Search Results (193)

Endometrial cancer (EC) is a heterogeneous malignancy characterized by diverse molecular and clinicopathological features. This study investigated somatic mutations in three hotspot-region genes commonly implicated in EC pathogenesis (KRAS, TP53, PTEN) and their associations with clinical characteristics and biomarkers, rather than comprehensive genomic profiling. Targeted next-generation sequencing (NGS) was used to analyze hotspot regions of KRAS (exons 2 and 4), TP53 (exons 4 and 7), and PTEN (exon 2), while mutation parameters, including mutant allele frequency (MAF), allelic depth, and variant frequency, were assessed alongside clinicopathological data. Pathogenic KRAS missense mutations (p.G12D and p.A146V), TP53 missense (p.G245C) and stop-gain (p.W91*) variants, and a pathogenic PTEN mutation (p.D52Y) were identified, with MAF values ranging from 36.2% to 77.1%. One patient also exhibited microsatellite instability-high (MSI-H) status. Serum CA125 concentrations were significantly higher in serous carcinoma than in endometrioid carcinoma and non-malignant cases, suggesting potential prognostic rather than diagnostic value. This suggests an association between CA125 levels and histological subtype rather than diagnostic or prognostic value, as this study did not evaluate survival, recurrence, or longitudinal outcomes. The detected mutations highlight disruptions in estrogen signaling, DNA damage response, and PI3K/AKT pathway regulation, illustrating the diversity of alterations detectable within these three hotspot regions in EC. These findings provide insight into the mutational status of KRAS, TP53, and PTEN hotspot regions in endometrial cancer and support the potential use of identified genetic alterations as biomarkers for precision medicine and targeted therapeutic strategies, while indicating that CA125’s clinical utility in EC, whether diagnostic or prognostic, remains to be established through outcome-based studies. This also reinforces CA125’s limited diagnostic but possible prognostic role in EC management. Full article

For four decades the central oncogenic drivers of human cancer the RAS GTPases, the transcription-factor MYC, mutant p53, and the protein-tyrosine phosphatases, fusion oncoproteins and intrinsically disordered regulators that surround them were regarded as undruggable: lacking deep, well-defined small-molecule binding pockets, governed by femtomolar substrate affinities, or driven through flat protein–protein interfaces that classical medicinal chemistry could not engage. The last decade has overturned that verdict. This narrative review argues that the convergence of three advances has made the undruggable proteome systematically approachable: the discovery of cryptic, allosteric and induced pockets through molecular dynamics and deep learning; the maturation of physics-based and machine-learned models that can read out binding from structure; and the rise in generative artificial intelligence that can design novel molecules conditioned directly on a three-dimensional target. We develop the argument in full formal detail. We set out the mathematics of modern molecular machine learning E(3)/SE(3)-equivariant graph neural networks, denoising diffusion and score-based generative models, and generative flow networks alongside the statistical mechanics of binding free energy (free-energy perturbation, thermodynamic integration, MM-PBSA), the kinetics of covalent inhibition, the equilibrium theory of ternary complexes and cooperativity that governs molecular glues and degraders, and the pharmacology that determines whether a designed molecule reaches and acts on a tumour. We then examine, target by target, the biology that made each oncoprotein intractable and the campaigns structural, chemical and increasingly computational that have begun to defeat it, distinguishing throughout what classical structural and computational work achieved, what machine learning demonstrably contributed, and what generative design has so far only promised: the switch-II pocket and the covalent KRAS-G12C and non-covalent KRAS-G12D and pan-RAS(ON) inhibitors; the mutation-created cavity of p53-Y220C and its first reactivators; the disordered MYC-MAX interface and the miniprotein Omomyc; and the allosteric tunnel of SHP2. These four are selected for mechanistic non-redundancy, on grounds we state explicitly, and the structured search framework and eligibility criteria underlying the review are documented. We foreground the newest evidence AlphaFold3, RoseTTAFold All-Atom, deep cryptic-pocket predictors, and the first generative-to-clinic existence proofs while maintaining candour about the field’s hard limits: the physical-validity and generalisation gaps of deep docking, the bounded accuracy and cost of free-energy methods, the synthesizability gap, dual-use risk, and a clinical attrition that artificial intelligence has not yet reduced. The synthesis we offer is not that the problem is solved but that it has changed in kind: from a search for the rare tractable target to the deliberate, computable engineering of molecules against targets once thought beyond reach. Full article

