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PURPOSE: Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at high risk for severe and fatal toxicity from fluoropyrimidine (FP) chemotherapy. Pre-treatment DPYD testing is standard of care in many countries, but not the United States (US). This survey assessed pre-treatment DPYD testing approaches in the US to identify best practices for broader adoption. METHODS: From August to October 2023, a 22-item QualtricsXM survey was sent to institutions and clinicians known to conduct pre-treatment DPYD testing and broadly distributed through relevant organizations and social networks. Responses were analyzed using descriptive analysis. RESULTS: Responses from 24 unique US sites that have implemented pre-treatment DPYD testing or have a detailed implementation plan in place were analyzed. Only 33% of sites ordered DPYD testing for all FP-treated patients; at the remaining sites, patients were tested depending on disease characteristics or clinician preference. Almost 50% of sites depend on individual clinicians to remember to order testing without the assistance of electronic alerts or workflow reminders. DPYD testing was most often conducted by commercial laboratories that tested for at least the four or five DPYD variants considered clinically actionable. Approximately 90% of sites reported receiving results within 10 days of ordering. CONCLUSION: Implementing DPYD testing into routine clinical practice is feasible and requires a coordinated effort among the healthcare team. These results will be used to develop best practices for the clinical adoption of DPYD testing to prevent severe and fatal toxicity in cancer patients receiving FP chemotherapy.
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Deficiencia de Dihidropirimidina Deshidrogenasa , Dihidrouracilo Deshidrogenasa (NADP) , Humanos , Estados Unidos , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Deficiencia de Dihidropirimidina Deshidrogenasa/diagnóstico , Neoplasias/tratamiento farmacológico , Antimetabolitos Antineoplásicos/efectos adversos , Encuestas y Cuestionarios , Fluorouracilo/efectos adversos , Fluorouracilo/administración & dosificaciónRESUMEN
This study describes the validation of a clinical RNA expression panel with evaluation of concordance between gene copy gain by a next-generation sequencing (NGS) assay and high gene expression by an RNA expression panel. The RNA Salah Targeted Expression Panel (RNA STEP) was designed with input from oncologists to include 204 genes with utility for clinical trial prescreening and therapy selection. RNA STEP was validated with the nanoString platform using remnant formalin-fixed, paraffin-embedded-derived RNA from 102 patients previously tested with a validated clinical NGS panel. The repeatability, reproducibility, and concordance of RNA STEP results with NGS results were evaluated. RNA STEP demonstrated high repeatability and reproducibility, with excellent correlation (r > 0.97, P < 0.0001) for all comparisons. Comparison of RNA STEP high gene expression (log2 ratio ≥ 2) versus NGS DNA-based gene copy number gain (copies ≥ 5) for 38 mutually covered genes revealed an accuracy of 93.0% with a positive percentage agreement of 69.4% and negative percentage agreement of 93.8%. Moderate correlation was observed between platforms (r = 0.53, P < 0.0001). Concordance between high gene expression and gene copy number gain varied by specific gene, and some genes had higher accuracy between assays. Clinical implementation of RNA STEP provides gene expression data complementary to NGS and offers a tool for prescreening patients for clinical trials.
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Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Reproducibilidad de los Resultados , Neoplasias/genética , Perfilación de la Expresión Génica/métodos , Biomarcadores de Tumor/genética , Dosificación de GenRESUMEN
The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We perform saturation mutagenesis of EGFR and assess function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach reveals enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, not associated with approved targeted therapies, are sensitive to afatinib and dacomitinib in vitro. Two glioblastoma patients with somatic EGFR G598V dimerization domain mutations show responses to dacomitinib treatment followed by within-pathway resistance mutation in one case. In summary, this comprehensive screen expands the landscape of functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations.
