EGFR

Overview

EGFR encodes the epidermal growth factor receptor tyrosine kinase, one of the best-established oncogenic drivers and therapeutic targets in non-small cell lung cancer.

Alterations observed in the corpus

  • Amplified in 45% of GBM cases; also harbors novel missense mutations in the extracellular domain; component of the RTK/RAS/PI3K pathway (altered in 88% of samples) PMID:18772890.
  • Pathogenic EGFR alterations detected in plasma ctDNA (vs tissue only) were associated with worse prognosis in advanced NSCLC PMID:36357680.
  • EGFR alterations were associated with worse metastasis-free survival in LUAD (p=0.002) and mutually exclusive with SMARCA4, STK11, KEAP1, and KRAS alterations PMID:37084736.
  • Adrenal gland metastases in LUAD had the highest proportion of EGFR activating mutations (133/202, 66%) PMID:37084736.
  • TP53/EGFR co-alteration with KEAP1 (q<0.001) and STK11 (q<0.001) was significant only in ever-metastatic LUAD primaries PMID:37084736.
  • In resected NSCLC brain metastases, EGFR alterations were enriched in patients who developed leptomeningeal disease (LMD): 45% vs 21% in non-progressors (p=0.044) PMID:37591896.
  • LMD patients frequently exhibited uncommon/non-canonical EGFR drivers (L861Q, G719A/S, A755G, N771_H773dup) in 45% of cases, with persistence despite TKI therapy PMID:37591896.
  • A vignette documented emergence then clearance of T790M under osimertinib while L861Q/G719S drivers persisted PMID:37591896.
  • EGFR alterations were negatively associated with SETD2 driver mutations in LUAD (q<0.05) in the MSK-CHORD cohort, indicating mutual exclusivity PMID:39506116.
  • EGFR mutations and high-level amplification were detected in CSF ctDNA from lung cancer patients with CNS involvement in the csf_msk_2024 cohort (1,007 CSF samples, 711 patients); acquired resistance mutations including p.T790M, p.C797S, p.L792H, p.L718Q, p.L718V, and p.G724S were identified in serial CSF samples, directly informing treatment changes PMID:39289779.
  • EGFR amplification identified as a resistance mechanism at progression in metastatic esophagogastric cancer (EGC) patients treated with pembrolizumab + trastuzumab + chemotherapy PMID:37406106.
  • EGFR exon 19 deletions (N=8), L858R (N=1), and G719C/L861Q (N=1) identified in patients who subsequently acquired BRAF fusions as a resistance mechanism to EGFR TKIs; BRAF fusions are a recurrent (2–4%) acquired resistance event after EGFR-directed therapy PMID:38922339.
  • EGFR alterations detected in plasma ctDNA were associated with venous thromboembolism (VTE) risk (adjusted HR = 1.62, 95% CI: 1.24–2.10; N=339) across multiple solid tumor types PMID:39147831.
  • EGFR surface expression (not mutation status) gates radiosensitization by C-MMAE (cetuximab-MMAE conjugate); EGFR+ lines (CAL-27, A549, CALU3, SCC-61, SCC-35, SQ-9G, HCT-116) accumulate C-MMAE and show dose-dependent G2/M arrest; LN229 (EGFR-low) is refractory PMID:27698471.
  • EGFR mutation status (SNaPshot PCR, exons 18–21) was annotated for 206/211 resected early-stage NSCLC patients in the Stanford NSCLC-Radiogenomics cohort as part of a paired radiogenomic dataset; per-subject status is provided as a data record rather than aggregate frequencies PMID:30325352.
  • EGFR/ERBB2 pathway was implicated by KEGG analysis in chordoma PDTOs (UCLA sarcoma biobank, n=194 specimens); chordomas were preferentially sensitive to TAK-285 (EGFR/ERBB2 kinase inhibitor, p=0.034) in patient-derived tumor organoid drug screening PMID:39305899.
  • Mutations enriched in never-smokers (P=0.0046); associated with lower overall mutation rate, copy number gain, and higher expression; mutually exclusive with KRAS (P<1e-7) and negatively correlated with STK11 (P=7e-6). PMID:18948947
  • EGFR targeted by cetuximab/panitumumab combination therapy in CRC; EGFR mutations detected at resistance to KRASG12C inhibition in some patients PMID:36355783
  • EGFR amplification in 3% of metastatic urothelial carcinoma samples in the UC-GENOME cohort PMID:36333289
  • EGFR assessed in gallbladder carcinoma (GBC) genomic landscape study PMID:36228155
  • EGFR mutation (22/247, 8.9%) independently associated with worse PFS on immunotherapy in advanced NSCLC (aHR = 2.14, 95% CI 1.06-4.31, P = 0.03) PMID:36038778
  • Recurrently mutated in HNSCC across 74 tumor-normal pairs by whole-exome sequencing (Broad cohort) PMID:21798893
  • Recurrently mutated in HNSCC across 32 primary tumors by whole-exome sequencing (Johns Hopkins cohort) PMID:21798897
  • EGFR amplification and expression correlate with erlotinib sensitivity across 947 cancer cell lines in the CCLE pharmacogenomic profiling study PMID:22460905
