Publications by authors named "Isa Mambetsariev"

43 Publications

Utility of Circulating Tumor DNA in Identifying Somatic Mutations and Tracking Tumor Evolution in Patients with Non-small Cell Lung Cancer.

Chest 2021 Apr 17. Epub 2021 Apr 17.

City of Hope Comprehensive Cancer Center, Duarte, CA 91010. Electronic address:

Background: The utility of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC).

Research Question: How does the utility of circulating tumor DNA (ctDNA) compare to that of solid tumor biopsy in non-small cell lung cancer (NSCLC) patients?

Methods: We retrospectively evaluated 370 adult NSCLC patients treated at the City of Hope between November 2015 and August 2019 to assess the utility of ctDNA in mutation identification, survival, concordance with matched tissue samples in thirty-two genes, and tumor evolution.

Results: A total of 1688 somatic mutations were detected in 473 ctDNA samples from 370 NSCLC patients. Of the 473 samples, 177 had at least one actionable mutation with currently available FDA-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rates [FDR] < 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR = 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR] 0.56, 95% CI: 0.37-0.85, p = 0.006). Overall survival was shorter in BRAF (HR 2.35, 95% CI: 1.24-4.6, p = 0.009, PIK3CA (HR 2.77, 95% CI: 1.56-4.9, P< 0.001 and KRAS-positive patients (HR 2.32, 95% CI: 1.30-4.1, P= 0.004). Gene-level concordance was 93.8% while the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsies. Treatment response and tumor evolution over time were detected in repeated ctDNA samples.

Interpretation: Although ctDNA exhibited similar utility to tissue biopsies, more mutations in targetable genes were missed in tissue biopsies. Therefore, the evaluation of ctDNA in conjunction with tissue biopsies may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC.
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http://dx.doi.org/10.1016/j.chest.2021.04.016DOI Listing
April 2021

Predicting Survival Duration With MRI Radiomics of Brain Metastases From Non-small Cell Lung Cancer.

Front Oncol 2021 5;11:621088. Epub 2021 Mar 5.

Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA, United States.

Brain metastases are associated with poor survival. Molecular genetic testing informs on targeted therapy and survival. The purpose of this study was to perform a MR imaging-based radiomic analysis of brain metastases from non-small cell lung cancer (NSCLC) to identify radiomic features that were important for predicting survival duration. We retrospectively identified our study cohort via an institutional database search for patients with brain metastases from EGFR, ALK, and/or KRAS mutation-positive NSCLC. We segmented the brain metastatic tumors on the brain MR images, extracted radiomic features, constructed radiomic scores from significant radiomic features based on multivariate Cox regression analysis ( < 0.05), and built predictive models for survival duration. Of the 110 patients in the cohort (mean age 57.51 ± 12.32 years; range: 22-85 years, M:F = 37:73), 75, 26, and 15 had NSCLC with EGFR, ALK, and KRAS mutations, respectively. Predictive modeling of survival duration using both clinical and radiomic features yielded areas under the receiver operative characteristic curve of 0.977, 0.905, and 0.947 for the EGFR, ALK, and KRAS mutation-positive groups, respectively. Radiomic scores enabled the separation of each mutation-positive group into two subgroups with significantly different survival durations, i.e., shorter vs. longer duration when comparing to the median survival duration of the group. Our data supports the use of radiomic scores, based on MR imaging of brain metastases from NSCLC, as non-invasive biomarkers for survival duration. Future research with a larger sample size and external cohorts is needed to validate our results.
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http://dx.doi.org/10.3389/fonc.2021.621088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973105PMC
March 2021

Therapeutic Potential of Olaparib in Combination With Pembrolizumab in a Young Patient With a Maternally Inherited BRCA2 Germline Variant: A Research Report.

Clin Lung Cancer 2021 Jan 27. Epub 2021 Jan 27.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA. Electronic address:

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http://dx.doi.org/10.1016/j.cllc.2021.01.009DOI Listing
January 2021

Durvalumab for Stage III EGFR-Mutated NSCLC After Definitive Chemoradiotherapy.

J Thorac Oncol 2021 Feb 12. Epub 2021 Feb 12.

Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California. Electronic address:

Introduction: In 2018, durvalumab was approved by the U.S. Food and Drug Administration as consolidation immunotherapy for patients with stage III NSCLC after definitive chemoradiotherapy (CRT). However, whether durvalumab benefits patients with EGFR-mutated NSCLC remains unknown.

Methods: We conducted a multi-institutional retrospective analysis of patients with unresectable stage III EGFR-mutated NSCLC who completed concurrent CRT. Kaplan-Meier analyses evaluated progression-free survival (PFS) between patients who completed CRT with or without durvalumab.

Results: Among 37 patients, 13 initiated durvalumab a median of 20 days after CRT completion. Two patients completed 12 months of treatment, with five patients discontinuing durvalumab owing to progression and five owing to immune-related adverse events (irAEs). Of 24 patients who completed CRT without durvalumab, 16 completed CRT alone and eight completed CRT with induction or consolidation EGFR tyrosine kinase inhibitors (TKIs). Median PFS was 10.3 months in patients who received CRT and durvalumab versus 6.9 months with CRT alone (log-rank p = 0.993). CRT and EGFR TKI was associated with a significantly longer median PFS (26.1 mo) compared with CRT and durvalumab or CRT alone (log-rank p = 0.023). Six patients treated with durvalumab initiated EGFR TKIs after recurrence, with one developing grade 4 pneumonitis on osimertinib.

