ERBB2

Overview

ERBB2 (HER2) is a receptor tyrosine kinase whose amplification and activating mutations drive multiple solid tumors and define HER2-directed therapy eligibility.

Alterations observed in the corpus

  • Mutations found in 8% of GBMs, primarily in the extracellular domain, suggesting a role in RTK activation PMID:18772890.
  • ERBB2 was among the genes altered less often in LUAD metastases than in matched primaries PMID:37084736.
  • ERBB2 amplification was identified in one female ovarian germ cell tumor treated with trastuzumab, without durable response PMID:36862133.
  • In urothelial carcinoma, ERBB2 was inversely associated with FGFR3 alterations overall but co-altered in 5% (19/414) of FGFR3-altered tumors, ranging from 2.5% in NMIBC to 11% in MIBC PMID:37682528.
  • ERBB2 mutations and amplification were detected in CSF ctDNA from lung cancer and breast cancer patients with CNS involvement in the csf_msk_2024 cohort (1,007 CSF samples, 711 patients) PMID:39289779.
  • ERBB2 amplification was a positive prognostic factor for PFS in metastatic EGC (HER2+ EGC, pembrolizumab + trastuzumab + chemotherapy trial); loss of HER2 expression was the most common resistance mechanism (48% of progressing patients) PMID:37406106.
  • ERBB2 alterations in 12% of cervical cancers (4% amplifications, 9% oncogenic mutations); enriched in undifferentiated endocervical adenocarcinoma (UEA, 28%); one patient with D769N mutation had exceptional response to HER kinase inhibitor (>5 years) PMID:37643132.
  • ERBB2 amplification enriched in Black endometrial carcinoma patients (12% vs 3%); therapeutic target for trastuzumab and trastuzumab deruxtecan PMID:37651310.
  • ERBB2 amplification trended higher in average-onset esophagogastric cancer (20% vs 15%, P=0.16) and was associated with improved survival (HR=0.65, P=0.01) in multivariable analysis PMID:37699004.
  • ERBB2 ctDNA alterations associated with VTE risk (adjusted HR = 1.72, 95% CI: 1.10–2.68; N=121) in a pan-cancer liquid biopsy cohort PMID:39147831.
  • ERBB2 (HER2) surface expression gates T-MMAE (trastuzumab-MMAE) and T-DM1 (trastuzumab emtansine) radiosensitization; HER2+ lines (OE19, NCI-N87, CALU3, BT474) show sub-nanomolar T-DM1 IC50 and G2/M arrest; HER2− lines (HCT-116, CAL-27, LN229) are ~100-fold less sensitive PMID:27698471.
  • ERBB2 was used as a treatment-decision biomarker in the NLP-extraction pipelines for BRCA and NSCLC in the MSK-CHORD 24,950-patient real-world clinicogenomic dataset PMID:39506116.
  • EGFR/ERBB2 pathway implicated by KEGG analysis in chordoma PDTOs in the UCLA sarcoma PDTO study (n=194 specimens); chordomas were preferentially sensitive to TAK-285 (EGFR/ERBB2 kinase inhibitor, p=0.034) PMID:39305899.
  • ERBB2 was among genes listed in the other-MAPK-mutant subtype gene set within the 2,336-patient PAAD MSK-IMPACT cohort (pdac_msk_2024) PMID:39753968.
  • ERBB2 alterations detected in 14% of pretreatment plasma cfDNA from 201 metastatic urothelial carcinoma patients in the CALGB 90601 trial (MSK-ACCESS panel); multivariable OS HR 1.64 (95% CI 1.08–2.49; p=0.019) for shorter survival after cisplatin-based chemotherapy; authors highlight HER2-directed ADCs (trastuzumab deruxtecan, disitamab vedotin) as relevant targeted options PMID:40256659.
  • 4 mutations plus amplification identified in 188 primary LUAD tumours (TSP cohort, n=188). PMID:18948947
  • Subtype switching observed via HER2 amplification gain (participant AFR3: E668Q activating mutation) or loss (participant AFE4: deletion of HER2 amplification under trastuzumab pressure) PMID:36585450
  • Mutations and amplifications more frequent in advanced bladder disease (q = 0.001); 38% discordance in matched primary-metastasis pairs PMID:36543146
  • ERBB2 E363V detected in CRC patient ctDNA at resistance to KRASG12C + EGFR inhibition PMID:36355783
  • ERBB2 amplification in 7% of metastatic urothelial carcinoma (UC-GENOME cohort) PMID:36333289
  • ERBB2 GOF mutations (6%) and amplifications (10%) in GBC; amplification is OncoKB level 3B actionable; 10 patients received HER2-directed therapy PMID:36228155
  • ERBB2 mutation and amplification assessed in advanced NSCLC immunotherapy cohort; neither reached significance for PFS outcomes (P = 0.48 and P = 0.47) PMID:36038778
  • Identified as a significantly mutated gene in HNSCC whole-exome sequencing of 74 tumor-normal pairs (Broad cohort) PMID:21798893
