Publications by authors named "David P Carbone"

205 Publications

Linear Endobronchial Ultrasound in the Era of Personalized Lung Cancer Diagnostics-A Technical Review.

J Clin Med 2021 Nov 30;10(23). Epub 2021 Nov 30.

Comprehensive Cancer Center, Division of Thoracic Surgery, Department of Surgery, The Ohio State University, Columbus, OH 43210, USA.

Major advances in molecular profiling for available targeted treatments and immunotherapy for lung cancer have significantly increased the complexity of tissue-based diagnostics. Endobronchial ultrasound-guided transbronchial needle aspirations (EBUS-TBNA) are commonly performed for diagnostic biopsies and lymph node staging. EBUS-TBNA has increasingly become one of the main sources of tumor cells for molecular analyses. As a result, there is a growing need for high quality EBUS-TBNA samples with adequate cellularity. This has increased the technical demands of the procedure and has created additional challenges, many of which are not addressed in the current EBUS guidelines. This review provides an overview of current evidence on the technical aspects of EBUS-TBNA in light of comprehensive sample processing for personalized lung cancer management. These include sonographic lymph node characterization, optimal needle choice, suction biopsy technique, and the role of rapid on-site evaluation. Attention to these technical details will be important to maximize the throughput of EBUS-TBNA biopsies for molecular testing.
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http://dx.doi.org/10.3390/jcm10235646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8658311PMC
November 2021

Lung cancer-associated T cell repertoire as potential biomarker for early detection of stage I lung cancer.

Lung Cancer 2021 Dec 28;162:16-22. Epub 2021 Sep 28.

Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, China; Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, China; Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Changsha, China. Electronic address:

Background: Early detection of lung cancer in asymptomatic patients remains challenging, especially for stage I. Considering the substantial interaction with tumor immunogenicity, we hypothesized that lung cancer-associated TCR (LC-aTCR) may serve as potential biomarker in early detection of stage I lung cancer.

Methods: Individuals who received low-dose computed tomography (LDCT) screening were enrolled in the study. Surgical tissues and peripheral blood specimens were collected and performed with DNA-based T cell repertoire (TCR) sequencing. The motif-based algorithm was used to deconstruct specific lung cancer-associated TCRs (LC-aTCRs).

Results: A total of 146 individuals participating in the real-world LDCT screening project were enrolled in this study, including 52 patients with pathologically-confirmed stage I lung cancer and 94 non-cancer controls. We developed a motif-based algorithm to define 80 LC-aTCRs in the training cohort. Moreover, in the validation cohort, high sensitivity and specificity was showed in stage I lung cancer with 72% and 91% respectively, and the AUC of the ROC curve was 0.91 (95% CI: 0.85 ∼ 0.96).

Conclusion: This work provides inspiration for stage I lung cancer detection by using blood TCR profiling data. The combination of TCR-based assay and routine screening deserves further testing in larger cohorts.
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http://dx.doi.org/10.1016/j.lungcan.2021.09.017DOI Listing
December 2021

Comparison of Tumor Microenvironments Between Primary Tumors and Brain Metastases in Patients With NSCLC.

JTO Clin Res Rep 2021 Oct 20;2(10):100230. Epub 2021 Sep 20.

Division of Medical Oncology, Department of Internal Medicine, James Thoracic Center, The Ohio State University, Columbus, Ohio.

Introduction: This study investigates the immune profile of the primary lung tumors and the corresponding brain metastasis from patients with NSCLC using multiplex fluorescence immunohistochemistry.

Methods: The study evaluated 34 patients who underwent autopsy or surgical resection for brain metastasis and autopsy, surgical resection, or core biopsy for primary lung cancer. We compared the densities of various immune cells in the primary tumors and the brain metastases by multiplex fluorescence immunohistochemical analysis.

Results: The density of CD4-positive (CD4) T-cells, CD8-positive T-cells, and CD4 Foxp3-positive T-cells were statistically higher in both tumor and stromal areas in primary lung cancer specimens when compared with brain metastases samples ( < 0.0001). Only CD204-positive cells were statistically higher in the tumor areas of the brain metastases ( = 0.0118). Tumor-infiltrating lymphocytes associated with brain metastases positively correlated with overall survival, but primary lung tumor-infiltrating lymphocytes did not. The density of CD4 and CD4 Foxp3-positive T-cells in brain metastases with radiation was statistically higher in the carcinoma and stromal areas compared with those without radiation ( = 0.0343,  = 0.0173).

Conclusions: Our findings that CD204-positive cells were higher in brain metastases may have broader implications for treatment as these macrophages may be immunosuppressive and make the immune environment less reactive. Furthermore, the finding that the density of CD4 T-cells was higher in cancer and stroma areas of brain metastases after radiotherapy supports the addition of immunotherapy to radiation therapy in the treatment of brain metastases in NSCLC.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501504PMC
October 2021

Psychological Symptom Trajectories and Non-Small Cell Lung Cancer Survival: A Joint Model Analysis.

Psychosom Med 2021 Oct 9. Epub 2021 Oct 9.

Department of Psychology, 1835 Neil Avenue, The Ohio State University Department of Biomedical Informatics and Center for Biostatistics, College of Medicine, The Ohio State University Department of Internal Medicine, Division of Medical Oncology, College of Medicine, The Ohio State University.

Objective: Lung cancer remains the number one cause of cancer-related mortality worldwide, but less known is that lung cancer patients are among the most psychologically disabled of all cancer groups. Patients with stage-IV non-small cell lung cancer (NSCLC) were studied to test the hypothesis that trajectories of depression and/or anxiety symptoms following diagnosis would show an adverse relationship with survival, beyond relevant controls.

Methods: Patients with stage-IV NSCLC (N = 157) were enrolled (ClinicalTrials.gov Identifier: NCT03199651) at diagnosis and completed validated measures for depressive symptoms (Patient Health Questionnaire-9; PHQ9) and anxiety symptoms (Generalized Anxiety Disorder-7; GAD7). Patients were reassessed every 1-to 2-months thru 24-months (16 assessments; 80% average completion rate) and survival monitored. Joint statistical models provided simultaneous modeling of longitudinal (psychological) and time-to-event (survival) processes. Control variables were age, sex, marital status, education, smoking status, cancer type, and treatment received.

