Rare EGFR exon 20 S768I mutation predicts resistance to targeted therapy: a report of two cases
TypeCase Report; Letter/Correspondence
KeywordLung cancer; Lung neoplasms; Targeted therapy; Chemotherapy; Pemetrexed; Cisplatin; Epidermal growth factor receptor (EGFR); Mortality; Resistance
Journal TitleJournal of Thoracic Oncology
MetadataShow full item record
AbstractThe importance of submitting data of clinical response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients with uncommon EGFR mutations has been encouraged.1 In view of this, we present two cases of a rare EGFR mutation that appears to confer resistance to TKIs. Case 1, a 56-year-old Afro-Caribbean male presenting with hemoptysis, breathlessness, and weight loss. Performance status was 1, with no significant past medical history and 1 pack year smoking history. Imaging showed a right middle lobe mass, mediastinal lymphadenopathy, and liver metastases. Mediastinal biopsy confirmed poorly differentiated adenocarcinoma (TTF+, CK7+, and CK20−). EGFR mutation analysis of selected regions of exons 18 to 21, using real-time polymerase chain reaction, revealed missense mutation in exon 20 at nucleotide 2303 resulting in serine to isoleucine substitution at codon 768. After commencing gefitinib 250 mg daily, computed tomography scan after 6 weeks showed disease progression with new liver and bony metastases. Within 2 weeks of switching to 3-weekly pemetrexed (500 mg/m2) and cisplatin (70 mg/m2), his exercise tolerance improved and imaging after 4 cycles demonstrated a partial response. Unfortunately, he was admitted to hospital with pneumonia after his third cycle of maintenance pemetrexed (500 mg/m2) and died 4 days later. Case 2, a 65-year-old Caucasian female presenting with acute onset shortness of breath. Performance status was 0, with no significant past medical history and 20 pack year smoking history. Imaging showed a right lower lobe pulmonary embolism with incidental right upper lobe mass, right lung metastases, and extensive subcarinal, mediastinal, and retroperitoneal lymphadenopathy. Mediastinal biopsy confirmed poorly differentiated adenocarcinoma (TTF+, CK7+, and CK20−). EGFR mutation analysis reported the same exon 20 missense mutation described in case 1. She had six cycles of pemetrexed (500 mg/m2) and cisplatin (70 mg/m2) chemotherapy with a good partial response. Within 2 months of commencing treatment with maintenance erlotinib (150 mg daily), imaging showed progression of all lesions. Despite early disease stabilization on switching to oral vinorelbine (60 mg/m2), computed tomography scan after 4 months revealed further progression. She was unfit for further treatment and died 2 months later. A number of rare EGFR mutations exist to which response to targeted therapy is unclear. The exon 20 missense mutation S768I is one of these. In Asian populations, prevalence of this mutation is less than 5% although it is more commonly seen in combination with other mutations.2 In our region, prevalence of this single mutation is 1.5% (unpublished data). In vitro, cells expressing S768I mutation are less sensitive to EGFR-targeted treatment than wild-type cells.3 However, reports of clinical outcome in these patients are conflicting.4,5 Our two cases add to the evidence that the S768I mutation causes insensitivity to TKI therapy. However, both cases did show response to platinum-based chemotherapy. Furthermore, these cases continue to highlight the importance of publishing treatment response data for cases of rare EGFR mutant lung cancers to guide clinical decision making.
CitationPallan L, Taniere P, Koh P. Rare EGFR exon 20 S768I mutation predicts resistance to targeted therapy: a report of two cases. J Thorac Oncol. 2014 Oct;9(10):e75. doi: 10.1097/JTO.0000000000000308. PMID: 25521406.
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