Publications by authors named "Jeremy Fricke"

11 Publications

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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

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

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

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

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

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

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