2012/08/31 12:48

Case study 10 (diagnose)

What is the MOST common mutation found in pulmonary adenocarcinoma?
    •    EGFR (epidermal growth factor receptor) L858R
    •    KRAS
    •    EML4-ALK (echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase)
    •    EGFR 15 bp deletion
    •    T790M
KRAS mutation is the most common mutation found in pulmonary adenocarcinoma, followed by mutations in the EGFR gene. Contrary to EGFR mutation and EML4-ALK translocations, there is no current specific targeted therapy for patients carrying a mutant KRAS adenocarcinoma.
KRAS mutation is associated with a worse prognosis because these tumors are resistant to thyrosine kinase inhibitors and adjuvant chemotherapy. KRAS mutation is associated with smoking history and appears to be mutually exclusive with other mutations such as EGFR and ALK.1-3
    1.    Boldrini L, Alì G, Gisfredi S, et al. Epidermal growth factor receptor and K-RAS mutations in 411 lung adenocarcinoma: a population-based prospective study. Oncol Rep. 2009;22:683-691.
    2.    Woo T, Okudela K, Yazawa T, et al. Prognostic value of KRAS mutations and Ki-67 expression in stage I lung adenocarcinomas. Lung Cancer. 2009;65:355-362.
    3.    Riely G, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc. 2009;15:201-206.

The use of the diagnostic term non–small-cell lung cancer (NSCLC) is no longer recommended. A pathologist will more likely be asked to further classify NSCLC into adenocarcinomas and squamous cell carcinoma by the treating physician. Which of the following options is NOT a reason for this change?

    •    Discovery of activating mutations in the EGFR (epidermal growth factor receptor) gene in adenocarcinomas
    •    Potential use of the drug pemetrexed
    •    Potential use of the drug bevacizumabPotential use of the drug bevacizumab
    •    Potential use of crizotinib in patients carrying ALK translocation
    •    Toxicity of platinum-based chemotherapies

The current classification of lung cancer recognizes 4 major histologic subtypes, namely squamous cell carcinoma, adenocarcinoma, large-cell carcinoma, and small-cell lung carcinoma (SCLC). Until recently, most of the diagnosis of lung carcinoma was based on distinguishing SCLC from other tumors generally designated as NSCLC because these 2 categories were the most relevant for directing therapy.

However, advances in thoracic medical oncology have led to a paradigm shift in NSCLC diagnosis, resulting in a new emphasis on accurate NSCLC subtyping. Specifically, 2 novel agents have challenged NSCLC as clinically relevant diagnostic category.
              First, it has been demonstrated that patients with the diagnosis of squamous cell carcinoma are at increased risk for life-threatening complications if treated with bevacizumab, a humanized antibody against vascular endothelial growth factor.

             In addition, in the case of pemetrexed, an antifolate that inhibits multiple enzymes in purine and pyrimidine synthesis, patients with squamous cell carcinoma showed no response to the drug in comparison to a good response observed in patients with the diagnosis of nonsquamous cell carcinoma.1 For these reasons, these 2 new drugs are only recommended for use in patients with a diagnosis of nonsquamous cell carcinoma (adenocarcinoma and large-cell carcinoma).

              Other developments include the identification of genetic alterations, which have been described almost exclusively in adenocarcinoma, that confer susceptibility to therapeutic agents or resistance to chemotherapeutic drugs. For example, tumors with EGFR mutations have a better outcome and respond to the tyrosine kinase inhibitors erlotinib and gefitinib as a first-line therapy, whereas patients without EGFR mutations seem to have a better outcome with standard chemotherapy.2

               Furthermore, translocation in the EML4-ALK (echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase) gene has been described predominantly in adenocarcinomas. This translocation confers susceptibility to a specific inhibitor, crizotinib, which is currently undergoing clinical testing.3

Complications from platinum-based chemotherapy are not a reason to subclassify NSCLC.

    1.    Scagliotti G, Hanna N, Fossella F, et al. The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist. 2009;14:253-263.
    2.    Marks JL, Broderick S, Zhou Q, et al. Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J Thorac Oncol. 2008;3:111-116.
    3.    Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010:363:1693-1703.


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