Pathogenic variants in CHEK2 are associated with an adverse prognosis in symptomatic early onset breast cancer

Abstract

PURPOSE: Checkpoint Kinase 2 (CHEK2) is frequently included in multi-gene panels, we describe the associated outcomes amongst carriers of CHEK2 pathogenic variants in young symptomatic breast cancer patients.
PATIENTS AND METHODS: 2344 participants in the Prospective Outcomes in Sporadic Versus Hereditary Breast Cancer (POSH) Study were included. Participants had a diagnosis of primary invasive breast cancer at the age of 40 years or younger. Summary statistics were used to compare tumour characteristics amongst CHEK2+ carriers with CHEK2-. Kaplan Meier curves were used to demonstrate Overall Survival (OS) and Distant Disease Free Survival (DDFS).
RESULTS: Overall, 53/2344 (2.3%) of cases had a pathogenic CHEK2 variant. CHEK2+ associated tumours were significantly more likely to be grade 2, Oestrogen Receptor (ER) and Progesterone Receptor (PR) positive compared to CHEK2- (grade 2, 28/52 (53.8%) versus 803/2229 (36.0%) (p=0.029)). CHEK2 associated tumours were significantly more likely to present with nodal involvement (N1, 37/53 (69.8%) versus 1169/2253 (51.9%) (p=0.0098) and demonstrated a trend towards multifocality. A higher proportion of CHEK2+ with invasive breast cancer were obese compared to CHEK2- (28.3% versus 18.8%, p=0.039). Univariate and multivariable analysis revealed that Overall Survival (OS) and Distant Disease Free Survival (DDFS) was significantly worse in CHEK2+ versus CHEK2- (OS HR, 1.58 (95%CI, 1.01-2.48 (p=0.043))).
CONCLUSIONS: This work highlights the adverse prognosis associated with breast cancer in CHEK2 pathogenic variant carriers. It also identifies a potential association between obesity, family history and breast cancer risk in young CHEK2 gene carriers.

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Identifiers

ORCID for W.J. Tapper: orcid.org/0000-0002-5896-1889

ORCID for D.M. Eccles: orcid.org/0000-0002-9935-3169

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