bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of amrubicin for previously treated patients with malignant pleural mesothelioma.
Authors: Akagi Kazumasa , Ikeda Takaya , Nakatomi Katsumi , Taniguchi Hirokazu , Shimada Midori , Gyotoku Hiroshi , Dotsu Yosuke , Umeyama Yasuhiro , Tomono Hiromi , Kitazaki Takeshi , Fukuda Masaaki , Soda Hiroshi , Senju Hiroaki , Takemoto Shinnosuke , Yamaguchi Hiroyuki , Fukuda Minoru , Mukae Hiroshi
Published: May 2020

e21095

Background: Malignant pleural mesothelioma (MPM) is a rare disease with few effective treatments and poor prognosis. Although pemetrexed (PEM) and cisplatin for the first-line treatment, and nivolumab for the second-line are considered as the standard treatment for patients with unresectable disease, these effects are still limited. There are no other effective agents for second-line treatment, although PEM-based regimens, vinorelbine, gemcitabine are recommended by some guidelines. Novel therapeutic strategies for the treatment of MPM are urgently required. Amrubicin (AMR) is a chemically synthesized anthracycline-based anticancer drug that inhibits cell growth by stabilizing the cleavable complex via topoisomerase II. The same anthracycline; adriamycin was one of the key drugs for MPM prior to the appearance of PEM, but its efficacy against MPM has not been revealed. Thus, we planned a phase II study of AMR therapy for previously treated MPM. Methods: Eligibility criteria were previously treated patients with unresectable MPM, performance status 0-2, age≦75, and adequate hematological, hepatic and renal function. Patients were treated with injections of AMR 35 mg/m2 on days 1, 2, and 3. The treatments were repeated every 3-4 weeks. The primary endpoint was the response rate (RR), the secondary endpoints were safety, progression-free survival time (PFS), overall survival time (OS). Results: Although the number of target cases was 32 cases, case registration was delayed and evaluation was performed with 10 cases enrolled. Patients' characteristics were as follows: male/female = 9/1; performance status 0/1/2 = 0/10/0; median age (range) = 67 (49-73); histology epithelial/sarcomatoid/mixed = 4/3/3; stage (IMIG) I/II/III/IV/postoperative recurrence = 0/1/4/4/1. RR was 10.0% (1/10), median PFS was 1.6 months and median OS was 6.6 months. Disease control rate was 50.0% (5/10). Adverse events of Grade 3 or 4 were neutropenia 60.0% (6/10), thrombocytopenia 10.0% (1/10), anemia 10.0% (1/10), febrile neutropenia 10.0% (1/10), and pneumonia 10.0% (1/10). Conclusions: This study demonstrated that AMR therapy for previously treated MPM was tolerable. The efficacy was limited, but may be effective in some cases. Clinical trial information: UMIN000006381 .
Extensive small cell lung cancer (SCLC) chemotherapy: A population kinetics assessment.
Authors: Stewart David J. , Brule Stephanie Yasmin
Published: May 2020

e21101

Background: Most progression-free (PFS) and overall survival (OS) curves fit exponential decay models on nonlinear regression analysis (NLRA). Log-linear curve shape varies with tumor & therapy type: straight line vs inflection to right (2 phase decay due to 2 distinct subpopulations with differing sensitivities) vs convex (downward inflection, eg due to stopping therapy that is slowing tumor growth).1 We compared SCLC to other cancers. Methods: As previously described,1 we did NLRA of published PFS & OS curves for etoposide-platinum in SCLC. We also assessed various therapies in other cancers. We calculated PFS & OS half-lives and classified curves by log-linear shape. Results: Of 18 evaluable SCLC PFS curves, 14 (78%) were highly convex & 18 (100%) were moderately or highly convex, compared to 35/888 (4%) highly convex & 186 (21%) moderately or high convex curves for other cancers (p < 0.0001). Of 24 evaluable SCLC OS curves, 12 (50%) were highly convex & 24 (100%) were moderately or highly convex, compared to 15/363 (4%) being highly convex & 87 (24%) moderately or highly convex for other cancers (p < 0.0001). In SCLC, 6 vs 4 cycles induction therapy minimally changed PFS half-life (median across studies 5.5 vs 5.2 months, p = 0.27) or OS half-life (9.5 vs 10.4 months, p = 0.06). PFS half-life correlated with OS half-life for other cancers (n 320, Spearman r 0.81, p < 0.0001) but not for SCLC (n 18, r 0.04, p = 0.86). Post progression survival (PPS) correlated positively with PFS half-life for other cancers (n 376, r 0.68, p < 0.0001) but correlated negatively for SCLC (n 18, r -0.43, p = 0.07). SCLC PFS curves had an initial downward inflection at a median of 2.9 months (where 87% of patients are still progression-free), followed by a 2nd inflection point at 4.5 months (where 71% are still progression-free). Median PFS half-life was 14.6 months prior to the 1st inflection point vs 1.9 months after the 2nd inflection point. Our analysis methods1 suggest that after the 2nd PFS inflection point, 23% of patients would progress by the next scan if scans are done every 3 weeks, while 40% would progress by the next scan if they are done every 6 weeks. Conclusions: PFS & OS curves for SCLC are more often highly convex than for other cancers since SCLC is sensitive to chemotherapy but progresses rapidly after induction therapy is completed. Giving 6 rather than 4 induction cycles makes no OS difference. New maintenance strategies are needed. Very short PFS half-lives post induction suggest that frequent follow up scans should be done for patients who are candidates for 2nd line therapy. 1. Stewart. Cancer Med 2019; 8:6871
Genomic characterization of circulating tumor DNA from Chinese advanced small-cell lung cancer to reveal potential therapeutic opportunities.
Authors: Yang Jing , Lu Jingli , Zhang Qiwen , Fu Xiaomin , Chen Hui , Zhao Xiaochen , Bai Yuezong , Zhang Xiaojian
Published: May 2020

