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PURPOSE: In metastatic colorectal cancer (mCRC), RAS mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether RAS mutations ever become clonally undetectable. METHODS: CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. RAS mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression. RESULTS: Among the 95 patients with KRAS/NRAS mutations in their archival tumor tissue, 6.3% (6/95) had undetectable RAS mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to RAS-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-RAS-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent RAS mutations (75%), P = .046. The likelihood of synchronous metastases at cancer diagnosis (33% v 63%; P = .15) or liver metastases at trial baseline (50% v 68.5%; P = .17) was not significantly different between patients with disappearing versus persistent RAS mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; P = .52) was not significantly different between those with disappearing versus persistent RAS mutations. The disappearance of RAS mutations was not associated with primary tumor sidedness (P = .41), archival BRAF/MEK/ERK-mutant status (P = .16/1.00/.09), nor baseline ctDNA HER2 amplifications (P = 1.00). CONCLUSION: We identified a 3.2%-6.3% prevalence of the neo-RAS-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.
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ADN Tumoral Circulante , Neoplasias Colorrectales , Mutación , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/sangre , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Masculino , Femenino , Canadá , Persona de Mediana Edad , Anciano , Proteínas Proto-Oncogénicas p21(ras)/genética , Adulto , Metástasis de la NeoplasiaRESUMEN
Genomic mutations impact non-small cell lung cancer (NSCLC) biology. The influence of sex and age on the distribution of these alterations is unclear. We analyzed circulating-tumor DNA from individuals with advanced NSCLC from March 2018 to October 2020. EGFR, KRAS, ALK, ROS1, BRAF, NTRK, ERBB2, RET, MET, PIK3CA, STK11, and TP53 alterations were assessed. We evaluated the differences by sex and age (<70 and ≥70) using Fisher's exact test. Of the 34,277 samples, 30,790 (89.83%) had a detectable mutation and 19,923 (58.12%) had an alteration of interest. The median age of the ctDNA positive population was 69 (18-102), 16,756 (54.42%) were female, and 28,835 (93.65%) had adenocarcinoma. Females had more alterations in all the assessed EGFR mutations, KRAS G12C, and ERBB2 ex20 ins. Males had higher numbers of MET amp and alterations in STK11 and TP53. Patients <70 years were more likely to have alterations in EGFR exon 19 del/exon 20 ins/T790M, KRAS G12C/D, ALK, ROS1, BRAF V600E, ERBB2 Ex20ins, MET amp, STK11, and TP53. Individuals ≥70 years were more likely to have alterations in EGFR L861Q, MET exon 14 skipping, and PIK3CA. We provided evidence of sex- and age-associated differences in the distribution of genomic alterations in individuals with advanced NSCLC.
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PURPOSE: In addition to the existing biomarkers HER2 and PD-L1, FGFR2b has become an area of interest for the development of new targeted-based treatment. Given that clinical evaluation of FGFR2 targeted therapy is underway, we sought to elucidate the genomic landscape of FGFR2amp in gastroesophageal cancer (GEC) using a circulating tumor DNA (ctDNA) platform. MATERIALS AND METHODS: We retrospectively evaluated the Guardant Health database from 2017 to 2022 for patients with GECs with Guardant360 ctDNA next-generation sequencing (NGS) performed. We assessed co-occurring genetic alterations for patients who harbored FGFR2amp versus FGFR2null. We also explored real-world evidence database with Guardant Health, publicly available genomic databases (MSK cohort using cBioPortal), and pooled clinical data from large-volume cancer centers for FGFR2amp GECs. RESULTS: Less than 4% of patients with GEC in the Guardant Health database were identified to be FGFR2amp. The most commonly co-occurring gene mutations were TP53, CTNNB1, CDH1, and RHOA. Upon interrogation of the MSK cohort, these same genes were not significant on tissue NGS in the FGFR2amp cohort of GEC. In the pooled institutional cohort, we noted that FGFR2amp tumors were most commonly involving the gastroesophageal junction (GEJ). The overall survival of these patients was noted at 13.1 months. CONCLUSION: FGFR2 is a validated target in GECs, and the contexture of FGFR2amp will be important in defining patient subgroups with responses to FGFR2-directed therapy. Using ctDNA to provide a more detailed genomic landscape in patients with GECs will allow the advancement of targeted therapy in the near future for these aggressive cancers.
