Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay Journal Article

Authors: Arcila, M. E.; Oxnard, G. R.; Nafa, K.; Riely, G. J.; Solomon, S. B.; Zakowski, M. F.; Kris, M. G.; Pao, W.; Miller, V. A.; Ladanyi, M.
Article Title: Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay
Abstract: Background: The epidermal growth factor receptor (EGFR) mutation T790M is reported in approximately 50% of lung cancers with acquired resistance to EGFR inhibitors and is a potential prognostic and predictive biomarker. Its assessment can be challenging due to limited tissue availability and under-detection at low mutant allele levels. Here, we sought to determine the feasibility of tumor rebiopsy and to more accurately assess the prevalence of the T790M using a highly sensitive locked nucleic acid (LNA) PCR/sequencing assay. MET amplification was also analyzed. Methods: Patients with acquired resistance were rebiopsied and samples were studied for sensitizing EGFR mutations. Positive cases were evaluated for T790M using standard PCR-based methods and a subset were re-evaluated with an LNA-PCR/sequencing method with an analytical sensitivity of approximately 0.1%. MET amplification was assessed by FISH. Results: Of 121 patients undergoing tissue sampling, 104 (86%) were successfully analyzed for sensitizing EGFR mutations. Most failures were related to low tumor content. All patients (61/61) with matched pretreatment and resistance specimens showed concordance for the original sensitizing EGFR mutation. Standard T790M mutation analysis on 99 patients detected 51(51%) mutants. Retesting of 30 negative patients by the LNA-based method detected 11 additional mutants for an estimated prevalence of 68%. MET was amplified in 11% of cases (4/37). Conclusions: The re-biopsy of lung cancer patients with acquired resistance is feasible and provides sufficient material for mutation analysis in most patients. Using high sensitivity methods, the T790M is detected in up to 68% of these patients. ©2011 AACR.
Keywords: adult; controlled study; human tissue; aged; gene mutation; major clinical study; cancer patient; sensitivity and specificity; genetic analysis; polymerase chain reaction; gene amplification; lung non small cell cancer; mutational analysis; fluorescence in situ hybridization; feasibility study; nucleic acid analysis; mutation rate; drug treatment failure; lung biopsy; genomic dna; epidermal growth factor receptor kinase inhibitor; scatter factor receptor; locked nucleic acid; copy number variation
Journal Title: Clinical Cancer Research
Volume: 17
Issue: 5
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2011-03-01
Start Page: 1169
End Page: 1180
Language: English
DOI: 10.1158/1078-0432.ccr-10-2277
PROVIDER: scopus
PMCID: PMC3070951
PUBMED: 21248300
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 23 June 2011" - "CODEN: CCREF" - "Source: Scopus"
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MSK Authors
  1. Khedoudja Nafa
    181 Nafa
  2. William Pao
    141 Pao
  3. Vincent Miller
    262 Miller
  4. Marc Ladanyi
    864 Ladanyi
  5. Gregory J Riely
    344 Riely
  6. Maureen F Zakowski
    275 Zakowski
  7. Geoffrey R Oxnard
    24 Oxnard
  8. Stephen Solomon
    266 Solomon
  9. Maria Eugenia Arcila
    336 Arcila
  10. Mark Kris
    598 Kris