e21111

Background: Molecular profiling via next-generation sequencing (NGS) has been applied to select patients benefiting from targeted therapy or immunotherapy. Sequencing of blood-derived circulating tumor DNA (ctDNA) presents an alternative for advanced cancers given the challenge of obtaining tumor biopsies. We identified potentially actionable genomic alterations (GAs) in Chinese advanced small-cell lung cancer (SCLC) patients using ctDNA testing. Methods: Blood samples from 119 patients with advanced SCLC were sequenced via target deep sequencing covering 150 or 189 cancer-related genes and 100 microsatellite loci. Blood tumor mutation burden (bTMB), defined as the number of somatic single-nucleotide variants, short insertions and deletions (SNV/Indels) in examined coding region, was calculated in 93 patients. High bTMB was set to 10 that ranks top 25% in all SCLC patients. Results: The total number of GAs was 1156 in 127 genes, with an average of 9.7 GAs per sample ranging from 1 to 31. All patients harbored at least one GA and 107/119 patients had at least one GA with clinical significance. TP53 (82.4%) was the commonly altered gene followed by RB1 (57.1%), LRP1B (41.2%), FAT1 (25.2%), FAM135B (23.5%), PIK3CA (21%). GAs were detected frequently in cell cycle pathway (83.2%), PI3K/AKT/mTOR pathway (33.6%), RTK-RAS-MAPK pathway (29.4%), and DDR pathway (10.1%). Overall, 54 (45.4%) patients had alterations with therapeutic relevance, including 2 high blood microsatellite instability and 23 high bTMB that might benefit from immune checkpoint inhibitors. Actionable SNV/Indels were identified, including EGFR mutation (3), KRAS/HRAS mutation (5), DNA damage repair (DDR) pathway (4; including ATM, BRCA1, BRCA2), and PI3K/AKT/mTOR pathway (10; including PIK3CA, PTEN) that might benefit from EGFR tyrosine kinase inhibitors, RAS inhibitors, PARP inhibitors and mTOR inhibitors, respectively. We also found amplification of HER2 (3), FGFR1 (14), and MET (3) that might benefit from anti-HER2 antibodies, FGFR1 inhibitors and MET inhibitors, respectively. Conclusions: To our knowledge, this is the first large-scale analysis of blood-derived ctDNA in Chinese advanced SCLC. Potentially actionable GAs were detected in 45.4% patients. Deep sequencing of ctDNA could provide molecular profiles and might optimize treatment decision in advanced SCLC.
Safety and activity of Combined AVElumab with Axitinib in unresectable or metastatic Thymomas B3 and Thymic carcinomas: The CAVEATT study.
Authors: Conforti Fabio , Pala Laura , Catania Chiara , Zucali Paolo Andrea , Della Vigna Paolo , Pirola Sara , Stucchi Sara , Pennacchioli Elisabetta , Queirolo Paola , Giaccone Giuseppe , De Pas Tommaso Martino
Published: May 2020

e21114

Background: Patients (pts) with advanced B3 thymoma (B3T) and thymic carcinoma (TC) resistant to chemotherapy have limited treatment options. Treatment with Anti-PD1 showed not negligible toxicity and limited activity, and anti-VEGFR drugs obtained limited and short lasting antitumor responses. No data on combined anti-PD1/PD-L1 with antiangiogenic drugs are available in B3T/TC. We report preliminary results on safety and activity of avelumab combined with axitinib in this pts population. Methods: The CAVEATT is a single arm, multicentric, phase II trial in immunotherapy-naive pts with advanced B3T or TC, progressing after at least one line of platinum based chemotherapy. Prior therapy with antiangiogenic drugs is allowed. Pts received Avelumab 10 mg/kg iv every 2 weeks and Axitinib 5 mg twice a day until progression or toxicity. The primary objective of the study is overall response rate (ORR) by RECIST 1.1; secondary endpoints include ORR by irRC and ITMIG, and QoL by EORTC QLQ-C30. An interim futility analysis is planned after the enrollment of the first 18 patients. If at least 5 out of 18 patients will obtain a PR, the accrual will continue to reach the total number of 33 pts, according with a Simon’s minimax design. Tumor and blood samples are collected at baseline and whenever feasible at disease progression, to identify predictive biomarkers of response and mechanisms of resistance to treatment. Results: 1 pt with B3T and 12 with TC were enrolled from April 2019 to January 2020. Median age was 59 years (range 33-77). 8 pts received ≥2 previous line of therapies, and 6 pts were pretreated with an antiangiogenic drug. The median follow-up was 5.1 months. 10 pts were evaluable for response. The proportions of patients who achieved a partial response (PR) or a stable disease (SD) were respectively 40% (95% CI 17%–69%) and 60% (95% CI 30%–83%). The median PFS was 7.9 months (95% CI 2.5–NA) 12 pts were evaluable for toxicity. Treatment-related adverse events (AE) of grade 1 or 2 occurred in 7 (58%) pts, and the most common was diarrhea (3 pts). Grade ≥3 AEs occurred in 2 (17%) pts: 1 had G3 hyperthension and 1 G3 hand foot syndrome, both leading to axitinib drug reduction. No immune-related AEs (irAEs) were observed. No patient stopped treatment for toxicity, 5 pts stopped for progressive disease, and 8 pts are still on treatment. Conclusions: Preliminary results suggest promising antitumor activity and a good toxicity profile of the combination of axitinib and avelumab in pts with advanced B3T and TC. Accrual is ongoing to reach the target of 33 pts Clinical trial information: 2017-004048-38 .
Nivolumab for thymic epithelial tumors: Case series.
Authors: Aydiner Adnan , Ak Naziye
Published: May 2020

