Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

NBCS Collaborators; ABCTB Investigators; KConFab Investigators; KConFab Investigators

doi:10.1186/s13058-021-01450-7

Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

NBCS Collaborators
, ABCTB Investigators
, KConFab Investigators
, KConFab Investigators

Department of Cancer Genetics
University of Oslo
Faculty of Medicine
Department of Research
Vestre Viken Hospital
Section for Breast and Endocrine Surgery
Department of Pathology
Department of Tumor Biology
Department of Oncology
Department of Oncology
Breast Cancer Research Consortium
Department of Medical Genetics
University of Sydney
Research Department
Peter Maccallum Cancer Centre
University of Melbourne
Antoni van Leeuwenhoek Hospital
Queensland Institute of Medical Research
National Institutes of Health
University of Toronto
University of California at Irvine
German Cancer Research Center
Fred Hutchinson Cancer Research Center
University of Wisconsin-Milwaukee
Lund University
University of Hamburg
Friedrich-Alexander University Erlangen-Nürnberg
University of Copenhagen
University of Cambridge
Ruhr University Bochum
University of Utah
Kaiser Permanente
University of Pisa
Oncology and Genetics Unit
Roswell Park Cancer Institute
Mayo Clinic
University of Sheffield
Karolinska Institutet
Hannover Medical School
International Agency for Research on Cancer
University of Westminster
University of Southampton
Brigham and Women's Hospital
Harvard University
University of Manchester
Manchester University NHS Foundation Trust
University of California at Los Angeles
Curtin University
Instituto de Investigación Sanitaria de Santiago de Compostela
University of California at San Diego
Hospital Clínico San Carlos de Madrid
Cancer Council Victoria
Centre for Epidemiology and Biostatistics
Monash University
University of Oulu
Université Paris-Saclay
Heidelberg University
Helmholtz Zentrum München - German Research Center for Environmental Health
University of Cologne
University of Southern California
University of Eastern Finland
Erasmus University Rotterdam
Robert Bosch Foundation
University of Tübingen
University of Oxford
Pomeranian Medical University in Szczecin
Ulm University
Stanford University
KU Leuven
City of Hope National Medical Center
Flanders Institute for Biotechnology
University of Hawai'i at Mānoa
Heraklion University Hospital
Cyprus Institute of Neurology and Genetics
University Health Network
Helsinki University Hospital
University of North Carolina at Chapel Hill
Queen's University Belfast
American Cancer Society
Fondazione IRCCS Istituto Nazionale dei Tumori
FIRC Institute of Molecular Oncology
MASA
Technion-Israel Institute of Technology
Hospital Universitario Puerta de Hierro Majadahonda
University College London Hospitals NHS Foundation Trust
University Hospital of Larissa
King's College London
SS Cyril and Methodius University in Skopje
Department of Clinical Pathology
University of Western Australia
Royal Marsden Hospital
Cornell University
Columbia University
Leiden University
University of Birmingham
Northern Finland Laboratory Centre Oulu
Uppsala University

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.

METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15).

RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy.

CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.

Original language	English
Article number	86
Pages (from-to)	86
Journal	Breast Cancer Research
Volume	23
Issue number	1
DOIs	https://doi.org/10.1186/s13058-021-01450-7
State	Published - Aug 18 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Breast Neoplasms/drug therapy
Female
Genome-Wide Association Study
Germ-Line Mutation
Humans
Polymorphism, Single Nucleotide
Prognosis
Survival Analysis

Access to Document

10.1186/s13058-021-01450-7

Cite this

NBCS Collaborators, ABCTB Investigators, KConFab Investigators, & KConFab Investigators (2021). Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment. Breast Cancer Research, 23(1), 86. Article 86. https://doi.org/10.1186/s13058-021-01450-7

@article{af4fe20205ca4fc0acd41b0db3473aa4,

title = "Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment",

abstract = "BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15).RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95\% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95\% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95\% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95\% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy.CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.",

keywords = "Breast Neoplasms/drug therapy, Female, Genome-Wide Association Study, Germ-Line Mutation, Humans, Polymorphism, Single Nucleotide, Prognosis, Survival Analysis",