Results: Depression and anxiety symptoms significantly decreased with time since diagnosis. The two-year trajectory of depressive symptoms was significantly associated with cancer survival after adjustment for covariates [Hazard ratio = 1.09 per unit increase in PHQ9, 95% CI 1.03-1.15, p = 0.002]. Anxiety was marginally significant in the unadjusted (p = 0.053) but not the adjusted (p = 0.39) model.

Conclusions: For the first time, joint model analyses test the interaction of a longitudinal trajectory of psychological symptoms, assessed from diagnosis through 24 months, and cancer survival. New data show the continuation of depressive and anxiety symptoms through treatment and thereafter. Immunotherapy and targeted therapies have dramatically improved survival for patients with advanced NSCLC, however novel data suggest their benefit may be constrained by depressive symptoms.
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http://dx.doi.org/10.1097/PSY.0000000000001027DOI Listing
October 2021

Genomic and Transcriptomic Characterization of Relapsed SCLC Through Rapid Research Autopsy.

JTO Clin Res Rep 2021 Apr 11;2(4):100164. Epub 2021 Mar 11.

Division of Medical Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Introduction: Relapsed SCLC is characterized by therapeutic resistance and high mortality rate. Despite decades of research, mechanisms responsible for therapeutic resistance have remained elusive owing to limited tissues available for molecular studies. Thus, an unmet need remains for molecular characterization of relapsed SCLC to facilitate development of effective therapies.

Methods: We performed whole-exome and transcriptome sequencing of metastatic tumor samples procured from research autopsies of five patients with relapsed SCLC. We implemented bioinformatics tools to infer subclonal phylogeny and identify recurrent genomic alterations. We implemented immune cell signature and single-sample gene set enrichment analyses on tumor and normal transcriptome data from autopsy and additional primary and relapsed SCLC data sets. Furthermore, we evaluated T cell-inflamed gene expression profiles in neuroendocrine (, ) and non-neuroendocrine (, ) SCLC subtypes.

Results: Exome sequencing revealed clonal heterogeneity (intertumor and intratumor) arising from branched evolution and identified resistance-associated truncal and subclonal alterations in relapsed SCLC. Transcriptome analyses further revealed a noninflamed phenotype in neuroendocrine SCLC subtypes (, ) associated with decreased expression of genes involved in adaptive antitumor immunity whereas non-neuroendocrine subtypes (, ) revealed a more inflamed phenotype.

Conclusions: Our results reveal substantial tumor heterogeneity and complex clonal evolution in relapsed SCLC. Furthermore, we report that neuroendocrine SCLC subtypes are immunologically cold, thus explaining decreased responsiveness to immune checkpoint blockade. These results suggest that the mechanisms of innate and acquired therapeutic resistances are subtype-specific in SCLC and highlight the need for continued investigation to bolster therapy selection and development for this cancer.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474405PMC
April 2021

Lung Cancer Stem Cells and Their Clinical Implications.

Cold Spring Harb Perspect Med 2021 Sep 27. Epub 2021 Sep 27.

Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA.

It is now widely accepted that stem cells exist in various cancers, including lung cancer, which are referred to as cancer stem cells (CSCs). CSCs are defined in this context as the subset of tumor cells with the ability to form tumors in serial transplantation and cloning assays and form tumors at metastatic sites. Mouse models of lung cancer have shown that lung CSCs reside in niches that are essential for the maintenance of stemness, plasticity, enable antitumor immune evasion, and provide metastatic potential. Similar to normal lung stem cells, Notch, Wnt, and the Hedgehog signaling cascades have been recruited by the CSCs to regulate stemness and also provide therapy-driven resistance in lung cancer. Compounds targeting β-catenin and Sonic hedgehog (Shh) activity have shown promising anti-CSC activity in preclinical murine models of lung cancer. Understanding CSCs and their niches in lung cancer can answer fundamental questions pertaining to tumor maintenance and associated immune regulation and escape that appear important in the quest to develop novel lung cancer therapies and enhance sensitivity to currently approved chemo-, targeted-, and immune therapeutics.
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http://dx.doi.org/10.1101/cshperspect.a041270DOI Listing
September 2021

Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis.

Blood Cancer Discov 2021 Sep 16;2(5):434-449. Epub 2021 Jul 16.

Department of Medicine, University of California, San Francisco, San Francisco, California.

Acute myeloid leukemia patients refractory to induction therapy or relapsed within one year have poor outcomes. Autocrine production of hepatocyte growth factor by myeloid blasts drives leukemogenesis in pre-clinical models. A phase Ib trial evaluated ficlatuzumab, a first-in-class anti-HGF antibody, in combination with cytarabine in this high-risk population. Dose-limiting toxicities were not observed, and 20 mg/kg was established as the recommended phase II dose. The most frequent treatment-related adverse event was febrile neutropenia. Among 17 evaluable patients, the overall response rate was 53%, all complete remissions. Phospho-proteomic mass cytometry showed potent on-target suppression of p-MET after ficlatuzumab treatment and that attenuation of p-S6 was associated with clinical response. Multiplexed single cell RNA sequencing using prospectively acquired patient specimens identified interferon response genes as adverse predictive factors. The ficlatuzumab and cytarabine combination is well-tolerated with favorable efficacy. High-dimensional analyses at single-cell resolution represent promising approaches for identifying biomarkers of response and mechanisms of resistance in prospective clinical studies.
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http://dx.doi.org/10.1158/2643-3230.BCD-21-0055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425277PMC
September 2021

AKT3-mediated IWS1 phosphorylation promotes the proliferation of EGFR-mutant lung adenocarcinomas through cell cycle-regulated U2AF2 RNA splicing.

Nat Commun 2021 07 30;12(1):4624. Epub 2021 Jul 30.

Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.

AKT-phosphorylated IWS1 regulates alternative RNA splicing via a pathway that is active in lung cancer. RNA-seq studies in lung adenocarcinoma cells lacking phosphorylated IWS1, identified a exon 2-deficient U2AF2 splice variant. Here, we show that exon 2 inclusion in the U2AF2 mRNA is a cell cycle-dependent process that is regulated by LEDGF/SRSF1 splicing complexes, whose assembly is controlled by the IWS1 phosphorylation-dependent deposition of histone H3K36me3 marks in the body of target genes. The exon 2-deficient U2AF2 mRNA encodes a Serine-Arginine-Rich (RS) domain-deficient U2AF65, which is defective in CDCA5 pre-mRNA processing. This results in downregulation of the CDCA5-encoded protein Sororin, a phosphorylation target and regulator of ERK, G2/M arrest and impaired cell proliferation and tumor growth. Analysis of human lung adenocarcinomas, confirmed activation of the pathway in EGFR-mutant tumors and showed that pathway activity correlates with tumor stage, histologic grade, metastasis, relapse after treatment, and poor prognosis.
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http://dx.doi.org/10.1038/s41467-021-24795-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324843PMC
July 2021

Real-world insights into patients with advanced NSCLC and MET alterations.