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ADN Tumoral Circulante , Neoplasias Esofágicas , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos , Neoplasias Gástricas , Humanos , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/sangre , Neoplasias Esofágicas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/sangre , Neoplasias Gástricas/patología , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Anciano , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , AdultoRESUMEN
Pathogenic germline variants (PGVs) may be under-detected as causative etiologies in patients with non-small cell lung cancer (NSCLC). The prevalence of PGVs has been reported between 1 and 15% of patients, depending on the patient population. The rate within Hispanic/Latinx populations remains unknown. We retrospectively analyzed the genomic results (Guardant360, Redwood City, CA, USA) of 878 patients with advanced or metastatic NSCLC at five centers in South Florida, USA, from 2019 to 2022 to analyze the rate of incidental PGVs (iPGVs) identified via circulating cell-free tumor DNA (ctDNA). We then stratified the results by tumor histology, age, gender, race, ethnicity, genetic pathway, and co-mutations. Twenty-one iPGVs were identified (21/878 = 2.4%). Among the 21 iPGVs identified, 14 patients were female (66.7%) and 7 were male (33.3%), with a median age of 67 years and tobacco history of 2.5 pack-years. In total, 52.4% of patients identified as Hispanic/Latinx (n = 11) of any race; 19.0% as Ashkenazi Jewish (n = 4), 9.5% as non-Hispanic/Latinx black (n = 2), and 19.0% as non-Hispanic/Latinx white (n = 4). iPGVs in the homologous recombination repair pathway were solely expressed in this cohort (10 ATM, 8 BRCA2, and 3 BRCA1). In total, 76% (16/21) of patients with iPGVs co-expressed somatic alterations, with 56% (9/16) demonstrating alterations in targetable genes. Overall, our real-world findings offer a point prevalence of iPGVs in patients with NSCLC of diverse populations, such as patients who report Hispanic/Latinx ethnicity.
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Although V600E accounts for the majority of the BRAF mutations in metastatic colorectal cancer (mCRC), non-V600 BRAF variants have been shown in recent years to represent a distinct molecular subtype. This study provides a comprehensive profile of BRAF variants in mCRC using a large genomic database of circulating tumor DNA (ctDNA) and analyzing clinical outcomes in a cohort of patients with atypical (non-V600) BRAF variants (aBRAF; class II, class III, unclassified). Overall, 1733 out of 14,742 mCRC patients in the ctDNA cohort had at least one BRAF variant. Patients with atypical BRAF variants tended to be younger and male. In contrast to BRAFV600E, BRAF class II and III variants and their co-occurrence with KRAS/NRAS mutations were increased at baseline and especially with those patients predicted to have prior anti-EGFR exposure. Our clinical cohort included 38 patients with atypical BRAF mCRC treated at a large academic referral center. While there were no survival differences between atypical BRAF classes, concurrent RAS mutations or liver involvement was associated with poorer prognosis. Notably, patients younger than 50 years of age had extremely poor survival. In these patients, the high-frequency KRAS/NRAS co-mutation and its correlation with poorer prognosis underlines the urgent need for novel therapeutic strategies. This study represents one of the most comprehensive characterizations to date of atypical BRAF variants, utilizing both ctDNA and clinical cohorts.
