Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing

Yu, Helena A.; Arcila, Maria E.; Hellmann, Matthew D.; Kris, Mark G.; Ladanyi, Marc; Riely, Gregory J.

doi:10.1093/annonc/mdt573

Cited by 182 publications

(153 citation statements)

References 26 publications

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“…In this regard, it has been shown that L858R-positive tumors have low-level T790M clones at a higher incidence than Del19-positive tumors. In the analysis of the Korean group [26], 75% of the de novo T790M were within the L858R group; however, only 25% were in the Del19 group.This is in line with Yu et al [23], who showed that de novo T790M mutations are ∼80% concurrent with L858R and only 20% coexistent with Del19 mutations. Whether this preference of T790M for L858R holds true in the acquired resistance setting is unclear.…”

Section: Discussionsupporting

confidence: 92%

Afatinib in Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations Pretreated With Reversible EGFR Inhibitors

Heigener

Schümann²,

Sebastian

et al. 2015

The Oncologist

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Background. Afatinib, an irreversible ErbB family blocker, is approved for treatment of patients with previously untreated non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations. Efficacy of afatinib in EGFR tyrosine kinase inhibitor-naïve (TKI-naïve) patients with uncommon EGFR mutations (other than exon 19 deletions or exon 21 point mutations) has been reported; however, efficacy in TKI-pretreated patients with uncommon EGFR mutations is unknown. Materials and Methods. In the afatinib compassionate use program (CUP), patients with advanced or metastatic, histologically confirmed NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment were enrolled. Demographic data, mutation type, response rates, time to treatment failure (TTF), and safety in patients harboring uncommon EGFR mutations were reported.

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Section: Discussionsupporting

confidence: 92%

Afatinib in Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations Pretreated With Reversible EGFR Inhibitors

Heigener

Schümann²,

Sebastian

et al. 2015

The Oncologist

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“…A number of efforts have been made to detect the pretreatment T790M mutation in recent studies (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Using a ddPCR method, we identified the T790M mutation in 79.9% (n ¼ 373) of samples, which was a far higher frequency than in previous reports that used direct sequencing (1.0%-7.5%, n ¼ 34-783; refs.…”

Section: Discussionmentioning

confidence: 61%

“…11-15), matrix-assisted laser desorption/ionization timeof-flight mass spectrometry (1.9%-31.2%, n ¼ 48-579; refs. 15,19), TaqMan assay (34.9%, n ¼ 129; ref. 16), and an allele-specific selective androgen-receptor modulators assay (38.5%, n ¼ 26; ref.…”

Section: Discussionmentioning

confidence: 99%

“…Using conventional DNA sequencing such as the Sanger method, the pretreatment T790M mutation was found in 1% to 8% of patients concurrently with an EGFR-activating mutation (12)(13)(14)(15). Utilizing more sensitive detection methods such as the Scorpion Amplification Refractory Mutation System, the reported incidence of pretreatment T790M was higher: 2% to 79% in EGFR-activating mutation-positive samples (11,(15)(16)(17)(18)(19)(20). The evidence is so far limited for the clinical relevance of pretreatment T790M identified at extremely low frequencies.…”

Section: Introductionmentioning

confidence: 99%

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Ultra-Sensitive Detection of the Pretreatment EGFR T790M Mutation in Non–Small Cell Lung Cancer Patients with an EGFR-Activating Mutation Using Droplet Digital PCR

Watanabe

Kawaguchi

Isa

et al. 2015

Clinical Cancer Research

202

173

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Purpose: The resistance to the EGFR tyrosine kinase inhibitors (TKI) is a major concern in non-small cell lung cancer (NSCLC) treatment. T790M mutation in EGFR accounts for nearly 50% of the acquired resistance to EGFR-TKIs. Earlier studies suggested that T790M mutation was also detected in TKI-na€ ve NSCLCs in a small cohort. Here, we use an ultra-sensitive droplet digital PCR (ddPCR) technique to address the incidence and clinical significance of pretreatment T790M in a larger cohort.Experimental Design: ddPCR was established as follows: wildtype or T790M mutation-containing DNA fragments were cloned into plasmids. Candidate threshold was identified using wild-type plasmid, normal human genomic DNA, and human A549 cell line DNA, which expresses wild type. Surgically resected tumor tissues from 373 NSCLC patients with EGFR-activating mutations were then examined for the presence of T790M using ddPCR.Results: Our data revealed a linear performance for this ddPCR method (R 2 ¼ 0.998) with an analytical sensitivity of approximately 0.001%. The overall incidence of the pretreatment T790M mutation was 79.9% (298/373), and the frequency ranged from 0.009% to 26.9%. The T790M mutation was detected more frequently in patients with a larger tumor size (P ¼ 0.019) and those with common EGFRactivating mutations (P ¼ 0.022), as compared with the others.Conclusions: The ultra-sensitive ddPCR assay revealed that pretreatment T790M was found in the majority of NSCLC patients with EGFR-activating mutations. ddPCR should be utilized for detailed assessment of the impact of the low frequency pretreatment T790M mutation on treatment with EGFR-TKIs. Clin Cancer Res; 21(15); 3552-60. Ó2015 AACR.

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“…Several studies have been done to determine if tumor cells containing the T790M mutation are present prior to EGFR-TKI treatment initiation or if they develop from cancer stem cells during treatment. These studies have found very few TKI-resistant cells prior to treatment thereby suggesting that the T790M mutation more commonly arises due to selective pressure during EGFR-TKI therapy (10,19). Three other point mutations have been implicated in EGFR-TKI resistance (D761Y, L747S, T854A), however they have been reported only occasionally and their mechanism of resistance is less understood (10).…”

Section: T790m Mutationmentioning

confidence: 99%

Emerging uses of biomarkers in lung cancer management: molecular mechanisms of resistance

2017

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Management of patients with advanced non-small cell lung cancer (NSCLC) has recently been transformed by molecularly targeted and immunotherapeutic agents. In patients with EGFR/ALK/ ROS mutated NSCLC, first line molecular therapy is the standard of care. Moreover, immune checkpoint inhibitors are revolutionary treatment options for advanced NSCLC and are now the standard of care in front-line or later line settings. Both classes of agents have led to improved patient outcomes, however, primary resistance and development of acquired resistance to both targeted and immunotherapeutic agents is commonly observed, limiting the use of these agents in clinical settings. In this review, we will discuss the most recent advances in understanding the mechanisms of primary and acquired resistance, progress in the spectrum of assays detecting causative molecular events and the development of new generations of inhibitors to overcome acquired resistance.

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Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing

Abstract: De novo EGFR T790M mutations are rare (<1%) when identified by standard sensitivity methods. TKI therapy for patients with baseline EGFR T790M detected by standard molecular analysis has limited benefit.

Cited by 182 publications

References 26 publications

Afatinib in Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations Pretreated With Reversible EGFR Inhibitors

Afatinib in Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations Pretreated With Reversible EGFR Inhibitors

Ultra-Sensitive Detection of the Pretreatment EGFR T790M Mutation in Non–Small Cell Lung Cancer Patients with an EGFR-Activating Mutation Using Droplet Digital PCR

Emerging uses of biomarkers in lung cancer management: molecular mechanisms of resistance

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