e21115

Background: Metastatic and unresectable thymoma (T) or Thymic Carcinoma (TC) have limited treatment options, especially after first line. Methods: Patients with unresectable or recurrent thymic tumors who used minimum one dose of Nivolumab at any line of treatment were evaluated retrospectively. Even though standart dose of nivolumab is 3mg/kg dosage, due to financial concerns we used low dose regimen mostly. Results: 8 patients with TC (n = 3), T (n = 4) and mixt histology (n = 1) were included to study. Patients used nivolumab between April 2018 and August 2019, as median 3rd line of treatment. One patient used as first line treatment due to chemoresistant disease at neoadjuvant line. Three patients had previous myasthenia gravis that had to be controlled before treatment. Four patients showed moderate (n = 2) or severe (n = 2) adverse events with nivolumab treatment. Interestingly, two severe adverse events were occurred at first dose even with 40 mg nivolumab and required cessation of treatment permanently. Median follow-up time was 16.1 months (range: 12.7-165.4). The median number of nivolumab received was four (range: 1 – 18). Best response was partial response. Two patients progressed at the 3rd and 5th month of treatment. One of the patients with inoperable disease initially underwent surgery after nivolumab therapy. Duration of response for one patient with TC and one patient with T B2 were 9 and 14 months, respectively. Median survival time after nivolumab was 7.4 months (range: 2-22.1). Conclusions: Despite the small number of patients, nivolumab is an option for T and TC patients. Low dose nivolumab may also be very toxic for T, especially in patients with known myasthenia gravis history. [Table: see text]
Investigation of immune repertoires in thymoma.
Authors: Pathak Priyadarshini , Cox Mary , Dave Utpal P. , Loehrer Patrick J.
Published: May 2020

e21117

Background: Paraneoplastic autoimmune manifestations are seen in 30 to 40% of thymoma cases. Thymus plays the main role in T- cell maturation with ‘negative selection’ of autoreactive T-cells. Due to reasons not well understood, this function is deranged in thymomas resulting in dysregulation of immune function, loss of ‘self-tolerance’ and autoreactivity. The low cost and high-throughput of next generation sequencing techniques now make it feasible to analyze extensive T-cell receptor(TCR) gene rearrangements in peripheral blood lymphocytes. Methods: 40 patients with thymoma were identified between December, 2010 and September, 2019 at Indiana University. Whole blood samples were collected after diagnosis of thymoma but prior to thymectomy. 20 patients developed paraneoplastic manifestations at some point during the disease course. Genomic DNA was isolated from whole blood samples and TCR analysis performed using a commercially available next generation sequencing assay. This was compared with the control population of 20 patients who did not demonstrate any paraneoplastic features during their disease course. Patients were matched based on age, clinical stage and WHO classification. Results: Paraneoplastic manifestations seen in the 20 patients included Myasthenia Gravis (n = 12), Good’s Syndrome (n = 2), immune mediated cytopenia (n = 3) including pure red cell aplasia, pure white cell aplasia and thrombocytopenia, neurologic manifestations such as encephalitis (n = 2), Autoimmune Autonomic Neuronopathy(n = 1) and Isaac’s Syndrome (n = 2). Some patients also demonstrated more than one paraneoplastic syndrome. The onset and course of these manifestations varied; onset prior to diagnosis of thymoma, onset after thymectomy and improving or worsening clinical features after thymectomy. Since the exact mechanism of autoimmunity is still unknown, we attempted to detect differences in TCR subsets between these two groups. Our study shows that it is technically feasible to interrogate the peripheral blood lymphocytes of thymoma patients for TCR gene clonality and diversity. Conclusions: Diverse autoimmune syndromes can be described in thymoma patients with varying clinical course and severity. Although our study is underpowered, TCR gene sequencing is efficient and may not only improve our understanding of these paraneoplastic syndromes but also identify biomarkers for their diagnosis. Our research could also potentially lead to development of targeted treatment options in the future based on TCR manipulation.
Clonal dominance of EGFR and efficacy of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in NSCLC.
Authors: Ai Xinghao , Chen Rongrong , Cui Jiuwei , Zhang Jiexia , Lin Wen , Xie Congying , HU Xiaohua , Zhang Junping , Jiao Xiaodong , Rao Chuangzhou , Yang Weihua , Chang Lianpeng , Xia Xuefeng , Yi Xin , Lu Shun
Published: May 2020

e21501

Background: Though EGFR mutations in lung cancer are identified most often on the trunks of tumor phylogenetic trees in early stage, whether EGFR would always be the dominant clone in the advanced stage is unknown, as cancer evolution often follows a branched trajectory, with divergent subclones evolving simultaneously. The impact of clonal dominance of EGFR on outcomes with targeted therapies has not been explored. Methods: Paired tumor and plasma samples at diagnosis were obtained from systemic treatment naïve patients with advanced NSCLC in the clinical trial (NCT03059641). cfDNA and tumor DNA were sequenced by target-capture deep sequencing of 1021 genes related to solid tumors, with blood cells as the germline control. Clonal dominance analysis was performed on the basis of the CCF determined for SNVs and clustered in plasma or tumor sequencing data using a modified version of Pyclone. PFS was estimated using Kaplan-Meier method and compared using log-rank test. Results: From February 2017 to December 2019, 300 advanced NSCLC patients were enrolled prospectively from 14 centers cross China. One hundred and fourteen EGFR mutant patients treated with EGFR-TKI were followed until disease progression (PD). The medium follow-up time was 10 month (1-27 months) and 92 (80.7%) patients have reached PD, with the ORR of 74.6% (85/114), mPFS of 10.5 months. Clonal dominance analysis of EGFR showed 76 patients had EGFR as the dominant clone according to tissue NGS results, and 66 patients as the dominant clone according to plasma cfDNA NGS results (p = 0.04). The ORR was significantly higher for patients with EGFR as dominant clone according to plasma cfDNA NGS results (84.8% vs 60.9%, p = 0.016), and PFS was significantly longer (12 vs 8 months, HR = 2.58). There was no difference when using tissue NGS results to analyze EGFR clonal dominance. However, if comparing patients who were defined as EGFR dominant clone by both tissue and plasma (n = 44) with those defined as EGFR nondominant (n = 9), EGFR dominance was associated with higher ORR (84.1% vs 44.4%, p = 0.01), and longer PFS (11 vs 6 months, HR = 9.88) significantly. Moreover, multivariate Cox proportional hazard ratio analysis demonstrated it as an independent prognostic indicator of EGFR-TKIs. Conclusions: Clonal dominance of EGFR in the pretreatment plasma cfDNA is associated with the efficacy of EGFR-TKIs in NSCLC. This study indicated the importance of evaluating clonal dominance in the current clinical practice and future trial designs. Clinical trial information: NCT03059641.
Alterations in STK11 to limit response to immune checkpoint inhibitors in lung cancer.
Authors: Fricke Jeremy , Mambetsariev Isa , Pharaon Rebecca , Baroz Angel Ray , Zhao Dan , Massarelli Erminia , Koczywas Marianna , Salgia Ravi
Published: May 2020

