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    1year
    Clinical and genomic landscape of ERBB2 and ERBB3 mutated breast cancer (SABCS 2023)
    Here we describe the clinical and genomic characteristics of a large cohort of ERBB2/3-mut breast cancers. We identify a notable enrichment of ERBB2/3-mut in lobular histology and metastatic tumors and tendency for co-alteration with CDH1 and multiple transcription factors reflecting the unique biology of ERBB2/3-mut breast cancers. Further analyses on an expanded cohort (n >6000 pts), including outcomes on HER2-directed antibody-drug conjugates (T-DXd) and targeted therapies such as PI3K inhibitors, will be presented at the 2023 SABCS Annual Meeting.
    Clinical
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    HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • ARID1A (AT-rich interaction domain 1A) • NF1 (Neurofibromin 1) • RUNX1 (RUNX Family Transcription Factor 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • CDH1 (Cadherin 1) • FOXA1 (Forkhead Box A1) • MAP3K1 (Mitogen-Activated Protein Kinase Kinase Kinase 1) • GATA3 (GATA binding protein 3)
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    HER-2 negative • HER-2 mutation • HER-2 L755S • HER-2 S310F • HER-2 V777L • ERBB3 mutation • HER-2 G778_P780dup • ERBB3 G284R
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    MSK-IMPACT
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    Enhertu (fam-trastuzumab deruxtecan-nxki)
    over1year
    Pathogenic HER3 dimerization domain mutations create a structural bias towards un-conventional EGFR-HER3 signalling axis in breast cancer. (PubMed, Int J Biol Macromol)
    Due to this unusual ligand mediated interaction, cancer cells were found susceptible to EGFR targeted therapeutics i.e. Gefitinib and Erlotinib. Further, in TCGA analysis, BC patients harbouring HER3-D297Y mutation showed increased p-EGFR levels as compared to the patients harbouring HER3-WT and HER3-G284R mutations. For the first time, this comprehensive study showed the importance of specific hotspot mutations in HER3 dimerization domain can defy the Trastuzumab therapy, rather cells become susceptible to the EGFR inhibitors.
    Journal
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    HER-2 (Human epidermal growth factor receptor 2) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3)
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    EGFR mutation • HER-2 mutation • HER-2 S310F • ERBB3 mutation • ERBB3 G284R
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    Herceptin (trastuzumab) • erlotinib • gefitinib
    over1year
    Characterization of diverse targetable alterations in ERBB2 and ERBB3 in 93,465 non-small cell lung cancers (NSCLC). (ASCO 2023)
    Background: Recently, fam-trastuzumab deruxtecan-nxki was approved for NSCLC with selected activating ERBB2 (HER2) mutations. Patritumab deruxtecan, a novel HER3 directed antibody drug conjugate, exhibits in vitro activity against HER3 mutations... Diverse ERBB2 and ERBB3 alt in NSCLC may predict sensitivity to anti-HER2/3 therapies, but not all classes of alts are detected/reported by all profiling assays. Utilization of comprehensive testing to guide biomarker definitions, treatment selection, and clinical trial enrollment is imperative.
    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3)
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    HER-2 mutation • ERBB3 mutation • ERBB3 G284R • ERBB3 V104L
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    FoundationOne® Liquid CDx
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    Enhertu (fam-trastuzumab deruxtecan-nxki) • patritumab deruxtecan (U3-1402)
    almost4years
    [VIRTUAL] Evaluation of somatic and germline mutations in ampullary carcinoma reveals actionable targets in multiple signaling pathways (AACR 2021)
    The BRAF N581I mutation is resistant to BRAF inhibitor vemurafenib but sensitive to MEK inhibitor trametinib. The PIK3CA N1044K mutation is oncogenic but its sensitivity to PIK3CA inhibitor alpelisib is unknown... Through comprehensive genomic characterization of Chinese AC patients, we identified multiple actionable mutations in multiple signaling pathways. Our findings indicated that molecular profiling can provide clinical benefits to a significant portion of AC patients.
    Tumor Mutational Burden • MSi-H Biomarker • PARP Biomarker
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    KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • FGFR2 (Fibroblast growth factor receptor 2) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • PALB2 (Partner and localizer of BRCA2) • SMAD4 (SMAD family member 4) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • CHEK2 (Checkpoint kinase 2) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • ELF3 (E74 Like ETS Transcription Factor 3) • MAP2K4 (Mitogen-Activated Protein Kinase Kinase 4)
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    TP53 mutation • KRAS mutation • MSI-H/dMMR • BRAF mutation • HER-2 amplification • PIK3CA mutation • HER-2 mutation • FGFR2 mutation • PALB2 mutation • FGFR2 amplification • CHEK2 mutation • U2AF1 mutation • ERBB3 mutation • ERBB3 G284R • HER-2 R678Q
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    Mekinist (trametinib) • Zelboraf (vemurafenib) • Piqray (alpelisib)
    over4years
    [VIRTUAL] Genomic architecture of gallbladder cancer: Results of a first prospective study. (ASCO 2020)
    Phase 2 trial of frontline Trastuzumab combined with chemotherapy is ongoing... GBC is enriched in 28% of patients with ERBB2 & ERBB3 amplifications and/or mutations. FGFR2 mutation is rare in GBC. PIK3CA aberrations are common.
    Clinical • PD(L)-1 Biomarker • IO biomarker
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    HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MSI (Microsatellite instability) • FGFR2 (Fibroblast growth factor receptor 2) • FGFR3 (Fibroblast growth factor receptor 3) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3)
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    PD-L1 expression • KRAS mutation • HER-2 amplification • PIK3CA mutation • MET amplification • FGFR2 mutation • NF1 mutation • FGFR2 amplification • FGFR3 mutation • KRAS G12A • PIK3CA amplification • HER-2 S310F • HER-2 V777L • KRAS G12 • KRAS G13 • NF2 mutation • ERBB3 mutation • HER-2 L869R • ERBB3 G284R • FGFR3 amplification
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    Herceptin (trastuzumab)