Conclusions: In this study, patients with EGFR-mutated NSCLC did not benefit with consolidation durvalumab and experienced a high frequency of irAEs. Patients who initiate osimertinib after durvalumab may be susceptible to incident irAEs. Consolidation durvalumab should be approached with caution in this setting and concurrent CRT with induction or consolidation EGFR TKIs further investigated as definitive treatment.
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http://dx.doi.org/10.1016/j.jtho.2021.01.1628DOI Listing
February 2021

The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC).

Cell Rep Med 2021 Jan 19;2(1):100186. Epub 2021 Jan 19.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

KRAS is a frequent oncogenic driver in solid tumors, including non-small cell lung cancer (NSCLC). It was previously thought to be an "undruggable" target due to the lack of deep binding pockets for specific small-molecule inhibitors. A better understanding of the mechanisms that drive KRAS transformation, improved KRAS-targeted drugs, and immunological approaches that aim at yielding immune responses against KRAS neoantigens have sparked a race for approved therapies. Few treatments are available for KRAS mutant NSCLC patients, and several approaches are being tested in clinicals trials to fill this void. Here, we review promising therapeutics tested for KRAS mutant NSCLC.
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http://dx.doi.org/10.1016/j.xcrm.2020.100186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817862PMC
January 2021

Co-stimulatory and co-inhibitory immune markers in solid tumors with alterations.

Future Sci OA 2020 Nov 25;7(2):FSO662. Epub 2020 Nov 25.

Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA.

The implication of alterations in solid tumors and the immune microenvironment remains elusive. Formalin-fixed, paraffin-embedded samples of 21 patients with solid tumors harboring alterations were used for immunohistochemical staining. Extracted RNA was analyzed with the NanoString nCounter human PanCancer immune profiling panel (NanoString Technologies, Inc., WA, USA). Patients were diagnosed with lung (n = 10), breast (n = 5), genitourinary (n = 3) or colorectal cancer (n = 3). Eleven had a missense mutation, four had an exon 14 splice site mutation and six had amplification. , , , , , and genes were significantly differentially expressed in -altered cancers. alterations may have a role in various solid tumors as potential therapeutic targets and combination therapy candidates with immune checkpoint inhibitors.
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http://dx.doi.org/10.2144/fsoa-2020-0159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787173PMC
November 2020

Prolonged survival and response to tepotinib in a non-small-cell lung cancer patient with brain metastases harboring exon 14 mutation: a research report.

Cold Spring Harb Mol Case Stud 2020 12 17;6(6). Epub 2020 Dec 17.

Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California 91010, USA.

Tyrosine kinase inhibitors (TKIs) have transformed the standard of care in lung cancer. A number of TKIs have been discovered that specifically target oncogenes, including MET receptor tyrosine kinase. Second-generation MET TKIs are showing improved efficacy over first-generation TKIs. Herein, we report a case of a patient with metastatic lung adenocarcinoma harboring a exon 14 splice site mutation who has had prolonged disease control by a second-generation MET-TKI tepotinib. A 66-yr-old man was diagnosed with stage IV lung adenocarcinoma. He was started on carboplatin, paclitaxel, and bevacizumab, but had severe toxicity. He was switched to pembrolizumab as his tumor was PD-L1 70%, and molecular testing was not yet performed because of insufficient tissue. A bronchoscopy with endobronchial ultrasound was performed and a exon 14 splice site mutation was detected by next-generation sequencing. Upon progression, he was then enrolled in a clinical trial of tepotinib and continues with stable disease for more than 45 cycles and 31 mo. The MET receptor tyrosine kinase and the ligand hepatocyte growth factor (HGF) have been implicated as oncogenes and drivers of non-small-cell lung cancer (NSCLC). Newer MET TKIs including capmatinib and tepotinib more recently showed not only improved localized control and response, but early data suggests intracranial activity as compared to first-generation MET TKIs, both in the front-line and the refractory setting. This is a case report demonstrating an effective duration of response in a patient with widely metastatic lung adenocarcinoma harboring a MET exon 14 mutation.
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http://dx.doi.org/10.1101/mcs.a005785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784494PMC
December 2020

Activation of EPHA2-ROBO1 Heterodimer by SLIT2 Attenuates Non-canonical Signaling and Proliferation in Squamous Cell Carcinomas.

iScience 2020 Nov 16;23(11):101692. Epub 2020 Oct 16.

Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA.

The tyrosine kinase receptor ephrin receptor A2 (EPHA2) is overexpressed in lung (LSCC) and head and neck (HNSCC) squamous cell carcinomas. Although EPHA2 can inhibit tumorigenesis in a ligand-dependent fashion via phosphorylation of Y588 and Y772, it can promote tumorigenesis in a ligand-independent manner via phosphorylation of S897. Here, we show that EPHA2 and Roundabout Guidance Receptor 1 (ROBO1) interact to form a functional heterodimer. Furthermore, we show that the ROBO1 ligand Slit Guidance Ligand 2 (SLIT2) and ensartinib, an inhibitor of EPHA2, can attenuate growth of HNSCC cells and act synergistically in LSCC cells. Our results suggest that patients with LSCC and HNSCC may be stratified and treated based on their EPHA2 and ROBO1 expression patterns. Although ~73% of patients with LSCC could benefit from SLIT2+ensartinib treatment, ~41% of patients with HNSCC could be treated with either SLIT2 or ensartinib. Thus, EPHA2 and ROBO1 represent potential LSCC and HNSCC theranostics.
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http://dx.doi.org/10.1016/j.isci.2020.101692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644594PMC
November 2020

Hyperprogression on immunotherapy with complete response to chemotherapy in a NSCLC patient with high PD-L1 and STK11: A case report.

Medicine (Baltimore) 2020 Nov;99(46):e22323

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA.

