Breast Cancer: Recurrent Genomic Alterations: Difference between revisions

|2

|Gain of function

|amplification, sequence variants, other structural rearrangement

|Diseases: metaplastic BC, basal- like or claudin low TNBC. Therapy: EGFR amplification (pre-existing or de novo) associates with resistance to hormone therapy.

|-

|''EP300''

|2

|Other/Complex

|sequence variants, other structural rearrangement, altered expression

|Diseases: TNBC, adenoid cystic carcinoma, metaplastic BC; Therapy: possible implications for aldo-keto reductase inhibitor. Ep300 is a a histone acetyltransferase and functions as transcriptional activator of CDH1.

|-

|''ERBB2''

|1

|Gain of function

|amplification, altered expression, sequence variants

|Also known as HER2. Diseases: Amplification in 15% of BC. Sequence variants associated with apocrine and pleomorphic lobular features. Therapy: anti-HER2 mAb (trastuzumab and pertuzumab) for classical overexpression/amplification per ASCO/CAP guidelines, and antibody-drug conjugate (ADC) therapy for HER2-low and ultralow expression per DESTINY-04 and -06 and DAISY trials; HER2 mutations associated with resistance to CDK4/6 inhibitors and resistance to hormone therapy

|-

|''ERBB3''

|2

|Gain of function

|sequence variants, amplification

|Diseases: lobular BC, TNBC case report indicated exceptional response to trastuzumab (PMID: 34250408)

|-

|''ERBB4''

|2

|Other/Complex

|sequence variants, altered expression

|Diseases: ER positive, HER2 negative BC (typically ERBB4 overexpression), enriched in acinic cell carcinoma. ERBB4 activating mutations may be sensitive to ErbB family inhibitor afatinib. Complex mechanisms with either gain or loss of function being oncogenic; thus, targeted therapy must be informed by mechanism of mutation.

|-

|''ESR1''

|1

|Gain of function

|sequence variants, amplification, fusion, altered expression

|Therapy: Hotspot mutations in ligand binding domain (LBD) occur in patients with prior AI therapy, conferring resistance to aromatase inhibitors, SERMs (e.g. tamoxifen). May be responsive to SERDs (e.g. fulvestrant; elacestrant, imlunestrant, vepdegestrant). Specific point mutations associated with differential response to fulvestrant. Tyr537Ser and Asp538Gly mutants involve hydrogen bonding of the mutant amino acids with Asp351, thus favoring the agonist conformation of the receptor (ligand independent signaling). N-terminal ESR1 fusions lack an intact LBD. Fusions often co-ccur with sequence alterations (polyclonality). Diseases: ER positive BC, metastatic BC with prior endocrine therapy. Diagnosis: Nuclear expression of ER is a key biomarker for HR positive primary breast cancer. Prognosis: mutations, amplification, and fusions associated with decreased overall survival.

|-

|''ETV6''

|1

|Gain of function

|fusion, other structural rearrangement

|Diseases: Secretory carcinoma. Prognosis: favorable (clinically indolent). Low mutation burden, simple genomes. structural rearrangement (fusion) with NTRK3 in secretory carcinoma. BCL2L14–ETV6 (cryptic adjacent gene rearrangement) in 4.4%-12.2% TNBC ass'ed with more aggressive histologic features like necrosis and high tumor grade. BCL2L14–ETV6 in TNBC associated with more aggreessive behaviour

|-

|''FAT1''

|2

|Loss of function

|sequence variants, other structural rearrangement, altered expression

|Diseases: metaplastic BC, basal- like or claudin low TNBC; Resistance to CDK4/6 inhibitors. Blacks more likely to have compared to whites

|-

|''FBXO4''

|2

|Loss of function

|sequence variants, altered expression

|Recurrent mutations in phyllodes tumors, low expression associated with poor prognosis

|-

|''FBXW7''

|2

|Loss of function

|epigenetic modification, other structural rearrangement, sequence variants

|Therapy: chemoresistance (emerging evidence). Diseases: TNBC, adenoid cystic carcinoma (rare sequence variants). Mutations often heterozygous. Mutated in Microglandular adenosis (MGA) with or without associated TNBC, low expression associated with poor prognosis, new population studies

|-

|''FGFR1''

|1

|Gain of function

|fusion, amplification, sequence variants, altered expression

|Diseases: mucinous BC, invasive micropapillary carcinoma, ER-positive luminal B; Therapy: resistance to endocrine therapy; potential sensitivity to FGFR1 inhibitors. Loss is associated with independent poor prognosis in TNBC-preganancy associated carcinomas

|-

|''FGFR2''

|1

|Gain of function

|fusion, amplification, sequence variants

|ER+ metastatic tumors resistant to ER-targeted theapies, resistance to CDK4/6 inhibitors, resistance to HER2 targeted therapies

|-

|''FGFR3''

|1

|Gain of function

|fusion, altered expression, amplification, sequence variants

|ER+ metastatic BC resistant to endocrine therapy

|-

|''FGFR4''

|1

|Gain of function

|fusion, altered expression, amplification, sequence variants

|ER+ metastatic tumors resistant to ER-targeted theapies. Amplification mostly seen in HER2 subtype

|-

|''FLNA''

|2

|Loss of function

|sequence variants, other structural rearrangement

|Diseases: phyllodes tumor

|-

|''FOLR1''