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Background: The limited availability of targeted therapies in thyroid cancer (TC) has challenged conventional treatment algorithms and has established urgency for the identification of targetable genomic abnormalities. In addition to widely adopted tissue-based next-generation sequencing (NGS), plasma-based circulating tumor DNA (ctDNA) NGS is rapidly emerging as a genomic biomarker detection method and is steadily gaining utility across solid tumors. To date, plasma-based genomic alterations in TC have not been determined. Herein, we profile potential actionable mutations detected through ctDNA in patients with TC subtypes. Methods: A retrospective data analysis of the Guardant Health, Inc. database was performed using the commercially available Guardant360® plasma-NGS test on TC samples from adult patients collected between 2016 and 2021. The landscape of genomic alterations and blood tumor mutation burden (bTMB) were analyzed in patients with different types of TC: anaplastic TC (ATC), papillary TC (PTC), follicular TC (FTC), oncolytic carcinoma of the thyroid (OCA), poorly differentiated TC (PDTC), medullary TC (MTC), and TC not otherwise specified (TC NOS). Results: Of the 1094 patients included most of the patients n = 876 had TC NOS, and 20% had a specific diagnosis (92 ATC, 62 PTC, 14 FTC, 16 OCA, 2 PDTC, and 32 MTC patients). The median age was 65 (range 10-98) and 47.3% were male. 78.3% of patients had one or more genomic alteration detected by ctDNA NGS. TP53 (46.9%) was the most common mutation detected among all TC. BRAFV600E was detected in 27.2% of ATC, 35.7% of PTC, and in none of FTC. RAS was detected in 18.5% of ATC, 11.9% of PTC, and 62.5% of FTC. RET, ALK, and NTRK fusions were seen in 1.1%, 0.5%, and 0.2% of all TC, respectively. RET mutations were detected in 66.7% of MTC. bTMB analysis was performed on 159 patients. The mean bTMB was higher in ATC compared with other types of TC (p = 0.0011, 0.0557, and <0.0001, respectively). Conclusions: Plasma-based comprehensive NGS is a promising NGS method in TC; however, future validation of the clinical utility by analysis of paired tumor and plasma samples is needed.
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ADN Tumoral Circulante , Prolina/análogos & derivados , Tiocarbamatos , Neoplasias de la Tiroides , Adulto , Humanos , Masculino , Anciano , Femenino , ADN Tumoral Circulante/genética , Estudios Retrospectivos , Neoplasias de la Tiroides/patología , Mutación , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento/métodosRESUMEN
PURPOSE: In metastatic colorectal cancer, the detection of RAS mutations by circulating tumor DNA (ctDNA) has emerged as a valid and noninvasive alternative approach to determining RAS status. However, some RAS mutations may be missed, that is, false negatives can occur, possibly compromising important treatment decisions. We propose a statistical model to assess the probability of false negatives when performing ctDNA testing for RAS. METHODS: Cohorts of 172 subjects with tissue and multipanel ctDNA testing from MD Anderson Cancer Center and 146 subjects from Massachusetts General Hospital were collected. We developed a Bayesian model that uses observed frequencies of reference mutations (the maximum of APC and TP53) to provide information about the probability of KRAS false negatives. The model was alternatively trained on one cohort and tested on the other. All data were collected on Guardant assays. RESULTS: The model suggests that negative KRAS findings are believable when the maximum of APC and TP53 frequencies is at least 8% (corresponding posterior probability of false negative <5%). Validation studies demonstrated the ability of our tool to discriminate between false-negative and true-negative subjects. Simulations further confirmed the utility of the proposed approach. CONCLUSION: We suggest clinicians use the tool to more precisely quantify KRAS false-negative ctDNA results when at least one of the reference mutations (APC, TP53) is observed; usage may be especially important for subjects with a maximum reference frequency of <8%. Extension of the methodology to predict false negatives of other genes is possible. Additional reference genes can also be considered. Use of personal training data sets is supported. An open-source R Shiny application is available for public use.