Rationale: Patients reporting high PD-L1 expression have shown to respond well to immunotherapy; however, some patients develop hyperprogressive disease upon initiation of immune checkpoint inhibitors. We report a patient with lung cancer and 100% PD-L1 expression who developed hyperprogressive disease while treated with pembrolizumab and responded well to salvage chemotherapy with carboplatin and pemetrexed.

Patient Concerns: A 66-year-old African American female with 25-pack year smoking history, diabetes mellitus type 2, essential thrombocytosis, and a history of papillary thyroid carcinoma developed relapsed lung adenocarcinoma after 13 months of no evidence of disease.

Diagnosis: Surveillance imagine showed subcarinal and hilar lymphadenopathy, which was confirmed as recurrent lung adenocarcinoma via bronchoscopy. In addition, a brain scan showed a 5 mm enhancing left insular lesion. PD-L1 was reported as 100% expression. Staging was reported as stage IVB TxN3M1c lung adenocarcinoma.

Interventions: One fraction of radiation with a total dose of 20 Gray was delivered to the left insular lesion. The patient initiated pembrolizumab (200 mg) every 3 weeks. She was then treated with salvage chemotherapy consisting of carboplatin (AUC 5) and pemetrexed (500 mg/m) every 3 weeks for 3 cycles.

Outcomes: The brain lesion resolved after the radiation therapy. The patient developed hyperprogression with a large pericardial effusion and right pleural effusion after 2 treatments of pembrolizumab. Her PD-L1 expression decreased from 100% to 0% over a 10-week period. Salvage chemotherapy with carboplatin and pemetrexed resulted with 20 months of ongoing to evidence of disease.

Lessons: Immune checkpoint inhibitor-related hyperprogressive disease may respond to second-line salvage chemotherapy. Complete PD-L1 expression loss was observed after the patient's treatment and could be a marker of hyperprogressive disease or tumor immunoevasion.
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http://dx.doi.org/10.1097/MD.0000000000022323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668523PMC
November 2020

Rapid progression of disease from immunotherapy following targeted therapy: insights into treatment management and sequence.

J Thorac Dis 2020 Sep;12(9):5096-5103

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.

With emerging promising therapeutic regimens in non-small cell lung cancer (NSCLC), the standard-of-care treatments for a variety of histologic and mutated subgroups in NSCLC has been regularly shifting in response to landmark clinical trials. However, with the availability of a range of therapeutic agents, clear grouping of patient populations to appropriate treatment strategies is essential. In this review, we illustrate past and current treatment strategies in NSCLC, specifically focusing on targeted therapy and immunotherapy. We describe a complex clinical scenario that oncologists will encounter of patients with multiple actionable mutations such as epidermal growth factor receptor (EGFR) sensitizing mutations and high expression of programmed death-ligand 1 (PD-L1). Recent data regarding sequential therapy of EGFR tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) demonstrate severe adverse interactions between the therapies that impact patient quality-of-life and outcomes. As we enter further into an era of personalized and precision medicine, guidelines and standard-of-care therapies are essential to define separate patient groups based on molecular testing, histology, comorbidities, and more. This article explores the current status of generally understudied patient groups in NSCLC and proposes future directions in therapeutic strategies.
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http://dx.doi.org/10.21037/jtd.2019.08.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578509PMC
September 2020

Role of immunotherapy and co-mutations on KRAS-mutant non-small cell lung cancer survival.

J Thorac Dis 2020 Sep;12(9):5086-5095

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.

Background: mutations reported in non-small cell lung cancer (NSCLC) represent a significant percentage of patients diagnosed with NSCLC. However, there still remains no therapeutic option designed to target KRAS. In an era with immunotherapy as a dominant treatment option in metastatic NSCLC, the role of immunotherapy in.

Kras: mutated patients is not clear.

Methods: Eligible patients diagnosed with NSCLC and found to have a mutation were identified in an institutional lung cancer database. Demographic, clinical, and molecular data was collected and analyzed.

Results: A total of 60 patients were identified for this retrospective analysis. Majority of patients were Caucasian (73%), diagnosed with stage IV (70%) adenocarcinoma (87%), and had a codon 12 mutation (78%). Twenty percent of patients were treated with immunotherapy. Median overall survival was 28 months in the cohort and patients who received immunotherapy were found to have better survival versus those who did not (33 22 months, P=0.31). Furthermore, there was an association between high survival and patients who received immunotherapy (P=0.007).

Conclusions: Patients with mutations have a unique co-mutation phenotype that requires further investigation. Immunotherapy seems to be an effective choice of treatment for KRAS positive patients in any treatment-line setting and yields better outcomes than conventional chemotherapy. The relationship between immunotherapy and mutations requires further studies to confirm survival advantage.
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http://dx.doi.org/10.21037/jtd.2020.04.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578487PMC
September 2020

A Non-genetic Mechanism Involving the Integrin β4/Paxillin Axis Contributes to Chemoresistance in Lung Cancer.

iScience 2020 Aug 22;23(9):101496. Epub 2020 Aug 22.

Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010-3000, USA. Electronic address:

Tumor heterogeneity and cisplatin resistance are major causes of tumor relapse and poor survival. Here, we show that in lung cancer, interaction between paxillin (PXN) and integrin β4 (ITGB4), components of the focal adhesion (FA) complex, contributes to cisplatin resistance. Knocking down PXN and ITGB4 attenuated cell growth and improved cisplatin sensitivity, both in 2D and 3D cultures. PXN and ITGB4 independently regulated expression of several genes. In addition, they also regulated expression of common genes including USP1 and VDAC1, which are required for maintaining genomic stability and mitochondrial function, respectively. Mathematical modeling suggested that bistability could lead to stochastic phenotypic switching between cisplatin-sensitive and resistant states in these cells. Consistently, purified subpopulations of sensitive and resistant cells re-created the mixed parental population when cultured separately. Altogether, these data point to an unexpected role of the FA complex in cisplatin resistance and highlight a novel non-genetic mechanism.
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http://dx.doi.org/10.1016/j.isci.2020.101496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502350PMC
August 2020

Progressive Neurologic Changes in a Patient With Metastatic Non-Small-Cell Lung Cancer: Cancer Effects or a Secondary Diagnosis?

