Osimertinib benefit inEGFR-mutant NSCLC patients withT790M-mutation detected by circulating tumour DNA

Remón, Jordi; Caramella, Caroline; Jovelet, Cécile; Lacroix, Ludovic; Lawson, Andrew; Smalley, Sarah; Howarth, Karen; Gale, Davina; Green, E.; Plagnol, Vincent; Rosenfeld, Nitzan; Planchard, David; Bluthgen, M.V.; Gazzah, Anas; Pannet, Chloe; Nicotra, Claudio; Auclin, Édouard; Soria, Jean Charles; Besse, Benjamin

doi:10.1093/annonc/mdx017

Cited by 152 publications

(146 citation statements)

References 20 publications

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“…A number of generations of inhibitors (e.g., erlotinib, gefitinib, afatinib, and osimertinib) have been developed to target specific EGFR mutations that are frequently found in untreated lung cancer and recurrent lung cancers [41–47]. Therefore, lung cancer management is known to benefit from longitudinal sampling, monitoring, and selection of different inhibitors [48]. The fact that EGFR mutations can vary over time further highlights the significance of longitudinal monitoring of multiple plasma samples during the disease progression and post-treatment.…”

Section: Resultsmentioning

confidence: 99%

Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages

et al. 2017

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BackgroundSolid tumors residing in tissues and organs leave footprints in circulation through circulating tumor cells (CTCs) and circulating tumor DNAs (ctDNA). Characterization of the ctDNA portraits and comparison with tumor DNA mutational portraits may reveal clinically actionable information on solid tumors that is traditionally achieved through more invasive approaches.MethodsWe isolated ctDNAs from plasma of patients of 103 lung cancer and 74 other solid tumors of different tissue origins. Deep sequencing using the Guardant360 test was performed to identify mutations in 73 clinically actionable genes, and the results were associated with clinical characteristics of the patient. The mutation profiles of 37 lung cancer cases with paired ctDNA and tumor genomic DNA sequencing were used to evaluate clonal representation of tumor in circulation. Five lung cancer cases with longitudinal ctDNA sampling were monitored for cancer progression or response to treatments.ResultsMutations in TP53, EGFR, and KRAS genes are most prevalent in our cohort. Mutation rates of ctDNA are similar in early (I and II) and late stage (III and IV) cancers. Mutation in DNA repair genes BRCA1, BRCA2, and ATM are found in 18.1% (32/177) of cases. Patients with higher mutation rates had significantly higher mortality rates. Lung cancer of never smokers exhibited significantly higher ctDNA mutation rates as well as higher EGFR and ERBB2 mutations than ever smokers. Comparative analysis of ctDNA and tumor DNA mutation data from the same patients showed that key driver mutations could be detected in plasma even when they were present at a minor clonal population in the tumor. Mutations of key genes found in the tumor tissue could remain in circulation even after frontline radiotherapy and chemotherapy suggesting these mutations represented resistance mechanisms. Longitudinal sampling of five lung cancer cases showed distinct changes in ctDNA mutation portraits that are consistent with cancer progression or response to EGFR drug treatment.ConclusionsThis study demonstrates that ctDNA mutation rates in the key tumor-associated genes are clinical parameters relevant to smoking status and mortality. Mutations in ctDNA may serve as an early detection tool for cancer. This study quantitatively confirms the hypothesis that ctDNAs in circulation is the result of dissemination of aggressive tumor clones and survival of resistant clones. This study supports the use of ctDNA profiling as a less-invasive approach to monitor cancer progression and selection of appropriate drugs during cancer evolution.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0468-1) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages

et al. 2017

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“…Compared to tissue biopsy, liquid biopsy, especially ctDNA sequencing, allows comprehensive and longitudinal monitoring of tumour genomics non‐invasively. While the correlation of ctDNA and efficacy of EGFR‐TKI has been extensively investigated, this work presents one of the most comprehensive ctDNA genomic analyses of tumour evolution during osimertinib treatment, which is a third‐generation EGFR‐TKI. The present study demonstrated that ctDNA is an important approach to predict prognosis and monitor response.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, several studies have demonstrated the spatial heterogeneity of T790M. However, either T790M alone or T790M/sensitizing mutation ratio failed to consistently predict the outcome from osimertinib, indicating a complex clinical interpretation for T790M status. Similarly, in our study, T790M existence and clonal status in plasma failed to identify two subgroups with significantly different PFS, although patients who lost detectable T790M during treatment were more likely to develop early resistance and have a shorter PFS.…”

