Association Between Younger Age and Targetable Genomic Alterations and Prognosis in Non-Small-Cell Lung Cancer

Abstract

Importance: Non-small-cell lung cancer (NSCLC) diagnosed in young patients is rare, and the genomics and clinical characteristics of this disease are poorly understood. In contrast, the diagnosis of other cancers at a young age has been demonstrated to define unique disease biology. Herein, we report on the association of young age with targetable genomic alterations and prognosis in a cohort of 2237 patients with NSCLC.

Objective: To determine the relationship between young age at diagnosis and the presence of a potentially targetable genomic alteration, disease prognosis, and natural history.

Design, setting, and participants: A cohort of all 2237 patients with NSCLC who were genotyped at the Dana-Farber Cancer Institute between January 2002 and December 2014 were identified. Tumor genotype, patient characteristics, and clinical outcomes were collected and studied at a National Cancer Institute-designated comprehensive cancer center. Multivariate logistic regression was used to analyze the relationship between age and mutation status, and multivariate Cox proportional hazard models were fitted for survival analysis.

Main outcomes and measures: The frequency of targetable genomic alterations by defined age categories as well as the association of these age groups with survival. Age categories used in this analysis were younger than 40, 40 to 49, 50 to 59, 60 to 69, and 70 years or older.

Results: A cohort of 2237 patients with NSCLC was studied. Of the 2237 participants, 1939 (87%) had histologically confirmed adenocarcinoma, 269 (12%) had NSCLC not otherwise specified, and 29 (1%) had squamous histologic findings; 1396 (63%) had either stage IIIB or IV cancers; and median (range) age was 62 (20-95) years. We found that gene mutations for EGFR (P = .02) and ALK (P < .001) were associated with cancer diagnosis at a younger age, and a similar trend existed for ERBB2 (P = .15) and ROS1 (P = .10) but not BRAF V600E (P = .43). Among patients tested for all 5 targetable genomic alterations (n = 1325), younger age was associated with an increased frequency of a targetable genotype (P < .001). Those diagnosed at 50 years or younger have a 59% increased likelihood of harboring a targetable genotype. While presence of a potentially targetable genomic alteration treated with a targeted agent was associated with improved survival, the youngest and oldest age groups had similarly poor outcomes even when a targetable genotype was present.

Conclusions and relevance: Younger age is associated with an increased likelihood of harboring a targetable genotype and is an underappreciated clinical biomarker in NSCLC. The survival of young patients with NCSLC is unexpectedly poor compared with other age groups, suggesting more aggressive disease biology. These findings underscore the importance of comprehensive genotyping, including next-generation sequencing, in younger patients with lung cancer.

Figure 1

The frequency of potentially targetable genomic alterations is highest among young patients and steadily decreases with age (A) whereas KRAS exhibits the opposite trend. Complete genotyping refers to testing for all 5 targetable alteration. Association with younger age is apparent when each individual alteration is considered including EGFR mutations (B), ALK rearrangements (C), ROS1 rearrangements (D) and HER2 exon 20 insertions (E) whereas BRAF V600E appears more common among older patients (F). Mt: mutation wt: wild-type.

Figure 2

The survival of patients possessing a targetable alteration is lowest among patients >70 and those <40 as demonstrated by these KM plots (A). All other age groups that possess a targetable alteration have significantly improved survival compared to the oldest age group (A) (p<0.01). There is no significant difference in survival between age groups among patients that do not possess a potentially targetable alteration (B, p=0.41).