JCO Oncol Pract 2021 Jan 9;17(1):52-53. Epub 2020 Jul 9.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA.

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http://dx.doi.org/10.1200/JOP.19.00701DOI Listing
January 2021

Evaluation of Omics-Based Strategies for the Management of Advanced Lung Cancer.

JCO Oncol Pract 2021 Feb 8;17(2):e257-e265. Epub 2020 Jul 8.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA.

Purpose: Omic-informed therapy is being used more frequently for patients with non-small-cell lung cancer (NSCLC) being treated on the basis of evidence-based decision-making. However, there is a lack of a standardized framework to evaluate those decisions and understand the association between omics-based management strategies and survival among patients. Therefore, we compared outcomes between patients with lung adenocarcinoma who received omics-driven targeted therapy versus patients who received standard therapeutic options.

Patients And Methods: This was a retrospective study of patients with advanced NSCLC adenocarcinoma (N = 798) at City of Hope who received genomic sequencing at the behest of their treating oncologists. A thoracic oncology registry was used as a clinicogenomic database to track patient outcomes.

Results: Of 798 individuals with advanced NSCLC (median age, 65 years [range, 22-99 years]; 60% white; 50% with a history of smoking), 662 patients (83%) had molecular testing and 439 (55%) received targeted therapy on the basis of the omic-data. A fast-and-frugal decision tree (FFT) model was developed to evaluate the impact of omics-based strategy on decision-making, progression-free survival (PFS), and overall survival (OS). We calculated that the overall positive predictive value of the entire FFT strategy for predicting decisions regarding the use of tyrosine kinase inhibitor-based targeted therapy was 88% and the negative predictive value was 96%. In an adjusted Cox regression analysis, there was a significant correlation with survival benefit with the FFT omics-driven therapeutic strategy for both PFS (hazard ratio [HR], 0.56; 95% CI, 0.42 to 0.74; < .001) and OS (HR, 0.51; 95% CI, 0.36 to 0.71; < .001) as compared with standard therapeutic options.

Conclusion: Among patients with advanced NSCLC who received care in the academic oncology setting, omics-driven therapy decisions directly informed treatment in patients and was correlated with better OS and PFS.
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http://dx.doi.org/10.1200/OP.20.00117DOI Listing
February 2021

MET receptor in oncology: From biomarker to therapeutic target.

Adv Cancer Res 2020 17;147:259-301. Epub 2020 Jun 17.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States. Electronic address:

First discovered in the 1984, the MET receptor tyrosine kinase (RTK) and its ligand hepatocyte growth factor or HGF (also known as scatter factor or SF) are implicated as key players in tumor cell migration, proliferation, and invasion in a variety of cancers. This pathway also plays a key role during embryogenesis in the development of muscular and nervous structures. High expression of the MET receptor has been shown to correlate with poor prognosis and resistance to therapy. MET exon 14 splicing variants, initially identified by us in lung cancer, is actionable through various tyrosine kinase inhibitors (TKIs). For this reason, this pathway is of interest as a therapeutic target. In this chapter we will be discussing the history of MET, the genetics of this RTK, and give some background on the receptor biology. Furthermore, we will discuss directed therapeutics, mechanisms of resistance, and the future of MET as a therapeutic target.
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http://dx.doi.org/10.1016/bs.acr.2020.04.006DOI Listing
September 2020

Complex Oncological Decision-Making Utilizing Fast-and-Frugal Trees in a Community Setting-Role of Academic and Hybrid Modeling.

J Clin Med 2020 Jun 16;9(6). Epub 2020 Jun 16.

Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA.

Non-small cell lung cancer is a devastating disease and with the advent of targeted therapies and molecular testing, the decision-making process has become complex. While established guidelines and pathways offer some guidance, they are difficult to utilize in a busy community practice and are not always implemented in the community. The rationale of the study was to identify a cohort of patients with lung adenocarcinoma at a City of Hope community site (n = 11) and utilize their case studies to develop a decision-making framework utilizing fast-and-frugal tree (FFT) heuristics. Most patients had stage IV (N = 9, 81.8%) disease at the time of the first consultation. The most common symptoms at initial presentation were cough (N = 5, 45.5%), shortness of breath (N = 3, 27.2%), and weight loss (N = 3, 27.2%). The Eastern Cooperative Oncology Group (ECOG) performance status ranged from 0-1 in all patients in this study. Distribution of molecular drivers among the patients were as follows: EGFR (N = 5, 45.5%), KRAS (N = 2, 18.2%), ALK (N = 2, 18.2%), MET (N = 2, 18.2%), and RET (N = 1, 9.1%). Seven initial FFTs were developed for the various case scenarios, but ultimately the decisions were condensed into one FFT, a molecular stage IV FFT, that arrived at accurate decisions without sacrificing initial information. While these FFT decision trees may seem arbitrary to an experienced oncologist at an academic site, the simplicity of their utility is essential for community practice where patients often do not get molecular testing and are not assigned proper therapy.
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http://dx.doi.org/10.3390/jcm9061884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356888PMC
June 2020

Association of molecular characteristics with survival in advanced non-small cell lung cancer patients treated with checkpoint inhibitors.

