title: 'Non-classical' HER2 FISH results in breast cancer: a multi-institutional study.
abstract: The 2013 CAP/ASCO HER2 Testing Guidelines Update modified HER2 FISH categories such that some cases with 'monosomy', 'co-amplification/polysomy', low-level increased HER2 signals or clustered heterogeneity now are considered amplified or equivocal. This study examines the frequency and clinico-pathologic characteristics of breast cancers with equivocal or 'non-classical' HER2 FISH results. Breast cancers (2001-2014) with HER2 FISH results, HER2 immunohistochemistry, ER, grade, and age from three institutions (Stanford, UCSF, UWMC) were collected. HER2 FISH was interpreted using the updated recommendations. Amplified cases with non-classical results were grouped into the following categories: (1) 'monosomy' (ratio ≥2.0, mean HER2/cell<4.0); (2) 'co-amplified' (ratio<2.0, mean HER2/cell ≥6.0); (3) 'low amplified' (ratio ≥2.0, mean HER2/cell 4.0-5.9). Heterogeneous cases with clustered HER2-positive cells were also included. Of 8068 cases, 5.2% were equivocal and 4.6% had a 'non-classical' HER2 amplified result; 1.4% 'monosomy', 0.8% 'co-amplified', 2.1% 'low amplified', and 0.3% clustered heterogeneity. These cancers had a high frequency of ER positive (80.4%), Nottingham grade 3 (52.1%) results. The highest percentage of grade 3 cancers (66.7%) and positive HER2 immunohistochemistry (31.7%) was in the 'co-amplified' group. The 'monosomy' group had the highest percent grade 1 cancers (13.3%) and was most frequently HER2 immunohistochemistry negative (30.1%). Equivocal cases had very similar characteristics to the 'low-amplified' category. Cases with non-classical HER2 amplification or equivocal results are typically ER positive, higher grade cancers. 'Co-amplified' cases have the highest frequencies of aggressive characteristics and 'monosomy' cases the highest frequencies of lower risk features. With little clinical outcomes data currently available on these non-classical HER2 results, these results support the current classification scheme for HER2 FISH, with case-by-case correlation with additional clinical-pathologic factors when evaluating whether to offer HER2-targeted therapies in these non-classical cases.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Ballard
authors.affiliation: University of Washington Medical Center, Seattle, WA, USA.
authors.forename: Florencia
authors.initials: F
authors.lastname: Jalikis
authors.affiliation: University of California at San Francisco School of Medicine, San Francisco, CA, USA.
authors.forename: Gregor
authors.initials: G
authors.lastname: Krings
authors.affiliation: University of Washington Medical Center, Seattle, WA, USA.
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Schmidt
authors.affiliation: University of California at San Francisco School of Medicine, San Francisco, CA, USA.
authors.forename: Yunn-Yi
authors.initials: YY
authors.lastname: Chen
authors.affiliation: University of Washington Medical Center, Seattle, WA, USA.
authors.forename: Mara H
authors.initials: MH
authors.lastname: Rendi
authors.affiliation: University of Washington Medical Center, Seattle, WA, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Dintzis
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.|Palo Alto VA Healthcare System, Palo Alto, CA, USA.
authors.forename: Kristin C
authors.initials: KC
authors.lastname: Jensen
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: West
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Sibley
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Troxell
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Kimberly H
authors.initials: KH
authors.lastname: Allison
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D060787:Neoplasm Grading; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human