create pseudo-individual patient data. Results: A total of 29 studies were analyzed, including 2,401 patients with SAT most of which underwent adrenalectomy. The average age of the group was 60.8 ±3.54years. Lung cancer was the most common PT (33.3%), followed by renal cancer (24.7%). About two thirds (67.7%) of patients had isolated metastasis. The average time from PT diagnosis to adrenal metastasis was 22.4 ±11.11 months. Data of 1,712 patients were used to estimate the combined 5-year OS. The median OS was 35.7 months [95% Confidence interval (CI): 29.1 - 50.4]. One, three, and five-year OS were 80.9% [95% CI: 75.6 - 84.6], 49.6% [95% CI: 43.4 - 56.8], and 38.2% [95% CI: 32.2 - 44.5], respectively. Conclusions: The results of this metanalysis and systematic literature review provide insight into the long-term survival of patients with secondary adrenal tumors who underwent adrenalectomy. The study highlights the need for further research to identify the risk factors that play a role in the clinical outcome of adrenalectomy in patients with adrenal metastasis.
Sensitive detection of CSF-derived cell-free DNA at the CNV level by shallow whole-genome sequencing for diagnosis and characterization of CNS metastases.
Authors: Yubin Li , Shi Zongkun , An Juan , Xu Weiran , Hua Yichun , Zheng Xixi , Ding Xiaosheng , Shi Hui , Nie Yanli , Zhou Lili , Cao Dandan , Li Xiaoyan
Published: June 2023

e21185

Background: The cfDNA targeted capture sequencing technology has been gradually applied to research central nervous system (CNS) metastases. But targeted sequencing usually requires at least 5 ng of cfDNA. Due to the limited amount of cerebrospinal fluid (CSF) that can be collected there are not many samples that can meet the requirements of targeted sequencing. Methods: This study assessed the use of shallow whole-genomic sequencing (sWGS) of blood and CSF samples obtained from 35 patients with lung cancer to identify tumor-derived cfDNA. Among them, 6 cases had no intracranial metastasis, 22 had only PMs, and 7 had LMs. Some of these cases underwent irregular follow-up. For blood samples, 5 ng cfDNA was used for library preparation. For CSF samples, try to use trace DNA to prepare libraries, regardless of whether the Qubit assays can quantify the concentration. Cytologic analysis was also performed on CSF samples from the LM cases. A total of 35 peripheral blood samples and 31 cerebrospinal fluid samples were subjected to sWGS tests, and the arm-level CNV and tumor proportion were analyzed.Cytologic analysis was also performed on CSF samples from the LMs. Results: The lowest concentration of cfDNA in 35 plasma samples was 2.20 ng/mL. But when the cfDNA was extracted from the CSF, 50% (6/12) of the LM samples and 70.59% (12/17) of the samples with only PMs could not be quantified by Qubit assays. All libraries were all successfully prepared from the samples that could not quantify cfDNA. For CSF samples from LM cases, the sensitivity of detecting tumor signals by the sWGS test was 90.9% (10/11), higher than 81.8% (9/11) by CSF cytologic analysis. For samples from PM cases, the sensitivity of detecting tumor signals by the sWGS test was 75% (21/28); among them, the detection sensitivity of samples with a total amount of cfDNA not less than 5 ng was 90% (9/10), while the detection sensitivity of samples with the total amount of cfDNA less than 5 ng was 66.67% (12/18). Three patients underwent multiple CSF cfDNA tests, of which one case with RANO evaluation as PR had a decrease in the tumor fraction in CSF cfDNA, while only one of the two cases with RANO SD evaluation had stable tumor fraction in CSF cfDNA. Conclusions: We established a method for detecting CNVs by sWGS using trace amounts of cfDNA. Using the sWGS test improves the sensitivity of the detection of LMs. Compared with targeted capture sequencing, our method reduces the requirement for the amount of cfDNA, which can be more widely used in the detection of CNS metastases, especially in PM-only patients with extremely low CSF cfDNA concentrations.
Real-world healthcare costs amongst non-small cell lung cancer (NSCLC) patients tested with a host immune classifier (HIC).
Authors: Iams Wade Thomas , Le Kimberly , Princic Nicole , Marlin Taylor
Published: June 2023