Lung Cancer 2021 09 16;159:96-106. Epub 2021 Jul 16.

Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA. Electronic address:

Objectives: To describe characteristics, treatment and outcomes of non-small cell lung cancer (NSCLC) patients with MET alterations (MET exon 14 [METex14] skipping or MET amplification [METamp]) in real-world clinical care.

Methods: This non-interventional cohort study used real-world data extracted from electronic medical records from academic oncology sites in Israel, The Netherlands, Taiwan, and the USA. Patients had confirmed diagnosis of advanced (Stage IIIB-IV) NSCLC harboring MET alterations (date of diagnosis = index date) between 1 Jan 2010 and 30 Sept 2018. Medical history was assessed prior to and at the index date (baseline period), and outcomes from first date of treatment to death, loss to follow-up, or end of study period.

Results: A total of 117 patients were included (METex14 n = 70; METamp n = 47); testing methods were heterogeneous. Concomitant oncogenic mutations were more common in the METamp cohort than METex14. Patients in the METex14 cohort were older than those in METamp, and a larger proportion were never smokers. Anticancer first-line therapies received by patients (METex14; METamp) included chemotherapy only (44%; 41%), MET inhibitors (33%; 29%), immune checkpoint inhibitor (ICI) mono-(12%; 15%) and combination-therapy (8%; 3%). Second-line therapies included chemotherapy (35%; 30%) and MET inhibitors (30%; 39%). In the METex14 cohort, objective response rate (ORR) was generally low (first-line 28%; second-line 30%); no patients who received ICIs had a response. In the METamp cohort, ORR was 36% in first-line and 22% in second-line. Median (95% confidence interval) overall survival from start of first-line therapy was 12.0 months (6.8, 19.2) in the METex14 cohort and 22.0 months (9.8, 31.2) in METamp.

Conclusions: Heterogeneous treatments reflect the changing landscape and availability of new treatments, as well as the high unmet medical need in older, METex14 patients who had more advanced disease at diagnosis. MET-targeted therapies could be beneficial in patients with these rare MET alterations.
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http://dx.doi.org/10.1016/j.lungcan.2021.06.015DOI Listing
September 2021

Weighting tumor-specific TCR repertoires as a classifier to stratify the immunotherapy delivery in non-small cell lung cancers.

Sci Adv 2021 May 19;7(21). Epub 2021 May 19.

State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Analysis of T cell receptor (TCR) repertoires may contribute to better understanding of the response to immunotherapy. By deep sequencing of the TCR β chain complementarity-determining regions in the paired biopsies and peripheral blood specimens of 31 patients with non-small cell lung cancer (NSCLC) treated with anti-programmed death 1 (PD-1) or PD-ligand 1 (PD-L1) therapy, we developed a previously unidentified index, the TCR-based immunotherapy response index (TIR index), that estimated the degree of overlap of the TCR repertoire between tumor-infiltrating lymphocytes and circulating PD-1CD8T cells (shared TCR clones). This index correlated with response and survival outcomes of anti-PD-(L)1 treatment. All the TCR sequences of neoantigen-stimulated T cells were included in the shared TCR clones, indicating that TCR clones involved in TIR index estimation represented tumor-specific T cells. Therefore, the TIR index is a feasible approach for assessing tumor-specific TCR and stratifying patients with NSCLC for anti-PD-(L)1 therapy.
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http://dx.doi.org/10.1126/sciadv.abd6971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133747PMC
May 2021

Predicting ROR1/BCL2 combination targeted therapy of small cell carcinoma of the lung.

Cell Death Dis 2021 06 4;12(6):577. Epub 2021 Jun 4.

Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, OH, 43210, USA.

Small cell lung cancer (SCLC) remains a deadly form of cancer, with a 5-year survival rate of less than 10 percent, necessitating novel therapies. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is emerging as a therapeutic target and is co-expressed with BCL2 in multiple tumor types due to microRNA coregulation. We hypothesize that ROR1-targeted therapy is effective in small cell lung cancer and synergizes with therapeutic BCL2 inhibition. Tissue microarrays (TMAs) and formalin-fixed paraffin-embedded (FFPE) SCLC patient samples were utilized to determine the prevalence of ROR1 and BCL2 expression in SCLC. Eight SCLC-derived cell lines were used to determine the antitumor activity of a small molecule ROR1 inhibitor (KAN0441571C) alone and in combination with the BCL2 inhibitor venetoclax. The Chou-Talalay method was utilized to determine synergy with the drug combination. ROR1 and BCL2 protein expression was identified in 93% (52/56) and 86% (48/56) of SCLC patient samples, respectively. Similarly, ROR1 and BCL2 were shown by qRT-PCR to have elevated expression in 79% (22/28) and 100% (28/28) of SCLC patient samples, respectively. KAN0441571C displayed efficacy in 8 SCLC cell lines, with an IC50 of 500 nM or less. Synergy as defined by a combination index of <1 via the Chou-Talalay method between KAN0441571C and venetoclax was demonstrated in 8 SCLC cell lines. We have shown that ROR1 inhibition is synergistic with BCL2 inhibition in SCLC models and shows promise as a novel therapeutic target in SCLC.
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http://dx.doi.org/10.1038/s41419-021-03855-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178315PMC
June 2021

Genetic Ancestry Affects Somatic Alterations in Lung Cancers.

Cancer Discov 2021 06;11(6):1320-1321

James Thoracic Center, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

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http://dx.doi.org/10.1158/2159-8290.CD-20-1861DOI Listing
June 2021

STK11/LKB1 Loss of Function Is Associated with Global DNA Hypomethylation and -Adenosyl-Methionine Depletion in Human Lung Adenocarcinoma.

Cancer Res 2021 08 27;81(16):4194-4204. Epub 2021 May 27.

Department of Internal Medicine, The Ohio State University, Columbus, Ohio.

