Impact of KRASG12D subtype and concurrent pathogenic mutations on advanced non-small cell lung cancer outcomes

Abstract

Purpose: Mutations in the Kirsten rat sarcoma viral (KRAS) oncogene constitute a significant driver of lung adenocarcinoma, present in 10-40% of patients, which exhibit heterogeneous clinical outcomes, mainly driven by concurrent genetic alterations. However, characterization of KRAS mutational subtypes and their impact on clinical outcomes in Latin America is limited.

Methods: A cohort study was conducted at the National Cancer Institute (INCan) of Mexico. Individuals with advance-staged of adenocarcinoma and KRAS mutations, detected by next-generation sequencing, having undergone at least one line of therapy were included for analysis. Clinical and pathological characteristics were retrieved from institutional database from June 2014 to March 2023.

Results: KRAS was identified in fifty-four (15.6%) of 346 patients, among which 50 cases were included for analysis. KRAS^G12D (n = 16, 32%) and KRAS^G12C (n = 16, 32%) represented the most prevalent subtypes. KRAS^G12D mutations were associated with female (p = 0.018), never smokers (p = 0.108), and concurrences with EGFR (25.0% vs. 17.6%, p = 0.124) and CDKN2A (18.8% vs. 14.7%, p = 0.157). KRAS^G12D patients showed a better ORR (66.6% vs. 30.0%; OR 4.66, 95% CI 1.23-17.60, p = 0.023) and on multivariate analysis was significantly associated with better PFS (HR 0.36, 95% CI 0.16-0.80; p = 0.012) and OS (HR 0.24, 95% CI 0.08-0.70; p = 0.009).

Conclusions: To our knowledge, this study represents the first effort to comprehensively characterize the molecular heterogeneity of KRAS-mutant NSCLC in Latin American patients. Our data reinforce the current view that KRAS-mutated NSCLC is not a single oncogene-driven disease and emphasizes the prognostic impact of diverse molecular profiles in this genomically defined subset of NSCLC. Further validation is warranted in larger multicenter Latin American cohorts to confirm our findings.

Keywords: Comutations; Immunotherapy; KRAS G12D; Non-small cell lung carcinoma; STK11; TP53.

Fig. 1

A, clinical characteristics and comutations of KRAS-mutated NSCLC patients. B, structural representation, and frequency of KRAS mutations. C, smoking history according to packs per year in KRAS^G12D or KRAS^non-G12D groups. D, Tumor mutational burden in KRAS^G12D and KRAS^non-G12D groups. E, assessment of PD-L1 TPS expression according to KRAS^G12D mutation. F, number of commutations between individuals with in KRAS^G12D and KRAS^non-G12D. mutations G, Association probability of KRAS with other driver genes. KRAS, Kirsten rat sarcoma viral oncogene homolog. G12C, missense substitution of glycine for cysteine. G12D, missense substitution of glycine for aspartate. G12V, missense substitution of glycine for valine. G12A, missense substitution of glycine for alanine. G12S, missense substitution of glycine for serine. V14I, missense substitution of valine for isoleucine. P34L, missense substitution of proline for leucine. Q61H, missense substitution of glutamine for histidine, K117N, missense substitution of lysine for asparagine. A66A, silent mutation coding for alanine in both original and mutated forms. Amp, amplification. TP53, tumor protein p53. STK11, Serine/Threonine Kinase 11. EGFR, epidermal growth factor receptor gene. EGFR mutations detected were: G719S and S768l (n = 1), Q787Q (n = 5), G288Vfs*5 (n = 1) and G403E (n = 1). GNAS, guanine nucleotide-binding protein, alpha stimulating complex locus. ATM, ataxia telangiectasia mutated. HER2, human epidermal growth factor receptor 2. CDKN2A, Cyclin-Dependent Kinase Inhibitor 2A. MET, mesenchymal-epithelial transition factor. RB1, Retinoblastoma 1. PI3KCA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha. PDGFRA, platelet-derived growth factor receptor alpha. SPEN, Spen Family Transcriptional Repressor. CTNNB1, Catenin Beta 1. KDR, Kinase Insert Domain Receptor. SMADD4, SMA- and MAD-related protein 4. BRCA1, breast cancer gene. HNF1A, hepatocyte nuclear factor 1 alpha. CREBBP, CREB Binding Protein. ESR, estrogen receptor 1. ERBBB4, Erb-B2 Receptor Tyrosine Kinase 4. MYC, MYC Proto-Oncogene. SDHD, Succinate Dehydrogenase Complex Subunit D. CBL, Casitas B-lineage Lymphoma. NTRK3, neurotrophic receptor tyrosine kinase 3. CDKN2B, cyclin dependent kinase inhibitor 2B. ROS1, ROS Proto-Oncogene 1. KEAP1, Kelch-like ECH-associated protein 1. ALK, anaplastic lymphoma kinase. TMB, tumor mutational burden. PD-L1, programmed death ligand 1. TPS, tumor proportion score. Tobacco exposure index was calculated by multiplying smoked cigarette packs and years of exposure, then this result was divided into 20. Comparisons in figures C-F were performed using Mann–Whitney test according to normal distribution determined by the Kolmogorov–Smirnov test. Significant p values were defined as less than 0.05

Fig. 2

Prevalence of co-mutations in individuals with G12D mutations. KRAS, Kirsten rat sarcoma viral oncogene homolog. G12D, missense substitution of glycine for aspartate. TP53, tumor protein p53. STK11, Serine/Threonine Kinase 11. EGFR, Epidermal Growth Factor Receptor. GNAS, guanine nucleotide-binding protein, alpha stimulating. ATM, Ataxia-Telangiectasia Mutated. HER2, human epidermal growth factor receptor 2. MET, mesenchymal-epithelial transition factor. CDKN2A, Cyclin-Dependent Kinase Inhibitor 2A. RB1, Retinoblastoma 1. PI3KCA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha. Comparisons were performed by Pearson Chi-Square test. Significance was set at p-values < 0.05

Fig. 3

A, Type of responses to all treatments according to KRAS^G12D mutation. B, progression-free survival of individuals with KRAS^G12D or KRAS^non−G12D mutations after all treatments. C, overall survival of patients having KRAS G12D or non-G12D mutations after all treatments. D, therapeutic responses to immunotherapy according to KRAS G12D mutation. E, progression-free survival of individuals having in KRAS^G12D and KRAS^non−G12D mutations undergoing immunotherapy or chemotherapy. F, overall survival of individuals having in KRAS^G12D and KRAS^non−G12D mutations undergoing immunotherapy or chemotherapy. G, therapeutic responses to immunotherapy in individuals harboring or not TP53 comutation. H, progression-free survival of patients having or not comutation with TP53 after immunotherapy or chemotherapy. I, overall survival of patients having or not comutation with TP53 after immunotherapy or chemotherapy. J, therapeutic responses to immunotherapy of individuals having or not STK11 comutation. K, progression-free survival of patients having or not comutation with STK11 after immunotherapy or chemotherapy. L, overall survival of patients having or not comutation with STK11 after immunotherapy or chemotherapy. IO, immunotherapy. ICI, immune checkpoint inhibitors. CT, chemotherapy. PFS, progression-free survival. OS, overall survival. KRAS, Kirsten rat sarcoma viral oncogene homolog. G12D, missense substitution of glycine for aspartate. TP53, tumor protein p53. STK11, Serine/Threonine Kinase 11. PFS was calculated from diagnosis to progression to first-line treatment. OS was determined by the period between diagnosis and death for any cause. Log-rank test was performed to determine statistical differences between Kaplan-Meyer curves. p<0.05 were considered as significative