  • High-level amplifications in 5% of triple-negative breast cancer (TNBC) cases in a 65-tumor WGS cohort (BCCRC); classified as clinically actionable PMID:22495314
  • Rare amplification event (<1% of patients) identified through the CNA-expression landscape in METABRIC (2,000 tumors); potentially relevant for tyrosine kinase inhibitor targeting PMID:22522925
  • Alteration status profiled across NCI-60 cell lines in CellMiner pharmacogenomics study; EGFR mutations correlate with differential drug response patterns PMID:22802077
  • Amplification in 7% and L861Q activating mutation in 2 cases; canonical adenocarcinoma EGFR mutations (L858R, exon 19 del) essentially absent in LUSC; in COSMIC analysis, significantly mutated PMID:22960745
  • Activating mutations in 17% of 183 LUAD cases; novel in-frame C-terminal deletion (exons 25-26, vIVb variant) validated as oncogenic and erlotinib-sensitive; anti-correlated with KRAS (P = 3.3e-4) and associated with never/light smokers PMID:22980975
  • Amplified and mutated in breast cancer (TCGA, 510 tumors); enriched in the basal-like subtype PMID:23000897
  • Mutated in 3 EAC tumors (p.S447Y, p.S1153I), predicted non-deleterious by Polyphen-2; upstream regulators of RAC1 GEF pathway also recurrently mutated in EAC PMID:23525077
  • Focal high-level amplification in 16% (6/38) of oral squamous cell carcinoma (OSCC); established drug target for cetuximab in HNSCC PMID:23619168
  • Over-expressed in the PI3K/AKT/mTOR alteration module with corresponding phospho-receptor increase in clear-cell renal cell carcinoma (CCRCC); over-expression and phosphorylation linked to prior lapatinib response data in CCRCC PMID:23792563
  • Altered in 57% of GBM overall; alterations include amplification, point mutations (extracellular and kinase domain), EGFRvIII (exon 2–7 deletion), C-terminal deletion variants, Δ12–13 (28.7%) and Δ14–15 splice variants, and focal fusions (EGFR-SEPT14, SEC61G-EGFR); diverse co-existing variants within the same tumor pose challenges for single targeted inhibitors PMID:24120142
  • Focal amplification of EGFR detected in 11% of muscle-invasive bladder cancers in TCGA urothelial carcinoma comprehensive genomic characterization PMID:24476821
  • Focal amplification observed in 139 esophageal squamous cell carcinoma (ESCC) samples by whole-exome/targeted sequencing PMID:24686850
  • Mentioned as RTK signaling component relevant to HCC targeted therapy landscape in a 2014 HCC genomics review PMID:24735922
  • Activating mutations in EGFR occur in ~1% of HCCs across WES cohorts (n=1,289); not a major driver but noted as part of the mutational landscape of hepatocellular carcinoma. PMID:24798001
  • EGFR is overexpressed in a substantial fraction of NPC tumors, driving proliferation, metastasis, and resistance via PI3K/AKT and MAPK; targeted with cetuximab, nimotuzumab, pimurutamab, EGFR ADCs (becotatug vedotin/MRG003), and bispecific ADCs (BL-B01D1 targeting EGFR×ERBB3; GEN1286 targeting EGFR×MET). PMID:24952746
  • ERBB-pathway member (with ERBB2, ERBB3, ERBB4) cited in the context of prior GBC whole-exome data showing recurrent ERBB-pathway mutations that activate AKT PMID:24997986
  • Altered in 11% of gastric adenocarcinoma (STAD) cases in the TCGA cohort; alterations include amplification in CIN tumours and elevated pY1068 phosphorylation PMID:25079317
  • Activating mutations in 14% of LUAD (TCGA, n=230); cancer-associated mutations enriched in females, terminal lobe (TL), and TRU transcriptional subtype; in-frame insertions specifically enriched in TL; mutually exclusive with KRAS PMID:25079552
  • Metastasis-private high-level amplification (chr 7p) detected in metastatic CRC; co-amplified with CARD11, ETV1, and IKZF1; may represent an actionable event in RAS/RAF wild-type patients missed by primary-only sequencing PMID:25164765
  • Not significantly mutated in 39 aggressive cSCC tumors; discussed as a largely unsuccessful therapeutic target (gefitinib, cetuximab trials) in cSCC PMID:25303977
  • Activating alterations in 13.6–20% of cholangiocarcinoma (CCA); overexpression is an independent poor-prognostic factor in iCCA and eCCA; bypass signaling via wild-type EGFR contributes to FGFR-inhibitor resistance. PMID:25526346
  • S720F rare activating allele (also seen in NSCLC) plus high-level amplification (significant GISTIC peak) in cSCC; patients with EGFR alterations are candidates for trials of agents already used in lung/head-and-neck SCC PMID:25589618
  • Transactivated by TGR5 (GPBAR1)/Src signaling to amplify ERK1/2 proliferative signaling in cholangiocytes in the context of cholangiocarcinoma PMID:25608663