e21503

Background: The use of immune checkpoint inhibitors (ICIs) drastically transformed the treatment of lung cancer. However, a variety of response rates have been observed in patients due to intrinsic or acquired resistances. STK11 mutated patients represent a subgroup of lung cancer patients with diminished outcomes when given ICIs, with some of these patients developing hyperprogressive disease (HPD). Methods: In this study, a retrospective cohort of 384 lung cancer patients previously treated with ICIs was identified from the City of Hope Thoracic Registry (THOR) with a cutoff date of November 11, 2018. Next-generational sequencing (NGS) was performed on 246 patients. 24 of these patients were harboring an alteration in STK11. Data was collected on these patients until December 31, 2019. HPD was exclusively defined by time-to-treatment failure (TTF) < 2 months (TTF is defined as the time from the start of treatment with ICI to ICI discontinuation for any reason, including progression, patient preference, toxicity, or death). Overall survival (OS) and progression free survival (PFS) was started from the initiation of ICI therapy. OS and PFS was calculated between 2 groups (HPD vs non-HPD) using the Mantel-Cox Log-rank test. Results: Almost half (11/13; 45.8%) of the patients with STK11 developed HPD. There was a significant difference between HPD and non-HPD patients in median OS (2 vs 23 months; p = 0.0013) and median PFS (1 v 9 months; p < 0.0001). The median age was 66 (range, 41-90) years old with the majority of patients female (14/24; 58.3%). Most of the patients are deceased (16/24; 66.7%). 91.7% of STK11 patients histologically were adenocarcinoma and 91.7% were smokers with a median pack year history of 40 (range, 4-90). All of the patients had metastatic disease presenting with stage IV disease (21/24; 87.5%). ICI therapies used were pembrolizumab (11/24; 45.8%), Atezolizumab (8/24; 33.3%), nivolumab (4/24; 16.7%), and durvalumab (1/24; 4.2%). PD-L1 expression varied: negative (8/24; 33.3%), 1%- < 50% (7/24; 29.2%), ≥50% (4/24; 16.7%), and not reported (5/24; 20.8%). The most commonly occurring co-mutations were found in TP53 (14/24; 58.3%), KRAS (12/24; 50.0%), SMARCA4 (9/24; 37.5%), PRKDC (8/24; 33.3%) and LRP1B (8/24; 33.3%). Three patients had a pathological co-mutation that is targetable (1 ALK rearrangement, 1 EGFR exon 19 deletion, and 1 RET fusion). Conclusions: STK11 patients who developed HPD had worse OS and PFS compared to STK11 patients without HPD. These results are preliminary and additional analysis is needed to compare differences between various cohorts.
Liquid biopsy: Safety and efficacy in a tool for molecular profiling of advanced non-small cell lung cancer (NSCLC).
Authors: Rizwan Saleha , Otaibi Zachary , Lo Herman , Khan Talal , Wegner Rodney E. , Finley Gene Grant
Published: May 2020

e21506

Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with a broad spectrum of targeted therapies already available or in clinical trials. Among the NSCLC patients, 23% to 25% harbor a mutation in a gene associated with approved or emerging targeted therapy. These therapies have changed the therapeutic landscape of NSCLC with significantly improved clinical outcomes in advanced metastatic NSCLC patients. It is imperative to test for these gene alterations in order to identify patients who could potentially benefit from these efficacious targeted therapies and to avoid therapies unlikely to provide clinical benefit. A major limitation in obtaining molecular testing occurs when minimally invasive techniques are used to obtain tissue sample resulting in insufficient yield for testing. In such cases, the utilization of circulating tumor DNA (ctDNA), commonly known as liquid biopsy, has proven very beneficial. In a study utilizing ctDNA, increased detection rates were found when using ctDNA in addition to tissue testing and a > 98.2% concordance rate was found. We report results of 40 NSCLC patients from our institute who had liquid biopsy with or without tissue profiling done. Methods: We molecularly profiled 40 newly diagnosed advanced NSCLC patients using both tissue and liquid biopsies. Tissue was assayed using the John Hopkins university molecular panel and liquid biopsies were performed by Biocept. Results: 14 out of 40 (35%) patients had insufficient or no tissue for molecular testing. Concordant results were found in 17 out of the 26 (65.4%) patients who had both tissue and liquid molecular testing done. Liquid Biopsy detected additional mutations in 5 (19.2%) patients which were not picked up on tissue and led to change in management in 4 patients. 12 out of 40 (30%) patients had repeat liquid biopsies done at progression of disease with new mutations detected on 4 patients revealing resistance to current treatment and change in treatment. Conclusions: Liquid Biopsy reveals high concordance rates with tissue genotyping and increases rate of detection of targetable mutations in NSCLC. It offers a safe and effective alternative when additional tissue is needed to identify genetic mutations.
Could soluble levels of CD40L and galectin-9 be possible prognostic biomarkers and therapeutic targets in NSCLC?
Authors: Costa Guilherme Jorge , da Matta Marina Catena , Torres Leuridan Cavacante , Casarini Dulce Elena
Published: May 2020