Background: PDAC is a highly aggressive malignancy driven predominantly by activating KRAS mutations, and allele-specific and pan-RAS inhibitors have emerged as candidate targeted therapies. Evidence supporting them is dominated by experimental studies of which the models differ widely in how faithfully they reproduce human disease, and clinical maturity is uneven across alleles. Objectives: The objective of this study was to evaluate allele-stratified RAS-inhibitor activity across KRAS subtypes in PDAC, synthesizing experimental and clinical evidence separately, and determine whether the principal conclusions of the review survive when the experimental evidence is stratified by the level of model validation achieved. Methods: PubMed, Cochrane Library, Scopus, and Google Scholar were searched from inception to 26 June 2026, with a pre-specified updated search in June 2026. Experimental studies were appraised with a modified JBI Critical Appraisal Checklist for Quasi-Experimental Studies supplemented by preclinical-specific reporting domains, and were independently classified by the highest level of model validation achieved, from conventional two-dimensional cell lines through to multi-model validation spanning patient-derived and immunocompetent in vivo systems; clinical studies were appraised with ROBINS-I. Experimental and clinical evidence was synthesized separately. Single-arm proportions from KRAS G12C trials were pooled on the logit scale using inverse-variance random-effects meta-analysis with Hartung–Knapp confidence intervals, and certainty was rated using GRADE. Results: Twenty-four studies were included (twenty experimental and four early-phase, single-arm clinical trials). Four of the twenty experimental studies (20%) rested on conventional two-dimensional cell lines alone, nine (45%) incorporated patient-derived material, seven (35%) used immunocompetent models, and fourteen (70%) reproduced their principal finding in at least two independent model classes. The allele-dependent pattern of single-agent activity persisted when cell-line-only studies were set aside, whereas 6 of the 17 studies reporting combination strategies provided no confirmation in any higher-order system. Across three single-arm KRAS G12C trials, the pooled objective response rate was 36.9% (95% CI, 9.8–75.7%; I² = 66.2%; individual trials 21.1%, 45.5%, and 46.9%), the pooled disease control rate was 85.9% (95% CI, 62.1–95.8%; I² = 0%; individual datasets 81.8%, 84.2%, and 93.8%), and the grade ≥ 3 treatment-related adverse event rate was 23.8% (95% CI, 11.2–43.5%; I² = 0%). GRADE certainty was very low for all three outcomes. Conclusions: The available evidence is consistent with allele-dependent activity of RAS-targeted therapy in PDAC and supports biomarker-guided treatment selection, but the clinical evidence base is confined to small, single-arm, early-phase trials of KRAS G12C inhibitors. The pooled estimates are exploratory descriptions of observed activity in selected early-phase populations, not comparative estimates of treatment efficacy. KRAS G12D-directed therapy remains at a substantially earlier stage of clinical validation than KRAS G12C-directed therapy despite a much larger preclinical literature. Full article