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ADN Tumoral Circulante , Neoplasias del Colon , Humanos , ADN Tumoral Circulante/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Teorema de Bayes , Mutación/genéticaRESUMEN
Purpose: Analysis of circulating tumor DNA (ctDNA) in patients with metastatic prostate cancer (mPC) provides an opportunity to identify and monitor genomic alterations during a patient's treatment course. We evaluated whether the presence of specific gene amplifications (GAs) and plasma copy number (PCN) alterations are associated with disease features. Methods: This is a single-institution retrospective study of patients with mPC who underwent ctDNA profiling using Guardant360® (Guardant Health Inc.). This test identifies single nucleotide variants (SNVs) and GAs of select genes by next-generation sequencing. A total of 155 men with mPC were studied. Patients were stratified by GA status. The Kaplan-Meier method and multivariate cox regression models were used to estimate overall survival (OS) or failure-free survival (FFS) from either the date of GA detection or the initiation of systemic therapy. The chi-square test was used to evaluate associations between clinical factors and GAs. Results: The presence of liver and/or lung metastases was associated with GAs of BRAF, CDK6, PI3KCA, and FGFR1. Survival analyses were completed on a subset of 83 patients with metastatic castration-resistant prostate cancer (mCRPC). Median OS was improved in patients with 1 GA compared to patients with ≥2 GAs, whether determined from the date of initial GA(s) detection (14.9 mo vs. 8.9 mo) or date of therapy initiation nearest to GA detection (16.7 mo vs. 9.0 mo). Patients without GAs had not reached median OS. Patients with androgen receptor (AR) GA only were also found to have better median OS compared to patients with AR GA plus at least one other additional GA (19.3 mo vs. 8.9 mo). Patients with PIK3CA GA had significantly lower median OS compared to patients with GAs that did not have a PIK3CA GA (5.9 mo vs. 16.0 mo). In patients with AR and/or MYC GA(s), median OS improved in those with reduced AR or MYC PCN during therapy compared to those without such a reduction (25.1 mo vs. 15.9 mo). Conclusions: The association of select GAs with survival provides an additional tool for assessing mCRPC prognosis and informing management. Serial monitoring of ctDNA GAs is also useful to guide prognosis and therapeutic response.
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INTRODUCTION: Defining clinically relevant MET amplification levels in non-small cell lung cancer (NSCLC) remains challenging. We hypothesize that oncogene overlap and MET amplicon size decline with increase in MET plasma copy number (pCN), thus enriching for MET-dependent states. PATIENTS AND METHODS: We interrogated cell-free DNA NGS results of 16,782 patients with newly diagnosed advanced NSCLC to identify those with MET amplification as reported using Guardant360. Co-occurring genomic mutations and copy number alterations within each sample were evaluated. An exploratory method of adjusting for tumor fraction was also performed and amplicon size for MET was analyzed when available. RESULTS: MET amplification was detected in 207 (1.2%) of samples. pCN ranged from 2.1 to 52.9. Of these, 43 (20.8%) had an overlapping oncogenic driver, including 23 (11.1%) METex14 skipping or other MET mutations. The degree of (non-MET) oncogene overlap decreased with increases in pCN. Patients with MET pCN ≥ 2.7 had lower rates of overlapping drivers compared to those with MET pCN < 2.7 (6.1% vs. 16.3%, P = .033). None of the 7 patients with pCN > 6.7 had an overlapping driver. After adjusting for tumor fraction, adjusted pCN (ApCN) was also lower for those with overlapping drivers than those without (median ApCN 4.9 vs. 7.3, P =.024). There was an inverse relationship between amplicon size and pCN. CONCLUSIONS: We propose that a high MET pCN and/or ApCN, together with the absence of overlapping oncogenic drivers and small MET amplicon size, will enrich for patients most likely to derive benefit from MET targeted therapy.