e21508

Background: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all cases of lung cancer. The immune system is now recognized to have the potential to destroy cancer cells. TIM-3 binds to Galectin-9 (GAL9) causing suppression of cytokine production, cell cycle arrest and cell death. Soluble CD40L (sCD40L) that is released by activated T lymphocytes and platelets. Therefore, we hypothesized that soluble forms immune checkpoint receptors and their ligands, such as TIM-3, GAL9 and CD40L may also prognostic implications of NSCLC. Objectives: Evaluate the soluble levels of CD40L, TIM-3 and GAL9 in patients with NSCLC in III and IV stages of disease. Methods: Samples of blood were collected from a cohort prospective involving 32 patients between 50 and 80 years old (65 + 8,6 years). Enzyme-linked immunosorbent assay was used to quantify expression these receptors. A non-parametric test was used to compare all groups (Mann-Whitney U-test). Statistical significance was defined as p<0.05. Data analysis was performed using GraphPadPrism v8.3. Results: Our results showed higher levels GAL-9 and TIM3 in patients with stage III and IV than controls ( p<0.05). As also, higher expression of CD40L was identified in patients stage III than stage IV ( p<0.0001) and controls ( p=0.007). It wasn’t seen significant different expression of CD40L between stage IV patients and controls. Analyzing GAL9, it was identified higher level in patients stage III than stage IV ( p<0.0001). Expression of TIM-3 wasn’t significant difference between patients with stage III and IV. When analysing in ratio between CD40L/TIM3, TIM3/GAL9 and CD40L/GAL9 in all groups, only TIM-3/GAL9 ratio had a positive correlation in patients stage IV (r=0.688; p<0.0001). By histology, patients with squamous cell carcinoma had higher levels of CD40L than adenocarcionoma ( p=0.01), but no significant difference was identified between expression of TIM3 e GAL9 and histological subtypes. Conclusions: This study showed expression sCD40L and GAL9 were higher stage III than stage IV in patients NSCLC. It can be inferred that soluble CD40L and GAL9 receptors are possible prognostic biomarkers and potential therapeutic targets in NSCLC.
Comprehensive cross-platform comparison of methodologies for noninvasive EGFR mutation testing: Results of the RING observational trial.
Authors: Romero Atocha , Molina-Vila Miguel Angel , Jantus-Lewintre Eloisa , Insa Amelia , Cruz Patricia , Collazo Ana , Perez Altozano Javier , Juan-Vidal Oscar , Diz Pilar , Cobo Manuel , Hernandez Berta , Vazquez-Estevez Sergio , Benitez Gretel , Guirado Maria , Rodriguez-Festa Alejandro , Calabuig-Fariñas Silvia , Rosell Rafael , Camps Carlos , Royuela Ana , Provencio-Pulla Mariano
Published: May 2020

e21518

Background: Several platforms for non-invasive EGFR testing are currently used in the clinical setting, with sensitivities ranging from 30 to 100%. Comparison studies in prospective cohorts remain limited and reports evaluating mutant allelic fractions (MAFs) are particularly scarce. The RING observational trial (ClinicalTrials.gov identifier NCT03363139) was designed to comprehensively analyze the concordance between methodologies for EGFR mutation detection in blood. Methods: Seventy-two EGFR mutant NSCLC patients were enrolled in the trial. Plasma samples were prospectively collected at progression to first line Tyrosine Kinase Inhibitor and tested for EGFR mutations by 7 methodologies; cobas EGFR Mutation Test v2, Therascreen EGFR Plasma RGQ PCR Kit, QuantStudio 3D Digital PCR System, a 5-nuclease real-time PCR assay in presence of PNA, OncoBEAM EGFR and NGS with two different gene panels, Ion Torrent Oncomine and GeneRead QIAact Lung DNA UMI Cancer Panel. Results: The agreement between all methodologies for was almost perfect for the detection of deletions in exon 19 (K = 0.86; 95%CI: 0.76-0.96) and substantial for exon 21 point mutations (K = 0.76; 95%CI: 0.63-0.89). Regarding the p.T790M resistance mutation, concordance was lower but still substantial (K = 0.68; 95%CI: 0.57-0.79). If only NGS-based technologies were considered, the agreement was almost perfect for sensitizing mutations and substantial for the resistance mutation (K = 0.84; 95%CI: 0.68-1.00, K = 0.86; 95%CI: 0.69-1.00 and K = 0.77; 95%CI: 0.60-0.95 for exon 19, exon 21 and p.T790M, respectively). Most discordant samples between methodologies had mutant allele fractions (MAFs) ≤0.5%. Sensitizing mutations were always present at higher MAFs than concomitant p.T790M, explaining the lower concordance observed for this variant. MAFs obtained by different methodologies showed an excellent reproducibility (intraclass correlation coeficients 0.85-0.97). Similarly, Passing–Bablok regression analysis showed a high correlation between methodologies when assessing MAFs. Conclusions: Our results support the use of liquid biopsies for non-invasive EGFR testing in the clinical setting and highlight the need to systematically report MAFs.
Evaluation of TKI toxicity according to inflammatory markers and body mass index in patients with non-small cell lung cancer (NSCLC) harboring an EGFR mutation: A retrospective observational study.
Authors: Runciman Thanya , Motta Guerrero Rodrigo , Aliaga Macha Carlos , Carracedo Carlos F.
Published: May 2020