STK11 (liver kinase B1, LKB1) is the fourth most frequently mutated gene in lung adenocarcinoma, with loss of function observed in up to 30% of all cases. Our previous work identified a 16-gene signature for LKB1 loss of function through mutational and nonmutational mechanisms. In this study, we applied this genetic signature to The Cancer Genome Atlas (TCGA) lung adenocarcinoma samples and discovered a novel association between LKB1 loss and widespread DNA demethylation. LKB1-deficient tumors showed depletion of -adenosyl-methionine (SAM-e), which is the primary substrate for DNMT1 activity. Lower methylation following LKB1 loss involved repetitive elements (RE) and altered RE transcription, as well as decreased sensitivity to azacytidine. Demethylated CpGs were enriched for FOXA family consensus binding sites, and nuclear expression, localization, and turnover of FOXA was dependent upon LKB1. Overall, these findings demonstrate that a large number of lung adenocarcinomas exhibit global hypomethylation driven by LKB1 loss, which has implications for both epigenetic therapy and immunotherapy in these cancers. SIGNIFICANCE: Lung adenocarcinomas with LKB1 loss demonstrate global genomic hypomethylation associated with depletion of SAM-e, reduced expression of DNMT1, and increased transcription of repetitive elements.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373682PMC
August 2021

Functional Disability Among Older Versus Younger Adults With Advanced Non-Small-Cell Lung Cancer.

JCO Oncol Pract 2021 06 3;17(6):e848-e858. Epub 2021 May 3.

Department of Psychology, The Ohio State University, Columbus, OH.

Purpose: To determine patient and disease characteristics associated with functional disability among adults with advanced non-small-cell lung cancer (NSCLC).

Methods: In a prospective cohort of participants newly diagnosed with advanced NSCLC and beginning systemic treatment, functional disability in usual activities, mobility, and self-care was measured using the EuroQol-5D-5L at baseline. Demographics, comorbidities, brain metastases, Eastern Cooperative Oncology Group performance status (ECOG PS), and psychologic variables (depression [Patient Health Questionnaire-9] and anxiety [Generalized Anxiety Disorder 7-item scale]) were captured. Patients were classified into two disability groups (none-slight or moderate-severe) on the basis of total functional status scores. Differences between disability groups were determined (chi-square and tests). Associations between patient characteristics and baseline disability were assessed using logistic regression.

Results: Among 173 participants, mean age was 63.3 years, 56% were male, 83% had ECOG PS 0-1, and 41% had brain metastases. Baseline disability was present in 39% of participants, with patients having moderate to severe disability in usual activities (37.6%), mobility (26.6%), and self-care (5.2%). Depressive and/or anxiety symptoms ranged from none to severe (Patient Health Questionnaire 9-item scale M = 6.5, SD = 5.3). Depressive symptoms were the only characteristic associated with a higher odds of baseline disability (adjusted odds ratio [aOR]: 1.26; 95% CI, 1.15 to 1.38; < .001). Participants with poorer ECOG PS (aOR: 4.64; 95% CI, 1.84 to 11.68; = .001) and depressive symptoms (aOR: 1.15; 95% CI, 1.07 to 1.24; < .001) had higher odds of moderate-severe mobility disability compared with the none-slight disability group.

Conclusion: More than one third of all adults with advanced NSCLC have moderate-severe functional disability at baseline. Psychologic symptoms were significantly associated with moderate-severe baseline disability.
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http://dx.doi.org/10.1200/OP.20.01004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258136PMC
June 2021

Bone Metastases, Skeletal-Related Events, and Survival in Patients With Metastatic Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.

J Natl Compr Canc Netw 2021 Apr 20;19(8):915-921. Epub 2021 Apr 20.

3Division of Medical Oncology, and.

Background: Bone metastases and skeletal-related events (SREs) are a frequent cause of morbidity in patients with metastatic non-small cell lung cancer (mNSCLC). Data are limited on bone metastases and SREs in patients with mNSCLC treated using immune checkpoint inhibitors (ICIs), and on the efficacy of bone-modifying agents (BMAs) in this setting. Here we report the incidence, impact on survival, risk factors for bone metastases and SREs, and impact of BMAs in patients with mNSCLC treated with ICIs in a multi-institutional cohort.

Patients And Methods: We conducted a retrospective study of patients with mNSCLC treated with ICIs at 2 tertiary care centers from 2014 through 2017. Overall survival (OS) was compared between patients with and without baseline bone metastases using a log-rank test. A Cox regression model was used to evaluate the association between OS and the presence of bone metastases at ICI initiation, controlling for other confounding factors.

Results: We identified a cohort of 330 patients who had received ICIs for metastatic disease. Median patient age was 63 years, most patients were treated in the second line or beyond (n=259; 78%), and nivolumab was the most common ICI (n=211; 64%). Median OS was 10 months (95% CI, 8.4-12.0). In our cohort, 124 patients (38%) had baseline bone metastases, and 43 (13%) developed SREs during or after ICI treatment. Patients with bone metastases had a higher hazard of death after controlling for performance status, histology, line of therapy, and disease burden (hazard ratio, 1.57; 95% CI, 1.19-2.08; P=.001). Use of BMAs was not associated with OS or a decreased risk of SREs.

Conclusions: Presence of bone metastases at baseline was associated with a worse prognosis for patients with mNSCLC treated with ICI after controlling for multiple clinical characteristics. Use of BMAs was not associated with reduced SREs or a difference in survival.
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http://dx.doi.org/10.6004/jnccn.2020.7668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752085PMC
April 2021

Predictors of Response, Progression-Free Survival, and Overall Survival in Patients With Lung Cancer Treated With Immune Checkpoint Inhibitors.

J Thorac Oncol 2021 07 9;16(7):1086-1098. Epub 2021 Apr 9.

Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio. Electronic address:

Monoclonal antibodies that target immune checkpoint proteins, so-called immune checkpoint inhibitors, prevent tumor evasion of the immune system and are often effective in the treatment of lung cancer. Studies have revealed improved objective response rates, progression-free survival, and overall survival with immune checkpoint inhibitors when used in both first and subsequent-line settings. Unfortunately, only a subset of unselected patients with lung cancer responds to these therapies. An important area of ongoing research is to identify biomarkers that can predict which patients are most likely to derive clinical benefit. This review will discuss established and emerging biomarkers from some of the clinical trials that have demonstrated the efficacy of immune checkpoint inhibitors for the treatment of both NSCLC and SCLC.
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http://dx.doi.org/10.1016/j.jtho.2021.03.017DOI Listing
July 2021

Checkpoint inhibitor immunotherapy toxicity and overall survival among older adults with advanced cancer.