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Carcinoma de Pulmón de Células no Pequeñas , Ácidos Nucleicos Libres de Células , ADN Tumoral Circulante , Neoplasias Pulmonares , Humanos , Carcinogénesis/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Ácidos Nucleicos Libres de Células/genética , ADN Tumoral Circulante/genética , Variaciones en el Número de Copia de ADN/genética , Exones , Neoplasias Pulmonares/patología , Oncogenes , Proteínas Proto-Oncogénicas c-met/genéticaRESUMEN
BACKGROUND: Elevated serum carcinoembryonic antigen (CEA) is used to identify "treatment emergent" forms of castration-resistant prostate cancer (CRPC) such as aggressive variant prostate cancer (AVPC). However, its individual utility as a prognostic marker and the genetic alterations associated with its expression have not been extensively studied in CRPC. METHODS: This study retrospectively analyzed clinical outcomes and circulating tumor DNA profiles in 163 patients with CRPC and elevated or normal serum CEA. These same patients were then classified as AVPC or non-AVPC and compared to determine the uniqueness of CEA-associated gene alterations. RESULTS: Patients with elevated CEA demonstrated higher rates of liver metastasis (37.5% vs. 19.1%, p = 0.02) and decreased median overall survival from CRPC diagnosis (28.7 vs. 73.2 mo, p < 0.0001). In addition, patients with elevated CEA were more likely to harbor copy number amplifications (CNAs) in AR, PIK3CA, MYC, BRAF, CDK6, MET, CCNE1, KIT, RAF1, and KRAS. Based on variant allele frequency we also defined "clonal" single-nucleotide variants (SNVs) thought to be driving disease progression in each patient and found that CEA expression was negatively correlated with clonal AR SNVs and positively correlated with clonal TP53 SNVs. Of these genetic associations, only the increases in clonal TP53 SNVs and KRAS amplifications were recapitulated among patients with AVPC when compared to patients without AVPC. CONCLUSIONS: Together these findings suggest that CEA expression in CRPC is associated with aggressive clinical behavior and gene alterations distinct from those in AVPC.
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Antígeno Carcinoembrionario , ADN Tumoral Circulante , Neoplasias Hepáticas , Neoplasias de la Próstata Resistentes a la Castración , Antígeno Carcinoembrionario/sangre , Antígeno Carcinoembrionario/metabolismo , ADN Tumoral Circulante/genética , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Masculino , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Receptores Androgénicos/metabolismo , Estudios RetrospectivosRESUMEN
BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and heterogeneous malignancy with poor prognosis. We aimed to evaluate the feasibility of next-generation sequencing (NGS) testing of circulating cell-free tumor DNA (ctDNA) in patients with ACC, to characterize the genomic landscape of alterations, and to identify potential clinically actionable mutations. METHODS: Retrospective analysis of genomic data from 120 patients with ACC who had ctDNA testing between 12/2016 and 10/2021 using Guardant360 (Guardant Health, CA) was performed. ctDNA NGS analysis interrogated single nucleotide variants, fusions, indels, and copy number amplifications of up to 83 genes. The frequency of genomic alterations, landscape of co-occurring mutations, and pathogenic/likely pathogenic alterations with potential targeted therapies was identified. The prevalence of alterations identified in ctDNA was compared to those detected in tissue using a publicly available database (cBioPortal). RESULTS: The median age of this cohort was 53 years (range 21-81), and 56% of patients were female. Ninety-six patients (80%) had ≥1 somatic alteration detected. TP53 (52%), EGFR (23%), CTNNB1 (18%), MET (18%), and ATM (14%) were found to be the most frequently altered genes in ACC samples. Pathogenic and/or likely pathogenic mutations in therapeutically relevant genes were observed in 56 patients (47%) and included EGFR, BRAF, MET, CDKN2A, CDK4/6, and ATM. The most frequent co-occurring mutations were EGFR + MET (9%), MET + CDK4 (7%), EGFR + CDK4 (7%), and BRAF + MET (7%). The frequencies of mutations detected in ctDNA were similar to those detected in tissue. CONCLUSIONS: Utilizing blood-based NGS to characterize genomic alterations in advanced ACC is feasible in over 80% of patients. Almost half of the patients had actionable mutations with approved therapies in other cancers. This approach might inform the development of personalized treatment options or identify clinical trials available for this aggressive malignancy.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , ADN Tumoral Circulante , Neoplasias de la Corteza Suprarrenal/genética , Carcinoma Corticosuprarrenal/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Receptores ErbB/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Retrospectivos , Adulto JovenRESUMEN
Atypical carcinoids are a rare subset of neuroendocrine tumors that originate from cells within the bronchopulmonary tree. Compared to typical carcinoids, atypical carcinoids are associated with a worse prognosis. EML4-ALK fusions are reported in 5% of non-small cell lung carcinoma, but are rare in atypical carcinoids with only five previously reported cases. We report a case of a 70-year-old female with atypical carcinoid with metastasis to the liver and axial skeleton. She did not respond to standard of care chemotherapy with carboplatin and etoposide and was elected to enroll in hospice because of worsening clinical status. However, a circulating tumor DNA (ctDNA) sample was obtained the same day which revealed an EML4-ALK fusion gene. She immediately began therapy with the second-generation ALK inhibitor alectinib, with a remarkable symptomatic and radiographic response. Seven months later, the disease progression was demonstrated in the liver and the patient was switched to the third-generation ALK inhibitor lorlatinib. At the time of writing, the patient has continued to demonstrate sustained clinical, radiographic, and biochemical responses while on lorlatnib for two years. The dramatic treatment results highlighted in this case make the argument to consider ctDNA after the diagnosis of locally advanced or metastatic atypical carcinoid.