e21522

Background: The standard treatment for patients with advance EGFR mutated NSCLC are Tirosine Kinasa inhibitors (TKI), we face in our clinical practice a different profile of toxicity; there is limited data of Inflammatory markers in this especial population. The aim of our study is to determine whether neutrophil lymphocyte ratio (NLR), lymphocyte platelet ratio(PLR), RDW-CV and body mass index (BMI) are related to the develop of this toxicity. Methods: We retrospectively analyzed data of patients with EGFRm NSCLC at Aliada Clinic between January 2016 to December 2019. Inflammatory markers were obtained from laboratory tests performed during the first visit as outpatient. The BMI kg/m2 at the start of the treatment was defined as the weight (kg) divided by the height (m) squared. Adverse event (AE) were graded according CTCAE v5.0. Results: A total of 164 patients were diagnosed with advanced NSCLC, of these 50 patients were assessed, 29 women and 21 men. The average age was 58.9 years, median of 59.5 ( 38 to 83; SD: 11.7). The most frequent EGFR mutation was deletion 19 (59.6%) followed by L858R mutation ( 23.1%) . The median BMI was 25.18 (16.2 to 41.3 kg/m2) 46.2% were normal, 36.5% were overweight, and 11.5 % were obese. 80% present any grade of AE. The most frequent AE was skin related: 75% (90 % grade I or II) follow by gastrointestinal: 57.6% (74 % grade I or II). There were no significant differences between NLR according to toxicity grade I-II vs III-IV (media: 3.44 and 4.32; P = 0.46); PLR according toxicity grade I-II vs III-IV (media: 229.41 and 251-50; P = 0.78); and RDW-CV according to toxicity grade I-II vs III-IV (media: 14.17 and 14.4; P = 0.74). Similarly, no significant differences were observed among toxicity profiles in relation to BMI (p = 0.2). Finally, there was no impact of severity of toxicity on progression-free survival (p = 0.64) or overall survival 24,33 months (IC 95% 16,05 – 32,6; p = 0.9). Conclusions: There was no relation between inflammatory markers and the grade of toxicity in patients with EGFRm advance NSCLC receiving TKIs. We suggest increase the population to validate our results.
Genomic alterations profiling by liquid biopsy and their association to immune checkpoints inhibitors (ICI) response in a cohort of non-small cell lung cancer (NSCLC) patients.
Authors: Callejo Ana , Carbonell Caterina , Iranzo Patricia , Pardo Aranda Nuria , Navarro Alejandro , Martinez-Marti Alex , Cedres Perez Susana , Gutierrez Raquel , Recasens Sergi , Madrenas Raquel , Sanchez Laura , Saoudi Nadia , Assaf Juan David , Masnou Mar , Frigola Joan , Amat Ramon , Felip Enriqueta
Published: May 2020

e21524

Background: In metastatic NSCLC, identification of biomarkers of response to immune checkpoint inhibitors (ICI) is still an unmet need. Liquid biopsy, including the detection of circulating tumor DNA (ctDNA) in patients’ bloodstream, is an emerging tool for detecting and monitoring genetic alterations. Mutations in specific genes as KRAS or STK11, in combination with PDL1, have been suggested as potential biomarkers to select responders to ICI. Methods: Digital NGS of ctDNA was analyzed by Guardant360 in samples from 89 patients with advanced NSCLC treated with ICI between 2017 to 2019. Plasma samples after progression to ICI were obteined from 40 patients and we focus in this subgroup to explore mutations of genes commonly alterated in lung cancer and correlate them with clinical outcomes. Results: Forty patients were included in the analysis with a median age of 64.5 years and 62.5% were diagnosed with adenocarcinoma. Fourteen patients were treated with single agent ICI as first line, 19 patients as second line and 7 in third line. A median of 4 mutations per patient were detected (range 0-13). Mutations (mut) in TP53 were found in 85% of the patients, KRAS in 34%, STK11 in 22% and both genes KRAS and STK11 were alterated in 12.5% of the patients. Globally, median PFS (mPFS) of the patients treated with ICI was 7.5 months. mPFS in patients harboring KRAS mutations was 4.9 m ( vs 10.1 m in patients without KRASmut, logrank test p-value = 0.031) and 4.1 m in those patients with STK11 mutations (vs 9.5 m in patients without STK11mut, logrank test p-value = 0.034). Additionally, mutations in both genes were also associated to statistically significant shorter mPFS 3.9 m vs 9.5 m (logrank test p-value < 0.01). Conclusions: Our results support the idea that tumor alterations identified by liquid biopsy panels can potentially contribute as biomarkers of response to ICI in NSCLC. When analyzing the mutational panorama after ICI treatment, we find that those patients exhibiting KRAS and/or STK11 mutations in their ctDNA have a shorter PFS.
Concurrent somatic alterations of TP53 and RB1 in Chinese lung adenocarcinoma with or without EGFR mutations.
Authors: WANG JUN , Chen Gang , Zhang Bicheng , Sun Jianguo , Liang Jing , Liu Xiaolin , Li Yan , Wang Baocheng
Published: May 2020

