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The type of epidermal growth factor receptor (EGFR) mutation, L858R or exon 19 deletion, detected in either tissue or circulating free DNA, was significantly associated with outcomes in a study of patients with advanced NSCLC, a study has shown.
The findings were published online Feb. 26 in JAMA Oncology.
The results suggest the potential of liquid biopsies or circulating free (cfDNA) as a substitute for tumor biopsy to detect EGFR mutations.
“The amount of tumor tissue obtained by biopsy is often insufficient, especially in advanced NSCLC, raising the question of whether cfDNA may be used as a surrogate liquid biopsy for the noninvasive assessment of EGFR mutations,” wrote Dr. Niki Karachaliou and associates (JAMA Oncol. 2015 Feb. 26 [doi:10.1001/jamaoncol.2014.257]).
From 173 patients with oncogenic EGFR mutations (identified by tumor biopsy) enrolled in the EURTAC trial, 97 blood samples were suitable for analysis to detect EGFR mutations in cfDNA, and 76 (78%) EGFR mutations were detected from the blood samples. The investigators developed a novel peptide nucleic acid-mediated PCR assay with 78% sensitivity and 100% specificity, an improvement from sensitivity rates for other methods reported to be below 65%.
Overall, the median OS for the 173 patients enrolled in the EURTAC study was 22.9 months (95% CI, 17.0-30.9) for those in the erlotinib arm vs. 22.1 months (16.5-28.4) for the chemotherapy arm. As in previous study findings, OS for patients with the exon 19 deletion detected in tissue were significantly longer than for those with L858R mutations (25.0 months [18.9-30.9] vs 17.7 [13.5-23.5]; P = .001). In the subset of 97 samples that underwent cfDNA analysis, the OS for those with exon 19 deletions was 30.0 months (19.3-37.7) vs. 13.7 months (7.1-17.7) for L858R mutations (P < .001). Among the 40 samples in the erlotinib arm with EGFR mutations detected in cfDNA, the median OS for exon 19 deletions was 34.4 months (22.9-not reached) vs 13.7 months (2.6-21.9) for L858R mutations (P = .001).
Patients with L858R mutations detected in both tissue and cfDNA had significantly shorter median OS than did those with L858R detected in tissue only (13.7 vs 27.7 months; HR, 2.22; P = .03), reported Dr. Karachaliou of Quiron-Dexeus University Hospital, Barcelona.
For patients in the erlotinib arm, progression-free survival was longer for those with exon 19 deletions than L858R mutations, detected both in tissue and cfDNA. No significant difference in PFS was seen in the chemotherapy arm based on EGFR mutation type.
“The shorter OS – both for all patients and for those receiving erlotinib therapy – observed in the present study among patients with L858R mutations in tissue or cfDNA reinforces this concept of the existence of more than one clinical phenotype of EGFR-mutant NSCLC and suggests that in future analyses, outcomes of patients with exon 19 deletions and those with L858R mutations should not be pooled,” Dr. Karachaliou wrote.
Citing the favorable comparison between their assay and previous methods, the authors concluded that “cfDNA may be a promising method for screening for EGFR mutations in clinical studies, minimizing the need for invasive tumor biopsies.”
Several studies have shown that patients with advanced NSCLC and with activating EGFR mutations have higher response rates to EGFR tyrosine kinase inhibitor (TKI) therapy. Karachaliou et al. demonstrated the relationship between EGFR mutation status as determined by analysis of cfDNA and outcomes. Importantly, the cfDNA data are consistent with mutation data from tissue samples in showing that although both EGFR mutation types benefit from TKI therapy, exon 19 deletions have higher median PFS and OS than L858R mutations.
Other studies similarly show different outcomes depending on the type of EGFR mutation. The IPASS trial examined gefitinib, LUX-3 and LUX-6 studied afatinib, and JO25567 compared erlotinib alone or in combination with bevacizumab; all demonstrated greater benefits of TKI therapy in patients with exon 19 deletions. The mechanism to explain the observed differences remains unclear. Given the negative prognostic indication, patients with L858R mutations should be considered for more aggressive treatment strategies, such as targeting EGFR with afatinib plus cetuximab or higher doses of TKIs.