  • Focal amplification in 15% of HPV(-) vs 6% of HPV(+) HNSCC; rare EGFRvIII isoform in 1/279 tumors; part of RTK/RAS/PI(3)K alteration in 62% of HPV(-) and 61% of HPV(+) tumors PMID:25631445
  • Low-frequency but FDA-druggable alteration in HCC (MAP kinase / RTK pathway) PMID:25822088
  • Focal amplifications in 3 desmoplastic melanoma tumors with IHC-confirmed overexpression; authors identify as potentially targetable RTK alteration PMID:26343386
  • Overexpressed in invasive lobular breast cancer (ILC) at total and phospho levels (Y1068, Y1173); highest in the reactive-like ILC mRNA subtype PMID:26451490
  • Mentioned in study PMID:26824661
  • EGFR is among the recurrently mutated RTKs identified as low-frequency hits in advanced thyroid cancers (PDTC/ATC) profiled by MSK-IMPACT 341-gene panel (n=117 tumors) PMID:26878173
  • Kinase-domain duplication detected in lung ADC sample TCGA-49-4512 (separately reported as afatinib-responsive); complex indels in EGFR or MET found in 11 tumors; EGFR p.G719A identified as a recurrent neoepitope hotspot candidate PMID:27158780
  • EGFR mutations more prevalent in young lung cancer (YLC) vs older NSCLC (e.g. 60.6% vs 52.5% in Hsu et al.); exon 19 deletions enriched; drives use of gefitinib and osimertinib in YLC; FLAURA and AURA3 subgroup analyses show consistent outcomes by age PMID:27346245
  • Present in the untreated primary (TURBT) of patient WCM117 but absent from post-chemotherapy metastases in urothelial carcinoma, indicating it was private to the eradicated clone PMID:27749842
  • Amplified or mutated in 19% of ESCCs and some EACs in the TCGA esophageal carcinoma multi-platform study; EGFR alterations co-occur with ERBB2/KRAS/VEGFA amplifications in EAC subsets PMID:28052061.
  • Alterations in EGFR (including amplification, missense, and truncating mutations) were profiled across multiple cancer types in a large-scale targeted sequencing study PMID:28336552
  • EGFR alterations including activating mutations and fusions were identified as clinically actionable findings in a pan-cancer sequencing cohort PMID:28373299
  • Driver SNVs detected in LUAD within the TRACERx ctDNA study; not associated with pre-operative ctDNA detection rate within the LUAD subset PMID:28445469
  • Hotspot A289V missense mutation in 1/19 oligodendroglioma cases (FISH-confirmed 1p/19q-codeleted); EGFR amplification observed in 1p/19q-intact glioblastoma-like cases PMID:28472509
  • Tumor-type-specific alteration localization: extracellular N-terminal domain in glioma vs kinase domain in lung cancer; EGFRvIII (exon 2-7 deletion) detected in 65 cases across MSK-IMPACT cohort PMID:28481359
  • Recurrent oncogene amplification in CCA (n=11 of 71 WGS cases); co-amplified with MYC, MDM2, and CCND1 in Fluke-associated cholangiocarcinoma subsets PMID:28667006.
  • Recurrently amplified focal SCNA in MIBC; high EGFR protein expression in the basal-squamous subtype (RPPA cluster 3), proposed as a candidate for EGFR inhibitor therapy in muscle-invasive bladder cancer PMID:28988769
  • Oncogenic alterations in 8% of CIN-subtype esophagogastric cancers; listed among potentially targetable kinases, often concurrent with other actionable kinases (ERBB2, ERBB3, FGFR2, MET, CDK4, FGFR1) suggesting combination strategies are needed PMID:29122777
  • Hotspot mutations in 4 of 1,134 colorectal adenocarcinomas (two L861Q, one L858R, one R776H) — potentially TKI-sensitizing; one S492R allele observed as a cetuximab-resistance mechanism after 1.5 years of treatment; EGFR amplification co-occurred with ERBB2 amplification in one acquired-resistance case PMID:29316426
  • Activating mutations in 17/240 (7%) advanced NSCLC patients treated with anti-PD-(L)1; EGFR-mutant patients were significantly underrepresented in the durable clinical benefit group (only 7% DCB rate), attributed to the link between EGFR mutations, never-smoker status, and low tumor mutation burden PMID:29337640
  • Cited as the paralogous receptor to ERBB2 whose exon 20 insertions resist first/second-generation TKIs, providing context for the SUMMIT basket trial findings; EGFR exon 20 insertions in LUAD showed minimal ORR but a PFS tail with neratinib suggesting activity worth exploring in combination PMID:29420467
  • EGFR was among the genes assessed in the TCGA pan-cancer fusion landscape (9,624 samples, 33 cancer types); EGFR fusions are catalogued but were not among the top-recurrent fusion events reported; the study provides a reference pan-cancer fusion compendium relevant to EGFR fusion biology PMID:29617662.