J Geriatr Oncol 2021 06 21;12(5):813-819. Epub 2021 Feb 21.

Div. of Medical Oncology, Dept. of Internal Medicine, The Ohio State University Wexner Medical Center, USA. Electronic address:

Objectives: Despite growing evidence that checkpoint inhibitor immunotherapy (IO) toxicity is associated with improved treatment response, the relationship between immune-related adverse events (irAEs) and overall survival (OS) among older adults [age ≥ 70 years (y)] remains unknown. The study goal was to determine differences in OS based on age and ≥ grade 3 (G3) irAEs.

Materials And Methods: This was a retrospective cohort study of 673 patients with advanced cancer. Patients who received ≥1 dose of IO at our institution from 2011 to 2018 were eligible. The primary outcome was OS from the start of first line of IO treatment, compared between four patient groups stratified by age and ≥ G3 irAEs with adjustment for patient characteristics using a Cox proportional hazards model.

Results And Conclusion: Among all 673 patients, 35.4% were ≥ 70y, 39.8% had melanoma, and 45.6% received single-agent nivolumab. Incidence and types of ≥G3 irAEs did not differ by age. Median OS was significantly longer for all patients with ≥G3 irAEs (unadjusted 21.7 vs. 11.9 months, P = 0.007). There was no difference in OS among patients ≥70y with ≥G3 irAEs (HR 0.94, 95% CI 0.61-1.47, P = 0.79) in the multivariable analysis. Patients <70y with ≥G3 irAEs had significantly increased OS (HR 0.33, 95% CI 0.21-0.52, P < 0.001). Younger patients, but not older adults, with high-grade irAEs experience strong survival benefit. This difference may be due to the toll of irAEs themselves or the effects of treatments for irAEs, such as corticosteroids. Factors impacting OS of older adults after irAEs must be determined and optimized.
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http://dx.doi.org/10.1016/j.jgo.2021.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184608PMC
June 2021

First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial.

Lancet Oncol 2021 02 18;22(2):198-211. Epub 2021 Jan 18.

Department of Thoracic Oncology, Airway Research Center North, German Center for Lung Research, LungClinic, Grosshansdorf, Germany.

Background: First-line nivolumab plus ipilimumab has shown improved overall survival in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to investigate whether the addition of a limited course (two cycles) of chemotherapy to this combination would further enhance the clinical benefit.

Methods: This randomised, open-label, phase 3 trial was done at 103 hospitals in 19 countries. Eligible patients were aged 18 years or older with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) by an interactive web response system via permuted blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for two cycles; experimental group), or chemotherapy alone (every 3 weeks for four cycles; control group). Randomisation was stratified by tumour histology, sex, and PD-L1 expression. The primary endpoint was overall survival in all randomly assigned patients. Safety was analysed in all treated patients. Results reported here are from a pre-planned interim analysis (when the study met its primary endpoint) and an exploratory longer-term follow-up analysis. This study is active but no longer recruiting patients, and is registered with ClinicalTrials.gov, number NCT03215706.

Findings: Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles of chemotherapy (n=361 [50%]) or four cycles of chemotherapy alone (n=358 [50%]). At the pre-planned interim analysis (median follow-up 9·7 months [IQR 6·4-12·8]), overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months [95% CI 13·2-16·2] vs 10·7 months [9·5-12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55-0·87]; p=0·00065). With 3·5 months longer median follow-up (median 13·2 months [IQR 6·4-17·0]), median overall survival was 15·6 months (95% CI 13·9-20·0) in the experimental group versus 10·9 months (9·5-12·6) in the control group (HR 0·66 [95% CI 0·55-0·80]). The most common grade 3-4 treatment-related adverse events were neutropenia (in 24 [7%] patients in the experimental group vs 32 [9%] in the control group), anaemia (21 [6%] vs 50 [14%]), diarrhoea (14 [4%] vs two [1%]), increased lipase (22 [6%] vs three [1%]), and asthenia (tjree [1%] vs eight [2%]). Serious treatment-related adverse events of any grade occurred in 106 (30%) patients in the experimental group and 62 (18%) in the control group. Seven (2%) deaths in the experimental group (acute kidney failure, diarrhoea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia; one patient each) and six (2%) deaths in the control group (anaemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient each) were treatment related.

Interpretation: Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favourable risk-benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC.

Funding: Bristol Myers Squibb.
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http://dx.doi.org/10.1016/S1470-2045(20)30641-0DOI Listing
February 2021

Treatment of Non-Small-Cell Lung Cancer Based on Circulating Cell-Free DNA and Impact of Variation Allele Frequency.

Clin Lung Cancer 2021 07 2;22(4):e519-e527. Epub 2020 Dec 2.

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Comprehensive Cancer Center, Columbus, OH.

Background: Next-generation sequencing of circulating cell-free DNA (cfDNA) can identify sensitizing and resistance mutations in non-small-cell lung cancer (NSCLC). cfDNA is helpful when tissue is insufficient for genomic testing or repeat biopsy is not feasible or poses unacceptable risk. Here we report the experience of cfDNA testing at the time of diagnosis and how this intervention can help avoid further invasive interventions, how it can be used to determine initiation of therapy, and how variation allele frequency of the somatic alteration affects response to subsequent treatment.

Patients And Methods: This is a single-institution retrospective study of patients with advanced NSCLC who had cfDNA from plasma tested using the Guardant360 panel, which identifies somatic genomic alterations by massive parallel sequencing of target genes. An institutional Clinical Laboratory Improvement Amendments tissue panel using fluorescence in situ hybridization (for MET, RET, ROS1, and ALK) and next-generation sequencing for selected genes was used for tissue analysis. Actionable mutations are those with US Food and Drug Administration-approved targeted therapies (EGFR, ALK, ROS, BRAF, NTRK fusions) or therapies soon to be approved (RET fusions and MET amplifications, or MET exon 14 skipping mutation).