  • ERBB2 amplification is among the top genomic features predicting lapatinib and other drug sensitivities in the CCLE pharmacogenomic profiling of 947 cancer cell lines PMID:22460905
  • Somatic mutations in 2/65 TNBC cases; classified as clinically actionable in a WGS cohort (BCCRC) PMID:22495314
  • Amplification defines IntClust 5 in the METABRIC cohort (2,000 tumors); includes both HER2-enriched (ER-negative) and luminal (ER-positive) cases; patients pre-trastuzumab era had worst survival in this subgroup PMID:22522925
  • Identified as somatically mutated in breast cancer WES cohort (Sanger Institute, 100 tumors); ERBB2 mutations detected beyond HER2 amplification events PMID:22722201
  • Recurrently mutated in breast cancer WES/WGS cohort (Broad Institute, 103 tumors); ERBB2 somatic mutations identified in context of PIK3CA/AKT pathway co-alterations PMID:22722202
  • Somatic mutations including amplification detected in TCGA colorectal adenocarcinoma cohort (276 tumors) PMID:22810696
  • Rare mutations (3 or fewer events) in 183 LUAD cases; copy-number gain observed; could not be statistically nominated due to low frequency PMID:22980975
  • Amplified in HER2-enriched breast cancer subtype (TCGA, 510 tumors); ERBB2 amplification defines the HER2-enriched intrinsic subtype PMID:23000897
  • Mutated in 5 EAC tumors (kinase-domain p.D769Y ×2 and p.G776V), variants previously reported in other cancers; EAC represents a novel disease context for these alterations PMID:23525077
  • Focally amplified with protein overexpression in 25% of serous/serous-like endometrial tumours; amplification reported in 27% of uterine serous carcinomas, forming basis for HER2-targeted therapy hypothesis; mutually exclusive with FBXW7 in WNT module analysis PMID:23636398
  • Focal high-level amplification in 6.2% (6/97) of high-grade bladder tumors with corresponding mRNA up-regulation and 3+ HER2 IHC; framed as a validated actionable target analogous to breast/gastroesophageal disease PMID:23897969
  • Focal amplification in bladder TCC PMID:24121792
  • ERBB2 recurrently mutated in 1.4% of rhabdomyosarcoma (RMS) cases; identified as part of a 93%-targetable kinase axis alongside FGFR4, IGF1R, PDGFRA, and MET in RMS genomic characterization PMID:24436047
  • ERBB2 mutation or amplification in 9% of muscle-invasive bladder cancers (significant by COSMIC restriction); alteration frequency comparable to TCGA HER2-positive breast cancer but with fewer amplifications and more mutations; supports ongoing ERBB2-targeted therapy trials PMID:24476821
  • Mentioned in the context of RTK signaling and targeted therapy landscape in HCC (2014 genomics review) PMID:24735922
  • ERBB-pathway member cited in context of prior GBC whole-exome data (Li et al. Nat Genet 2014) showing recurrent ERBB-pathway mutations activating AKT in GBC PMID:24997986
  • Altered in 17% of CIN gastric adenocarcinoma (STAD) cases; alterations include focal amplification and recurrent S310F-class hotspot mutations (3% mutation overall); established drug target in CIN subtype PMID:25079317
  • Activating in-frame insertion and point mutations (n=5) and focal amplification in the oncogene-negative subset of LUAD (TCGA, n=230) PMID:25079552
  • Amplification/overexpression in 4–6% iCCA and 3–20% eCCA; targetable with pertuzumab + trastuzumab (MyPathway ORR 23%) and trastuzumab-deruxtecan (ORR 22.0%, mPFS 4.6 mo, mOS 7.0 mo in CCA). PMID:25526346
  • Amplification and mutation confirmed in gastric cancer (GC) cohort (294 Tianjin cases); standard trastuzumab target. PMID:25583476
  • Focal amplification in HPV(-) HNSCC (3%); part of the RTK alteration landscape in HPV-negative head and neck squamous cell carcinoma PMID:25631445
  • Low-frequency but FDA-druggable alteration in HCC (MAP kinase / RTK pathway) PMID:25822088
  • Significant association with T stage in UTUC PMID:26278805
  • Recurrent S310F hotspot missense mutation in 4 desmoplastic melanoma tumors; identified as potentially targetable RTK alteration PMID:26343386
  • Amplification and mutations identified among upstream drivers of AKT activation in ILC; previously reported in relapsed ILC (Ross et al., 2013) PMID:26451490
  • ERBB2 mutations are among the single-case alterations replicating findings from the prior whole-exome ATC study in the MSK-IMPACT 341-gene cohort of 117 advanced thyroid cancers (PDTC/ATC) PMID:26878173