Background: KRAS mutations are common oncogenic drivers in metastatic lung cancer (mLC) and may have prognostic and therapeutic implications. Circulating tumor DNA (ctDNA) analysis offers a minimally invasive approach for detecting tumor-specific alterations and monitoring tumor dynamics. This pilot study investigated the concordance between tissue and plasma KRAS mutational status and evaluated its clinical significance. Methods: Forty patients with mLC (25 males, 15 females; mean age 70.8 years) were included. KRAS mutations were analyzed in formalin-fixed paraffin-embedded tumor tissue using next-generation sequencing and in baseline plasma ctDNA using the Biocartis Idylla™ system. Concordance was assessed using Cohen’s kappa statistics. Associations with clinicopathological characteristics and survival outcomes (overall survival (OS), progression-free survival (PFS), and time to progression (TTP)) were examined. Longitudinal ctDNA monitoring was performed in a subset of patients. Results: KRAS mutations were detected in 14/36 (38.89%) of tumor tissues and 12/40 (30.00%) of plasma samples, predominantly involving codon 12, with G12C as the most frequent variant. Tissue–plasma concordance was assessed in the 36 patients with matched samples and was substantial (κ = 0.64), while mutation subtype showed almost perfect agreement among concordant cases (percentage of agreement: 88.9%, κ = 0.80, p = 0.002, 95% CI: 0.4400–1.0000). No significant associations were observed with clinicopathological variables. Longitudinal analysis revealed dynamic ctDNA changes, with molecular progression occasionally preceding clinical progression. Patients with KRAS-mutated ctDNA had shorter PFS and OS compared to those with wild-type ctDNA (median PFS: 134 vs. 146 days; median OS: 163 vs. 193 days). Conclusions: Plasma ctDNA detection of KRAS mutations identifies a poor-prognosis subgroup of mLC patients and provides dynamic insights into tumor evolution. Serial ctDNA monitoring may anticipate disease progression and support real-time assessment of treatment response, highlighting its potential role in translational research and precision oncology. Full article

Background: Approximately 13% of NSCLC cases have KRAS G12C mutations. As therapeutic strategies targeting KRAS G12C-mutant NSCLC evolve, it is important to understand clinical presentation and current outcomes for these patients. Methods: This retrospective study used data from two US nationwide databases, an electronic health records (EHR) database and a clinico-genomic database (CGDB) of EHR data linked to data from comprehensive genomic profiling tests. Eligible patients had advanced NSCLC, initiated first-line therapy from August 2018 to December 2022, and had KRAS test results. Clinicopathologic characteristics, treatments, real-world progression-free survival (rwPFS), and overall survival (OS) were analyzed. Results: There were 1227 patients with KRAS G12C-mutant NSCLC in the EHR database and 447 in the CGDB. First-line regimen was platinum-based chemotherapy plus pembrolizumab for 46% and pembrolizumab monotherapy for 20%. Less than 40% of patients received second-line therapy. Median (95% CI) OS for KRAS G12C-mutant NSCLC patients in the EHR was 17.0 (15.2–18.9) months. Variables significantly associated with shorter OS included PD-L1 <1%, brain metastases, STK11 co-mutation, and poor performance status. Patients treated with platinum-based chemotherapy plus pembrolizumab had median rwPFS of 5.3 (4.5–7.3) months and OS of 12.8 (11.1–17.3) months in the CGDB; median OS was 15.6 (12.5–18.6) months in the EHR. Patients with PD-L1 ≥ 50% treated with pembrolizumab monotherapy had median rwPFS of 4.6 (3.0–15.6) months and OS of 20.4 (10.3–38.5) months in the CGDB; median OS was 22.1 (18.7–30.7) in the EHR. Conclusions: These data provide a real-world benchmark of outcomes for patients with KRAS G12C-mutant NSCLC receiving the current standard of care and indicate an unmet need for more effective first-line therapies. Full article

KRAS G12C mutation is a clinically relevant driver in non-small cell lung cancer (NSCLC), yet the signaling networks that modulate malignant behavior in this context remain incompletely defined. In this study, we examined the functional role of FOXD3 and its relationship with NF-κB signaling in KRAS G12C-mutant NSCLC models. Stable FOXD3 overexpression was established in SW1573 and LU65 cells. FOXD3 reduced cell viability, migration, and invasion while increasing caspase 3/7 activity in both cell lines. Transcriptomic profiling in LU65 cells followed by Hallmark enrichment analysis identified TNFα signaling via NF-κB as a prominently altered pathway associated with FOXD3 overexpression. Consistently, NF-κB dual-luciferase assays showed reduced basal NF-κB transcriptional activity in FOXD3-overexpressing cells. TNFα stimulation partially reversed the inhibitory effects of FOXD3 on proliferation, migration, and invasion and attenuated FOXD3-induced apoptosis. In addition, stable FOXD3 overexpression suppressed xenograft growth in vivo. Collectively, these findings support a functional association between FOXD3 overexpression and reduced NF-κB-related transcriptional activity in KRAS G12C-mutant NSCLC models, although the present data do not establish direct causal mediation by NF-κB. Full article

