Introduction: KRAS alterations (KRASalt) NSCLC accounts for 29% to 33% of lung adenocarcinomas, and 17% to 55% of these patients develop brain metastases. KRASalt status appears to have a limited effect on overall survival (OS) in patients with early-stage NSCLC and its effect on prognosis is largely unknown. Few studies document the prevalence of brain metastases within each KRAS subtype. In the current study, we examined the prevalence of patients with NSCLC and brain metastases to determine the prevalence of KRAS alterations.
Methods: Analyses were completed using Tempus Lens, which aggregates de-identified data from samples tested with the Tempus Database and enables real-time cohort identification and analysis. Data from both liquid and solid tissue biopsy were included in this study.
Results: Using Tempus Lens, 4321 cases of brain metastasis linked to the curated diagnosis of NSCLC were identified. In the overall cohort, KRASalt were identified in 28.93% (1250/4321) of patients. KRAS p.G12C was the most prevalent alteration, appearing in 11.32% (488/4321) of cases compared to the most common EGFR subtype, p.L858R, at 6.04% (261/4321). Approximately 34.88% (436/1250) of observed KRASalt cases were identified using liquid biopsy testing, suggesting that blood-based testing may be a viable diagnostic for detecting brain metastases with KRAS alterations. Among the KRASalt subgroup (n = 1250), the most frequent KRAS alterations were: p.G12C (39%, 489), p.G12V (18%, 227), p.G12D (12.48%,156), p.G12A (6.16%, 77), and p.G13C (5.28%, 66). Additionally, co-alterations were observed in TP53 (63%, 783), LRP1B (38%, 479), STK11 (29%, 357), KEAP1 (24%, 299), CDKN2A (21%, 265). PD-L1 status data was available for 732 cases, of which 67.2% (492/732) were positive for PD-L1. The remaining 32.8% were negative and therefore ineligible for first-line IO monotherapy.
Conclusions: This study details the most prevalent KRAS alterations and co-mutations among KRASalt NSCLC. KRAS p.G12C was the most frequently observed alteration and co-mutations were found in TP53, LRP1B, STK11, KEAP1, and CDKN2A. Our findings have therapeutic implications as co-alterations with STK11/KEAP1 are associated with worse outcomes. Further drug development for KRAS inhibitors with CNS activity is warranted.
KRAS Alteration Prevalences
|
Any KRAS Alteration |
G12C |
G12V |
G12D |
G12A |
G13C |
| Overall Cohort |
1250 |
489,(39%) |
227, (18%) |
156, (13%) |
77, (6%) |
66, (5%) |
| Sex |
|
|
|
|
|
|
| Female |
711, (57%) |
295, (60%) |
130, (57%) |
87, (56%) |
43, (56%) |
38, (58%) |
| Male |
539, (43%) |
194, (40%) |
97, (43%) |
69, (44%) |
34, (44%) |
28, (42%) |
| Co-Alteration |
|
|
|
|
|
|
| TP53 |
783, (63%) |
306, (63%) |
139, (61%) |
94, (60%) |
46, (60%) |
46, (70%) |
| LRP1B |
479, (38%) |
201, (41%) |
70, (31%) |
59, (38%) |
27, (35%) |
23, (35%) |
| STK11 |
357, (29%) |
137, (28%) |
56, (25%) |
40, (25%) |
21, (27%) |
22, (33%) |
| KEAP1 |
299, (24%) |
109, (23%) |
49, (22%) |
43, (28%) |
17, (22%) |
20, (30%) |
| CDKN2A |
265, (21%) |
99, (20%) |
53, (23%) |
36, (23%) |
12, (16%) |
15, (23%) |
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