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

Pathogenic variants in CHEK2 are associated with an adverse prognosis in symptomatic early onset breast cancer
Pathogenic variants in CHEK2 are associated with an adverse prognosis in symptomatic early onset breast cancer
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.
2473-4284
472-485
Greville-Heygate, S.L.
a952c82d-8775-45a5-9c60-478348fb02f2
Maishman, T.
cf4259a4-0eef-4975-9c9d-a2c3d594f989
Tapper, W.J.
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Cutress, R.I.
68ae4f86-e8cf-411f-a335-cdba51797406
Copson, Ellen
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Dunning, A.M.
a30b82d4-625c-47b4-b8fa-fed0c075acf5
Durcan, L.
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Haywood, L.
0a17426c-f1c1-4eff-bb1b-262d3bf64c73
Jones, Louise J.
246f319c-2650-4ddf-a067-2d2489c6fbd8
Eccles, D.M.
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Greville-Heygate, S.L.
a952c82d-8775-45a5-9c60-478348fb02f2
Maishman, T.
cf4259a4-0eef-4975-9c9d-a2c3d594f989
Tapper, W.J.
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Cutress, R.I.
68ae4f86-e8cf-411f-a335-cdba51797406
Copson, Ellen
a94cdbd6-f6e2-429d-a7c0-462c7da0e92b
Dunning, A.M.
a30b82d4-625c-47b4-b8fa-fed0c075acf5
Durcan, L.
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Haywood, L.
0a17426c-f1c1-4eff-bb1b-262d3bf64c73
Jones, Louise J.
246f319c-2650-4ddf-a067-2d2489c6fbd8
Eccles, D.M.
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23

Greville-Heygate, S.L., Maishman, T., Tapper, W.J., Cutress, R.I., Copson, Ellen, Dunning, A.M., Durcan, L., Haywood, L., Jones, Louise J. and Eccles, D.M. (2020) Pathogenic variants in CHEK2 are associated with an adverse prognosis in symptomatic early onset breast cancer. JCO Precision Oncology, 3, 472-485. (doi:10.1200/PO.19.00178).

Record type: Article

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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Accepted/In Press date: 3 March 2020
e-pub ahead of print date: 4 May 2020
Published date: 2020

Identifiers

Local EPrints ID: 437225
URI: http://eprints.soton.ac.uk/id/eprint/437225
ISSN: 2473-4284
PURE UUID: cee6af99-258f-41a3-9e3f-84c27da32ece
ORCID for W.J. Tapper: ORCID iD orcid.org/0000-0002-5896-1889
ORCID for D.M. Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 22 Jan 2020 17:32
Last modified: 22 Nov 2021 07:58

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Contributors

Author: S.L. Greville-Heygate
Author: T. Maishman
Author: W.J. Tapper ORCID iD
Author: R.I. Cutress
Author: Ellen Copson
Author: A.M. Dunning
Author: L. Durcan
Author: L. Haywood
Author: Louise J. Jones
Author: D.M. Eccles ORCID iD

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