Genomic landscape of lung cancer in the young

Abstract

BackgroundLung cancer in the young is a rare entity of great interest due to the high frequency of targetable mutations. In this study, we explored the genomic landscape of non-small cell lung cancer (NSCLC) in young patients and compared it with genetic alterations in older patients.MethodsComparative study of the genomic profile of NSCLC young (≤40 years old) vs older patients (>40 years old) from Instituto Nacional de Enfermedades Neoplásicas (INEN) in Lima, Peru. Archival paraffin-embedded tumor samples were profiled with FoundationOne CDx assay to identify short variants alterations (insertions and deletions), copy number variations (CNV), tumor mutational burden and microsatellite instability in 324 driver genes and rearrangements in 28 commonly rearranged genes. A targetable alteration was defined as any alteration in a driver oncogene for which an FDA approved therapy existed at the time of study enrollment.ResultsOverall, 62 tumors were profiled, 32 from young and 30 from older patients. All clinicopathological features (smoking status, clinical stage, and histology) were similar between groups, except for gender (65.6% of females in the younger group vs 40% in the older group, P=0.043). At least one actionable mutation was present in 84.4% and 83.3% in younger and older patients, respectively. Alteration rates in the main genes were: BRAF, 3.1%(n=1) vs 0%; EGFR, 46.9% (n=15) vs 43.3% (n=13); ERBB2, 12.5% (n=4) vs 16.7% (n=5); KRAS, 15.6% (n=5) vs 16.7% (n=5); ALK, 6.3% (n=2) vs 3.3% (n=1); RET, 0.0% vs 3.3% (n=1); ROS1, 3.1% (n=1) vs 3.3% (n=1); NTRK1, 0.0% vs 3.3% (n=1) and MET, 3.1% (n=1) vs 13.3% (n=4). Mean TMB was 4.04 Mut/Mb (SD ± 3.98) for young vs 8.06 Mut/Mb (SD ± 9.84) for older patients (P=0.016). There were not significant differences in CNV, frequency of gene rearrangements, or microsatellites instability.ConclusionNSCLC in the young in our cohort was characterized by a high frequency of actionable genetic aberrations and a low TMB, which was also true for our older patients. The enrichment of actionable mutations in young patients described in other reports might be attributed to differences in the etiology and clinicopathological characteristics between younger and older patients and therefore not be applicable to all populations.

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“…Specific, clinically significant alterations with an associated FDA-approved targeted therapy were detected as enriched in younger patient tumors including two EGFR deletions, E746-A750 and L747-E749, and an ALK fusion, EML4-ALK. These observations align with a growing body of research conducted across various geographical regions worldwide (3,6,7,(9)(10)(11)(12)(13). We showed that younger patient tumors had significantly lower prevalence of certain genomic alterations including KRAS SNVs and MET exon 14 skipping mutations, which have previously been reported to be associated with older age (3,13,43).…”

“…One strength of our study is the novel way in which we defined the younger patients with NSCLC. Most age-related NSCLC studies to date use an analysis approach where a single age cutoff is selected (typically 40 to 50 years) to classify younger patients, and then compared that singularly defined group against older patients (3,6,7,(9)(10)(11)(12)(13). This analytical approach poses inherent biases based on the age threshold chosen to define younger and older patients as shown by the various age thresholds at which an association was detected in the current study (Table 2, column "Oldest age group first detected for").…”

“…Younger patients with NSCLC represent a clinically significant patient population with distinct clinicopathological features. Further, younger patients have higher prevalence of adenocarcinoma histology, are more likely to be females and never-smokers and are more likely to present with advanced disease at the time of diagnosis compared to older patients (4)(5)(6)(7)(8). At the genomic-level, younger patient tumors have been shown to be enriched for clinically actionable genomic alterations including certain drivermutations in EGFR, ALK, ERBB2, and ROS1 and deficient in MET exon 14 skipping mutations compared to older patient tumors (3,6,7,(9)(10)(11)(12)(13).…”

“…Further, younger patients have higher prevalence of adenocarcinoma histology, are more likely to be females and never-smokers and are more likely to present with advanced disease at the time of diagnosis compared to older patients (4)(5)(6)(7)(8). At the genomic-level, younger patient tumors have been shown to be enriched for clinically actionable genomic alterations including certain drivermutations in EGFR, ALK, ERBB2, and ROS1 and deficient in MET exon 14 skipping mutations compared to older patient tumors (3,6,7,(9)(10)(11)(12)(13). Younger patients have tumors with lower tumor mutational burden (TMB) suggesting they may have reduced responses to immunotherapy compared to older patients (7,14).…”

“…At the genomic-level, younger patient tumors have been shown to be enriched for clinically actionable genomic alterations including certain drivermutations in EGFR, ALK, ERBB2, and ROS1 and deficient in MET exon 14 skipping mutations compared to older patient tumors (3,6,7,(9)(10)(11)(12)(13). Younger patients have tumors with lower tumor mutational burden (TMB) suggesting they may have reduced responses to immunotherapy compared to older patients (7,14). Younger patient tumors have also been shown to have differentially expressed immune-related genes compared to older patient tumors (14), although more needs to be done to assess the importance of this finding in NSCLC.…”