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BACKGROUND: Brigatinib, a second generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is central nervous system (CNS) penetrant and active against anaplastic lymphoma kinase (ALK) resistance mutations. We prospectively studied the activity of brigatinib in patients with disease progression after second generation ALK TKIs. METHODS: Patients with stage IIIB/IV ALKâ¯+â¯non-small cell lung cancer (NSCLC), and progressive disease after second ALK TKIs were eligible. Cohort A enrolled patients with disease progression on any second ALK TKI, cohort B enrolled patients with disease progression after first-line therapy with alectinib, and cohort C enrolled patients who experienced disease progression on standard dose brigatinib. Brigatinib treatment was 90â¯mg daily for seven days and then escalated to 180â¯mg daily in cohorts A and B, and 240â¯mg daily in cohort C. The primary endpoint was objective response rate (ORR), and a 2-stage design was used. The intended enrollment was 20 patients in stage 1, and 20 patients in stage 2. RESULTS: The study was closed due to slow accrual. Between March 2017 and June 2020, 32 patients received study therapy; three patients in cohort A moved to cohort C after initial progression for a total of 35 study subjects. Of the 32 patients, 16 (50%) were male, the median age was 55â¯years (range 32-76), and patients received a median number of 2 prior ALK TKI's (range 1-3). Cohort A enrolled 27 patients, cohort B enrolled four patients, and cohort C enrolled four patients. The ORR in cohorts A, B, and C was 33% (95% confidence interval (CI: 16% to 54%), 25% (95% CI: 0.63% to 81%), and 0%, respectively. CONCLUSION: Brigatinib has activity in ALK positive NSCLC patients with disease progression after second generation ALK TKIs.
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BACKGROUND: Somatic genomic testing is recommended by numerous expert guidelines to inform targeted therapy treatment for patients with advanced nonsquamous non-small cell lung cancer (aNSCLC). The NILE study was a prospective observational study that demonstrated noninferiority of cell-free circulating tumor DNA (cfDNA)-based tumor genotyping compared to tissue-based genotyping to find targetable genomic alterations in patients with newly diagnosed nonsquamous aNSCLC. As the cohort has matured, clinical outcomes data can now be analyzed. METHODS: This prospective, multicenter North American study enrolled patients with previously untreated nonsquamous aNSCLC who had standard of care (SOC) tissue genotyping performed and concurrent comprehensive cfDNA analysis (Guardant360). Patients with targetable genomic alterations, as defined by NCCN guidelines, who were treated with physician's choice of therapy had objective response rates, disease control rate, and time to treatment collected and compared to published outcomes. RESULTS: Among 282 patients, 89 (31.6%) had an actionable biomarker, as defined by NCCN, detected by tissue (21.3%) and/or cfDNA (27.3%) analysis. Sixty-one (68.5%) of these were treated with an FDA-approved targeted therapy guided by somatic genotyping results (EGFR, ALK, ROS1). Thirty-three patients were eligible for clinical response evaluation and demonstrated an objective response rate of 58% and disease control rate of 94%. Twenty-five (76%) and 17 (52%) achieved a durable response > 6 months and 12 months, respectively. The time to treatment (TtT) was significantly faster for cfDNA-informed biomarker detection as compared to tissue genotyping (18 vs. 31 days, respectively; P = .0008). CONCLUSIONS: cfDNA detects guideline-recommended biomarkers at a rate similar to tissue genotyping, and therapeutic outcomes based on plasma-based comprehensive genomic profiling are comparable to published targeted therapy outcomes with tissue profiling, even in community-based centers.
