Lung Adenocarcinoma (LUAD)

Overview

Lung Adenocarcinoma is the most common Non-Small Cell Lung Cancer histology (parent NSCLC).

Cohorts in the corpus

nsclc_ctdx_msk_2022: 1,127 adults with stage IV/recurrent NSCLC (LUAD and LUSC) profiled by plasma ctDNA (Resolution Bioscience ctDx Lung) at MSK and GenesisCare PMID:36357680.
luad_mskcc_2023_met_organotropism: 2,532 LUAD specimens from 2,309 MSK patients profiled on MSK-IMPACT with a WES subcohort for mutational signature analysis PMID:37084736.
bm_nsclc_mskcc_2023: 180/233 (77%) of the resected NSCLC brain metastasis cohort were LUAD; LUAD-restricted downstream analysis used 179 BM, 37 primary tumors, 34 extracranial metastases PMID:37591896.
msk_chord_2024: 5,957 LUAD patients included in the MSK-CHORD SETD2 biomarker analysis PMID:39506116.
csf_msk_2024: LUAD patients included within the lung cancer subset (n=188) of the MSK CSF ctDNA cohort; CSF samples profiled by MSK-IMPACT PMID:39289779.
Bakr 2018 published the NSCLC-Radiogenomics Stanford cohort with 135/211 patients being LUAD; pre-treatment CT imaging linked to RNA-seq expression subtypes and somatic mutations, providing an imaging-genomics resource for LUAD PMID:30325352.