e21187

Background: The HIC is a proteomic test that measures immune response in patients diagnosed with NSCLC. The blood based HIC stratifies patients into two groups, HIC-H and HIC-C which helps evaluate the patient’s prognosis and response to treatment. Currently, no real-world studies have described healthcare costs amongst patients tested with the HIC. This subset analysis of HIC claims examined costs among patients with NSCLC prior to and after using the HIC proteomic test. Methods: HIC test results were retrospectively queried using MarketScan Commercial and Medicare Supplemental Databases using data between January 1, 2016 to June 30, 2021 linked to Biodesix data files. Patients were included if they were age 18 and older on index date (date of HIC testing), underwent a HIC proteomic test, were continuously enrolled in the MarketScan database for the 6-months before index (pre-index period) and one month post-index, and had at least one non-diagnostic medical claim of lung cancer during the pre-index period. Healthcare costs were measured per patient per month (PPPM) during the pre-index and post-index period and compared between HIC-H and HIC-C cohorts. All-cause healthcare costs analyzed included inpatient costs, outpatient costs, outpatient pharmacy costs, total medical costs (inpatient + outpatient), and total costs (total medical + outpatient pharmacy). Results: Of the 328 included patients, 260 patients were HIC-H and 68 were HIC-C. On index, 178 patients had non-metastatic lung cancer and 150 patients had metastatic lung cancer. When examining healthcare costs prior to HIC testing, total costs and inpatient costs were higher amongst HIC-C patients ($10,299 vs $9,689 and $4,032 vs $3,218, respectively) although not statistically significant. HIC-C patients had significantly higher biopsy costs compared to HIC-H patients ($1,285 vs $400, P < 0.05) even though less HIC-C patients underwent a lung biopsy (41% vs 53%, P = 0.091). When assessing healthcare costs post HIC testing, total medical costs were significantly higher in the HIC-C patients ($25,255 vs $17,210, P < 0.05). Although not statistically significant, HIC-C patients had higher inpatient costs and total costs ($9,903 vs $5,583 and $26,237 vs $18,652, respectively). Amongst the patients had significantly higher inpatient costs ($18,580 vs $4,278, P < 0.05), total medical costs ($29,574 vs $12,446, P < 0.05) and total costs ($31,316 vs $13,500, P < 0.05). Conclusions: Patients with NSCLC who are identified as HIC-C have higher healthcare costs, including lung cancer diagnostic and total costs, prior to and post HIC testing. Utilization of the HIC test may help to identify patients who may benefit from additional health system navigation support to mitigate their anticipated increased health care costs.
CD57+CD8+ T cells and response to PD-1/PD-L1 blockade in patients with NSCLC.
Authors: Zhou Jianya , Sun Wenjia , Zeng Xun , Zheng Jing , Qu Jingjing , Jiang Nan , Zhou Jianying
Published: June 2023

e21189

Background: Immune checkpoint inhibitors (ICIs) are currently widely used and have made significant advances in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Despite available biomarker stratification, clinical responses vary. Thus, potential biomarkers for identifying patients who will benefit from the immunotherapy are urgently needed. Methods: We applied mass cytometry (CyTOF) to deeply analyze the association of cell subpopulations in PBMC before and after single-agent immunotherapy with clinical outcomes in advanced NSCLC. We then performed flow cytometry of peripheral blood and multiplex immunohistochemistry/immunofluorescence (mIHC/IF) of tumor samples to validate our conclusion. In addition, RNA sequencing (RNA-seq) was performed to explore the mechanism of the ICIs treatment efficacy of NSCLC. Results: In a prospective cohort (n = 20), high CD57+ CD8+ T cell proportion in PBMC detected by CyTOF was associated with good response ( p= 0.014) in advanced NSCLC patients. The result was confirmed in an independent, prospective cohort (n = 30) using flow cytometry, and the specificity and sensitivity of flow cytometry was then assessed in this cohort. CD57+CD8+ T cell proportion, as determined by flow cytometry, successfully stratified responders and non-responders to ICIs ( P< 0.001). We also confirmed this result in FFPE samples (n = 31) ( p= 0.004). In addition, transcriptomic differences between CD57+CD8+ T cells and CD57-CD8+ T cells were found performed by RNA sequencing (RNA-seq). Conclusions: Our results suggest that CD57+CD8+ T cell proportion may serve as a predictive value of response to PD-1/PD-L1 checkpoint blockade. Further validation in additional NSCLC cohorts is warranted.
Combining plasma and tissue next-generation sequencing provides optimal treatment selection for metastatic NSCLC: A comparative study.
Authors: Samol Jens , Bharwani Lavina D. , Chia Puey Ling , Chia Yee hong , Gehlot Pritish , Heah Kai Xin , Heong Valerie , Kulendran Lavenia , Lim Jianri , Muthu Vaishnavi , Teo Hui Lin , Vong Elise , Yeo Chong Ming , Rajah Lisa , Tan Min-Han
Published: June 2023