e21526

Background: Endothelial growth factor receptor (EGFR)-mutant lung adenocarcinoma displays diverse responses to tyrosine kinase inhibitor therapy. Concurrent somatic alterations represent different biological substantial proportion of patients with EGFR mutations and impacts their prognosis. Methods: We conducted this retrospective study to clarify the comprehensive concurrent genetic alterations of TP53 and RB1 and tumor mutational burden (TMB) in 712 EGFR-mutant or EGFR-wild type lung adenocarcinoma by next generation sequencing-based gene panel tests. Results: EGFR was the most frequently mutated gene altered in 58.0% (413/712) of lung adenocarcinoma, followed by TP53 altered in 56.7%, KRAS altered in 13.3%, and RBM10 altered in 11.2% of all patients. Concurrent genetic alteration of TP53 and RB1 is more likely to be found in EGFR-mutant patients than in EGFR-wild type patients, with a frequency of 11.4% (45/413) and 4.3% (13/299), respectively (p = 0.003). However, the frequency of TP53 and RB1 concurrent alteration was similar in lung cancer with sensitive EGFR mutation compared to those with non-sensitive mutation (10.5% versus 11.6%). TP53 mutation was most frequently found in patients with RB1 mutation (58/61), irrespective of EGFR mutational status. Furthermore, significant difference was found regarding median TMB in patients with mutant EGFR compared to those with non-mutant EGFR (3.8 versus 4.3; p < 0.001). Median TMB was higher for patients with TP53 and RB1 concurrent alteration than those without concurrent alteration in all patients (5.4 versus 4.3, p = 0.018). Conclusions: Our data showed that high prevalence of concurrent somatic alterations of TP53 and RB1 genes among lung adenocarcinoma patients with EGFR mutations, which might help understand several key biological processes and develop potential therapeutic strategies.
Expression of immune response markers in Arab patients with lung cancer.
Authors: Jazieh Abdul Rahman , Bounedjar Adda , Bamefleh Hanaa , Al-Fayea Turki , Almaghraby Hatim Q. , Belarabi Ayed , Ouahioune Wahiba , Derbouz Zoubir , Alkaiyat Mohammad , Alkattan Khaled , Damlaj Moussab , Khalbuss Walid
Published: May 2020

e21543

Background: Programmed death-ligand 1 (PD-L1) is a marker for checkpoint inhibitors use in management of solid tumor especially non-small cell lung cancer (NSCLC). Our study aimed at determining the patterns of PD-L1 expression and CD8 immunostains in patients with NSCLC in Arab population. Methods: Archival tumor tissue form patients with confirmed diagnosis of NCSLC were obtained and stained for PD-L1 using antibody 22C3 by Dako using Immuno-histochemistry stain (IHC) and giving Tumor Proportion Score (TPS) a percentage number from 0 to 100% of stained tumor cells. Tumors were categorized into negative expressers (TPS<1%), low positive (TPS 1-49%), and high positive (TPS 50% -100%). Correlation of expression with clinical and pathological features including CD8+ lymphocyte density was analyzed. Results: Two hundred NSCLC cases were included in the study from 6 centers in Saudi Arabia and Algeria. Median age was 65 years (28-93) and majority were males (75%) with stage 4 NSCLC (64%). The TPS was high in 37 patients (18%), low in 60 patients (30%), and negative in 103 patients (52%). In a univariate analysis, the following were significant predictors of any PD-L1 expression (>1%): male gender, being Saudi national patients, high expression of CD8+ and the presence of tumor infiltrating lymphocytes. In the multivariate analysis, only high expression of CD8+ cells (>2+) was significant with Odd Ratio (OR) of 4.4 (95% Confidence interval 1.5-12.9, p value of 0.003). Conclusions: PD-L1 expression in our population is similar to the published literature and correlated with the density of CD8+ cells. Validation of the predictive value of this marker in our population and identifying easier and reliable methods to test for it is warranted.
Human skin biomarkers and his relation with the response to treatment to tyrosine kinase inhibitors in advanced EGFR mutated lung adenocarcinoma.
Authors: Rodriguez Cid Jeronimo Rafael Rafael , Castañeda-Zárraga Anahi , Flores-Mariñelarena Rodrigo Rodrigo , Vega-Memije María Elisa , Fernández Garibay Valeria Michelle , Trinidad-Bibiano Héctor , Martínez-Herrera José Fabián , Sánchez-Ríos Carla Paola , Alatorre-Alexander Jorge , Martinez Luis Manuel , Santillan-Doherty Patricio
Published: May 2020

e21544

Background: A relationship between EGFR signaling pathway expression in skin and the use of targeted cancer therapies has been consistently demonstrated. Nonetheless, consistent evidence to support the use of skin biopsies as a surrogate for therapeutic evaluation. Methods: The present study is a prospective single-blind analysis of skin biopsies of patients with confirmed advanced EGFR mutated lung adenocarcinoma. Immunohistochemistry was performed with EGFR, p27, Ki67, STAT3, and MAPK, as well as an H&E histopathological analysis, looking for their relationship with the response to treatment with tyrosine kinase inhibitors. ROC curve analysis was used to determine the cutoff value for each biomarker selected dichotomizing the response to treatment as mentioned in the tissue samples section (adequate response or no response). Kaplan Meier analysis for progression-free survival was performed. Results: From the 35 biopsies obtained, 21 (60%) of the patients were women and 14 (40%) men; the mean age of participants was 60.6±11.7 years. Twelve patients (34.3%) were at the pre-treatment group, 12 (34.3%) had an adequate response to treatment and 11 (31.4%) were at the no response to treatment group. The median progression-free survival was 9 months. The next biomarkers were significantly related to an adequate response to treatment by using a bivariate correlation test: EGFR (p = 0.025), Ki67 (p = 0.015), STAT3 (p = 0.017), stratum corneum thickness (p = 0.039) and the number of layers of the stratum corneum(p = 0.041). A better median of progression-free survival was obtained on those with a value above of the cutoff preestablished of EGFR (21 months versus 7 months, 95% CI 0-46 versus 4.23-9.77, p = 0.025) and number of layers of the stratum corneum (21 months versus 8 months, 95% CI 0-43.81 versus 6.72-9.28, p = 0.030), however, for p27 a better median of progression-free survival was shown in those with a value below the cutoff before mentioned (21 months versus 8 months, 95% CI 8.17-33.83 versus 6.87-9.13, p = 0.031). Conclusions: We found a relationship between EGFR, Ki67, STAT3, stratum corneum, number of layers of stratum corneum, with the response to treatment, and better progression-free survival for high expression EGFR, number of layers of the stratum corneum and low expression for p27. The present study should incite to perform a further investigation to validate these markers as potential prognostic and predictive factors.
STK11/LKB1 revisited: A prognostic rather than predictive biomarker for immune checkpoint inhibitor in EGFR/ALKWT nonsquamous non-small cell lung cancer (NSCLC).
Authors: Zhao Hui , Qi Nan , Chen Dianjun , Li Donghui , Fu Yan , Xu Yu , Wang Guoqiang , Bai Yuezong , Du Nan
Published: May 2020