Recurrent alterations

Ever-metastatic primaries had higher TMB, chromosomal instability, and fraction of genome doubled than never-metastatic primaries PMID:37084736.
APOBEC signatures (SBS2/SBS13) more prevalent in metastases than primaries (18% vs 8%, p=0.012), particularly enriched in liver metastases PMID:37084736.
TP53, SMARCA4, CDKN2A inactivation correlated with site-specific shorter time to metastasis PMID:37084736.
TP53/EGFR co-alteration with KEAP1 (q<0.001) and STK11 (q<0.001) was significant only in ever-metastatic primaries PMID:37084736.
SMARCA4, STK11, KEAP1, and KRAS alterations were mutually exclusive with EGFR alterations PMID:37084736.
EGFR (p=0.002) and NF1 (p<0.001) alterations were associated with worse metastasis-free survival PMID:37084736.
SMARCA4 alterations strongly enriched in patients with bone metastasis (OR=6.47; time-to-bone-metastasis OR=2.79, p<0.001) PMID:37084736.
Adrenal gland metastases had the highest proportion of EGFR activating mutations (133/202, 66%) PMID:37084736.
KRAS G12C elevated in primaries that metastasized to liver (21%) vs matched liver metastases (6%, p<0.001) PMID:37084736.
SETD2 oncogenic driver mutations in 204/5,957 LUAD (3%) predicted longer OS and lower rates of CNS metastasis; positively associated with BRAF and ARID1A alterations and negatively associated with EGFR, MDM2, and mucinous subtype (q<0.05) PMID:39506116.
RB1 oncogenic alterations enriched in brain and liver metastases in pan-cancer MSK-CHORD analyses PMID:39506116.
In the brain-metastasis cohort, CDKN2A/CDKN2B alterations were enriched in BM vs PT (31% vs 18%, p=0.004); cell-cycle pathway alterations 52% BM vs 27% PT PMID:37591896.
Comparing LUAD PT BM+ vs BM−/EM−, TP53, MYC, SMARCA4, RB1, ARID1A, and FOXA1 alterations were enriched in PTs from patients who later developed BM; NKX2-1 alterations enriched in both BM and EM PMID:37591896.
ctDNA alterations not detected in time-matched tissue sequencing disproportionately featured subclonal resistance drivers RICTOR and PIK3CA PMID:36357680.
Pathogenic TP53, EGFR, or KRAS alterations detected in ctDNA (vs tissue only) were associated with worse prognosis PMID:36357680.
EGFR mutations and high-level amplification detected in CSF ctDNA; acquired resistance mutations (p.T790M, p.C797S, p.L792H, p.L718Q, p.L718V, p.G724S) identified in serial CSF samples from LUAD patients PMID:39289779.
KRAS mutations detected in CSF ctDNA; also observed as off-target resistance alteration in EGFR-mutant LUAD patients PMID:39289779.
ALK EML4::ALK fusions detected in CSF ctDNA from lung adenocarcinoma; resistance mutations p.G1202R and p.G1269A identified upon targeted therapy progression PMID:39289779.
Smoking mutational signatures identified in CSF ctDNA from lung adenocarcinoma samples (n=8 among 35 high-TMB samples) PMID:39289779.
TSP sequencing of 188 primary LUAD tumours identified 26 significantly mutated genes, including novel tumour suppressors NF1, ATM, RB1, APC and tyrosine kinases ERBB4, EPHA3, KDR beyond the canonical five (TP53, KRAS, STK11, EGFR, CDKN2A); 70% of tumours harboured MAPK pathway mutations PMID:18948947
In a 247-patient advanced NSCLC cohort (79% LUAD), multimodal DyAM model integrating CT radiomics, PD-L1 IHC, and genomics achieved AUC=0.80 for ICI response prediction; EGFR mutation (aHR=2.14) and STK11 mutation (aHR=2.53) were confirmed as independent negative predictors of PD-(L)1 blockade PMID:36038778
Broad Institute WES of 183 lung adenocarcinomas identified EGFR, KRAS, and STK11 as major drivers; MutSig analysis nominated RBM10, U2AF1, and ARID1A as newly significant genes PMID:22980975
A co-clinical trial in KRAS-mutant LUAD using GEM models running in parallel with a human phase II trial demonstrated that the murine arm delivered predictive response data for selumetinib + docetaxel in nine months and surfaced STK11 loss as a genetic modifier of resistance, prompting retrospective reanalysis of the human trial PMID:23999436.
SMARCA4 inactivating mutations occur in 5–8% of LUAD (TCGA data) and are associated with poor outcome; SMARCA4 loss creates a synthetic-lethal vulnerability to SMARCA2 inhibition PMID:24658004
TCGA multi-platform profiling of 230 resected LUADs (n=412 with prior published) identifies 18 significantly mutated genes including novel drivers RIT1 (2%) and MGA (8%, mutually exclusive with MYC amplification); MET exon 14 skipping in 4%; with focal MET/ERBB2 amplifications in oncogene-negative cases, 76% of LUADs now harbor a defined RTK/RAS/RAF activating event PMID:25079552
Pan-NSCLC WES of 660 LUAD and 484 LUSC tumour/normal pairs (nsclc_tcga_broad_2016); LUAD had median somatic mutation rate 8.7/Mb and 38 SMGs; novel LUAD drivers include PPP3CA, DOT1L, and CMTR2/FTSJD1; 76% of LUADs harboured an RTK/Ras/Raf alteration after adding SOS1, VAV1, RASA1, and ARHGAP35; 47% of LUADs had ≥5 predicted neoepitopes PMID:27158780
In young-onset lung adenocarcinoma review: 50–70% of YLC patients present with stage IV disease; median OS 26 months in Indian YLC cohort (Malik et al., n=133, TruSight Oncology 500); the subset <30 years had worse median OS of 15.67 months versus 26 months for 30–40-year-olds; EGFR mutations found in 35.51%, ALK rearrangement 65.7%, and ROS1 rearrangement 7.25% PMID:27346245.
860 recurrent/metastatic LUAD patients profiled by MSK-IMPACT (IMPACT341/410); actionable OncoKB level 1–4 alterations in 86.9%; EGFR sensitizing mutations 24.9%, KRAS 25.3%, ALK/ROS1 fusions; STK11 and KEAP1 enriched in tumors lacking actionable driver PMID:28336552
In the TRACERx cohort (n=58 LUAD), pre-operative ctDNA detection was only 19% (11/58) for LUAD vs 97% for LUSC; driver mutations in KRAS, EGFR, and TP53 were not associated with ctDNA detection within the LUAD subset; an expanded 28-SNV panel was required for improved sensitivity. PMID:28445469
In the MSK-IMPACT pan-cancer cohort, ALK, RET, and ROS1 fusions were enriched in LUAD but also detected in 11 additional tumor types; EML4-ALK fusions were the 3rd most common rearrangement (n=38) predominantly in LUAD; EGFR mutations localized to the kinase domain in lung cancer vs the extracellular N-terminal domain in glioma. PMID:28481359
Lung adenocarcinoma comprised 78% (187/240) of the anti-PD-(L)1 NSCLC cohort; EGFR-mutant LUAD had only 7% DCB rate (FDR p=0.013), attributed to low TMB from never-smoker biology; HER2 exon 20 insertion LUAD showed minimal RECIST response (1/26) to neratinib but median PFS 5.5 months PMID:29337640
In the SUMMIT trial, HER2 exon 20 insertion-driven LUAD (the predominant NSCLC histology in this cohort) showed minimal RECIST response (1/26) to single-agent neratinib, though median PFS of 5.5 months and a long-tail of >1-year responders suggest neratinib has activity worth pursuing in combinations PMID:29420467
MC3 pan-cancer mutation-calling project (10,510 TCGA pairs) included LUAD; LUAD and LUSC had the largest median number of SNVs per sample, consistent with tobacco-carcinogen mutagen exposure PMID:29596782
Pan-cancer fusion study (9,624 TCGA samples) identified EML4–ALK in 1.0% of LUAD (5 of 20 ALK-fusion samples); never-smokers had a dramatically higher rate of druggable fusions (20%) vs smokers (2.1%; chi-square p < 1e-6); RET fusions also detected in LUAD PMID:29617662
Pan-cancer aneuploidy study placed LUAD in the epithelial arm-level cluster (alongside BRCA and HCC) defined by 1q gain; <50% of LUAD tumors had 3p loss (vs ~80% in LUSC) and only 13% had 3q gain, contrasting sharply with the squamous LUSC signature PMID:29622463

