Non-Small Cell Lung Cancer (NSCLC)

Overview

Non-Small Cell Lung Cancer (parent LUNG); encompasses histologies including LUAD and LUSC.

Cohorts in the corpus

bm_nsclc_mskcc_2023: 233 patients with resected NSCLC brain metastasis (BM) profiled by MSK-IMPACT — 180 (77%) LUAD, 23 (10%) LUSC, 30 (13%) other NSCLC. Matched samples: 47 primaries, 42 extracranial metastases. Median age 67; 80% current/former smokers PMID:37591896.
msk_chord_2024: 7,809 NSCLC patients in the MSK-CHORD clinicogenomic harmonized real-world dataset at MSK PMID:39506116.
A549 and CALU3 (NSCLC cell lines, EGFR+/HER2+): preclinical ADC radiosensitization study with C-MMAE and T-MMAE. PMID:27698471
Commentary cohort: oligometastatic NSCLC patients treated on Gomez et al. Lancet Oncol 2016 RCT (≤3 metastases after first-line systemic therapy) cited as cross-tumor precedent for metastasis-directed local consolidative therapy. PMID:28045614
csf_msk_2024: Lung cancer was the most common primary cancer type in the MSK CSF ctDNA cohort (n=188 patients); NSCLC patients profiled by MSK-IMPACT (IMPACT468/IMPACT505) on CSF samples PMID:39289779.
Aerts 2014 introduced foundational CT radiomics across NSCLC cohorts Lung1 (n=422, Netherlands Cancer Institute), Lung2 (n=225, MAASTRO Clinic), and Lung3 (n=89, MD Anderson), deriving a 4-feature radiomic signature predictive of overall survival PMID:24892406.
Bakr 2018 published the NSCLC-Radiogenomics Stanford cohort pairing pre-treatment CT imaging with RNA-seq and somatic mutation data in 211 NSCLC patients (135 LUAD, 45 LUSC, 31 other); CT features linked to genomic subtypes PMID:30325352.

Recurrent alterations

TMB was higher in BM vs EM (median 8.8 vs 5.8; p=0.00766); FGA was higher in BM vs EM (p=2.77e-06) and vs PT (p=2.27e-07) PMID:37591896.
CDKN2A/CDKN2B alterations more frequent in BM (34%) vs PT (13%, p=0.003, q=0.04); cell-cycle pathway alterations 56% BM vs 32% PT (p=0.004, q=0.041) PMID:37591896.
Paired BM–BM samples showed high genomic concordance vs lower concordance in synchronous BM/PT pairs PMID:37591896.
NF1 alterations were more frequent in LMD patients (15%) PMID:37591896.
HLA-B mutations appeared as private BM events PMID:37591896.
EGFR mutations and high-level amplification detected in CSF ctDNA from lung cancer patients; acquired resistance mutations including p.T790M, p.C797S, p.L792H, p.L718Q, p.L718V, p.G724S identified in serial CSF samples PMID:39289779.
KRAS mutations detected in CSF ctDNA from lung cancer patients; also observed as off-target resistance alteration in EGFR-mutant patients PMID:39289779.
ALK EML4::ALK fusions in lung carcinomas; resistance mutations p.G1202R and p.G1269A detected in CSF upon targeted therapy progression PMID:39289779.
MET amplification and exon 14 skipping mutations detected in CSF; resistance mutation p.Y1230N emerged on crizotinib PMID:39289779.
RET and ROS1 rearrangements with diverse gene partners detected in CSF ctDNA from lung carcinomas PMID:39289779.
STK11 and KEAP1 mutations detected in CSF ctDNA from lung cancer patients PMID:39289779.
EGFR and ERBB2 surface expression levels (not mutation status) gate ADC binding and receptor-restricted radiosensitization in NSCLC cell lines (A549, CALU3). Adding cetuximab or trastuzumab to cytotoxic chemo-RT in NSCLC failed in prior trials; ADC delivery paradigm proposed as alternative. PMID:27698471
Oligometastatic NSCLC (≤3 metastases) may have a distinct biology attributable to 14q32-encoded microRNA-mediated attenuation of epithelial-mesenchymal transition; local consolidative therapy in this group prolonged PFS in the Gomez et al. RCT. PMID:28045614
DyAM multimodal ML framework (n=247 advanced NSCLC at MSK) integrating CT radiomics, PD-L1 IHC texture, and MSK-IMPACT genomics predicted PD-(L)1 blockade response with AUC=0.80 (95% CI 0.74-0.86), significantly outperforming TMB alone (AUC=0.61) and PD-L1 TPS alone (AUC=0.73); EGFR mutation (8.9%, aHR=2.14, P=0.03) and STK11 mutation (17.8%, aHR=2.53, P<0.005) were independent negative predictors of immunotherapy response PMID:36038778
Orthotopic implantation of resected NSCLC under the renal capsule of NOD-scid mice increased engraftment rates from 30-40% to 90% and enabled drug testing within 6-8 weeks; 11 of 16 evaluable PDX models showed concordant drug response between mouse and patient, with strong concordance particularly for resistance to conventional chemotherapy PMID:23999436.
Whole-exome sequencing of 34 advanced NSCLC patients treated with pembrolizumab showed higher nonsynonymous somatic mutation burden significantly associated with objective response, durable clinical benefit, and PFS (pooled Mann-Whitney P=0.0008; PFS HR 0.19, P=0.0004); a candidate cutoff of ≥178 nonsynonymous mutations, molecular smoking signature, neoantigen burden, and deleterious mutations in POLD1/POLE/MSH2 also correlated with efficacy. PMID:25765070
Largest NSCLC WES study to date (660 LUAD + 484 LUSC, n=1,144 total; nsclc_tcga_broad_2016): identified 6 genes SMG in both histologies (TP53, RB1, ARID1A, CDKN2A, PIK3CA, NF1), 14 pan-lung SMGs in joint analysis including KLF5 and EP300/CREBBP; ≥5 predicted neoepitopes in 47% of LUAD and 53% of LUSC, supporting broad immunotherapy applicability PMID:27158780
Narrative review of young-onset NSCLC (YLC, generally defined as age <40–50 years) synthesizing ≥40 studies: targetable alterations present in 57–70% of YLC vs ~52% in older patients (Sacher et al., p<0.001); ALK rearrangements, ROS1 fusions, and EGFR mutations are over-represented while KRAS, BRAF, and MET alterations are under-represented; Indian patients present approximately a decade earlier than the global median PMID:27346245.
Pre-operative ctDNA was detected in 48% (46/96) of early-stage NSCLCs in the TRACERx cohort, with a stark histology difference: 97% of LUSC vs 19% of LUAD; post-operative ctDNA detected relapse in 13/14 (93%) confirmed-relapse cases with a median 70-day lead-time over imaging. PMID:28445469
In 240 advanced NSCLC patients profiled by MSK-IMPACT and treated with anti-PD-(L)1, targeted-panel TMB correlated with WES at Spearman r=0.86 (p<0.001) and was higher in patients with durable clinical benefit (median 8.5 vs 6.6 SNVs/Mb, p=0.006); TMB and PD-L1 were independent predictors, together yielding 50% DCB rate; EGFR and STK11 mutations associated with lack of benefit PMID:29337640
In SUMMIT, 26 HER2-mutant NSCLC patients (predominantly LUAD with exon 20 insertions) achieved only 1 RECIST response to neratinib but median PFS 5.5 months with 6 patients on therapy >1 year; HER2 exon 20 insertions are analogous to EGFR exon 20 insertions resistant to first/second-generation TKIs PMID:29420467