Results: A total of 163 blood samples from 143 patients were evaluated, 82 at diagnosis and 81 at disease progression. A total of 94 cases had tissue and cfDNA testing performed within 12 weeks of each other. Seventy-six (81%) of 94 cases were concordant, of which 22 cases were concordantly positive and 54 concordantly negative. Eighteen (19%) of 94 cases were discordant, of which 11 had negative blood and positive tissue results, and 7 had positive blood and negative tissue results. cfDNA testing had a sensitivity of 67% (95% confidence interval [CI], 51%, 83%), specificity of 89% (95% CI, 81%, 97%), negative predictive value of 83% (95% CI, 74%, 92%), and positive predictive value of 76% (95% CI, 60%, 91%). Nineteen (21%) of 82 cfDNA samples analyzed at diagnosis had actionable mutations identified (4 EGFR exon 19 deletion, 2 EGFR exon 21 L858R, 2 EGFR L861Q, 1 L861R, 4 EML4-ALK fusion, 2 CD74-ROS1 fusion, 2 MET exon 14 skipping mutation, 2 KIF5B-RET fusion). Of the 82 patients with cfDNA testing performed at the time of diagnosis, 8 patients (10%) initiated targeted therapy on the basis of cfDNA results only, with 6 patients experiencing partial response, 1 patient complete response, and 1 patient stable disease. The response rate for patients who initiated targeted therapies on the basis of cfDNA only at diagnosis was 88%. Variant allele frequency had no impact on response.

Conclusions: Initiation of targeted therapy for advanced NSCLC was feasible based only on identification of actionable mutations by cfDNA testing in 9% of the cases for which tissue diagnosis could not be obtained. Actionable targets were identified by cfDNA in 20% of the samples sent at diagnosis. A substantial number of patients benefited from cfDNA testing at initial diagnosis because it identified actionable mutations that led to appropriate targeted treatments.
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http://dx.doi.org/10.1016/j.cllc.2020.11.007DOI Listing
July 2021

Whole-brain radiotherapy with and without concurrent erlotinib in NSCLC with brain metastases: a multicenter, open-label, randomized, controlled phase III trial.

Neuro Oncol 2021 06;23(6):967-978

Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Medical Center, Columbus, Ohio, USA.

Background: Erlotinib combined with whole-brain radiotherapy (WBRT) demonstrated a favorable objective response rate in a phase II single-arm trial of non-small cell lung cancer (NSCLC) patients with brain metastases. We assessed whether concurrent erlotinib with WBRT is safe and benefits patients in a phase III, randomized trial.

Methods: NSCLC patients with two or more brain metastases were enrolled and randomly assigned (1:1) to WBRT (n = 115) or WBRT combined with erlotinib arms (n = 109). The primary endpoint was intracranial progression-free survival (iPFS) and cognitive function (CF) was assessed by the Mini-Mental State Examination (MMSE).

Results: A total of 224 patients from 10 centers across China were randomized to treatments. Median follow-up was 11.2 months. Median iPFS for WBRT concurrent erlotinib was 11.2 months vs 9.2 months for WBRT-alone (P = .601). Median PFS and overall survival (OS) of combination group were 5.3 vs 4.0 months (P = .825) and 12.9 vs 10.0 months (P = .545), respectively, compared with WBRT-alone. In EGFR-mutant patients, iPFS (14.6 vs 12.8 months; P = .164), PFS (8.8 vs 6.4 months; P = .702), and OS (17.5 vs 16.9 months; P = .221) were not significantly improved in combination group over WBRT-alone. Moreover, there were no significant differences in patients experiencing MMSE score change between the treatments.

Conclusion: Concurrent erlotinib with WBRT didn't improve iPFS and excessive CF detriment either in the intent-to-treat (ITT) population or in EGFR-mutant patients compared with WBRT-alone, suggesting that while safe for patients already taking the drug, there is no justification for adding concurrent EGFR-TKI with WBRT for the treatment of brain metastases. Trial registration: Clinical trials.gov identifier: NCT01887795.
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http://dx.doi.org/10.1093/neuonc/noaa281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168818PMC
June 2021

Cost-Effectiveness Analysis of Nivolumab Plus Ipilimumab vs. Chemotherapy as First-Line Therapy in Advanced Non-Small Cell Lung Cancer.

Front Oncol 2020 8;10:1649. Epub 2020 Sep 8.

Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.

The CheckMate 227 trial has indicated that nivolumab plus ipilimumab compared with chemotherapy significantly increases long-term survival in the first-line setting of advanced non-small-cell lung cancer (NSCLC). A Markov model was built to estimate the cost and effectiveness of nivolumab plus ipilimumab vs. chemotherapy as the first-line therapy in patients with advanced NSCLC based on outcomes data from the CheckMate 227 trial. We calculated the cost and health outcomes at a willingness-to-pay (WTP) threshold of $150,000 per quality adjusted life year (QALY) in populations with different programmed death ligand 1 (PD-L1) expression levels (≥50, ≥1, and <1%) or a high tumor mutational burden (TMB) (≥10 mutations per megabase). Sensitivity analysis were used to test the model stability. The outcomes showed that the incremental costs and QALYs by using nivolumab plus ipilimumab were $124180.76 and 1.16, $70951.42 and 0.53, $144093.63 and 0.83 for the advanced NSCLC patients with a PD-L1 expression ≥50%, ≥1%, and <1%, which led to an incremental cost-effective ratio (ICER) of $107403.72, $133732.20, and $172589.15 per QALY, respectively. For patients with a high TMB, nivolumab plus ipilimumab contributed an extra 2.04 QALYs at a cost of $69182.50 per QALY. Nivolumab plus ipilimumab as first-line therapy makes a better cost-effective strategy than chemotherapy in advanced NSCLC patients with PD-L1 expression levels ≥50% and ≥1% or a high TMB, at a willingness-to-pay threshold of $150,000 per QALY, but not in the patients with a PD-L1 expression <1%.
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http://dx.doi.org/10.3389/fonc.2020.01649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507990PMC
September 2020

Specific Targeting of Notch Ligand-Receptor Interactions to Modulate Immune Responses: A Review of Clinical and Preclinical Findings.

Front Immunol 2020 14;11:1958. Epub 2020 Aug 14.

Department of Internal Medicine, James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, United States.