  • ERBB2 alterations are recurrent in plasmacytoid-variant bladder cancer profiled by WES and 341-gene IMPACT panel (n=31 tumors); flagged as a clinically actionable target supporting early use of targeted agents PMID:26901067
  • High-level amplification enriched in lung tumors lacking other RTK/Ras/Raf activating events (p < 0.01) in a pan-lung TCGA cohort PMID:27158780
  • Somatic mutation frequency 2.8% ER+, 3.2% ER- in breast cancer; codon 755 hotspot enriched in ER+ tumors; mutations observed in relapsed CDH1-mutant lobular carcinomas; mutually exclusive of AKT1 mutations within 17q12-amplified context PMID:27161491
  • ERBB2 (HER2) amplification reported at 13.8% in young lung cancer (YLC) vs 4.4% in older patients (Hou et al.); conflicting data exist across studies; identified as an actionable alteration in this age group PMID:27346245
  • ERBB2 identified as an actionable alteration in salivary duct carcinoma (SDCA) within a pan-head-and-neck NGS cohort sequenced with MSK-IMPACT (410-gene panel) PMID:27442865
  • Recurrent amplification (confirmed canonical breast-cancer event) in HR+/HER2− metastatic breast cancer (BRCA); amplitude at least as frequent as in early breast cancer (eBC) PMID:28027327.
  • Altered (amplification or mutation) in 32% of EACs vs 3% of ESCCs; 4 EACs had ERBB2 mutations without amplification; 6 amplified EACs expressed an ERBB2 exon-12–JUP 3′-UTR fusion transcript lacking transmembrane and tyrosine-kinase domains; trastuzumab-directed therapy is active in ERBB2-positive EAC PMID:28052061.
  • ERBB2 (HER2) amplification and activating mutations were identified across multiple cancer types in a large-scale targeted sequencing study PMID:28336552
  • ERBB2 alterations co-occurred with FBXW7 mutations and were evaluated in the context of targeted therapy response PMID:28445112
  • Focal amplification (>15 copies on triploid background) identified on a relapse-dominant subclone in patient CRUK0004 plasma; flagged as a potentially targetable relapse driver in NSCLC PMID:28445469
  • Hotspot S310F missense and amplification in high-grade NMIBC, almost exclusively in HGTis (6/12 specimens); mutually exclusive with FGFR3; together with FGFR3 covers 57% of high-grade NMIBC PMID:28583311
  • Amplification in 3.9–8.5% of CCAs; enriched in Fluke-positive tumors (10.4% vs 2.7%, p < 0.01) with average 14 copies and FISH validation; activating point mutations (S310F/Y, G292R, T862A, D769H, L869R, V842I, G660D) in 2% of cases. Defining co-feature of molecular Clusters 1 and 2; nominated as anti-HER2 therapeutic target PMID:28667006.
  • 12% mutated in MIBC (newly significant SMG); recurrent extracellular-domain S310 mutations (24/57 = 42% of ERBB2 mutations) attributable to APOBEC mutagenesis; recurrently amplified; RPPA HER2-high clusters 1 and 2 are candidates for trastuzumab or ado-trastuzumab-emtansine therapy PMID:28988769
  • Focal amplification in 25% of CIN-subtype esophagogastric cancers; NGS amplification level predicts trastuzumab PFS (top quartile: median PFS 24.3 mo); loss of ERBB2 amplification (16% of post-trastuzumab samples) and acquired ERBB2 exon 16 deletion (delta-16 HER2 variant) are recurrent acquired-resistance mechanisms PMID:29122777
  • Amplifications in 4% of MSS metastatic colorectal cancers — the most common RTK alteration in this cohort; one case co-occurred with EGFR S492R as a likely dual cetuximab-resistance mechanism, in 1,134 colorectal adenocarcinomas profiled by MSK-IMPACT PMID:29316426
  • Reported with low frequency among advanced NSCLC patients treated with anti-PD-(L)1 (n=240); too few events for response analysis in this TMB-focused study PMID:29337640
  • 125 patients with somatic ERBB2 (HER2) mutations enrolled in SUMMIT basket trial of neratinib across 21 cancer types; 31 unique alleles (domain distribution: kinase 66%, extracellular 26%, transmembrane/juxtamembrane 8%); most frequent: S310, L755, Y772_A775dup, V777; HER2 mutation clonal in 95%; breast cancer ORR8 32%; bladder and colorectal cohorts showed lineage-based resistance PMID:29420467
  • Four ERBB2 fusions (with partners PPP1R1B and IKZF3) identified in the TCGA pan-cancer fusion landscape; 3 of 4 had HPV integration within 1 Mb of ERBB2, suggesting fusions arise from local genomic instability induced by viral integration — a mechanism distinct from, but potentially complementary to, trastuzumab-targetable HER2 amplification PMID:29617662.