Detection of EGFR mutation in cfDNA has advantages over tissue biopsy. First, tumor samples are limited and biopsy procedures carry the risk of complications. The cfDNA “liquid biopsy” offers a noninvasive procedure that has potential for use in serial evaluations, rarely feasible with biopsies. Serial evaluations could monitor the emergence of drug resistance, such as the second site mutation at position T790M in EGFR, the most common mechanism of acquired resistance to TKI therapy. Finally, cfDNA provides information on the entire tumor landscape, including primary and metastatic cells, unlike tissue biopsy, which is confined to one tumor site. Given the heterogeneity of most lung cancers, a broad analysis would have benefits in devising optimal treatment strategies. Detecting specific mutations in cfDNA may help to identify patients who will respond better to alternative treatments.
Dr. Daniel Morgensztern is an oncologist at Washington University, St. Louis. Dr. Katerina Politi and Dr. Roy S. Herbst are at the Yale School of Medicine, New Haven, Conn. Dr. Morgensztern reported a consulting role with Boehringer-Ingelheim and an advisory role with Celgene. Dr. Politi reported receiving a grant from Astra Zeneca, ownership in MolecularMD/Memorial Sloan Kettering Cancer Center, and a consulting or advisory role with Takeda. Dr. Herbst reported a consulting role for Genentech. The authors made these remarks in an editorial accompanying the report by Dr. Karachaliou et al. (JAMA Oncol. 2015 Feb. 26 [doi:10.1001/jamaoncol.2014.278]).
Several studies have shown that patients with advanced NSCLC and with activating EGFR mutations have higher response rates to EGFR tyrosine kinase inhibitor (TKI) therapy. Karachaliou et al. demonstrated the relationship between EGFR mutation status as determined by analysis of cfDNA and outcomes. Importantly, the cfDNA data are consistent with mutation data from tissue samples in showing that although both EGFR mutation types benefit from TKI therapy, exon 19 deletions have higher median PFS and OS than L858R mutations.
Other studies similarly show different outcomes depending on the type of EGFR mutation. The IPASS trial examined gefitinib, LUX-3 and LUX-6 studied afatinib, and JO25567 compared erlotinib alone or in combination with bevacizumab; all demonstrated greater benefits of TKI therapy in patients with exon 19 deletions. The mechanism to explain the observed differences remains unclear. Given the negative prognostic indication, patients with L858R mutations should be considered for more aggressive treatment strategies, such as targeting EGFR with afatinib plus cetuximab or higher doses of TKIs.
Detection of EGFR mutation in cfDNA has advantages over tissue biopsy. First, tumor samples are limited and biopsy procedures carry the risk of complications. The cfDNA “liquid biopsy” offers a noninvasive procedure that has potential for use in serial evaluations, rarely feasible with biopsies. Serial evaluations could monitor the emergence of drug resistance, such as the second site mutation at position T790M in EGFR, the most common mechanism of acquired resistance to TKI therapy. Finally, cfDNA provides information on the entire tumor landscape, including primary and metastatic cells, unlike tissue biopsy, which is confined to one tumor site. Given the heterogeneity of most lung cancers, a broad analysis would have benefits in devising optimal treatment strategies. Detecting specific mutations in cfDNA may help to identify patients who will respond better to alternative treatments.
Dr. Daniel Morgensztern is an oncologist at Washington University, St. Louis. Dr. Katerina Politi and Dr. Roy S. Herbst are at the Yale School of Medicine, New Haven, Conn. Dr. Morgensztern reported a consulting role with Boehringer-Ingelheim and an advisory role with Celgene. Dr. Politi reported receiving a grant from Astra Zeneca, ownership in MolecularMD/Memorial Sloan Kettering Cancer Center, and a consulting or advisory role with Takeda. Dr. Herbst reported a consulting role for Genentech. The authors made these remarks in an editorial accompanying the report by Dr. Karachaliou et al. (JAMA Oncol. 2015 Feb. 26 [doi:10.1001/jamaoncol.2014.278]).
Several studies have shown that patients with advanced NSCLC and with activating EGFR mutations have higher response rates to EGFR tyrosine kinase inhibitor (TKI) therapy. Karachaliou et al. demonstrated the relationship between EGFR mutation status as determined by analysis of cfDNA and outcomes. Importantly, the cfDNA data are consistent with mutation data from tissue samples in showing that although both EGFR mutation types benefit from TKI therapy, exon 19 deletions have higher median PFS and OS than L858R mutations.
Other studies similarly show different outcomes depending on the type of EGFR mutation. The IPASS trial examined gefitinib, LUX-3 and LUX-6 studied afatinib, and JO25567 compared erlotinib alone or in combination with bevacizumab; all demonstrated greater benefits of TKI therapy in patients with exon 19 deletions. The mechanism to explain the observed differences remains unclear. Given the negative prognostic indication, patients with L858R mutations should be considered for more aggressive treatment strategies, such as targeting EGFR with afatinib plus cetuximab or higher doses of TKIs.
