Clinicopathologic and genetic analysis of invasive breast carcinomas in women with germline CHEK2 variants

Abstract

Purpose Germline pathogenic variants in checkpoint kinase 2 (CHEK2) are associated with a moderately increased risk of breast cancer (BC). The spectrum of clinicopathologic features and genetics of these tumors has not been fully established. Methods We characterized the histopathologic and clinicopathologic features of 44 CHEK2-associated BCs from 35 women, and assessed responses to neoadjuvant chemotherapy. A subset of cases (n = 23) was additionally analyzed using targeted next-generation DNA sequencing (NGS). Results Most (94%, 33/35) patients were heterozygous carriers for germline CHEK2 variants, and 40% had the c.1100delC allele. Two patients were homozygous, and five had additional germline pathogenic variants in ATM (2), PALB2 (1), RAD50 (1), or MUTYH (1). CHEK2-associated BCs occurred in younger women (median age 45 years, range 25–75) and were often multifocal (20%) or bilateral (11%). Most (86%, 38/44) were invasive ductal carcinomas of no special type (IDC-NST). Almost all (95%, 41/43) BCs were ER + (79% ER + HER2-, 16% ER + HER2 + , 5% ER-HER2 +), and most (69%) were luminal B. Nottingham grade, proliferation index, and results of multiparametric molecular testing were heterogeneous. Biallelic CHEK2 alteration with loss of heterozygosity was identified in most BCs (57%, 13/23) by NGS. Additional recurrent alterations included GATA3 (26%), PIK3CA (226%), CCND1 (22%), FGFR1 (22%), ERBB2 (17%), ZNF703 (17%), TP53 (9%), and PPM1D (9%), among others. Responses to neoadjuvant chemotherapy were variable, but few patients (21%, 3/14) achieved pathologic complete response. Most patients (85%) were without evidence of disease at time of study (n = 34). Five patients (15%) developed distant metastasis, and one (3%) died (mean follow-up 50 months). Conclusion Almost all CHEK2-associated BCs were ER + IDC-NST, with most classified as luminal B with or without HER2 overexpression. NGS supported the luminal-like phenotype and confirmed CHEK2 as an oncogenic driver in the majority of cases. Responses to neoadjuvant chemotherapy were variable but mostly incomplete.

Los olvidados: Non-BRCA variants associated with Hereditary breast cancer in Mexican population

“…There was an association between TNBC and BRCA and NTNBC patients with CHEK2 GPVs. Other reports associate TP53 with HER2 + BC 28 , CHEK2 with Luminal B 29 , or BRCA with TNBC 30 , both concordant with our results. There was insu cient statistical power to associate genotype-phenotype in the less frequent non-BRCA; further analysis with increased cases may address this topic.…”

A contemporary review of breast cancer risk factors and the role of artificial intelligence

“…Genetic mutations, such as BRCA1 (Breast Cancer Gene 1) and BRCA2 (Breast Cancer Gene 2): Genetic mutations, particularly in BRCA1 and BRCA2 genes, significantly increase hereditary breast cancer risk. Studies like ( 92 ) analyze the role of germline CHEK2 (Checkpoint Kinase 2) variants, while ( 97 ) advocate personalized prevention strategies ( 98 ). identifies genetic loci associated with contralateral breast cancer risk, and ( 3 ) explores molecular links between obesity and breast cancer.…”