e21193

Background: 64% of all NSCLC patients in the USA with targetable mutations do not receive therapy due to clinical practice gaps around biomarker identification, including guideline-recommended alterations. Similar diagnostic and access challenges are also seen in Asia, but the scope of these challenges may differ due to the different mutation profiles of NSCLC. To determine the biomarker gaps involved, we conducted a study evaluating 38 metastatic NSCLC patients who received 3 diagnostic molecular workflows, and compared all 3 results to determine potential practice gaps. This is the first study to our knowledge that evaluates 3 different diagnostic workflows for one cohort to determine relative performance. Methods: 386 newly diagnosed and pathologically confirmed patients with metastatic lung cancer were managed at our hospital over Aug 21 - Sep 22. 38 metastatic non-squamous NSCLC patients were recruited prospectively. The patients received 1 plasma NGS tests (LiquidHALLMARK, Lucence, Singapore), 1 tissue comprehensive genomic profiling (CGP) test, and a panel of single-gene molecular tests (Idylla EGFR, ALK-IHC, ROS1-FISH, PD-L1 IHC). Results: Of the 38 patients recruited for the prospective trial, liquid biopsy identified 24 actionable alterations (TAT 3-13 days), tissue NGS identified 23 actionable alterations (TAT 11-27 days) and single gene testing approach provided 17 actionable alterations (TAT variable). 6 patients did not have available tissue reports. In terms of patient numbers, liquid biopsy detected at least one G9 biomarker in 21/38 patients and tissue NGS detected at least one G9 biomarker in 22/32 patients. Combining tissue NGS and liquid biopsy provided 26/38 (68.4%) patients with targeted treatment options. Single gene testing identified at least one G9 biomarker in 16/38 (42.1%) patients. Combining tissue NGS, liquid biopsy and single gene test improved sensitivity to 73.7% (28/38 patients). Overall, an estimated 1 in 4 NSCLC patients (26.4%) would have been identified with a diagnostic strategy using combined tissue and liquid NGS, over current conventional single gene testing approaches. Conclusions: Combining tissue and liquid NGS profiling provides the best treatment selection outcomes for patients with metastatic NSCLC. Our study highlighted that a quarter of NSCLC patients in Singapore would be identified for eligible targeted treatments from adopting a nationwide NGS testing approach, ideally tissue and liquid combined, to improve cancer services.
Comparison of response from RECIST1.1 and abstraction in real-world patients with lung cancer.
Authors: Chen Lu , Davis Ryan , Lee Joe , Weberpals Janick , Wyatt Shelby , Ounadjela Souhila , Trinh Huong , Fruechtenicht Charlotta , Reyes Adriana , Huntley Melanie
Published: June 2023

e21194

Background: Treatment response in clinical trials with solid tumors is measured by applying RECIST1.1 to radiographic images. However, response in real-world data (RWD) studies is based on information abstracted from clinician's notes. Differences in these two approaches can lead to bias when comparing response in trials to RWD. This study investigates the relationship between response from (1) certified radiologists applying RECIST1.1 to images from routine care and (2) electronic health records (EHR) notes-abstraction in the same patients. Methods: The nationwide Flatiron Health (FH) EHR-derived de-identified database was used to identify patients diagnosed with advanced non-small-cell lung cancer (aNSCLC) on/after Jan 1, 2011, with a visit in the FH network within 90 days of diagnosis, first line treatment (1L), and ≥1 radiographic image both at baseline (8 weeks before or at 1L start) and during 1L. RECIST1.1 and response abstraction were applied retrospectively to images and EHR notes obtained from routine care, respectively. For each patient, time-point responses were determined by RECIST1.1 (rwRECIST) and abstraction (rwR) and dichotomized as unconfirmed best overall response (BOR, complete+partial response = responder, all others = non-responder), and confirmed BOR if patients had an additional assessment. Results: We included 157 patients (59% on chemotherapy, 15%/12% on cancer immunotherapy combination/alone, 10% on targeted therapies). Patients had an image taken every 11 weeks (median). All images were readable and 75% were optimal quality. Response rate was lower by rwRECIST than rwR (unconfirmed: 48% vs 59%; confirmed: 34% vs 55%). Concordance in BOR between rwRECIST and rwR was 68%/60% for unconfirmed/confirmed response. Disagreement between rwRECIST and rwR was higher than inter-reader variability between radiologists and was mainly in one direction (rwR higher, Table). The disagreement was driven by patients deemed responders by abstraction who did not meet the -30% target lesion size cutoff specified by RECIST1.1 or presence of new lesions. Conclusions: RECIST1.1 can be applied to images from aNSCLC routine oncology care, although limited by image availability and less frequent assessment than trials. Differences were observed in response measured by rwRECIST and by abstraction. [Table: see text]
Docetaxel as a subsequent line after progression to platinum-based chemotherapy and immunotherapy.
Authors: Garitaonaindia Yago , Calvo Virginia , Redondo Isabel , Uribarren Maria , Ospina Serrano Aylen Vanessa , Collazo Ana , Blanco Mariola , Lozano Carla , Martinez Cutillas Marta , Manso Marta , TRASEIRA CRISTINA , Aguado Ramon , Sanchez del Corral Maria Matilde , Provencio Mariano
Published: June 2023