Lung Cancer 2020 08 24;146:174-181. Epub 2020 May 24.

Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA; Division of Medical Oncology, Cedars-Sinai Medical Center, USA. Electronic address:

Objectives: Immune checkpoint inhibitors (ICIs) have changed the landscape of lung cancer therapy. However significant proportions of patients have primary or acquired resistance to ICIs. Molecular characterization is critical for patient selection and overcoming resistance to checkpoint inhibitors. The purpose of this study is to investigate the molecular characteristics associated with ICIs outcomes in advanced non-small cell lung cancer (NSCLC) patients.

Materials And Methods: All advanced stage NSCLC patients at City of Hope who received ICIs (pembrolizumab, nivolumab, atezolizumab, and durvalumab) were identified retrospectively. Overall survival (OS, from the start of the ICIs), Pathology and information on genomic alterations (GAs) including next-generation sequencing (NGS) data, tumor mutation burden (TMB), and Programmed death-ligand 1 (PD-L1) levels were collected. Chi-square and Fisher's exact test, Log-rank test were used for comparison of demographics, and survival curves respectively. Univariate and multivariate COX proportional hazards model was used for survival analysis.

Results: 346 NSCLC patients were identified. Univariate and multivariate analysis found the association of OS with PD-L1 level ≥50% (Hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.06-0.59; P < 0.01), EGFR (HR 7.38; 95% CI, 1.15-47.42; P < 0.05), and TET2 (HR 0.15; 95% CI, 0.03-0.90; P < 0.05). The median OS was not reached [NR] for the 12 patients who had genomic alterations (GAs) in TET2 (12/108, 11%) versus (vs) 11.5 months in TET2 negative patients (98/108, 89%). Interestingly, GAs in TET2 and FANCA were mutually exclusive and patients who had GAs in FANCA gene (6%) had shorter OS (5.5 months vs 14.5 months, Log-rank test, P < 0.05).

Conclusions: We described the clinical and molecular features of NSCLC patients treated with ICIs. The association of GAs in TET2 with longer OS and its mutual exclusivity with FANCA GAs were insightful for developing novel therapeutic strategies to improve ICIs outcomes in NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.025DOI Listing
August 2020

Non-Small Cell Lung Cancer from Genomics to Therapeutics: A Framework for Community Practice Integration to Arrive at Personalized Therapy Strategies.

J Clin Med 2020 Jun 15;9(6). Epub 2020 Jun 15.

Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA 91010, USA.

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, and therapeutic management has advanced with the identification of various key oncogenic mutations that promote lung cancer tumorigenesis. Subsequent studies have developed targeted therapies against these oncogenes in the hope of personalizing therapy based on the molecular genomics of the tumor. This review presents approved treatments against actionable mutations in NSCLC as well as promising targets and therapies. We also discuss the current status of molecular testing practices in community oncology sites that would help to direct oncologists in lung cancer decision-making. We propose a collaborative framework between community practice and academic sites that can help improve the utilization of personalized strategies in the community, through incorporation of increased testing rates, virtual molecular tumor boards, vendor-based oncology clinical pathways, and an academic-type singular electronic health record system.
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http://dx.doi.org/10.3390/jcm9061870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356243PMC
June 2020

Differentiating Peripherally-Located Small Cell Lung Cancer From Non-small Cell Lung Cancer Using a CT Radiomic Approach.

Front Oncol 2020 22;10:593. Epub 2020 Apr 22.

Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA, United States.

Lung cancer can be classified into two main categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which are different in treatment strategy and survival probability. The lung CT images of SCLC and NSCLC are similar such that their subtle differences are hardly visually discernible by the human eye through conventional imaging evaluation. We hypothesize that SCLC/NSCLC differentiation could be achieved via computerized image feature analysis and classification in feature space, as termed a radiomic model. The purpose of this study was to use CT radiomics to differentiate SCLC from NSCLC adenocarcinoma. Patients with primary lung cancer, either SCLC or NSCLC adenocarcinoma, were retrospectively identified. The post-diagnosis pre-treatment lung CT images were used to segment the lung cancers. Radiomic features were extracted from histogram-based statistics, textural analysis of tumor images and their wavelet transforms. A minimal-redundancy-maximal-relevance method was used for feature selection. The predictive model was constructed with a multilayer artificial neural network. The performance of the SCLC/NSCLC adenocarcinoma classifier was evaluated by the area under the receiver operating characteristic curve (AUC). Our study cohort consisted of 69 primary lung cancer patients with SCLC ( = 35; age mean ± SD = 66.91± 9.75 years), and NSCLC adenocarcinoma ( = 34; age mean ± SD = 58.55 ± 11.94 years). The SCLC group had more male patients and smokers than the NSCLC group ( < 0.05). Our SCLC/NSCLC classifier achieved an overall performance of AUC of 0.93 (95% confidence interval = [0.85, 0.97]), sensitivity = 0.85, and specificity = 0.85). Adding clinical data such as smoking history could improve the performance slightly. The top ranking radiomic features were mostly textural features. Our results showed that CT radiomics could quantitatively represent tumor heterogeneity and therefore could be used to differentiate primary lung cancer subtypes with satisfying results. CT image processing with the wavelet transformation technique enhanced the radiomic features for SCLC/NSCLC classification. Our pilot study should motivate further investigation of radiomics as a non-invasive approach for early diagnosis and treatment of lung cancer.
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http://dx.doi.org/10.3389/fonc.2020.00593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188953PMC
April 2020

Effects of selected deubiquitinating enzyme inhibitors on the proliferation and motility of lung cancer and mesothelioma cell lines.

Int J Oncol 2020 Jul 1;57(1):80-86. Epub 2020 Apr 1.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010‑3000, USA.

