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Spectrum of uncommon and compound epidermal growth factor receptor mutations in non-small-cell lung carcinomas with
Varsha Singh1, Aruna Nambirajan1, Prabhat Singh Malik2
1Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
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 EGFRTKI (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.
Insights
Uncommon and compound epidermal growth factor receptor (EGFR) mutations, including T790M, are found in about one-fifth of lung cancer patients. These mutations lead to poorer treatment response and faster disease progression compared to common EGFR mutations.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epidermal growth factor receptor (EGFR) mutations, particularly exon 19 deletions (exon19del) and exon 21 L858R (L858R), are primary drivers in lung adenocarcinomas (ADCAs).
- These common EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs).
- The clinical significance of uncommon and compound EGFR mutations for TKI efficacy remains unclear.
Purpose of the Study:
- To investigate the spectrum of EGFR mutations in non-small-cell lung carcinoma (NSCLC).
- To compare treatment responses and outcomes between patients with single common, single uncommon, and compound EGFR mutations.
Main Methods:
- A combined retrospective and prospective study analyzed 1227 tumor samples from TKI-naive NSCLC patients over 10 years.
- EGFR mutations were identified using a qPCR-based method.
- Objective response rates (ORRs) and survival outcomes were assessed.
Main Results:
- EGFR mutations were found in 31.8% of patients, with 79.5% being single common (exon19del/L858R), 6.6% single uncommon, and 13.8% compound mutations.
- Exon 20 T790M was the most frequent uncommon/compound mutation (10.2%).
- Patients with uncommon/compound mutations had significantly lower ORRs (47% for TKIs, 43% for chemotherapy) and shorter progression times (median 7 months) compared to those with common mutations (median 14.7 months).
- Baseline T790M mutations showed the poorest response to both TKIs (11% ORR) and chemotherapy (27% ORR).
Conclusions:
- Uncommon and compound EGFR mutations, including T790M, occur in approximately 20% of EGFR-mutant NSCLC patients.
- These mutations are associated with significantly inferior treatment response rates and earlier disease progression compared to common EGFR mutations (exon19del/L858R).
- Patients with baseline T790M mutations exhibit particularly poor outcomes with current therapies.