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Glioblastoma , Neoplasias Pulmonares , Humanos , Glioblastoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores ErbB/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , MutaciónRESUMEN
Background: Germline pathogenic variants in CHEK2 are associated with a moderate increase in the lifetime risk for breast cancer. Increased risk for other cancers, including non-medullary thyroid cancer (NMTC), has also been suggested. To date, data implicating CHEK2 variants in NMTC predisposition primarily derive from studies within Poland, driven by a splice site variant (c.444 + 1G>A) that is uncommon in other populations. In contrast, the predominant CHEK2 variants in non-Polish populations are c.1100del and c.470T>C/p.I157T, representing 61.1% and 63.8%, respectively, of all CHEK2 pathogenic variants in two large U.S.-based commercial laboratory datasets. To further delineate the impact of common CHEK2 variants on thyroid cancer, we aimed to investigate the association of three CHEK2 founder variants (c.444 + 1G>A, c.1100del, and c.470T>C/p.Ile157Thr) on NMTC susceptibility in three groups of unselected NMTC patients. Methods: The presence of three CHEK2 founder variants was assessed within three groups: (1) 1544 NMTC patients (and 1593 controls) from previously published genome-wide association study (GWAS) analyses, (2) 789 NMTC patients with germline exome sequencing (Oncology Research Information Exchange Network [ORIEN] Avatar), and (3) 499 NMTC patients with germline sequence data available in The Cancer Genome Atlas (TCGA). A case-control study design was utilized with odds ratios (ORs) calculated by comparison of all three groups with the Ohio State University GWAS control group. Results: The predominant Polish variant (c.444 + 1G>A) was present in only one case. The proportion of patients with c.1100del was 0.92% in the GWAS group, 1.65% in the ORIEN Avatar group, and 0.80% in the TCGA group. The ORs (with 95% confidence intervals [CIs]) for NMTC associated with c.1100del were 1.71 (0.73-4.29), 2.64 (0.95-7.63), and 2.5 (0.63-8.46), respectively. The proportion of patients with c.470T>C/p.I157T was 0.91% in the GWAS group, 0.76% in the ORIEN Avatar group, and 0.80% in the TCGA group, respectively. The ORs (with CIs) for NMTC associated with c.470T>C/p.I157T were 1.75 (0.74-4.39), 1.52 (0.42-4.96), and 2.31 (0.58-7.90), respectively. Conclusions: Our analyses of unselected patients with NMTC suggest that CHEK2 variants c.1100del and c.470T>C/p.I157T have only a modest impact on thyroid cancer risk. These results provide important information for providers regarding the relatively low magnitude of thyroid cancer risk associated with these CHEK2 variants.
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Quinasa de Punto de Control 2 , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Humanos , Estudios de Casos y Controles , Quinasa de Punto de Control 2/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Mutación de Línea Germinal , Neoplasias de la Tiroides/genéticaRESUMEN
Precision medicine has revolutionized clinical care for patients with cancer through the development of targeted therapy, identification of inherited cancer predisposition syndromes and the use of pharmacogenetics to optimize pharmacotherapy for anticancer drugs and supportive care medications. While germline (patient) and somatic (tumor) genomic testing have evolved separately, recent interest in paired germline/somatic testing has led to an increase in integrated genomic testing workflows. However, paired germline/somatic testing has generally lacked the incorporation of germline pharmacogenomics. Integrating pharmacogenomics into paired germline/somatic genomic testing would be an efficient method for increasing access to pharmacogenomic testing. In this perspective, the authors argue for the benefits of implementing a comprehensive approach integrating somatic and germline testing that is inclusive of pharmacogenomics in clinical practice.
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INTRODUCTION: The CYP2D6 enzyme metabolizes opioids commonly prescribed for cancer-related pain, and CYP2D6 polymorphisms may contribute to variability in opioid response. We evaluated the feasibility of implementing CYP2D6-guided opioid prescribing for patients with cancer and reported pilot outcome data. METHODS: Adult patients from two cancer centers were prospectively enrolled into a hybrid implementation-effectiveness clinical trial and randomized to CYP2D6-genotype-guided opioid selection, with clinical recommendations, or usual care. Implementation metrics, including provider response, medication changes consistent with recommendations, and patient-reported pain and symptom scores at baseline and up to 8 weeks, were assessed. RESULTS: Most (87/114, 76%) patients approached for the study agreed to participate. Of 85 patients randomized, 71% were prescribed oxycodone at baseline. The median (range) time to receive CYP2D6 test results was 10 (3-37) days; 24% of patients had physicians acknowledge genotype results in a clinic note. Among patients with CYP2D6-genotype-guided recommendations to change therapy (n = 11), 18% had a change congruent with recommendations. Among patients who completed baseline and follow-up questionnaires (n = 48), there was no difference in change in mean composite pain score (-1.01 ± 2.1 vs. -0.41 ± 2.5; p = 0.19) or symptom severity at last follow-up (3.96 ± 2.18 vs. 3.47 ± 1.78; p = 0.63) between the usual care arm (n = 26) and genotype-guided arm (n = 22), respectively. CONCLUSION: Our study revealed high acceptance of pharmacogenetic testing as part of a clinical trial among patients with cancer pain. However, provider response to genotype-guided recommendations was low, impacting assessment of pain-related outcomes. Addressing barriers to utility of pharmacogenetics results and clinical recommendations will be critical for implementation success.