e21197

Background: Docetaxel was the standard of care for patients with non-small cell lung cancer (NSCLC) after platinum-based chemotherapy failure. The introduction of immune checkpoint inhibitors (ICIs) has radically altered the first-line treatment for advanced/metastatic NSCLC without driver mutations. However, limited clinical data are known after failure of chemotherapy and immunotherapy. Efficacy of docetaxel after progressing to platinum-based chemotherapy and checkpoint inhibitors are scarce. The aim of this study is to evaluate docetaxel in patients with advanced NSCLC after chemotherapy and ICIs failure in a real-world scenario. Methods: Retrospective, single centre study, including patients treated with docetaxel after progression to platinum-based chemotherapy and immunotherapy. We analysed demographic characteristics, treatments received and survival. Long survivors to Docetaxel were defined as those who lived more than 12 months after initiating Docetaxel. Results: 65 patients were included in this study. Median age was 67.0 years and 67.7% were male. 63.1% were adenocarcinoma, 24.6% squamous-cell carcinoma and 12.3% other histologies. Objective response rate (ORR) for docetaxel was 21.0%, with a control disease rate of 42.1%. 55.7% experienced toxicity from the treatment. Median progression-free survival (PFS) and overall survival (OS) were respectively 2.0 months (1.3-2.7, IQ 95%) and 6.0 months (4.6-7.4, IQ 95%). 16 patients (24.6%) were long survivors. Differential characteristics of long survivors are shown in Table. Conclusions: Docetaxel displayed poor survival results in our study after progression to platinum-based chemotherapy and ICIs, arising the necessity of developing new therapies for this scenario. Despite these results, almost 25% of the patients lived more than one year. Objective response to docetaxel was significantly associated with surviving more than one year, and better ECOG and lacking hepatic metastases showed a non-significant trend. Clinical biomarkers predicting benefit of Docetaxel in this scenario are lacking. [Table: see text]
Using cell-free DNA to predict response to immunotherapy in non-small cell lung cancer pre- and post-treatment.
Authors: Rao Satyanarayan , Zukowski Alexis , Weirich Abigail , Kabos Peter , Stensland Elin Marie , Eide Inger Johanne Zwicky , Brustugun Odd Terje , Ramachandran Srinivas
Published: June 2023

e21198

Background: Despite revolutionizing cancer therapy, immune checkpoint inhibitors (ICI) still do not benefit a significant proportion of patients. The risks associated with ICI-related adverse events, mixed performance of PD-L1 staining in predicting treatment response and its high cost, present a clinical need for more precise methods to define disease states in the context of ICI treatment. ICI response is thought to depend on the phenotype of the tumor and the associated immune response, especially functional state of CD8+ T cells in the tumor microenvironment (TME). Methods: Here we show that the CD8+ T cell signatures from plasma cell-free DNA (cfDNA) could be used to predict response of patients to anti-PD-1 therapy, using samples collected before and shortly after start of treatment. Blood samples were drawn just before the first dose, 1 day to 1 week before the start of treatment and 45-60 days since start of treatment. The treatment duration varied depending on response. Response was evaluated by CT scans every 8-12 weeks. 11 of the samples are from patients with no or minor response ( < 6 months of treatment), and 12 are from patients with prolonged benefit of the medication ( > 1 year of treatment). Exhausted CD8+ T cells, one of the targets of immunotherapy treatment are epigenetically regulated. So, we utilized naïve and PD-1high CD8+ T cell ATAC-seq data to define the repertoire of accessible chromatin specific to these cell types. We found an enrichment of short cfDNA fragments at a significant fraction of these sites, enabling us to define responder-specific and non-responder-specific accessible PD-1high regions from cfDNA. Results: We used the enrichment of short- versus long-cfDNA fragments (reflecting transcription factor-nucleosome dynamics in tissue of origin of cfDNA) as a scoring function, and repeated-cross-validation as a classifier model to identify differentially enriched features between responders and non-responders. Our model accurately predicts the two classes of response both pre-treatment (mean test AUC = 0.86; SD = 0.14). Conclusions: Notably, in addition to generating an accurate classifier, our analysis enabled us to identify predominant transcription factor motifs from predictive ATAC-seq peaks that characterize both response and lack of response, paving the way for further understanding the mechanistic basis of patient-specific response to ICI. Our results suggest the possibility of personalized prediction of treatment response that is independent of specific tumor genotype.