Cancer types (linked)

  • GBM — mutated in 8% of cases; primarily extracellular domain mutations suggesting RTK activation PMID:18772890.
  • LUAD — depleted in metastases vs primaries PMID:37084736.
  • OGCT — amplification in one patient in the Make-an-IMPACT rare-cancer cohort PMID:36862133.
  • BLCA / UTUC — co-altered in 11% of FGFR3-altered MIBC PMID:37682528.
  • BRCA / NSCLC — mutations and amplification detected in CSF ctDNA from breast and lung cancer patients with CNS tumors PMID:39289779.
  • EGC — defining treatment-eligible biomarker; loss of HER2 as key resistance mechanism PMID:37406106; amplification associated with improved survival PMID:37699004.
  • CESC — altered in 12% overall; 28% in UEA subtype PMID:37643132.
  • UCEC — amplification enriched in Black patients (12% vs 3%) PMID:37651310.
  • HNSC / ESCA / BRCA / STAD / GB — HER2 expression level predicts ADC-mediated radiosensitization (T-DM1 + IR) in preclinical models; authors propose combining T-DM1 with IR warrants clinical evaluation in HER2+ locally advanced disease PMID:27698471.
  • CHDM — EGFR/ERBB2 pathway enriched in chordomas; TAK-285 (EGFR/ERBB2 kinase inhibitor) preferentially active in chordoma PDTOs vs pan-sarcoma (p=0.034) PMID:39305899.
  • BLCA (metastatic urothelial carcinoma) — alterations in 14% of cfDNA; independent predictor of shorter OS on cisplatin-based chemotherapy (multivariable HR 1.64, p=0.019) in CALGB 90601 PMID:40256659.

Co-occurrence and mutual exclusivity

  • Not reported in the corpus.

Therapeutic relevance

  • trastuzumab treatment of an ERBB2-amplified ovarian GCT did not produce a durable response PMID:36862133.
  • Pembrolizumab + trastuzumab + chemotherapy produced durable benefit in HER2+ EGC; uniform HER2 IHC 3+ and plasma ERBB2 amplification predicted response PMID:37406106.
  • Neratinib showed 25% ORR and 7.0-month median PFS in HER2-mutant cervical cancer; trastuzumab deruxtecan is under investigation PMID:37643132.
  • Trastuzumab deruxtecan shows clinical activity in ERBB2-low carcinosarcomas, expanding the therapeutic window PMID:37651310.
  • T-DM1 combined with ionizing radiation produced durable tumour control in HER2+ xenografts with a single 0.25 nmol dose + 3 IR fractions; the authors argue for speedy clinical evaluation given T-DM1’s existing FDA approval for HER2+ metastatic breast cancer PMID:27698471.
  • In metastatic urothelial carcinoma, ERBB2 cfDNA alterations independently predict shorter OS on cisplatin-based chemotherapy (multivariable HR 1.64, 95% CI 1.08–2.49; p=0.019); HER2-directed ADCs (trastuzumab deruxtecan, disitamab vedotin — with mUC response rates 33–83%) are flagged as therapeutic options for ERBB2-altered mUC PMID:40256659.

Open questions

  • None flagged in the corpus.

Sources

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