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Dolor en Cáncer , Neoplasias , Adulto , Humanos , Analgésicos Opioides/uso terapéutico , Dolor en Cáncer/tratamiento farmacológico , Dolor en Cáncer/genética , Citocromo P-450 CYP2D6/genética , Pautas de la Práctica en Medicina , Dolor/tratamiento farmacológico , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
Fluoropyrimidine (FP) chemotherapy is associated with severe, life-threatening toxicities, particularly among patients who carry deleterious germline variants in the DPYD gene. Pretreatment DPYD testing is standard of care throughout most of Europe; however, it has not been recommended in clinical practice guidelines in the United States. Due to increased risk of severe toxicity, a Citizen's Petition asked the US Food and Drug Administration (FDA) to update language in FP drug labels to recommend DPYD testing as part of a boxed warning and recommend FP dose reduction in patients carrying deleterious germline variants. In response, the FDA updated the capecitabine package insert to inform patients about the toxicity risk and test availability and consider DPYD testing. However, the FDA did not include a testing recommendation or requirement, or a boxed warning. Additionally, the FDA did not recommend FP dose adjustment in DPYD variant carriers. This review provides a critical assessment of the DPYD-FP pharmacogenetic association using the FDA's previously published Pharmacogenetic Pyramid, demonstrating that the evidence is compelling for recommending DPYD testing prior to FP treatment. Additionally, the FDA's stated concerns about recommending DPYD testing and DPYD-guided FP dose adjustment are addressed and discussed in the context of the FDA's other genetic testing and dose adjustment recommendations. We call on the FDA to follow our European counterparts in recommending DPYD testing and genotype-based dose adjustment to ensure patients with cancer receive safe and effective FP chemotherapy.
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Dihidrouracilo Deshidrogenasa (NADP) , Fluorouracilo , Estados Unidos , Humanos , Fluorouracilo/efectos adversos , United States Food and Drug Administration , Dihidrouracilo Deshidrogenasa (NADP)/genética , Capecitabina/efectos adversos , Genotipo , AntimetabolitosRESUMEN
Serotonin reuptake inhibitor antidepressants, including selective serotonin reuptake inhibitors (SSRIs; i.e., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), serotonin and norepinephrine reuptake inhibitors (i.e., desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine), and serotonin modulators with SSRI-like properties (i.e., vilazodone and vortioxetine) are primary pharmacologic treatments for major depressive and anxiety disorders. Genetic variation in CYP2D6, CYP2C19, and CYP2B6 influences the metabolism of many of these antidepressants, which may potentially affect dosing, efficacy, and tolerability. In addition, the pharmacodynamic genes SLC6A4 (serotonin transporter) and HTR2A (serotonin-2A receptor) have been examined in relation to efficacy and side effect profiles of these drugs. This guideline updates and expands the 2015 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and SSRI dosing and summarizes the impact of CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes on antidepressant dosing, efficacy, and tolerability. We provide recommendations for using CYP2D6, CYP2C19, and CYP2B6 genotype results to help inform prescribing these antidepressants and describe the existing data for SLC6A4 and HTR2A, which do not support their clinical use in antidepressant prescribing.