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Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Perfil Genético , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Evaluación de Resultado en la Atención de Salud , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , ADN Tumoral Circulante/genética , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , América del Norte , Estudios ProspectivosRESUMEN
METex14 skipping mutations occur in about 3-4% of lung adenocarcinoma patients and 1-2% of patients with other lung cancer histology. The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) are established oncogenic drivers of NSCLC. A mutation that results in loss of exon 14 in the MET gene leads to dysregulation and inappropriate signaling that is associated with increased responsiveness to MET TKIs. Results from GEOMETRY mono-1 and VISION Phase I/II clinical trials demonstrated significant clinical activity in patients treated with the MET Exon 14 skipping mutation inhibitors capmatinib and tepotinib with tolerable toxicity profile. In the GEOMETRY mono-1 trial, capmatinib was especially active in treatment-naïve patients supporting the upfront testing of this oncogenic driver. Tepotinib demonstrated superior activity in the pretreated patients in the VISION trial. Savolitinib is another MET TKI that has shown efficacy in the first- and second-line settings, including patients with aggressive pulmonary sarcomatoid carcinoma. These studies have demonstrated that these TKIs can cross the blood brain barrier and demonstrated some activity toward CNS metastases. MET Exon 14 skipping mutation is detected by NGS-based testing of liquid or tissue biopsies, with preference for RNA-based NGS. The activity of capmatinib and tepotinib is limited by the development of acquired resistance. Current research is focused on strategies to overcome resistance and improve the effectiveness of these agents. Our aim is to review the current status of MET Exon 14 skipping mutation as it pertains NSCLC.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-met/genética , Animales , Benzamidas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Ensayos Clínicos como Asunto , Humanos , Imidazoles/uso terapéutico , Neoplasias Pulmonares/genética , Mutación/efectos de los fármacos , Piperidinas/uso terapéutico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirazinas/uso terapéutico , Piridazinas/uso terapéutico , Pirimidinas/uso terapéutico , Triazinas/uso terapéuticoRESUMEN
Pembrolizumab has been approved by the US Food and Drug Administration for the treatment of metastatic or unresectable solid tumors that are microsatellite instability-high (MSI-H) or mismatch repair deficient. Blood-based circulating tumor DNA (ctDNA) assays have been validated to identify tumors with MSI-H status without the need for tissue biopsy. We report 2 patients with metastatic castration-resistant prostate cancer (mCRPC) who had prior treatment with multiple lines of therapy and underwent ctDNA testing, which detected MSI-H status. Both patients were treated with pembrolizumab, resulting in an excellent clinical response measured with liquid biopsies before and after initiation of therapy, which demonstrated a significant reduction in somatic-variant allele frequency in addition to a decrease in prostate serum antigen levels.