Purpose: This review aims to provide an updated overview of Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations in colorectal carcinoma (CRC), focusing on their role in tumorigenesis, prognostic implications, and recent advances in targeted therapy. Major findings: KRAS mutations occur in approximately 40% of colorectal cancers and play a central role in tumour initiation and progression through constitutive activation of MAPK pathways. Clinically, KRAS mutations are well established as predictors of resistance to anti-EGFR therapy. Increasing evidence also supports their role as prognostic biomarkers, with KRAS-mutant tumours associated with increased recurrence risk and reduced survival, including in patients undergoing hepatic metastasectomy. Therapeutically, recent advances, most notably KRAS G12C inhibitors and combination strategies targeting upstream or parallel pathways, have expanded treatment options, although efficacy varies across KRAS mutation subtypes. Conclusions: KRAS mutations have important implications for the behaviour, prognosis, and management of colorectal cancer. Integrating KRAS mutational status into clinical decision-making may enable more personalised prognostication and treatment strategies. Continued research is required to broaden effective targeted therapies for the diverse spectrum of KRAS-mutant disease. Full article

Metastatic colorectal cancer (mCRC) remains one of the leading causes of cancer deaths worldwide. Mutations of the RAS and BRAF genes and the location of the primary tumor determine the choice of systemic therapy. Panitumumab—a fully human anti-EGFR monoclonal antibody—is well-established in the treatment of patients with wild-type RAS and BRAF and left-sided tumor localization. The aim of this review is to summarize the role and potential of targeted therapies for colorectal cancer with monoclonal antibodies such as panitumumab or cetuximab, to provide current evidence on the position of panitumumab in the treatment of mCRC, and to discuss biomarkers and qualification strategies for targeted therapy, including the role of ctDNA in disease monitoring and rechallenge. The work is based on a narrative review of literature from the PubMed, Scopus, Web of Science and Google Scholar databases, including publications available until May 2026. The efficacy of panitumumab was confirmed in phase III studies: first-line (PRIME: prolongation of OS by 5.6 months) and second-line treatment. A key condition for eligibility is complete RAS and BRAF genotyping, assessment of MSI/dMMR status, HER2 amplification, and tumor location. ctDNA analysis enables monitoring of tumor clonal evolution and qualification for rechallenge—the CHRONOS study showed 30% objective responses with liquid biopsy-based selection. Associations with BRAF/MEK and KRAS G12C inhibitors and modulation of the immune microenvironment via the CCL5/CCR5 axis remain promising directions. Panitumumab occupies an important position in the treatment of patients with mCRC, but increasingly precise molecular stratification and dynamic monitoring of disease with ctDNA are becoming the basis for the effective and rational use of the drug. Unlike reviews that selectively focus on individual aspects of anti-EGFR therapy, the following work integrates all aspects: from molecular biology and biomarkers used to qualify patients to clinical data on panitumumab and new strategies in the fight against mCRC. Further development of next-generation sequencing methods and standardization of ctDNA panels will be crucial for the widespread deployment of targeted therapies in everyday clinical practice. The role of panitumumab is well established in appropriately selected patients with RAS wild-type, particularly left-sided, metastatic colorectal cancer (mCRC). Combining panitumumab with immune checkpoint inhibitors warrants further investigation, particularly in patients with MSS/pMMR mCRC. The observed activity of panitumumab in combination with nivolumab and ipilimumab provides a rationale for further clinical evaluation and monitoring. Full article

