Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
Joshua E. Reuss , Nishant Gandhi , Phillip Walker , Jorge J. Nieva , Jean Gabriel Bustamante Alvarez , Jennifer W Carlisle , Aakash Desai , Ari M. Vanderwalde , Patrick C. Ma , Stephen V. Liu
Background: With the emergence of effective targeted-therapies for KRAS G12C, and the development of promising agents for KRAS G12V and G12D among others, the identity of unique KRAS mutations in non-small cell lung cancer (NSCLC) has become increasingly relevant. Acquired KRAS mutations are a known mechanism of resistance observed across driver mutation-positive (DM+) NSCLC. The incidence and diversity of these acquired alterations, and whether they differ from those observed in de novoKRAS-mutated NSCLC, is unknown. Methods: NSCLC molecular profiles were obtained using next-generation sequencing (Caris Life Sciences) with paired whole-transcriptomic sequencing (Illumina NovaSeq) and immunohistochemistry (Caris Life Sciences). Demographic data were abstracted from medical records. KRAS mutation diversity was defined for de novo KRAS-mutated (KRASmt) NSCLC (KRAS as only identified driver –KRASmt_dn) and DM+ NSCLC with acquired KRAS mutations (concurrent KRASmt with other known driver –KRASmt_acq). Fisher’s exact test was used to compare the distribution of unique KRAS mutations between the groups. Due to the unique biology of NSCLC with class II/III BRAF mutations, this subset was removed from the KRASmt_acq subgroup for the final analysis. Results: A total of 5932 KRASmt NSCLC samples were identified, among which 5879 were KRASmt_dn and 53 were KRASmt_acq (see table). The distribution of unique KRAS mutations was not significantly different between groups (p = 0.14). Within the KRASmt_dn group, KRAS G12C was most common (40%), followed by G12V (19%), G12D (14%), G12A (7%) and Q61H/G13C (4% each). In the KRASmt_acq group, KRAS G12C was most common (30%), followed by G12D (19%), G12V (17%), Q61H (11%), G12A (7%), and G13C (6%). The most common observed driver mutations in the KRASmt_acq group were EGFR (38%) and MET (30%). In the EGFR group, KRAS G12D (25%), Q61H/G12C (20% each), G12V/G13C (10% each), and G12F/A/R (5% each) were observed. In the MET group, KRAS G12C (25%), G12D/V/A (19% each), Q61H (12%) and G12S (6%) were seen. Among 7 patients with a documented history of smoking in the KRASmt_acq group, KRAS G12D and Q61H were most common (29% each), followed by G12V/F and G13C (14% each). Conclusions: While the distribution of unique KRAS mutations did not differ significantly between KRASmt_dn and KRASmt_acq groups, acquired KRAS mutations were seen across DM+ NSCLC subsets, among which the frequency of observed mutations appeared to vary. The functional and immunological significance of these mutations, and their impact on clinical outcomes, warrants further investigation.
KRASmt _dn | KRASmt _acq | EGFR | MET | ALK | HER2 | ROS1 | BRAF Class 1 | |
---|---|---|---|---|---|---|---|---|
# of pts | 5879 | 53 | 20 | 16 | 7 | 6 | 1 | 3 |
G12C | 40% | 30% | 20% | 25% | 57% | 50% | 100% | - |
G12D | 14% | 19% | 25% | 19% | - | 33% | - | - |
G12V | 19% | 17% | 10% | 19% | 29% | - | - | 67% |
G12A | 7% | 7% | 5% | 19% | - | - | - | - |
Q61H | 4% | 11% | 20% | 12% | - | - | - | - |
G13C | 4% | 6% | 10% | - | - | - | - | 33% |
G12F | 2% | 2% | 5% | - | - | - | - | - |
G12R | 1% | 2% | 5% | - | - | - | - | - |
G12S | 2% | 4% | - | 6% | - | 17% | - | - |
Other | 7% | 2% | - | - | 14% | - | - | - |
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