Detection of EGFR mutation in cfDNA has advantages over tissue biopsy. First, tumor samples are limited and biopsy procedures carry the risk of complications. The cfDNA “liquid biopsy” offers a noninvasive procedure that has potential for use in serial evaluations, rarely feasible with biopsies. Serial evaluations could monitor the emergence of drug resistance, such as the second site mutation at position T790M in EGFR, the most common mechanism of acquired resistance to TKI therapy. Finally, cfDNA provides information on the entire tumor landscape, including primary and metastatic cells, unlike tissue biopsy, which is confined to one tumor site. Given the heterogeneity of most lung cancers, a broad analysis would have benefits in devising optimal treatment strategies. Detecting specific mutations in cfDNA may help to identify patients who will respond better to alternative treatments.
Dr. Daniel Morgensztern is an oncologist at Washington University, St. Louis. Dr. Katerina Politi and Dr. Roy S. Herbst are at the Yale School of Medicine, New Haven, Conn. Dr. Morgensztern reported a consulting role with Boehringer-Ingelheim and an advisory role with Celgene. Dr. Politi reported receiving a grant from Astra Zeneca, ownership in MolecularMD/Memorial Sloan Kettering Cancer Center, and a consulting or advisory role with Takeda. Dr. Herbst reported a consulting role for Genentech. The authors made these remarks in an editorial accompanying the report by Dr. Karachaliou et al. (JAMA Oncol. 2015 Feb. 26 [doi:10.1001/jamaoncol.2014.278]).
The type of epidermal growth factor receptor (EGFR) mutation, L858R or exon 19 deletion, detected in either tissue or circulating free DNA, was significantly associated with outcomes in a study of patients with advanced NSCLC, a study has shown.
The findings were published online Feb. 26 in JAMA Oncology.
The results suggest the potential of liquid biopsies or circulating free (cfDNA) as a substitute for tumor biopsy to detect EGFR mutations.
“The amount of tumor tissue obtained by biopsy is often insufficient, especially in advanced NSCLC, raising the question of whether cfDNA may be used as a surrogate liquid biopsy for the noninvasive assessment of EGFR mutations,” wrote Dr. Niki Karachaliou and associates (JAMA Oncol. 2015 Feb. 26 [doi:10.1001/jamaoncol.2014.257]).
From 173 patients with oncogenic EGFR mutations (identified by tumor biopsy) enrolled in the EURTAC trial, 97 blood samples were suitable for analysis to detect EGFR mutations in cfDNA, and 76 (78%) EGFR mutations were detected from the blood samples. The investigators developed a novel peptide nucleic acid-mediated PCR assay with 78% sensitivity and 100% specificity, an improvement from sensitivity rates for other methods reported to be below 65%.
Overall, the median OS for the 173 patients enrolled in the EURTAC study was 22.9 months (95% CI, 17.0-30.9) for those in the erlotinib arm vs. 22.1 months (16.5-28.4) for the chemotherapy arm. As in previous study findings, OS for patients with the exon 19 deletion detected in tissue were significantly longer than for those with L858R mutations (25.0 months [18.9-30.9] vs 17.7 [13.5-23.5]; P = .001). In the subset of 97 samples that underwent cfDNA analysis, the OS for those with exon 19 deletions was 30.0 months (19.3-37.7) vs. 13.7 months (7.1-17.7) for L858R mutations (P < .001). Among the 40 samples in the erlotinib arm with EGFR mutations detected in cfDNA, the median OS for exon 19 deletions was 34.4 months (22.9-not reached) vs 13.7 months (2.6-21.9) for L858R mutations (P = .001).
Patients with L858R mutations detected in both tissue and cfDNA had significantly shorter median OS than did those with L858R detected in tissue only (13.7 vs 27.7 months; HR, 2.22; P = .03), reported Dr. Karachaliou of Quiron-Dexeus University Hospital, Barcelona.
For patients in the erlotinib arm, progression-free survival was longer for those with exon 19 deletions than L858R mutations, detected both in tissue and cfDNA. No significant difference in PFS was seen in the chemotherapy arm based on EGFR mutation type.