Background/Objectives: High-grade pulmonary neuroendocrine carcinoma (HGNEC-L), including SCLC and LCNEC, is aggressive and usually treated according to SCLC paradigms. The clinical relevance of de novo actionable genomic alterations (AGA) remains incompletely defined. Methods: We performed a retrospective multicenter analysis of advanced HGNEC-L with de novo AGA, assessing rwORR, rwDCR, rwPFS, and OS. Findings were contextualized by a structured literature review and exploratory pooled reconstructed-IPD Cox analysis, with targeted therapy modeled as a source-stratified time-dependent covariate. Results: Ten patients from four tertiary centers were included. Most were women (90.0%) and never-smokers (70.0%); histology was LCNEC in 60.0% and SCLC/mixed SCLC in 40.0%. AGA included EGFR mutations (n = 6), EML4-ALK fusions (n = 2), KIF5B-RET fusion (n = 1), and KRAS p.G12C (n = 1). Targeted-containing regimens achieved rwORR 77.8%, rwDCR 88.9%, and median rwPFS 9.0 months (95% CI, 2.0–18.7), as opposed to 3.7 months for ICI-containing regimens and 2.6 months for chemotherapy alone. Median OS for the entire cohort was 17.2 months (95% CI, 4.8–36.3); overall survival did not differ significantly between patients with and without targeted-containing exposure (19.0 vs. 17.2 months; log-rank p = 0.50). In pooled reconstructed-IPD time-dependent Cox analysis (72 patients, 39 deaths), targeted therapy showed a favorable but non-significant OS association (HR, 0.89; 95% CI, 0.31–2.56; p = 0.831), maintained directionally in the age/sex-adjusted subset (HR, 0.54; 95% CI, 0.16–1.77; p = 0.306). Conclusions: De novo AGA-positive HGNEC-L represents a clinically relevant subgroup with potential sensitivity to genotype-matched targeted therapy, supporting comprehensive molecular profiling and early targeted therapy consideration. Full article

Approximately 30% of tumors contain an activating mutation in the oncogene KRAS, leading to increased cell proliferation that often promotes non-small cell lung cancers, colorectal adenocarcinomas, pancreatic ductal adenocarcinomas (PDAC), and other cancers. Among the most common point mutations in KRAS is G12D, an example of an oncogenic sequence present in tumor cells but not normal cells. We developed peptide nucleic acid (PNA) oligomers that selectively bind KRAS G12D sequences and fused them with novel cell-penetrating peptide flanking regions (CPP-PNA-G12D) then evaluated them. Electrophoretic mobility shift assays demonstrated in vitro binding to and selectivity for KRAS G12D over wild-type KRAS and KRAS G12C. Cells and nuclei were able to uptake CPP-PNA-G12D at high efficiency as shown by fluorescent microscopy and flow cytometry. Cell viability assays showed a striking dose-response effect in on-target cells expressing KRAS G12D, while relatively sparing off-target cells expressing KRAS G12C. CPP-PNA-G12D constructs were effective against a panel of PDAC cell lines and in female Balb/c mice bearing patient-derived xenografts. These results show promise for an enhanced PNA-delivery peptide conjugate strategy as a potential therapeutic strategy to selectively target KRAS mutant cancer cells, with the potential to expand this technology to additional cancer-derived mutant oncogenes. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies, with poor survival driven by late presentation, aggressive tumor biology, and limited responsiveness to conventional systemic therapy. Advances in molecular profiling have expanded opportunities for biomarker-guided and targeted therapeutic approaches. Methods: A literature review was conducted using PubMed and the Cochrane Library through July 2026, supplemented by abstracts and proceedings from major international oncology conferences. Results: Pancreatic cancer is driven mainly by somatic changes in KRAS, TP53, CDKN2A, and SMAD4. Established precision approaches include maintenance olaparib for selected platinum-sensitive tumors with germline BRCA1 or BRCA2 pathogenic variants, immune checkpoint inhibition for mismatch repair-deficient or microsatellite instability-high tumors, and tropomyosin receptor kinase inhibition for cancers with neurotrophic tyrosine receptor kinase gene fusions. Direct inhibition of KRAS and RAS represents a major therapeutic breakthrough. KRAS G12C inhibitors established proof of concept, while agents targeting the more common KRAS G12D mutation are showing encouraging early activity. In the randomized phase III RASolute 302 trial, the multiselective RAS inhibitor daraxonrasib improved survival compared with chemotherapy in previously treated metastatic disease with oncogenic RAS mutations. Early studies of zoldonrasib combinations have extended this progress to KRAS G12D-mutant disease, although confirmation is required. Molecular profiling, next-generation sequencing, patient-derived organoids, and circulating tumor DNA may further improve treatment selection and monitoring. Conclusions: Precision oncology is becoming clinically relevant in pancreatic ductal adenocarcinoma. KRAS- and RAS-directed therapies are central advances, but resistance, toxicity, limited durability, and access to comprehensive testing remain important challenges. Full article

