Spectrum of uncommon and compound epidermal growth factor receptor mutations in non-small-cell lung carcinomas with treatment response and outcome analysis: A study from India. (November 2020)

• Record Type: Journal Article
• Authors: Singh, Varsha; Nambirajan, Aruna; Malik, Prabhat Singh; Thulkar, Sanjay; Pandey, Ravindra Mohan; Luthra, Kalpana; Arava, Sudheer; Ray, Ruma; Mohan, Anant; Jain, Deepali
• Is Part Of: Lung cancer. Volume 149(2020)
• Page Start: 53
• Page End: 60
• Publication Date: 2020-11
• Subjects: Pathology -- Non-small cell lung cancer (adenocarcinoma); EGFR -- T790M -- TKI -- Chemotherapy -- Uncommon -- Compound mutation -- Lung adenocarcinoma -- Non-small-cell lung cancer -- Adenocarcinoma; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2020.07.038
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Collectively, uncommon and compound EGFR mutations are detected in 6.5 % of NSCLC patients. Single exon 20 T790M mutations were the third most frequent EGFR mutations. Uncommon/compound EGFR mutations showed poor treatment outcomes following EGFR TKI and chemotherapy. Abstract: Introduction: Mutations in the tyrosine kinase domain of the epidermal growth factor receptor gene ( EGFR ) are key driver alterations in lung adenocarcinomas (ADCAs). Exon 19 deletions (exon19del) and exon 21 L858R (L858R) mutations account for 70–90 % of all such alterations and predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs). However, the predictive value of uncommon and compound EGFR mutations for TKIs has not been clearly established. Objective: To assess the spectrum of EGFR mutations in non-small-cell lung carcinoma (NSCLC), and to compare the treatment responses and outcomes among single common, single uncommon, and compound mutations. Method: The study was of combined retrospective (January 2010–December 2015) and prospective (January 2016–February 2020) design spanning 10 years. Tumor samples from TKI-naive NSCLC patients were tested for EGFR mutations by a qPCR-based method. Objective response rates (ORRs) and survival outcomes were analyzed. Result: In total, 1227 tumor samples were tested. EGFR mutations were detected in 391 samples (31.8 %), and included 79.5 % (311/391) single common (exon19del/L858R), 6.6 % (26/391) single uncommon (non-exon19del/L858R), and 13.8 % (54/391) compound mutations. Exon 20 T790M mutations were most prevalent among uncommon/compound mutations (40/391, 10.2 %). Overall, patients with single uncommon/compound mutations responded poorly to both EGFR TKI (47 % ORR) and chemotherapy (43 % ORR), with significantly shorter time to progression (median 7 months) compared to those with exon19del/L858R mutations (median 14.7 months). Patients with baseline T790M mutations (single/compound) were least responsive to EGFR TKIs (11 % ORR) and chemotherapy (27 % ORR) and showed the shortest progression-free survival compared to other uncommon and compound mutations. Conclusion: Approximately one fifth of EGFR- mutant patients harbor uncommon and compound mutations. Unlike those with exon19del/L858R, these patients—particularly those with baseline T790M mutations—show significantly inferior response rates to treatment ( EGFR TKI or chemotherapy) and early disease progression.