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Breast Cancer Research and Treatment

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Open Access 13-12-2023 | Breast Cancer | Original Laboratory Investigation

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

Authors: Christopher J. Schwartz, Nikka Khorsandi, Amie Blanco, Rita A. Mukhtar, Yunn-Yi Chen, Gregor Krings

Published in: Breast Cancer Research and Treatment | Issue 1/2024

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.

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Title: Clinicopathologic and genetic analysis of invasive breast carcinomas in women with germline CHEK2 variants
Authors: Christopher J. Schwartz
Nikka Khorsandi
Amie Blanco
Rita A. Mukhtar
Yunn-Yi Chen
Gregor Krings
Publication date: 13-12-2023
Publisher: Springer US
Keywords: Breast Cancer
Breast Cancer
Metastasis
Published in: Breast Cancer Research and Treatment / Issue 1/2024
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-023-07176-8

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