KRAS G12C, long considered an undruggable oncogenic driver, has become one of the most consequential therapeutic targets in non-small cell lung cancer (NSCLC). The discovery of a cryptic binding pocket accessible in the GDP-bound state enabled covalent inhibitors—sotorasib and adagrasib—that have received regulatory approval for previously treated KRAS G12C-mutant NSCLC, with sotorasib demonstrating PFS and OS superiority over docetaxel in CodeBreaK 200 and adagrasib showing meaningful intracranial activity and a progression-free survival benefit over docetaxel in KRYSTAL-12. Yet response durability is limited by on-target switch-II pocket mutations, upstream RTK and SHP2-mediated bypass signaling, downstream MAPK and PI3K-AKT reactivation, phenotypic plasticity, and adverse modulation by co-occurring STK11, KEAP1, and TP53 alterations. Next-generation covalent inhibitors (divarasib, glecirasib, olomorasib), tri-complex RAS(ON) inhibitors (RMC-6291), pan-KRAS agents, and rationally designed combinations with EGFR, SHP2, SOS1, and PD-1 inhibitors are repositioning KRAS-directed therapy toward earlier lines of treatment. This review integrates the structural, signaling, and clinical biology of KRAS G12C with contemporary trial and real-world evidence to examine the emerging case for first-line KRAS G12C inhibition in genomically defined subsets of NSCLC. First-line use nonetheless remains investigational; platinum-based chemoimmunotherapy remains the standard of care outside of clinical trials, and a frontline indication will require confirmation from randomized phase III trials. Full article

Pancreatic cancer remains one of the most aggressive and lethal malignancies, characterized by late-stage diagnosis, profound molecular heterogeneity, and limited responsiveness to conventional cytotoxic therapies. Recent advances in molecular diagnostics and biomarker-driven treatment stratification have accelerated the development of precision therapeutic approaches aimed at improving outcomes in selected patient populations. This review highlights three mechanistically distinct yet complementary therapeutic strategies that illustrate the evolving landscape of personalized pancreatic cancer management. Adagrasib represents targeted inhibition of oncogenic KRAS G12C signaling, reflecting recent progress in directly targeting historically “undruggable” driver mutations. Dostarlimab illustrates the tissue-agnostic application of immune checkpoint blockade in pancreatic cancers harboring mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H), highlighting the growing importance of biomarker-defined immunotherapy-responsive subsets despite the limited pancreatic cancer-specific clinical evidence currently available. Trastuzumab deruxtecan represents a next-generation HER2-directed antibody–drug conjugate (ADC) and demonstrates the potential of HER2-targeted therapy in the small subgroup of patients with HER2-positive pancreatic cancer, although the available evidence is derived primarily from basket trials and tumor-agnostic clinical development. Collectively, these therapeutic approaches underscore the expanding role of biomarker-guided treatment strategies integrating targeted inhibition, immunotherapy, and precision cytotoxic payload delivery. This review summarizes the molecular rationale, available clinical evidence, therapeutic limitations, and resistance mechanisms associated with these approaches while discussing emerging directions in translational research, rational combination strategies, liquid biopsy applications, and precision oncology that may further refine individualized treatment algorithms for pancreatic cancer. Full article