“The shorter OS – both for all patients and for those receiving erlotinib therapy – observed in the present study among patients with L858R mutations in tissue or cfDNA reinforces this concept of the existence of more than one clinical phenotype of EGFR-mutant NSCLC and suggests that in future analyses, outcomes of patients with exon 19 deletions and those with L858R mutations should not be pooled,” Dr. Karachaliou wrote.
Citing the favorable comparison between their assay and previous methods, the authors concluded that “cfDNA may be a promising method for screening for EGFR mutations in clinical studies, minimizing the need for invasive tumor biopsies.”
The type of epidermal growth factor receptor (EGFR) mutation, L858R or exon 19 deletion, detected in either tissue or circulating free DNA, was significantly associated with outcomes in a study of patients with advanced NSCLC, a study has shown.
The findings were published online Feb. 26 in JAMA Oncology.
The results suggest the potential of liquid biopsies or circulating free (cfDNA) as a substitute for tumor biopsy to detect EGFR mutations.
“The amount of tumor tissue obtained by biopsy is often insufficient, especially in advanced NSCLC, raising the question of whether cfDNA may be used as a surrogate liquid biopsy for the noninvasive assessment of EGFR mutations,” wrote Dr. Niki Karachaliou and associates (JAMA Oncol. 2015 Feb. 26 [doi:10.1001/jamaoncol.2014.257]).
From 173 patients with oncogenic EGFR mutations (identified by tumor biopsy) enrolled in the EURTAC trial, 97 blood samples were suitable for analysis to detect EGFR mutations in cfDNA, and 76 (78%) EGFR mutations were detected from the blood samples. The investigators developed a novel peptide nucleic acid-mediated PCR assay with 78% sensitivity and 100% specificity, an improvement from sensitivity rates for other methods reported to be below 65%.
Overall, the median OS for the 173 patients enrolled in the EURTAC study was 22.9 months (95% CI, 17.0-30.9) for those in the erlotinib arm vs. 22.1 months (16.5-28.4) for the chemotherapy arm. As in previous study findings, OS for patients with the exon 19 deletion detected in tissue were significantly longer than for those with L858R mutations (25.0 months [18.9-30.9] vs 17.7 [13.5-23.5]; P = .001). In the subset of 97 samples that underwent cfDNA analysis, the OS for those with exon 19 deletions was 30.0 months (19.3-37.7) vs. 13.7 months (7.1-17.7) for L858R mutations (P < .001). Among the 40 samples in the erlotinib arm with EGFR mutations detected in cfDNA, the median OS for exon 19 deletions was 34.4 months (22.9-not reached) vs 13.7 months (2.6-21.9) for L858R mutations (P = .001).
Patients with L858R mutations detected in both tissue and cfDNA had significantly shorter median OS than did those with L858R detected in tissue only (13.7 vs 27.7 months; HR, 2.22; P = .03), reported Dr. Karachaliou of Quiron-Dexeus University Hospital, Barcelona.
For patients in the erlotinib arm, progression-free survival was longer for those with exon 19 deletions than L858R mutations, detected both in tissue and cfDNA. No significant difference in PFS was seen in the chemotherapy arm based on EGFR mutation type.
“The shorter OS – both for all patients and for those receiving erlotinib therapy – observed in the present study among patients with L858R mutations in tissue or cfDNA reinforces this concept of the existence of more than one clinical phenotype of EGFR-mutant NSCLC and suggests that in future analyses, outcomes of patients with exon 19 deletions and those with L858R mutations should not be pooled,” Dr. Karachaliou wrote.
Citing the favorable comparison between their assay and previous methods, the authors concluded that “cfDNA may be a promising method for screening for EGFR mutations in clinical studies, minimizing the need for invasive tumor biopsies.”
FROM JAMA ONCOLOGY
Key clinical point: The EGFR mutation L858R detected in both tissue and cfDNA predicted shorter OS and PFS than did the exon 19 deletion.
Major finding: Among patients treated with erlotinib, median OS was 34.4 months in those with exon 19 deletions compared with 13.7 months for L858R mutations detected in cfDNA (P = .001).
Data source: Blood samples from 97 patients with advanced NSCLC enrolled in the EURTAC trial, 49 treated with erlotinib and 48 with chemotherapy, were analyzed for EGFR mutations in cfDNA.
Disclosures: Dr. Karachaliou and most coauthors had no disclosures. One coauthor reported a consulting or advisory role with Roche. Another reported consulting or advisory roles with Lilly, Pfizer, Roche, Boehringer Ingelheim, Astra Zeneca, and Novartis.