Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Dec;22(12):2616-2624.
doi: 10.1093/annonc/mdr489. Epub 2011 Nov 9.

Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice

L V Sequist  1 , R S Heist  2 , A T Shaw  2 , P Fidias  2 , R Rosovsky  3 , J S Temel  2 , I T Lennes  2 , S Digumarthy  4 , B A Waltman  5 , E Bast  6 , S Tammireddy  6 , L Morrissey  6 , A Muzikansky  7 , S B Goldberg  2 , J Gainor  8 , C L Channick  9 , J C Wain  10 , H Gaissert  10 , D M Donahue  10 , A Muniappan  10 , C Wright  10 , H Willers  11 , D J Mathisen  10 , N C Choi  11 , J Baselga  2 , T J Lynch  12 , L W Ellisen  2 , M Mino-Kenudson  13 , M Lanuti  10 , D R Borger  2 , A J Iafrate  13 , J A Engelman  2 , D Dias-Santagata  13
Affiliations

Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice

L V Sequist et al. Ann Oncol. 2011 Dec.

Abstract

Background: Personalizing non-small-cell lung cancer (NSCLC) therapy toward oncogene addicted pathway inhibition is effective. Hence, the ability to determine a more comprehensive genotype for each case is becoming essential to optimal cancer care.

Methods: We developed a multiplexed PCR-based assay (SNaPshot) to simultaneously identify >50 mutations in several key NSCLC genes. SNaPshot and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory Improvement Amendments-certified tests. Here, we present analyses of the first 589 patients referred for genotyping.

Results: Pathologic prescreening identified 552 (95%) tumors with sufficient tissue for SNaPshot; 51% had ≥1 mutation identified, most commonly in KRAS (24%), EGFR (13%), PIK3CA (4%) and translocations involving ALK (5%). Unanticipated mutations were observed at lower frequencies in IDH and β-catenin. We observed several associations between genotypes and clinical characteristics, including increased PIK3CA mutations in squamous cell cancers. Genotyping distinguished multiple primary cancers from metastatic disease and steered 78 (22%) of the 353 patients with advanced disease toward a genotype-directed targeted therapy.

Conclusions: Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Distribution frequency (A) and overlap (B) of the genotypes observed. Genotypes observed are depicted in a pie chart showing frequency of each mutation with regard to all patients tested (A) as well as in a Venn diagram showing the overlap of patients with more than one mutation (B). Note that only 100 patients were screened for IDH1 and HER2 mutations, so the frequency depicted here may not be truly representative. Also note that TP53 screening only encompassed a minority of the ‘hot-spot’ mutations described in NSCLC for TP53.
Figure 2.
Figure 2.
Smoking status distribution by genotype. The proportion of patients that were never, former and current smokers are depicted in separate pie charts representing the overall study cohort and the subset positive for each of the major mutation types.
Figure 3.
Figure 3.
Survival among patients with stage III and IV non-small-cell lung cancer by KRAS mutation status (A) and EGFR mutation status (B). Mutant patients are depicted with a solid line and wild-type patients with a dashed line.
Figure 4.
Figure 4.
Flow of patients with advanced or recurrent non-small-cell lung cancer onto genotype-directed therapies.
See this image and copyright information in PMC

Comment in

References

    1. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344(14):1038–1042. - PubMed
    1. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347(7):472–480. - PubMed
    1. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–2139. - PubMed
    1. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–1500. - PubMed
    1. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101(36):13306–13311. - PMC - PubMed

MeSH terms

Substances