The post‑translational modification of proteins by ubiquitinating enzymes plays a central role in a number of cellular functions, such as cell proteolysis, DNA repair, and cell signaling and communication. Deubiquitinating enzymes (DUBs) disassemble ubiquitin chains and remove ubiquitin moieties from proteins. Targeting DUBs in cancer models has revealed an important role for these enzymes in tumorigenesis, and they therefore have emerged as attractive therapeutic targets. In the present study, the effects of three DUB inhibitors, PR‑619, RA‑9 and LDN‑91946, on a non‑small cell lung cancer cell line (A549) and a mesothelioma cell line (H2373) were investigated. PR‑619 significantly inhibited cell adhesion and the proliferation of both cell lines. RA‑9 exerted an inhibitory effect on the adhesion and proliferation of H2373 cells, whereas it had no effect on A549 cells. Notably, however, while PR‑619 attenuated the proliferation of both cell lines, it exerted an opposite effect on cell motility; in the case of A549 cells, there was a significant increase in cell motility, while for the H2373 cells, there was a significant decrease. Furthermore, protein phosphorylation kinetic analyses revealed that the effects were cell line‑specific. In H2373 cells, the phosphorylation of only one peptide corresponding to the P85A protein was significantly affected, and while LDN‑91946 treatment increased phosphorylation, treatment with RA‑9 or PR‑619 decreased its phosphorylation compared to the DMSO control. By contrast, in the case of A549 cells, the phosphorylation of 21 peptides was significantly affected by the same compounds. In light of the potential for the negative side‑effects of DUB inhibition, such as increased cancer cell motility, the data presented herein underscore the dire need for the development of specific DUB inhibitors and to elucidate the individual role of DUB family members in cancer biology before they can be specifically pharmacologically targeted.
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http://dx.doi.org/10.3892/ijo.2020.5034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252467PMC
July 2020

Radiomic prediction of mutation status based on MR imaging of lung cancer brain metastases.

Magn Reson Imaging 2020 06 13;69:49-56. Epub 2020 Mar 13.

Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte 91010, CA, United States.

Lung cancer metastases comprise most of all brain metastases in adults and most brain metastases are diagnosed by magnetic resonance (MR) scans. The purpose of this study was to conduct an MR imaging-based radiomic analysis of brain metastatic lesions from patients with primary lung cancer to classify mutational status of the metastatic disease. We retrospectively identified lung cancer patients with brain metastases treated at our institution between 2009 and 2017 who underwent genotype testing of their primary lung cancer. Brain MR Images were used for segmentation of enhancing tumors and peritumoral edema, and for radiomic feature extraction. The most relevant radiomic features were identified and used with clinical data to train random forest classifiers to classify the mutation status. Of 110 patients in the study cohort (mean age 57.51 ± 12.32 years; M: F = 37:73), 75 had an EGFR mutation, 21 had an ALK translocation, and 15 had a KRAS mutation. One patient had both ALK translocation and EGFR mutation. Majority of radiomic features most relevant for mutation classification were textural. Model building using both radiomic features and clinical data yielded more accurate classifications than using either alone. For classification of EGFR, ALK, and KRAS mutation status, the model built with both radiomic features and clinical data resulted in area-under-the-curve (AUC) values based on cross-validation of 0.912, 0.915, and 0.985, respectively. Our study demonstrated that MR imaging-based radiomic analysis of brain metastases in patients with primary lung cancer may be used to classify mutation status. This approach may be useful for devising treatment strategies and informing prognosis.
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http://dx.doi.org/10.1016/j.mri.2020.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237274PMC
June 2020

Precision medicine and actionable alterations in lung cancer: A single institution experience.

PLoS One 2020 11;15(2):e0228188. Epub 2020 Feb 11.

Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California, United States of America.

Objectives: Oncology has become more reliant on new testing methods and a greater use of electronic medical records, which provide a plethora of information available to physicians and researchers. However, to take advantage of vital clinical and research data for precision medicine, we must initially make an effort to create an infrastructure for the collection, storage, and utilization of this information with uniquely designed disease-specific registries that could support the collection of a large number of patients.

Materials And Methods: In this study, we perform an in-depth analysis of a series of lung adenocarcinoma patients (n = 415) with genomic and clinical data in a recently created thoracic patient registry.

Results: Of the 415 patients with lung adenocarcinoma, 59% (n = 245) were female; the median age was 64 (range, 22-92) years with a median OS of 33.29 months (95% CI, 29.77-39.48). The most common actionable alterations were identified in EGFR (n = 177/415 [42.7%]), ALK (n = 28/377 [7.4%]), and BRAF V600E (n = 7/288 [2.4%]). There was also a discernible difference in survival for 222 patients, who had an actionable alteration, with a median OS of 39.8 months as compared to 193 wild-type patients with a median OS of 26.0 months (P<0.001). We identified an unprecedented number of actionable alterations [53.5% (222/415)], including distinct individual alteration rates, as compared with 15.0% and 22.3% in TCGA and GENIE respectively.

Conclusion: The use of patient registries, focused genomic panels and the appropriate use of clinical guidelines in community and academic settings may influence cohort selection for clinical trials and improve survival outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228188PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012442PMC
April 2020

Phenotypic Switching of Naïve T Cells to Immune-Suppressive Treg-Like Cells by Mutant KRAS.

J Clin Med 2019 Oct 18;8(10). Epub 2019 Oct 18.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA.