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Trastorno Depresivo Mayor , Inhibidores Selectivos de la Recaptación de Serotonina , Humanos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2B6/genética , Farmacogenética , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Serotonina , Antidepresivos/uso terapéutico , Citalopram/uso terapéutico , GenotipoRESUMEN
Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured â¼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. SIGNIFICANCE: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Mutación , Factor 2 Relacionado con NF-E2/metabolismo , ADN Helicasas/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción/genéticaRESUMEN
Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are highly effective for treatment of EGFR- or ALK-mutated lung cancer. Nevertheless, they are associated with several unique toxicities. Although the available US Food and Drug Administration (FDA)-approved drug label can provide guidance for safety monitoring, its integration into clinical practice has not been previously described. We studied the conduct of safety monitoring activity (SMA) at a large academic institution. On the basis of FDA-approved drug labels, two drug-specific SMAs were identified for osimertinib, crizotinib, alectinib, or lorlatinib. Electronic medical records of patients initiated on these drugs from 2017 to 2021 were retrospectively reviewed. Each course of treatment was evaluated for the occurrence of SMAs and the corresponding adverse events. Analyses included 130 treatment courses from 111 unique patients. For each SMA evaluated, the prevalence of SMA conduct ranged from 10.0% to 84.6%. The most frequently conducted SMA was ECG for lorlatinib therapy and the least was creatine phosphokinase analysis for alectinib. We observed none of the assessed SMAs being conducted in 41 treatment courses (31.5%). EGFR inhibitor predicted a higher likelihood of both SMAs being conducted than ALK inhibitors (P = .02). Serious, grade 3 or 4 adverse events were observed in 21 treatment courses (16.2%), including one grade 4 transaminitis related to alectinib. On the basis of our experience, the conduct of SMA was more challenging to implement for ALK inhibitor than for EGFR inhibitor. Clinicians should be vigilant and review the FDA-approved drug label before prescribing.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Quinasa de Linfoma Anaplásico/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Estudios Retrospectivos , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores ErbB/uso terapéutico , Lactamas Macrocíclicas/efectos adversosRESUMEN
The development of targeted therapies over the past two decades has led to a dramatic change in the management of EGFR-mutant non-small cell lung cancer (NSCLC). While there are currently five approved EGFR tyrosine kinase inhibitors (TKIs) for treating EGFR-mutant NSCLC in the first-line setting, therapy selection after progression on EGFR TKIs remains complex. Multiple groups are investigating novel therapies and drug combinations to determine the optimal therapy and treatment sequence for these patients. In this review, we summarize the landmark trials and history of the approval of EGFR TKIs, their efficacy and tolerability, and the role of these therapies in patients with central nervous system metastasis. We also briefly discuss the mechanisms of resistance to EGFR TKIs, ongoing attempts to overcome resistance and improve outcomes, and finalize by offering treatment sequencing recommendations.
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BACKGROUND: Despite the increased demand for pharmacogenetic (PGx) testing to guide antidepressant use, little is known about how to implement testing in clinical practice. Best-worst scaling (BWS) is a stated preferences technique for determining the relative importance of alternative scenarios and is increasingly being used as a healthcare assessment tool, with potential applications in implementation research. We conducted a BWS experiment to evaluate the relative importance of implementation factors for PGx testing to guide antidepressant use. METHODS: We surveyed 17 healthcare organizations that either had implemented or were in the process of implementing PGx testing for antidepressants. The survey included a BWS experiment to evaluate the relative importance of Consolidated Framework for Implementation Research (CFIR) constructs from the perspective of implementing sites. RESULTS: Participating sites varied on their PGx testing platform and methods for returning recommendations to providers and patients, but they were consistent in ranking several CFIR constructs as most important for implementation: patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and identification of champions. CONCLUSIONS: This study demonstrates the feasibility of using choice experiments to systematically evaluate the relative importance of implementation determinants from the perspective of implementing organizations. BWS findings can inform other organizations interested in implementing PGx testing for mental health. Further, this study demonstrates the application of BWS to PGx, the findings of which may be used by other organizations to inform implementation of PGx testing for mental health disorders.
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BACKGROUND: Cancer of unknown primary (CUP) comprises a heterogeneous collection of malignancies that are typically associated with a poor prognosis and a lack of effective treatment options. We retrospectively evaluated the clinical utility of targeted next-generation sequencing (NGS) among CUP patients to assist with diagnosis and identify opportunities for molecularly guided therapy. PATIENTS AND METHODS: Patients with a CUP at Moffitt Cancer Center who underwent NGS between January 1, 2014 and December 31, 2019, were eligible for study inclusion. Next-generation sequencing results were assessed to determine the frequency of clinically actionable molecular alterations, and chart reviews were performed to ascertain the number of patients receiving molecularly guided therapy. RESULTS: Ninety-five CUP patients were identified for analysis. Next-generation sequencing testing identified options for molecularly guided therapy for 55% (n = 52) of patients. Among patients with molecularly guided therapy options, 33% (n = 17) were prescribed a molecularly guided therapy. The median overall survival for those receiving molecularly guided therapy was 23.6 months. Among the evaluable patients, the median duration of treatment for CUP patients (n = 7) receiving molecular-guided therapy as a first-line therapy was 39 weeks. The median duration of treatment for CUP patients (n = 8) treated with molecularly guided therapy in the second- or later-line setting was 13 weeks. Next-generation sequencing results were found to be suggestive of a likely primary tumor type for 15% (n = 14) of patients. CONCLUSION: Next-generation sequencing results enabled the identification of treatment options in a majority of patients and assisted with the identification of a likely primary tumor type in a clinically meaningful subset of patients.