Understanding and targeting Notch signaling effectively has long been valued in the field of cancer and other immune disorders. Here, we discuss key discoveries at the intersection of Notch signaling, cancer and immunology. While there is a plethora of Notch targeting agents tested , and in clinic, undesirable off-target effects and therapy-related toxicities have been significant obstacles. We make a case for the clinical application of ligand-derived and affinity modifying compounds as novel therapeutic agents and discuss major research findings with an emphasis on Notch ligand-specific modulation of immune responses.
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http://dx.doi.org/10.3389/fimmu.2020.01958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456812PMC
April 2021

Phase II Study of Immunotherapy With Tecemotide and Bevacizumab After Chemoradiation in Patients With Unresectable Stage III Non-Squamous Non-Small-Cell Lung Cancer (NS-NSCLC): A Trial of the ECOG-ACRIN Cancer Research Group (E6508).

Clin Lung Cancer 2020 11 12;21(6):520-526. Epub 2020 Jun 12.

Inova Cancer Institute, Fairfax, VA.

Introduction: Although chemoradiotherapy (CRT) is the standard of care for patients with unresectable stage III non-small-cell lung cancer (LA-NSCLC), most patients relapse. Tecemotide is a MUC1 antigen-specific cancer immunotherapy vaccine. Bevacizumab improves survival in advanced nonsquamous (NS)-NSCLC and has a role in immune modulation. This phase II trial tested the combination of tecemotide and bevacizumab following CRT in patients with LA-NSCLC.

Patients And Methods: Subjects with stage III NS-NSCLC suitable for CRT received carboplatin/paclitaxel weekly + 66 Gy followed by 2 cycles of consolidation carboplatin/paclitaxel ≤ 4 weeks of completion of CRT (Step 1). Patients with partial response/stable disease after consolidation therapy were registered onto step 2, which was 6 weekly tecemotide injections followed by every 6 weekly injections and bevacizumab every 3 weeks for up to 34 doses. The primary endpoint was to determine the safety of this regimen.

Results: Seventy patients were enrolled; 68 patients (median age, 63 years; 56% male; 57% stage IIIA) initiated therapy, but only 39 patients completed CRT and consolidation therapy per protocol, primarily owing to disease progression or toxicity. Thirty-three patients (median age, 61 years; 58% male; 61% stage IIIA) were registered to step 2 (tecemotide + bevacizumab). The median number of step 2 cycles received was 11 (range, 2-25). Step 2 worst toxicity included grade 3, N = 9; grade 4, N = 1; and grade 5, N = 1. Grade 5 toxicity in step 2 was esophageal perforation attributed to bevacizumab. Among the treated and eligible patients (n = 32) who were treated on step 2, the median overall survival was 42.7 months (95% confidence interval, 21.7-63.3 months), and the median progression-free survival was 14.9 months (95% confidence interval, 11.0-20.9 months) from step 1 registration.

Conclusions: This cooperative group trial met its endpoint, demonstrating tolerability of bevacizumab + tecemotide after CRT and consolidation. In this selected group of patients, the median progression-free survival and overall survival are encouraging. Given that consolidation immunotherapy is now a standard of care following CRT in patients with LA-NSCLC, these results support a role for continued investigation of antiangiogenic and immunotherapy combinations in LA-NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2020.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606595PMC
November 2020

Verification of a Blood-Based Targeted Proteomics Signature for Malignant Pleural Mesothelioma.

Cancer Epidemiol Biomarkers Prev 2020 10 30;29(10):1973-1982. Epub 2020 Jul 30.

James Thoracic Center, James Cancer Center, The Ohio State University Medical Center, Columbus, Ohio.

Background: We have verified a mass spectrometry (MS)-based targeted proteomics signature for the detection of malignant pleural mesothelioma (MPM) from the blood.

Methods: A seven-peptide biomarker MPM signature by targeted proteomics in serum was identified in a previous independent study. Here, we have verified the predictive accuracy of a reduced version of that signature, now composed of six-peptide biomarkers. We have applied liquid chromatography-selected reaction monitoring (LC-SRM), also known as multiple-reaction monitoring (MRM), for the investigation of 402 serum samples from 213 patients with MPM and 189 cancer-free asbestos-exposed donors from the United States, Australia, and Europe.

Results: Each of the biomarkers composing the signature was independently informative, with no apparent functional or physical relation to each other. The multiplexing possibility offered by MS proteomics allowed their integration into a single signature with a higher discriminating capacity than that of the single biomarkers alone. The strategy allowed in this way to increase their potential utility for clinical decisions. The signature discriminated patients with MPM and asbestos-exposed donors with AUC of 0.738. For early-stage MPM, AUC was 0.765. This signature was also prognostic, and Kaplan-Meier analysis showed a significant difference between high- and low-risk groups with an HR of 1.659 (95% CI, 1.075-2.562; = 0.021).

Conclusions: Targeted proteomics allowed the development of a multianalyte signature with diagnostic and prognostic potential for MPM from the blood.

Impact: The proteomic signature represents an additional diagnostic approach for informing clinical decisions for patients at risk for MPM.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541795PMC
October 2020

Brief report: inhaled corticosteroid use and the risk of checkpoint inhibitor pneumonitis in patients with advanced cancer.

Cancer Immunol Immunother 2020 Nov 29;69(11):2403-2408. Epub 2020 Jul 29.

Division of Medical Oncology, The Ohio State University, 320 W 10th Ave, Columbus, OH, USA.

Background: Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that may complicate treatment with immune checkpoint inhibitors (ICI) and can cause significant morbidity. We sought to identify predictors for the development of CIP, and whether the use of inhaled corticosteroids (ICS) at time of ICI may be protective.

Methods: Patients with advanced cancer treated with ICI from 2011 and 2018 were included in this study. CIP attribution to ICI was determined by treating physician at time of diagnosis. Predictors were assessed by univariate and multivariable Cox proportional hazard models.

Results: We identified 837 pts treated with ICI, of whom 30 (3.6%) developed grade 2 or higher CIP. 82 patients (9.8%) were receiving ICS at time of ICI and had increased risk of developing CIP with hazard ration (HR) of 4.22 (95% CI 1.93-9.21, p < 0.001) compared to those patients not receiving ICS. Patients with age ≥ 65 years had increased risk of developing CIP (HR 2.12, 95% CI 1.02-4.40, p = 0.044), as did 209 patients with lung cancer (198 NSCLC and 11 SCLC) compared to other types of cancers (HR 3.15, 95% CI 1.54-6.46, p = 0.002). In multivariable analysis, age ≥ 65 years, lung cancer diagnosis, and ICS use remained statistically associated with the development of CIP, with adjusted HR for ICS 3.09 (95% CI 1.32-7.24, p = 0.009).