e21548

Background: Previous retrospective studies identified the mutation of serine/threonine-protein kinase (STK11, also known as Liver Kinase B1 [LKB1]) as predictor to the benefit from immune checkpoint inhibitor (ICI) in KRAS-mutant lung adenocarcinoma. This conclusion was drawn from merely the patients receiving ICI, lacking the indispensable control group undergoing chemotherapy. Therefore, we hereby revisit the impact of STK11 mutation in both immunotherapeutic and chemotherapeutic cohorts, in addition to TCGA database as a control cohort representing prognosis. Methods: 6 immunotherapeutic cohorts involving 807 patient-level data (Van Allen, Rizvi-34, Rizvi-240, MSKCC-75, MSKCC-350, and POPLAR/OAK-atezolizumab), 1 chemotherapeutic cohort (POPLAR/OAK-docetaxel, n = 244), and TCGA database (n = 485) were included to comprehensively re-examine the questionably predictive effect of STK11 mutation on the benefit from immunotherapy in patients with EGFR/ALKWT non-squamous NSCLC. Results: In the 6 immunotherapeutic cohorts, STK11 mutation was associated with shorter progression-free survival (PFS, HR = 1.54, 95%CI 1.17-2.03, P = 0.002) and overall survival (OS, HR = 1.57, 95%CI 1.16-2.11, P = 0.003), but no statistically lower overall response rate (ORR, RR = 0.71, 95%CI 0.39-1.28, P = 0.251). Similarly, in the patients receiving docetaxel, worse ORR and PFS at borderline level and significantly reduced OS (HR = 1.82, 95%CI 1.18-2.80, P = 0.006) were observed. Specifically, in the POPLAR/OAK cohort retrieved from two randomized controlled trials comparing atezolizumab and docetaxel, STK11 mutation and treatment choice separately impacted on OS, but the interaction between these two variables was barely profound (HR 1.10, 95%CI 0.60-2.01, P = 0.766), indicating the prognostic, but not predictive utility of STK11 mutation. Furthermore, in TCGA database, STK11 mutation was linked with poorer prognosis, with the similar hazard ratio in immunotherapeutic cohorts. Conclusions: Genomic abberation of STK11 remarkably worsens prognosis among 6 immunotherapeutic cohorts, 1 chemotherapeutic cohort, and TCGA database, demonstrating the prognostic, but not predictive utility of STK11 mutation in patients with EGFR/ALKWT non-squamous NSCLC.
Characterization of ERBB2 alterations in non-small cell lung cancer.
Authors: Singh Vijendra , Feldman Rebecca , Sukari Ammar , Kim Chul , Mamdani Hirva , Spira Alexander I. , Bepler Gerold , Kim Edward S. , Raez Luis E. , Pai Sachin Gopalkrishna , Ikpeazu Chukwuemeka , Vanderwalde Ari M. , Xiu Joanne , Wozniak Antoinette J. , Borghaei Hossein , Liu Stephen V. , Nagasaka Misako
Published: May 2020

e21553

Background: ERBB2 alteration (mutation and/or amplification) is associated with poor survival in non-small cell lung cancer (NSCLC) and is commonly reported as a resistance mechanism to EGFR tyrosine kinase inhibitors. Several clinical trials are ongoing for the management of ERBB2-altered NSCLC. Here we report the prevalence of different ERBB2 alterations in NSCLC. Methods: We retrospectively analyzed ERBB2 alterations in NSCLC tumors that underwent next-generation sequencing (NGS) with Caris Life Sciences. De-identified pathological and molecular information was collected. ERBB2 copy number of greater than 6 was defined as amplification; mutations were classified among 7 groups based on their mechanism of action. Results: A total of 12946 NSCLC tumors with ERBB2 NGS results were available. Among them, 12492 had ERBB2 copy number alteration (CNA) data available. 321 tumors (2.5%) had ERBB2 alteration (mutation or amplification). Among them, ERBB2 was mutated in 197 tumors (1.5%) and amplified in 134 (1.1%) tumors. Type of ERBB2 mutation, respective median age and distribution among sex is in the table. 10 tumors with ERBB2 mutation (7.46%) also showed ERBB2 amplification. Six percent of tumors (8/135) with ERBB2 exon 20 insertion mutations had co-occurring ERBB2 amplification. One tumor for each extracellular domain (ECD) and transmembrane group had co-occurring ERBB2 amplification. Eight tumors with ERBB2 mutation had an overlapping EGFR L858R or exon19del mutation. Seven of these 8 tumors were from the ECD group (7/21) and all had mutations in the S310 locus. One tumor was from the transmembrane group. Conclusions: Exon 20 insertion mutation is the most commonly found ERBB2 mutation among NSCLC, a few of them had co-occurring ERBB2 amplification. One third of tumors with extracellular domain ERBB2 mutation had EGFR mutation. Tarloxitinib (NCT03805841), trastuzumab deruxtucan (NCT03505719), pyrotinib (NCT02500199), poziotinib (NCT03318939) are just a few of the novel ERBB2 inhibitors available in clinical trials. It will be critical to utilize next generation sequencing to effectively capture uncommon mutations and amplifications in ERBB2 so that patients may be offered therapy directly targeted to their genomic alterations. [Table: see text]