Subtypes

Among LUAD BM patients: LMD patients had more EGFR alterations (45% vs 21%, p=0.044); local progressors had more RB1 loss (24% vs 6%, p=0.022); multifocal regional progressors had MYC amplifications in 22% vs 0% (p=0.023) PMID:37591896.

Therapeutic landscape

Non-canonical EGFR mutations (L861Q, G719A/S, A755G, N771_H773dup) in BM may identify patients at elevated risk for LMD and partial resistance to osimertinib; persistence despite TKI therapy noted PMID:37591896.
Cell-cycle/CDKN2A-B loss enrichment in BM suggests a rationale for CDK4/6-directed strategies in CNS-tropic NSCLC, not tested here PMID:37591896.
Leptomeningeal involvement was a strong predictor of CSF ctDNA positivity in NSCLC (OR 20.17, 95% CI 9.65-42.16, p < 0.0001). CSF ctDNA had greater sensitivity than positive cytology for leptomeningeal disease (85.4% vs. 61.7%) and greater negative predictive value (80% vs. 66%) PMID:39289779.
Lung carcinomas had the highest rate of level 1 OncoKB actionable alterations among all tumor types in the CSF ctDNA cohort; 50.7% of ctDNA-positive samples carried a level 1 actionable alteration PMID:39289779.
Serial CSF ctDNA profiling identified clonal evolution and emergence of resistance mechanisms (EGFR gatekeeper mutations, ALK resistance mutations, MET resistance mutations), directly informing treatment changes PMID:39289779.
ATLAS RNA-expression classifier achieved 91.4% site-of-origin accuracy; NSCLC distinguished from SCLC by lineage de-differentiation score (AUC=0.963); classifier can identify neuroendocrine transformation. PMID:27634761
EGFR-directed (C-MMAE) and HER2-directed (T-MMAE) ADCs selectively radiosensitize receptor-expressing NSCLC lines without off-target toxicity, in contrast to cetuximab or free MMAE. PMID:27698471
Local consolidative therapy (e.g., SABR) in oligometastatic NSCLC (≤5 lesions, primarily ≤3 by clinical definition) may alter natural history; self-seeding biology and microRNA-driven attenuation of EMT provide a mechanistic rationale for metastasis-directed ablation. PMID:28045614
ctDNA detection independently associated with higher VTE rates in advanced NSCLC (HR=2.49, 95% CI 1.99–3.11); NSCLC comprised 34% of the 4,141-patient discovery cohort. The international generalizability cohort (n=463) specifically comprised advanced NSCLC patients (ctDX Lung panel); c-index 0.67 for ctDNA-based VTE prediction. PMID:39147831

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:23999436

This page was processed by crosslinker on 2026-05-14. - PMID:25765070

This page was processed by crosslinker on 2026-05-14. - PMID:27158780

This page was processed by entity-page-writer on 2026-05-15. - PMID:27346245 — Tansir et al. 2025, narrative review of young-onset NSCLC molecular landscape, epidemiology, and therapy.

PMID:28445469

This page was processed by entity-page-writer on 2026-05-15. - PMID:29337640 - PMID:29420467

This page was processed by entity-page-writer on 2026-05-15.