Conclusions: Patients treated with ICS at time of ICI initiation had an increased risk of developing CIP. We further identified older adults with age ≥ 65 years and lung cancers as independent risk factors for CIP.
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http://dx.doi.org/10.1007/s00262-020-02674-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572636PMC
November 2020

Circulating MicroRNAs and Extracellular Vesicle-Containing MicroRNAs as Response Biomarkers of Anti-programmed Cell Death Protein 1 or Programmed Death-Ligand 1 Therapy in NSCLC.

J Thorac Oncol 2020 11 19;15(11):1773-1781. Epub 2020 Jun 19.

Division of Medical Oncology, Department of Internal Medicine, James Thoracic Center, The Ohio State University, Columbus, Ohio; The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. Electronic address:

Introduction: Anti-programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) antibody therapy is a standard treatment for advanced NSCLC, and PD-L1 immunohistochemistry is used as a predictive biomarker for therapeutic response. However, because not all patients with NSCLC with high PD-L1 respond, and some patients with low PD-L1 expression exhibit durable benefit, more accurate predictive biomarkers are needed. Circulating microRNA (miRNA) and miRNA packaged in extracellular vesicles (EVs) are believed to play a role in intercellular communication among immune cells and between immune cells and tumor cells and may represent a good source of mechanism-related biomarkers.

Methods: Pretreatment plasma of patients with advanced NSCLC treated with single-agent anti-PD-1 or anti-PD-L1 antibody was used in this study. Plasma EVs were isolated using size-exclusion chromatography. Whole plasma and EV-containing RNAs were extracted. The miRNA profile was analyzed with a next-generation sequencing platform.

Results: Samples from 14 responders (patients who exhibited partial response or stable disease ≥6 mo) and 15 nonresponders (patients who exhibited progressive disease as per Response Evaluation Criteria in Solid Tumors) were analyzed. In total, 32 miRNAs (p = 0.0030-0.0495) from whole plasma and seven EV-associated miRNAs (p = 0.041-0.0457) exhibited significant concentration differences between responders and nonresponders. The results of some of these circulating miRNAs were validated in a separate cohort with eight responders and 13 nonresponders. The tumor PD-L1 level was also assessed using immunohistochemistry for patients involved in both cohorts.

Conclusions: Specific circulating miRNAs in whole plasma and plasma EVs are differentially expressed between responders and nonresponders and have potential as predictive biomarkers for anti-PD-1/PD-L1 treatment response.
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http://dx.doi.org/10.1016/j.jtho.2020.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641981PMC
November 2020

Clinical and Molecular Correlates of Tumor Mutation Burden in Non-Small Cell Lung Cancer.

Lung Cancer 2020 08 21;146:36-41. Epub 2020 May 21.

The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, United States. Electronic address:

Introduction: Recent clinical studies have identified tumor mutation burden (TMB) as a promising therapeutic biomarker of anti-tumor immune checkpoint blockade. However, given the relatively slow turnaround time and high expense in measuring TMB, tobacco smoking history (TSH) is an attractive replacement biomarker. The carcinogenic effects of tobacco smoking may be modified by the protective effects of genome stability genes. This study aims to test the associations between tobacco smoking, genome stability gene inactivation, and TMB.

Methods: Publicly available TSH and DNA somatic alteration data from NSCLC were downloaded from The Cancer Genome Atlas. Correlations and enrichments were calculated with Spearman and Fisher's exact test methods, respectively. Multivariate modeling of TMB was performed with penalized linear regression.

Results: 85% of never smokers in adenocarcinomas (LUAD) had low TMB, but a positive TSH was not predictive of hypermutancy. The limited utility of TSH in predicting TMB was reproduced on an independent LUAD dataset. To expand our search for predictors of TMB, we further investigated the contributions of genome stability related genes (GSGs) to TMB. 242/461 (52%) and 300/465 (65%) patients with LUAD and squamous carcinomas (LUSC), respectively, showed evidence of loss of function in at least one of the 182 GSGs. 182 GSGs from 16 pathways were assessed for associations with TMB high tumor status using Fisher's exact test. We performed univariate gene and pathway enrichments in TMB high tumors and found roles forPOLE, REV3L, and FANCE genes, as well as several key GSG pathways.

Conclusions: This study comprehensively tested the association between GSG, tobacco smoking, and TMB in NSCLC. In LUAD, never-smoking status was predictive of low TMB, but overall TSH was not an adequate surrogate biomarker for TMB in NSCLC. Furthermore, we identified an association between GSG inactivation and TMB.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.021DOI Listing
August 2020

Inferring the role of the microbiome on survival in patients treated with immune checkpoint inhibitors: causal modeling, timing, and classes of concomitant medications.

BMC Cancer 2020 May 6;20(1):383. Epub 2020 May 6.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

Background: The microbiome has been shown to affect the response to Immune Checkpoint Inhibitors (ICIs) in a small number of cancers and in preclinical models. Here, we sought to broadly survey cancers to identify those in which the microbiome may play a prognostic role using retrospective analyses of patients with advanced cancer treated with ICIs.

Methods: We conducted a retrospective analysis of 690 patients who received ICI therapy for advanced cancer. We used a literature review to define a causal model for the relationship between medications, the microbiome, and ICI response to guide the abstraction of electronic health records. Medications with precedent for changes to the microbiome included antibiotics, corticosteroids, proton pump inhibitors, histamine receptor blockers, non-steroid anti-inflammatories and statins. We tested the effect of medication timing on overall survival (OS) and evaluated the robustness of medication effects in each cancer. Finally, we compared the size of the effect observed for different classes of antibiotics to taxa that have been correlated to ICI response using a literature review of culture-based antibiotic susceptibilities.

Results: Of the medications assessed, only antibiotics and corticosteroids significantly associated with shorter OS. The hazard ratios (HRs) for antibiotics and corticosteroids were highest near the start of ICI treatment but remained significant when given prior to ICI. Antibiotics and corticosteroids remained significantly associated with OS even when controlling for multiple factors such as Eastern Cooperative Oncology Group performance status, Charlson Comorbidity Index score, and stage. When grouping antibiotics by class, β-lactams showed the strongest association with OS across all tested cancers.

Conclusions: The timing and strength of the correlations with antibiotics and corticosteroids after controlling for confounding factors are consistent with the microbiome involvement with the response to ICIs across several cancers.
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http://dx.doi.org/10.1186/s12885-020-06882-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201618PMC
May 2020
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