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Neoplasias Primarias Desconocidas , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Neoplasias Primarias Desconocidas/diagnóstico , Neoplasias Primarias Desconocidas/tratamiento farmacológico , Neoplasias Primarias Desconocidas/genética , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
There is growing interest in utilizing pharmacogenetic (PGx) testing to guide antidepressant use, but there is lack of clarity on how to implement testing into clinical practice. We administered two surveys at 17 sites that had implemented or were in the process of implementing PGx testing for antidepressants. Survey 1 collected data on the process and logistics of testing. Survey 2 asked sites to rank the importance of Consolidated Framework for Implementation Research (CFIR) constructs using best-worst scaling choice experiments. Of the 17 sites, 13 had implemented testing and four were in the planning stage. Thirteen offered testing in the outpatient setting, and nine in both outpatient/inpatient settings. PGx tests were mainly ordered by psychiatry (92%) and primary care (69%) providers. CYP2C19 and CYP2D6 were the most commonly tested genes. The justification for antidepressants selected for PGx guidance was based on Clinical Pharmacogenetics Implementation Consortium guidelines (94%) and US Food and Drug Administration (FDA; 75.6%) guidance. Both institutional (53%) and commercial laboratories (53%) were used for testing. Sites varied on the methods for returning results to providers and patients. Sites were consistent in ranking CFIR constructs and identified patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and the identification of champions as most important for implementation. Sites deployed similar implementation strategies and measured similar outcomes. The process of implementing PGx testing to guide antidepressant therapy varied across sites, but key drivers for successful implementation were similar and may help guide other institutions interested in providing PGx-guided pharmacotherapy for antidepressant management.
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Antidepresivos/uso terapéutico , Farmacogenética , Pruebas de Farmacogenómica , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Depresión/tratamiento farmacológico , Humanos , Farmacogenética/métodosRESUMEN
Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18-21 and are established driver mutations in non-small cell lung cancer (NSCLC)1-3. Targeted therapies are approved for patients with 'classical' mutations and a small number of other mutations4-6. However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown1,3,7-10. Here we characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC, and establish the structure-function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR-mutant NSCLC and suggest that a structure-function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations.
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Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Afatinib/uso terapéutico , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Reposicionamiento de Medicamentos , Resistencia a Antineoplásicos , Receptores ErbB/genética , Exones , Femenino , Humanos , Neoplasias Pulmonares/genética , Ratones , Simulación del Acoplamiento Molecular , Mutación , Relación Estructura-ActividadRESUMEN
It has recently been described that alternative oncogenic drivers may be found in KRAS wild-type (KRAS WT) pancreatic cancers. This study aimed to determine the incidence of targetable gene fusions present in KRAS WT pancreatic adenocarcinoma and response to targeted therapy. METHODS: One hundred consecutive patients with pancreatic adenocarcinoma who underwent targeted next-generation sequencing using DNA sequencing with RNA sequencing (n = 47) or without RNA sequencing (n = 53) at a single institution were included in the study. The frequency and landscape of targetable fusions in KRAS WT pancreatic adenocarcinoma was characterized and compared with the frequency of fusions in KRAS-mutated (KRAS MUT) pancreatic adenocarcinoma. Results were validated in two independent cohorts using data from AACR GENIE (n = 1,252) and TCGA (n = 150). The clinical history of fusion-positive patients who received targeted treatment is described. RESULTS: Pancreatic cancers from 13 of 100 patients (13%) were found to be KRAS WT. Targetable fusions were identified in 4/13 (31%) KRAS WT tumors compared with 0/87 (0%) KRAS MUT pancreatic adenocarcinomas (P = .0002). One patient with a novel MET fusion had a complete response to targeted therapy with crizotinib that is ongoing at 12+ months of treatment. In the validation cohorts, gene fusions were identified in 18/97 (19%) and 2/10 (20%) KRAS WT tumors reported in the AACR GENIE and TCGA cohorts, respectively. CONCLUSION: Oncogene fusions are present in KRAS WT pancreatic adenocarcinomas at an increased frequency when compared with KRAS MUT pancreatic adenocarcinomas. As these fusions may be susceptible to targeted therapy, molecular analyses for the detection of fusions in KRAS WT pancreatic adenocarcinomas may warrant increased consideration.