2012/11/06 23:08

Case study for non small cell lung cancer

A young Asian female, who has never smoked, presented with a cough and shortness of breath. Her symptoms did not improve after 2 courses of antibiotic therapy for presumed pneumonia. A chest X-ray demonstrated a 2-cm left lower lobe mass and some scattered opacities bilaterally and a later computed tomography (CT) scan demonstrated a dominant 2-cm nodule in the left lower lobe of the lung. A needle core biopsy of the dominant nodule demonstrated neoplastic proliferation composed of round to oval glands with a central luminal space surrounded by cells with round nuclei, with a relatively prominent nucleoli and eosinophilic cytoplasm. Five 5-μ thick formalin-fixed, paraffin-embedded unstained sections of the needle core biopsy of the main tumor nodule and 1 representative hematoxylin and eosin section were submitted to a molecular laboratory for EGFR (epidermal growth factor receptor) DNA mutational analysis. DNA sequencing was performed to reveal a mutation in EGFR exon 19. The 2 most common EGFR somatic mutations, exon 19 deletions and exon 21 L858R missense mutations, have been associated with in vitro and in vivo sensitivity to treatment with which of the following?

Cetuximab and dasatanib
Cetuximab and erlotinib
Dasatanib and imatinib
Gefitinib and erlotinib

Explanation

The 2 most common EGFR somatic mutations, exon 19 deletions and exon 21 L858R missense mutations, have been associated with in vitro and in vivo sensitivity to treatment with the EGFR-tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. These 2 different types of mutations are responsible for almost 90% of all EGFR somatic mutations identified in patients with non–small-cell lung cancer (NSCLC). Jackman et al investigated the prognostic significance of these 2 most common mutations in 36 patients with NSCLC who were treated with gefitinib or erlotinib (Table).1 Patients with an exon 19 deletion had a significantly longer overall survival compared with patients with an L858R mutation (38 vs 17 months; P = .04). There were also trends toward higher response rate (73% vs 50%) and improved time to progression (24 vs 10 months) for patients with an exon 19 deletion, although these were not independently significant in a multivariate analysis. A difference in response rate for patients treated with gefitinib compared with erlotinib was also noted (18 of 23 [78%] vs 3 of 9 [33%]; P = .04). No obvious difference in time to progression or overall survival was noted between gefitinib- and erlotinib-treated patients.

table

In EGFR-TKI responders, the most common mutations are in-frame deletions in exon 19 (45%), followed by a point mutation (CTG to CGG) in exon 21 at nucleotide 2573 which results in substitution of L858R (41%).

The presence of an exon 19 deletion is associated with a high EGFR-TKI response rate of 60% to 90%.

EGFR mutations, which typically predict rapid objective response to EGFR-TKIs, do not predict patient’s response to EGFR-targeting monoclonal antibodies. Cetuximab, a chimerized antibody of the immunoglobulin G1 subclass, has proven efficacy in colorectal cancer and head and neck cancer. In NSCLC, a phase II study in pretreated advanced-stage patients showed a response rate of 4.5%, but disease control rates and overall survival were comparable to that achieved with pemetrexed, docetaxel, and erlotinib in similar groups of patients. Early phase II trials and randomized phase II trials of cetuximab plus concurrent chemotherapy versus chemotherapy alone in unselected chemotherapy-naïve patients with advanced NSCLC favored the combination. Hirsch et al were the first to suggest that EGFR-fluorescein in situ hybridization is a predictive factor for selection of patients with NSCLC for cetuximab plus chemotherapy.2

References

  1. Jackman DM, Yeap BY, Sequist LV, et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res. 2006;12:3908-3914.
  2. Hirsch FR, Herbst RS, Olsen C, et al. Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol. 2008;26:3351-3357.




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