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Germline BRCA mutation and outcome in young-onset breast cancer: POSH, a prospective cohort study

Germline BRCA mutation and outcome in young-onset breast cancer: POSH, a prospective cohort study
Germline BRCA mutation and outcome in young-onset breast cancer: POSH, a prospective cohort study

BACKGROUND: Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer.

METHODS: We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing.

FINDINGS: Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0-9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5-98·4] vs 96·6% [95·8-97·3]; at 5 years: 83·8% [79·3-87·5] vs 85·0% [83·5-86·4]; at 10 years: 73·4% [67·4-78·5] vs 70·1% [67·7-72·3]; hazard ratio [HR] 0·96 [95% CI 0·76-1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89-97] vs 91% [88-94]; HR 0·59 [95% CI 0·35-0·99]; p=0·047) but not 5 years (81% [73-87] vs 74% [70-78]; HR 1·13 [0·70-1·84]; p=0·62) or 10 years (72% [62-80] vs 69% [63-74]; HR 2·12 [0·82-5·49]; p= 0·12).

INTERPRETATION: Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences.

FUNDING: Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant.

Journal Article
1474-5488
169-180
Copson, Ellen R.
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Maishman, Tom C.
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Tapper, Will J.
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Cutress, Ramsey I.
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Greville-Heygate, Stephanie
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Altman, Douglas G.
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Eccles, Bryony
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Durcan, Lorraine R.
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Jones, Louise
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Evans, D.Gareth
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Thompson, Alastair M.
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Pharoah, Paul
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Easton, Douglas F.
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Dunning, Alison M.
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Hanby, Andrew
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Lakhani, Sunil R.
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Eeles, Ros
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Gilbert, Fiona J.
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Hamed, Hisham
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Hodgeson, Shirley
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Simmonds, Peter
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Stanton, Louise
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Eccles, Diana
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Copson, Ellen R.
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Maishman, Tom C.
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Tapper, Will J.
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Cutress, Ramsey I.
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Greville-Heygate, Stephanie
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Altman, Douglas G.
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Eccles, Bryony
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Durcan, Lorraine R.
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Jones, Louise
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Evans, D.Gareth
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Thompson, Alastair M.
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Pharoah, Paul
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Easton, Douglas F.
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Dunning, Alison M.
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Hanby, Andrew
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Lakhani, Sunil R.
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Eeles, Ros
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Gilbert, Fiona J.
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Hamed, Hisham
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Hodgeson, Shirley
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Simmonds, Peter
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Stanton, Louise
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Eccles, Diana
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Copson, Ellen R., Maishman, Tom C., Tapper, Will J., Cutress, Ramsey I., Greville-Heygate, Stephanie, Altman, Douglas G., Eccles, Bryony, Durcan, Lorraine R., Jones, Louise, Evans, D.Gareth, Thompson, Alastair M., Pharoah, Paul, Easton, Douglas F., Dunning, Alison M., Hanby, Andrew, Lakhani, Sunil R., Eeles, Ros, Gilbert, Fiona J., Hamed, Hisham, Hodgeson, Shirley, Simmonds, Peter, Stanton, Louise and Eccles, Diana (2018) Germline BRCA mutation and outcome in young-onset breast cancer: POSH, a prospective cohort study. The Lancet Oncology, 19 (2), 169-180. (doi:10.1016/S1470-2045(17)30891-4).

Record type: Article

Abstract

BACKGROUND: Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer.

METHODS: We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing.

FINDINGS: Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0-9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5-98·4] vs 96·6% [95·8-97·3]; at 5 years: 83·8% [79·3-87·5] vs 85·0% [83·5-86·4]; at 10 years: 73·4% [67·4-78·5] vs 70·1% [67·7-72·3]; hazard ratio [HR] 0·96 [95% CI 0·76-1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89-97] vs 91% [88-94]; HR 0·59 [95% CI 0·35-0·99]; p=0·047) but not 5 years (81% [73-87] vs 74% [70-78]; HR 1·13 [0·70-1·84]; p=0·62) or 10 years (72% [62-80] vs 69% [63-74]; HR 2·12 [0·82-5·49]; p= 0·12).

INTERPRETATION: Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences.

FUNDING: Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant.

Text POSH studyFINAL Lancet Oncology Clean accepted 08NOV2017 - Accepted Manuscript
Restricted to Repository staff only until 8 August 2018.
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Submitted date: 2 November 2017
Accepted/In Press date: 8 November 2017
e-pub ahead of print date: 11 January 2018
Published date: February 2018
Additional Information: Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Keywords: Journal Article

Identifiers

Local EPrints ID: 415629
URI: https://eprints.soton.ac.uk/id/eprint/415629
ISSN: 1474-5488
PURE UUID: f8fac618-be38-4906-be18-a6c4ed179ddb

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Date deposited: 16 Nov 2017 17:30
Last modified: 24 May 2018 16:32

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Contributors

Author: Ellen R. Copson
Author: Tom C. Maishman
Author: Will J. Tapper
Author: Stephanie Greville-Heygate
Author: Douglas G. Altman
Author: Bryony Eccles
Author: Lorraine R. Durcan
Author: Louise Jones
Author: D.Gareth Evans
Author: Alastair M. Thompson
Author: Paul Pharoah
Author: Douglas F. Easton
Author: Alison M. Dunning
Author: Andrew Hanby
Author: Sunil R. Lakhani
Author: Ros Eeles
Author: Fiona J. Gilbert
Author: Hisham Hamed
Author: Shirley Hodgeson
Author: Peter Simmonds
Author: Louise Stanton
Author: Diana Eccles

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