Oncogenic (mutant) Ras protein Kirsten rat sarcoma viral oncogene homolog (KRAS) promotes uncontrolled proliferation, altered metabolism, and loss of genome integrity in a cell-intrinsic manner. Here, we demonstrate that CD4 T cells when incubated with tumor-derived exosomes from mutant (MT) KRAS non-small-cell lung cancer (NSCLC) cells, patient sera, or a mouse xenograft model, induce phenotypic conversion to FOXP3 Treg-like cells that are immune-suppressive. Furthermore, transfecting T cells with MT KRAS cDNA alone induced phenotypic switching and mathematical modeling supported this conclusion. Single-cell sequencing identified the interferon pathway as the mechanism underlying the phenotypic switch. These observations highlight a novel cytokine-independent, cell-extrinsic role for KRAS in T cell phenotypic switching. Thus, targeting this new class of Tregs represents a unique therapeutic approach for NSCLC. Since KRAS is the most frequently mutated oncogene in a wide variety of cancers, the findings of this investigation are likely to be of broad interest and have a large scientific impact.
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http://dx.doi.org/10.3390/jcm8101726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832522PMC
October 2019

Monitoring and Determining Mitochondrial Network Parameters in Live Lung Cancer Cells.

J Clin Med 2019 Oct 18;8(10). Epub 2019 Oct 18.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA.

Mitochondria are dynamic organelles that constantly fuse and divide, forming dynamic tubular networks. Abnormalities in mitochondrial dynamics and morphology are linked to diverse pathological states, including cancer. Thus, alterations in mitochondrial parameters could indicate early events of disease manifestation or progression. However, finding reliable and quantitative tools for monitoring mitochondria and determining the network parameters, particularly in live cells, has proven challenging. Here, we present a 2D confocal imaging-based approach that combines automatic mitochondrial morphology and dynamics analysis with fractal analysis in live small cell lung cancer (SCLC) cells. We chose SCLC cells as a test case since they typically have very little cytoplasm, but an abundance of smaller mitochondria compared to many of the commonly used cell types. The 2D confocal images provide a robust approach to quantitatively measure mitochondrial dynamics and morphology in live cells. Furthermore, we performed 3D reconstruction of electron microscopic images and show that the 3D reconstruction of the electron microscopic images complements this approach to yield better resolution. The data also suggest that the parameters of mitochondrial dynamics and fractal dimensions are sensitive indicators of cellular response to subtle perturbations, and hence, may serve as potential markers of drug response in lung cancer.
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http://dx.doi.org/10.3390/jcm8101723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832496PMC
October 2019

EPHA2 mutations with oncogenic characteristics in squamous cell lung cancer and malignant pleural mesothelioma.

Oncogenesis 2019 Sep 4;8(9):49. Epub 2019 Sep 4.

Department of Medical Oncology and Experimental Therapeutics, Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.

Squamous cell carcinoma (SCC) and malignant pleural mesothelioma (MPM) are thoracic malignancies with very poor prognosis and limited treatment options. It is an established fact that most of the solid tumors have overexpression of EPHA2 receptor tyrosine kinase. EPHA2 is known to exhibit opposing roles towards cancer progression. It functions in inhibiting cancer survival and migration via a ligand and tyrosine kinase dependent signaling (Y772). Whereas it is known to promote tumor progression and cell migration through a ligand-independent signaling (S897). We analyzed the expression profile and mutational status of the ephrin receptor A2 (EPHA2) in SCC and MPM cell lines and primary patient specimens. The EPHA2 receptor was found to be either overexpressed, mutated or amplified in SCC and MPM. In particular, the EPHA2 mutants A859D and T647M were interesting to explore, A859D Y772 dead mutant exhibited lower levels of phosphorylation at Y772 compared to T647M mutant. Molecular Dynamics simulations studies suggested that differential changes in conformation might form the structural basis for differences in the level of EPHA2 activation. Consequently, A859D mutant cells exhibited increased proliferation as well as cell migration compared to controls and T647M mutant. Kinomics analysis demonstrated that the STAT3 and PDGF pathways were upregulated whereas signaling through CBL was suppressed. Considered together, the present work has uncovered the oncogenic characteristics of EPHA2 mutations in SSC and MPM reinstating the dynamics of different roles of EPHA2 in cancer. This study also suggests that a combination of doxazosin and other EPHA2 inhibitors directed to inhibit the pertinent signaling components may be a novel therapeutic strategy for MPM and Non-small cell lung cancer patients who have either EPHA2 or CBL alterations.
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http://dx.doi.org/10.1038/s41389-019-0159-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726628PMC
September 2019

The Mitochondrion as an Emerging Therapeutic Target in Cancer.

Trends Mol Med 2020 01 18;26(1):119-134. Epub 2019 Jul 18.

Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA. Electronic address:

Mitochondria have emerged as important pharmacological targets because of their key role in cellular proliferation and death. In tumor tissues, mitochondria can switch metabolic phenotypes to meet the challenges of high energy demand and macromolecular synthesis. Furthermore, mitochondria can engage in crosstalk with the tumor microenvironment, and signals from cancer-associated fibroblasts can impinge on mitochondria. Cancer cells can also acquire a hybrid phenotype in which both glycolysis and oxidative phosphorylation (OXPHOS) can be utilized. This hybrid phenotype can facilitate metabolic plasticity of cancer cells more specifically in metastasis and therapy-resistance. In light of the metabolic heterogeneity and plasticity of cancer cells that had until recently remained unappreciated, strategies targeting cancer metabolic dependency appear to be promising in the development of novel and effective cancer therapeutics.
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http://dx.doi.org/10.1016/j.molmed.2019.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938552PMC
January 2020

Small Cell Lung Cancer Therapeutic Responses Through Fractal Measurements: From Radiology to Mitochondrial Biology.

J Clin Med 2019 Jul 16;8(7). Epub 2019 Jul 16.