Subtypes

Among 179 LUAD BM patients, 56% had intracranial progression after craniotomy+RT (regional 30%, local 14%, LMD 11%); median OS 2.7 years, median iPFS 1.2 years PMID:37591896.
LMD patients had more EGFR alterations (45% vs 21%, p=0.044), including uncommon drivers L861Q, G719A/S, A755G, N771_H773dup PMID:37591896.
Multifocal regional progressors had MYC amplifications in 22% vs 0% in local progressors (p=0.023) PMID:37591896.

Therapeutic landscape

ATLAS RNA-expression classifier (trained on 8,249 samples including TCGA/CCLE) achieved 91.4% accuracy for cancer site classification; LUAD represented in the 22-class site classifier with de-differentiation score prognostic for survival (HR 0.24, P=0.001) PMID:27634761.
BRAF fusions identified as acquired resistance mechanism to EGFR TKIs in LUAD (10/15 acquired BRAF fusion patients had EGFR-mutant LUAD); median time from EGFR TKI start to acquired BRAF fusion detection: 23 months (range 9–37) PMID:38922339.
ctDNA detection is an independent poor prognostic marker in advanced NSCLC (HR 2.05; 95% CI 1.74–2.42, P<0.001) PMID:36357680.
ctDNA-guided matching to targeted therapy improved OS among ctDNA-positive patients (HR 0.63; 95% CI 0.52–0.76, P<0.001) PMID:36357680.
Faster turnaround (11 vs 33 days) and lower failure rate (2% vs 13%) for ctDNA vs tissue sequencing support clinical use of liquid biopsy PMID:36357680.
Only ~4% of LUAD metastases carried therapeutically actionable alterations undetected in their matched primaries, limiting incremental benefit from routine re-biopsy PMID:37084736.
Non-canonical EGFR mutations in BM may identify patients at elevated risk for leptomeningeal disease and partial resistance to osimertinib PMID:37591896.
SETD2 mutation associated with longer time to next treatment or death following immune checkpoint blockade but not cytotoxic chemotherapy or molecularly targeted therapy; association held among TMB-low (<10 mut/Mb) patients and replicated in DFCI and commercial RWD validation cohorts PMID:39506116.
CSF ctDNA had greater sensitivity than positive cytology for leptomeningeal disease detection in lung cancer patients (85.4% vs. 61.7%), supporting its use as a complementary diagnostic modality PMID:39289779.
CSF liquid biopsy outperformed plasma for CNS cancer monitoring with significantly higher VAFs (median 36.4% vs. 2.3%) due to blood-brain barrier limiting tumor DNA shedding into peripheral blood 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 in lung cancer patients PMID:39289779.
ctDNA detection associated with higher venous thromboembolism (VTE) risk in LUAD patients as part of the pan-cancer VTE study (HR=2.49, 95% CI 1.99–3.11); the ctDNA-VTE association held across most cancer types including lung. PMID:39147831

Sources

This page was processed by crosslinker on 2026-05-09. - PMID:22980975

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This page was processed by entity-page-writer on 2026-05-11. - PMID:25079552

This page was processed by entity-page-writer on 2026-05-11. - 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 LUAD molecular landscape and therapy.

PMID:28336552 — Jordan et al. 2017; MSK-IMPACT prospective profiling of 860 recurrent/metastatic LUAD; actionable alterations in 86.9%.
PMID:28445469
PMID:28481359

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

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