Section: Discussionmentioning

confidence: 99%

Co‐mutational assessment of circulating tumour DNA (ctDNA) during osimertinib treatment for T790M mutant lung cancer

Xing

Han

Wang

et al. 2019

J Cellular Molecular Medi

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Osimertinib is designed to target the secondary resistant EGFR T790M mutant and has shown outstanding clinical efficacy. However, the prognostic prediction of osimertinib patients is a big problem in clinical practice. The resistance mechanism of osimertinib is also not fully understood. NGS and a 1021 gene capture panel were used to analyse the somatic mutation profile of thirty‐six lung adenocarcinoma patients' serial ctDNA samples. Progression‐free survival of subgroup patients is analysed. Patients harbour TP53 mutations and patients with higher TMB value in pre‐treatment samples showed a shorter PFS. Moreover, compared to CT evaluation, ctDNA changes generally correlated with treatment responses in most patients. Novel resistance mechanisms are discovered including EGFR mutations and alternative activation pathway. Our results implied a broad potential of ctDNA as an adjuvant tool in practical clinical management of NSCLC patients. ctDNA could help with clinical practice during osimertinib treatment, regarding monitoring tumour response, detecting development of heterogeneity, identifying potential resistance mechanisms, predicting treatment efficacy and patient outcome.

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“…The study also concluded that given the 30% false negative rate of plasma T790M testing, those with negative plasma T790M still needed a tissue biopsy to accurately determine the T790M status. Another study assessed the efficacy of osimertinib when T790M status was determined in ctDNA in 48 EGFR-mutant NSCLC patients with disease progression (42). The T790M mutation was detected in 50% of patients, with osimertinib achieving a partial response rate of 62.5% and a stable disease rate of 37.5%.…”

Section: Role Of Ctdna In the Resistance Settingmentioning

confidence: 99%

Circulating DNA in EGFR-mutated lung cancer

Singh¹,

Li²,

Cheng³

2017

Ann. Transl. Med.

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Circulating tumor DNA (ctDNA) consists of short double stranded DNA fragments that are released by tumors including non-small cell lung cancer (NSCLC). With the identification of driver mutations in the epidermal growth factor receptor (EGFR) gene and development of targeted tyrosine kinase inhibitors (TKIs), the clinical outcome of NSCLC patients in this subgroup has improved tremendously.The gold standard to assess EGFR mutation is through tissue biopsy, which can be limited by difficulty in accessing the tumor, inability of patients to tolerate invasive procedures, insufficient sample for molecular testing and inability to capture intratumoral heterogeneity. The great need for rapid and accurate identification of activating EGFR mutations in NSCLC patients paves the road for ctDNA technology.Studies have demonstrated ctDNA to be a reliable complement to tumor genotyping. Platforms like digital polymerase chain reaction (PCR) and next-generation sequencing based analyses have made it possible to identify EGFR mutations in plasma with high sensitivity and specificity. This article will provide an overview on ctDNA in the context of EGFR mutated NSCLC, especially its emerging applications in diagnosis, disease surveillance, treatment monitoring and detection of resistance mechanisms.

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Osimertinib benefit inEGFR-mutant NSCLC patients withT790M-mutation detected by circulating tumour DNA

Abstract: ctDNA from liquid biopsy can be used as a surrogate marker for T790M in tumour tissue.

Cited by 152 publications

References 20 publications

Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages

Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages

Co‐mutational assessment of circulating tumour DNA (ctDNA) during osimertinib treatment for T790M mutant lung cancer

Circulating DNA in EGFR-mutated lung cancer

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