City of Hope, Dept. of Medical Oncology and Therapeutics Research, Duarte, CA 91010, USA.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine disease with an overall 5 year survival rate of ~7%. Although patients tend to respond initially to therapy, therapy-resistant disease inevitably emerges. Unfortunately, there are no validated biomarkers for early-stage SCLC to aid in early detection. Here, we used readouts of lesion image characteristics and cancer morphology that were based on fractal geometry, namely fractal dimension (FD) and lacunarity (LC), as novel biomarkers for SCLC. Scanned tumors of patients before treatment had a high FD and a low LC compared to post treatment, and this effect was reversed after treatment, suggesting that these measurements reflect the initial conditions of the tumor, its growth rate, and the condition of the lung. Fractal analysis of mitochondrial morphology showed that cisplatin-treated cells showed a discernibly decreased LC and an increased FD, as compared with control. However, treatment with mdivi-1, the small molecule that attenuates mitochondrial division, was associated with an increase in FD as compared with control. These data correlated well with the altered metabolic functions of the mitochondria in the diseased state, suggesting that morphological changes in the mitochondria predicate the tumor's future ability for mitogenesis and motogenesis, which was also observed on the CT scan images. Taken together, FD and LC present ideal tools to differentiate normal tissue from malignant SCLC tissue as a potential diagnostic biomarker for SCLC.
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http://dx.doi.org/10.3390/jcm8071038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679065PMC
July 2019

Anaplastic Lymphoma Kinase (ALK)-positive Tumors: Clinical, Radiographic and Molecular Profiles, and Uncommon Sites of Metastases in Patients With Lung Adenocarcinoma.

Am J Clin Oncol 2019 04;42(4):337-344

Department of Medical Oncology and Therapeutic Research, City of Hope National Medical Center, Duarte, CA.

Introduction: Anaplastic lymphoma kinase (ALK) gene rearrangements are observed in about 4% to 8% non-small cell lung cancer (NSCLC). ALK+ tumors have been associated with increased pleural and pericardial disease. Our primary objective was to determine the uncommon sites of metastasis of ALK+ NSCLC. Secondary objectives included study of coexisting mutations and factors impacting survival of ALK+ NSCLC.

Methods: All patients with metastatic ALK+ NSCLC at the City of Hope Cancer Center in Duarte, California from 2010 to 2017 were selected for retrospective chart review. The demographic variables were collected. The molecular statuses of patients were evaluated through commercially available platforms for next-generation sequencing. Three-dimensional volumetric images were generated for the primary lesion and different sites of metastasis.

Results: Sixty two patients with ALK+ NSCLC were identified from 2010 to 2017. The median age was 59 with 36 (58%) female individuals and only 20 (32%) smokers. Twenty four patients had uncommon sites of metastasis which were thyroid, soft tissue, chest and abdominal wall, spleen, peritoneum, omentum, kidney, and ovary. Common characteristics of the primary lesions were right upper lobe location (N=23 [37%]), oval shape (N=22 [35%]), irregular margins (N=26 [42%]), solid lesions (N=27 [44%]), presence of pleural contact or effusion (N=22 [35%]). Twenty four patients had next-generation sequencing testing which showed coexisting mutations such as TP53 (N=8), EGFR (N=5), KRAS (N=3). Patients with uncommon sites of metastasis had a decreased median survival compared with common sites (39 vs. 82 m, P=0.046).

Conclusion: In NSCLC, ALK rearrangements may not be mutually exclusive mutations and can present with unique radiographic patterns. Patients with uncommon sites of metastasis may have worse outcomes.
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http://dx.doi.org/10.1097/COC.0000000000000508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597761PMC
April 2019

The DNA walk and its demonstration of deterministic chaos-relevance to genomic alterations in lung cancer.

Bioinformatics 2019 08;35(16):2738-2748

Department of Medical Oncology and Therapeutics Research.

Motivation: Advancements in cancer genetics have facilitated the development of therapies with actionable mutations. Although mutated genes have been studied extensively, their chaotic behavior has not been appreciated. Thus, in contrast to naïve DNA, mutated DNA sequences can display characteristics of unpredictability and sensitivity to the initial conditions that may be dictated by the environment, expression patterns and presence of other genomic alterations. Employing a DNA walk as a form of 2D analysis of the nucleotide sequence, we demonstrate that chaotic behavior in the sequence of a mutated gene can be predicted.

Results: Using fractal analysis for these DNA walks, we have determined the complexity and nucleotide variance of commonly observed mutated genes in non-small cell lung cancer, and their wild-type counterparts. DNA walks for wild-type genes demonstrate varying levels of chaos, with BRAF, NTRK1 and MET exhibiting greater levels of chaos than KRAS, paxillin and EGFR. Analyzing changes in chaotic properties, such as changes in periodicity and linearity, reveal that while deletion mutations indicate a notable disruption in fractal 'self-similarity', fusion mutations demonstrate bifurcations between the two genes. Our results suggest that the fractals generated by DNA walks can yield important insights into potential consequences of these mutated genes.

Availability And Implementation: Introduction to Turtle graphics in Python is an open source article on learning to develop a script for Turtle graphics in Python, freely available on the web at https://docs.python.org/2/library/turtle.html. cDNA sequences were obtained through NCBI RefSeq database, an open source database that contains information on a large array of genes, such as their nucleotide and amino acid sequences, freely available at https://www.ncbi.nlm.nih.gov/refseq/. FracLac plugin for Fractal analysis in ImageJ is an open source plugin for the ImageJ program to perform fractal analysis, free to download at https://imagej.nih.gov/ij/plugins/fraclac/FLHelp/Introduction.html.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/bty1021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691335PMC
August 2019