Cancer types (linked)

  • GBM — amplified in 45% of cases; key component of the RTK/RAS/PI3K pathway PMID:18772890.
  • LUAD / LUSC — prognostic via ctDNA detection and organotropism; worse MFS PMID:36357680 PMID:37084736.
  • NSCLC — non-canonical drivers enriched in leptomeningeal disease PMID:37591896; acquired resistance mutations (T790M, C797S, and others) detected in CSF ctDNA from patients with CNS metastases PMID:39289779; BRAF fusions as acquired resistance PMID:38922339.
  • EGC (esophagogastric) — EGFR amplification as resistance mechanism to HER2-directed therapy PMID:37406106.
  • Multiple solid tumors — EGFR ctDNA alterations associated with VTE risk PMID:39147831.
  • HNSC / NSCLC / ESCA / BRCA / STAD — EGFR expression level predicts radiosensitization by ErbB-directed ADC (C-MMAE) in preclinical cell-line and xenograft models PMID:27698471.
  • CHDM — EGFR/ERBB2 pathway enriched by KEGG analysis; TAK-285 (EGFR/ERBB2 kinase inhibitor) preferentially active in chordoma PDTOs vs pan-sarcoma (p=0.034) PMID:39305899.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • ctDNA-guided matching to EGFR-targeted therapy yielded longer OS in advanced NSCLC (HR 0.63) PMID:36357680.
  • Non-canonical EGFR mutations in brain metastases may identify patients at elevated risk for LMD and partial resistance to osimertinib; prior erlotinib exposure featured in EGFR-mutant LMD trajectories PMID:37591896.
  • Serial CSF ctDNA profiling identified clonal evolution and emergence of EGFR gatekeeper resistance mutations (T790M, C797S), directly informing treatment changes in NSCLC patients with CNS disease PMID:39289779.
  • ErbB-directed ADC radiosensitization (C-MMAE) requires EGFR surface expression; the broader ErbB family (EGFR, HER2, HER3, HER4) is framed as a tumour radioresistance driver, motivating EGFR-targeted ADC delivery as an alternative to signal-transduction inhibitors that suffer bypass-pathway resistance PMID:27698471.

Open questions

  • Whether non-canonical EGFR drivers cause leptomeningeal tropism or merely reflect osimertinib partial resistance is unresolved PMID:37591896.
  • Whether ctDNA-only subclonal resistance alterations should directly alter EGFR-directed treatment selection PMID:36357680.

Sources

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