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The recent approvals by the Food and Drug Administration several tumor-agnostic drugs have resulted in a paradigm shift in cancer treatment from an organ/histology-specific strategy to biomarker-guided approaches. RET gene fusions are oncogenic drivers in multiple tumor types and are known to occur in 1-2% of non-squamous NSCLC patients. RET gene fusions give rise to chimeric, cytosolic proteins with constitutively active RET kinase domain. Standard therapeutic regimens provide limited benefit for NSCLC patients with RET fusion-positive tumors, and the outcomes with immunotherapy in the these patients are generally poor. Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are potent and selective inhibitors that target RET alterations, including fusions and mutations, irrespective of the tissue of origin. Recently, the results from the LIBRETTO-001 and ARROW clinical trials demonstrated significant clinical benefits with selpercatinib and pralsetinib respectively, in NSCLC patients with RET gene fusions, with tolerable toxicity profiles. These studies also demonstrated that these RET-TKIs crossed the blood brain barrier with significant activity. As has been observed with other TKIs, the emergence of acquired resistance may limit long-term efficacy of these agents. Therefore, understanding the mechanisms of resistance is necessary for the development of strategies to overcome them.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas c-ret/genética , Proto-Oncogenes/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/patologíaRESUMEN
PURPOSE: Recent advances in molecular diagnostic technologies allow for the evaluation of solid tumor malignancies through noninvasive blood sampling, including circulating tumor DNA profiling (ctDNA). Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, often because of late presentation of disease. Diagnosis is often made using endoscopic ultrasound or endoscopic retrograde cholangiopancreatography, which often does not yield enough tissue for next-generation sequencing. With this study, we sought to characterize the ctDNA genomic alteration landscape in patients with advanced PDAC with a focus on actionable findings. MATERIALS AND METHODS: From December 2014 through October 2019, 357 samples collected from 282 patients with PDAC at Mayo Clinic underwent ctDNA testing using a clinically available assay. The majority of samples were tested using the 73-gene panel which includes somatic genomic targets, including complete or critical exon coverage in 30 and 40 genes, respectively, and in some, amplifications, fusions, and indels. Clinical data and outcome variables were available for 165 patients; with 104 patients at initial presentation. RESULTS: All patients included in this study had locally advanced or metastatic PDAC. Samples having at least one alteration, when variants of unknown significance (VUS) were excluded, numbered 266 (75%). After excluding VUS, therapeutically relevant alterations were observed in 170 (48%) of the total 357 cohort, including KRAS (G12C), EGFR, ATM, MYC, BRCA, PIK3CA, and BRAF mutations. KRAS, SMAD, CCND2, or TP53 alterations were seen in higher frequency in patients with advanced disease. CONCLUSION: Our study is the largest cohort to date that demonstrates the feasibility of ctDNA testing in PDAC. We provide a benchmark landscape upon which the field can continue to grow. Future applications may include use of ctDNA to guide treatment and serial monitoring of ctDNA during disease course to identify novel therapeutic targets for improved prognosis. IMPLICATIONS FOR PRACTICE: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis often due to late presentation of disease. Biopsy tissue sampling is invasive and samples are often inadequate, requiring repeated invasive procedures and delays in treatment. Noninvasive methods to identify PDAC early in its course may improve prognosis in PDAC. Using ctDNA, targetable genes can be identified and used for treatment.
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Adenocarcinoma , Carcinoma Ductal Pancreático , ADN Tumoral Circulante , Neoplasias Pancreáticas , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , ADN Tumoral Circulante/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genéticaRESUMEN
BACKGROUND: Plasma-based circulating cell-free tumor DNA (ctDNA) genomic profiling by next-generation sequencing (NGS)is an emerging diagnostic tool for pancreatic cancer (PC). The impact of detected genomic alterations and variant allele fraction (VAF) in tumor response to systemic treatments and outcomes is under investigation. METHODS: Patients with advanced PC who had ctDNA profiled at time of initial diagnosis were retrospectively evaluated. We considered the somatic alteration with the highest VAF as the dominant clone allele frequency (DCAF). ctDNA NGS results were related to clinical demographics, progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 104 patients were evaluated. Somatic alterations were detected in 84.6% of the patients. Patients with ≥ 2 detectable genomic alterations had worse median PFS (p < 0.001) and worse median OS (p = 0.001). KRAS was associated with disease progression to systemic treatments (80.4% vs 19.6%, p = 0.006), worse median PFS (p < 0.001) and worse median OS (p = 0.002). TP53 was associated with worse median PFS (p = 0.02) and worse median OS (p = 0.001). The median DCAF was 0.45% (range 0-55%). DCAF >0.45% was associated with worse median PFS (p<0.0001) and median OS (p=0.0003). Patients that achieved clearance of KRAS had better PFS (p=0.047), while patients that achieved clearance of TP53 had better PFS (p=0.0056) and OS (p=0.037). CONCLUSIONS: Initial detection of ctDNA in advanced PC can identify somatic alterations that may help predict clinical outcomes. The dynamics of ctDNA are prognostic of outcomes and should be evaluated in prospective studies.