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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 breast cancer prognosis. The primary aim of this study was to determine the impact of a germline BRCA1/2 mutation on outcomes in young onset breast cancer.

Method:
Patients were recruited from 127 UK oncology centres and were eligible if aged ≤ forty years at first diagnosis of invasive breast cancer. BRCA1/2 mutations were identified using blood DNA collected at recruitment. Clinicopathological, treatment and long term outcome data were collected from routine medical records. The primary outcome was overall survival (OS) of all BRCA1/2 carriers vs. all non-carriers, assessed using Cox proportional-hazards models, or flexible parametric survival models (FPSMs) for models which involved time-varying hazards. Recruitment was completed in 2008; long term follow-up continues.

Findings:
Between 2000-2008, 2733 women were recruited. Genotyping detected a pathogenic mutation in 337 (12·3%) of 2733 patients (201 BRCA1, 136 BRCA2). At a median follow-up of 8·2 years, (inter-quartile range: 6·0 to 9·9 years), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in OS between BRCA1/2 mutation carriers and non-carriers in multivariable analyses (OS: HR 0·96; 95% CI 0·76-1·22; p=0·76). However, in patients with triple negative breast cancer, (n=558), BRCA mutation carriers showed a different pattern of relapse over time compared to non-carriers and significantly better OS at two years, (HR 0.59 [95% CI 0·35-0·99], p=0·047).

Interpretation:
Young onset breast cancer patients have a high mortality and those who carry a BRCA gene mutation have similar survival to non-carriers. BRCA carriers presenting with triple negative breast cancer may have a survival advantage during the first few years after diagnosis compared to non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary cancer risks should take into account prognosis associated with the first malignancy and patient preference.
1474-5488
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 (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 breast cancer prognosis. The primary aim of this study was to determine the impact of a germline BRCA1/2 mutation on outcomes in young onset breast cancer.

Method:
Patients were recruited from 127 UK oncology centres and were eligible if aged ≤ forty years at first diagnosis of invasive breast cancer. BRCA1/2 mutations were identified using blood DNA collected at recruitment. Clinicopathological, treatment and long term outcome data were collected from routine medical records. The primary outcome was overall survival (OS) of all BRCA1/2 carriers vs. all non-carriers, assessed using Cox proportional-hazards models, or flexible parametric survival models (FPSMs) for models which involved time-varying hazards. Recruitment was completed in 2008; long term follow-up continues.

Findings:
Between 2000-2008, 2733 women were recruited. Genotyping detected a pathogenic mutation in 337 (12·3%) of 2733 patients (201 BRCA1, 136 BRCA2). At a median follow-up of 8·2 years, (inter-quartile range: 6·0 to 9·9 years), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in OS between BRCA1/2 mutation carriers and non-carriers in multivariable analyses (OS: HR 0·96; 95% CI 0·76-1·22; p=0·76). However, in patients with triple negative breast cancer, (n=558), BRCA mutation carriers showed a different pattern of relapse over time compared to non-carriers and significantly better OS at two years, (HR 0.59 [95% CI 0·35-0·99], p=0·047).

Interpretation:
Young onset breast cancer patients have a high mortality and those who carry a BRCA gene mutation have similar survival to non-carriers. BRCA carriers presenting with triple negative breast cancer may have a survival advantage during the first few years after diagnosis compared to non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary cancer risks should take into account prognosis associated with the first malignancy and patient preference.

Text POSH studyFINAL Lancet Oncology Clean accepted 08NOV2017 - Accepted Manuscript
Restricted to Repository staff only until 8 August 2018.
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More information

Submitted date: 2 November 2017
Accepted/In Press date: 8 November 2017
e-pub ahead of print date: 11 January 2018

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: 14 Feb 2018 17:31

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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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