Iressa case study..
Journal of Clinical Oncology, Vol 23, No 1 (January 1), 2005: pp. 235-237
© 2005 American Society of Clinical Oncology
DOI: 10.1200/JCO.2005.07.169
Unusual Cases in Multiple Myeloma and a Dramatic Response in Metastatic Lung Cancer
{ what makes this interesting is that this patient achieved major response although: is male, a former smoker, negative EGFR..author speaks to this}
CASE 4. Mutation of the Epidermal Growth Factor Receptor in an
Elderly Man With Advanced, Gefitinib-Responsive, Non–Small-Cell Lung Cancer
Daniel Cho, Olivier Kocher, Daniel G. Tenen, Balazs Halmos
Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
Jeffrey C. Lee, Matthew L. Meyerson, Pasi A. Janne
Departments of Medicine and Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
A 71-year-old white male presented in May 2001 with complaints of cough productive of clear sputum. He had quit smoking in 1987 after 40 years of smoking one pack per day, and denied any family history of malignancy. Chest computed tomography (CT) revealed a right lower lobe mass with ground glass opacities throughout the right lower lobe. A transbronchial biopsy revealed moderately differentiated adenocarcinoma (Fig 1). He was treated with carboplatin/paclitaxel (changed to docetaxel due to a reaction), then gemcitabine, but progressed through both regimens. By July 2002, patient had developed progressively worsening symptoms of cough, chest pain, and shortness of breath requiring home oxygen therapy (Fig 2). He was started on gefitinib at a dose of 250 mg orally once daily in August 2002 on a compassionate use protocol. Shortly after starting treatment he developed grade 1 to 2 acneiform rash and grade 1 diarrhea, but reported significant pulmonary symptom improvement. A CT performed at the end of the third month of treatment showed reduction in the right lower mass from 6 x 5 cm to 3.5 x 3.5 cm in size. His respiratory symptoms had improved enough to discontinue his home oxygen and he actually resumed singing with his church choir. CT scans performed at 3-month intervals continued to show progressive improvement to the point of radiographic complete remission between February and November of 2003. He remains clinically well without any symptoms except for skin dryness, hyperkeratosis, and a slight erythematous rash.
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Fig 1.
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Fig 2.
The epidermal growth factor (EGF), its receptor (EGFR), and their downstream pathways are key signaling molecules in the growth and proliferation of various epithelial malignancies.1 The EGFR is overexpressed in 40% to 80% of non–small-cell lung cancers (NSCLCs). Gefitinib is an anilinoquinazoline that inhibits activation of the EGFR tyrosine kinase via binding the ATP binding site. In phase II trials of single-agent gefitinib in advanced NSCLC, tumor responses were observed in 10% to 19% of patients.2,3 Phase III trials combining gefitinib with standard chemotherapy failed to show any improvement in overall or disease-free survival.4,5 Gefitinib was approved by the United States Food and Drug Administration for the treatment of patients with advanced NSCLC resistant to platinum and docetaxel-based chemotherapies based on compelling phase II data. Both early-phase studies as well as later experience have demonstrated unique sensitivity to gefitinib in particular subsets of patients. These patients tended to be nonsmokers, women, patients with bronchoalveolar histology, and patients with Japanese ethnicity.2,3,6 Recently, somatic mutations in the kinase domain of the EGFR gene have been identified which correlated with in vitro response of cell lines to gefitinib.7 Such mutations were also found in five of five patients responding to gefitinib, but were absent in four nonresponders. In untreated tumor samples, such mutations were much more common in Japanese than US patients. In vitro studies have confirmed that these somatic mutations result in enhanced activity of the EGFR tyrosine kinase when exposed to EGF, as well as to increased sensitivity to the inhibitory effect of gefitinib.8
We analyzed our patient's original tumor tissue for mutations in the EGFR gene after obtaining informed consent. Sequencing of exons 18 through 24 in both sense and antisense directions revealed a heterozygous in-frame 18-base pair deletion leading to a 6 amino acid deletion between residues 747 to 752 (Fig 3), identical to a previously described deletion.7 As all other deletion mutants described to date, this mutation also encompasses codons 747 to 750 within the catalytic intracellular kinase domain of the EGFR molecule. This deletion is hypothesized to lead to enhanced sensitivity to the effects of EGF and gefitinib secondary to increased binding affinity to both ATP and anilinoquinazolines. Our patient demonstrates a dramatic response to gefitinib monotherapy in a chemotherapy-refractory patient with advanced NSCLC found to possess a deletion mutation in the EGFR kinase domain. Our patient, being an elderly white male and a former smoker, demonstrates essentially none of the phenotypic features that might predict for the presence of an EGFR mutation or response to gefitinib except for adenocarcinoma histology. This suggests that selecting patients for targeted therapy based on these phenotypic features may not be satisfactory, and highlights the need for research directed at understanding the prevalence, natural history, and treatment responsiveness of patients with tumors carrying EGFR mutations or other abnormalities.
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Fig 3.
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Matthew L. Meyerson, Novartis. Research Funding: Matthew L. Meyerson, Novartis; Balazs Halmos, AstraZeneca. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
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7. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004[Abstract/Free Full Text]
8. 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 350:2129-2139, 2004[Abstract/Free Full Text] |