A single vaccine cannot prevent or treat all cancers; however, recurrent tumor-specific epitopes may facilitate the development of pre-manufactured, HLA-matched mRNA vaccines tailored for specific molecular subgroups. We define the shared tumor-specific epitope as a recurring peptide derived from a viral oncoprotein, a driver mutation, a frameshift, an altered protein C-terminus, or a fusion junction, and we employ a rigorous cancer-cell-only criterion: a target must be recurrent within a defined subgroup, absent from essential normal tissues at the peptide–HLA level, naturally presented on tumor cells, and sufficiently clonal to minimize immune escape. Under this criterion, we present fifteen sequence-anchored reference designs alongside one conceptual placeholder across thirteen candidates divided into four superclasses: viral oncoproteins (such as HPV16/18 E6 and E7 as attenuated antigenic reference designs; Merkel cell polyomavirus serving as a design-specific placeholder), recurrent driver neoepitopes (including KRAS G12/G13, IDH1 R132H, and H3 K27M), hematologic neoantigens (such as NPM1 Type A C-terminus; and a single CALR exon 9 construct encoding the shared novel C-terminus of types 1 and 2 mutations), and fusion junctions (notably EWS-FLI1 and BCR-ABL). Each open reading frame is anchored to a canonical accession with its documented event; representative ORFs are provided as reference designs, with the intended residue-level verification records. These sequence designs are intended as reference constructs and are not suitable as clinical-grade or manufacturing-ready products; they require independent residue-level validation and comprehensive safety assessments prior to laboratory or clinical application. The historical record of non-personalized vaccination—including HPV and hepatitis B prophylaxis, intravesical BCG, and unsuccessful tumor-associated antigen trials—frames both the potential and limitations of such approaches. The practical product is not a universal vaccine but rather a governed library aligned with specific genotype, viral etiology, HLA context, and clinical setting. Currently, none of these designs have established proof-of-benefit-tier evidence. Full article

Background: KRAS mutations are among the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and are associated with substantial molecular and immunological heterogeneity. However, the clinicopathological associations and prognostic relevance of KRAS mutation subtypes and co-occurring genomic alterations in relation to PD-L1 expression and survival outcomes remain incompletely understood, particularly in the immunotherapy era. Methods: This retrospective single-center study included 93 KRAS-mutant NSCLC patients identified among 543 consecutively sequenced cases between March 2024 and March 2025. KRAS mutation subtypes, co-mutations involving TP53, STK11, and KEAP1, PD-L1 expression status, clinicopathological features, and survival outcomes were evaluated. Overall survival was assessed using Kaplan–Meier analysis and Cox proportional hazards regression models. Results: KRAS mutations were detected in 17.1% of NSCLC patients. G12C was the most frequent KRAS subtype (38.7%), followed by G12V (18.3%) and G12D (14.0%). Co-occurring mutations were identified in 73.1% of cases, most commonly involving TP53 (40.9%) and STK11 (33.3%). PD-L1 expression was negative in 48.4% of patients, low in 28.0%, and high in 23.7%. No significant association was identified between KRAS mutation subtype and PD-L1 expression (p = 0.663). STK11-mutated tumors demonstrated a trend toward lower PD-L1 expression levels compared with STK11 wild-type tumors. However, none of the molecular variables retained independent prognostic significance. Immunotherapy was associated with significantly prolonged overall survival (median OS: 24 vs. 7 months, p = 0.013) and remained independently associated with improved survival in multivariate analysis (HR: 0.376, 95% CI: 0.204–0.694, p = 0.002). Advanced-stage disease independently predicted worse survival outcomes (HR: 13.43, 95% CI: 1.81–99.79, p = 0.011). Conclusions: KRAS mutation subtypes and co-occurring genomic alterations demonstrated limited independent prognostic significance in this real-world NSCLC cohort. In contrast, immunotherapy was associated with improved overall survival in this retrospective cohort. These findings should be interpreted as observational and hypothesis-generating rather than evidence of predictive treatment benefit. Larger prospective studies integrating genomic and immune biomarkers are warranted. Full article