author = "\{NBCS Collaborators\} and \{ABCTB Investigators\} and \{KConFab Investigators\} and \{KConFab Investigators\} and Anna Morra and Maria Escala-Garcia and Jonathan Beesley and Renske Keeman and Sander Canisius and Ahearn, \{Thomas U.\} and Andrulis, \{Irene L.\} and Hoda Anton-Culver and Volker Arndt and Auer, \{Paul L.\} and Annelie Augustinsson and \{Beane Freeman\}, \{Laura E.\} and Heiko Becher and Beckmann, \{Matthias W.\} and Sabine Behrens and Bojesen, \{Stig E.\} and Bolla, \{Manjeet K.\} and Hermann Brenner and Thomas Br{\"u}ning and Buys, \{Saundra S.\} and Bette Caan and Daniele Campa and Federico Canzian and Castelao, \{Jose E.\} and Jenny Chang-Claude and Chanock, \{Stephen J.\} and Cheng, \{Ting Yuan David\} and Clarke, \{Christine L.\} and B{\o}rresen-Dale, \{Anne Lise\} and Sahlberg, \{Kristine K.\} and Lars Ottestad and Rolf K{\aa}resen and Ellen Schlichting and Holmen, \{Marit Muri\} and Toril Sauer and Vilde Haakensen and Olav Engebr{\aa}ten and Bj{\o}rn Naume and Alexander Foss{\aa} and Kiserud, \{Cecile E.\} and Reinertsen, \{Kristin V.\} and {\AA}slaug Helland and Margit Riis and J{\"u}rgen Geisler and \{Grenaker Aln{\ae}s\}, \{Grethe I.\} and Colonna, \{Sarah V.\} and Couch, \{Fergus J.\} and Angela Cox and Cross, \{Simon S.\} and Daly, \{Mary B.\}",

note = "{\textcopyright} 2021. The Author(s).",

year = "2021",

month = aug,

day = "18",

doi = "10.1186/s13058-021-01450-7",

language = "English",

volume = "23",

pages = "86",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "BioMed Central Ltd.",

number = "1",

}

NBCS Collaborators, ABCTB Investigators, KConFab Investigators & KConFab Investigators 2021, 'Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment', Breast Cancer Research, vol. 23, no. 1, 86, pp. 86. https://doi.org/10.1186/s13058-021-01450-7

Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment. / NBCS Collaborators; ABCTB Investigators; KConFab Investigators et al.
In: Breast Cancer Research, Vol. 23, No. 1, 86, 18.08.2021, p. 86.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

AU - NBCS Collaborators

AU - ABCTB Investigators

AU - KConFab Investigators

AU - Morra, Anna

AU - Escala-Garcia, Maria

AU - Beesley, Jonathan

AU - Keeman, Renske

AU - Canisius, Sander

AU - Ahearn, Thomas U.

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Auer, Paul L.

AU - Augustinsson, Annelie

AU - Beane Freeman, Laura E.

AU - Becher, Heiko

AU - Beckmann, Matthias W.

AU - Behrens, Sabine

AU - Bojesen, Stig E.

AU - Bolla, Manjeet K.

AU - Brenner, Hermann

AU - Brüning, Thomas

AU - Buys, Saundra S.

AU - Caan, Bette

AU - Campa, Daniele

AU - Canzian, Federico

AU - Castelao, Jose E.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Cheng, Ting Yuan David

AU - Clarke, Christine L.

AU - Børresen-Dale, Anne Lise

AU - Sahlberg, Kristine K.

AU - Ottestad, Lars

AU - Kåresen, Rolf

AU - Schlichting, Ellen

AU - Holmen, Marit Muri

AU - Sauer, Toril

AU - Haakensen, Vilde

AU - Engebråten, Olav

AU - Naume, Bjørn

AU - Fosså, Alexander

AU - Kiserud, Cecile E.

AU - Reinertsen, Kristin V.

AU - Helland, Åslaug

AU - Riis, Margit

AU - Geisler, Jürgen

AU - Grenaker Alnæs, Grethe I.

AU - Colonna, Sarah V.

AU - Couch, Fergus J.

AU - Cox, Angela

AU - Cross, Simon S.

AU - Daly, Mary B.

PY - 2021/8/18

Y1 - 2021/8/18

N2 - BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15).RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy.CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.

AB - BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15).RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy.CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.

KW - Breast Neoplasms/drug therapy

KW - Female

KW - Genome-Wide Association Study

KW - Germ-Line Mutation

KW - Humans

KW - Polymorphism, Single Nucleotide

KW - Prognosis

KW - Survival Analysis

UR - https://www.scopus.com/pages/publications/85114653695

U2 - 10.1186/s13058-021-01450-7

DO - 10.1186/s13058-021-01450-7

M3 - Article

C2 - 34407845

SN - 1465-5411

VL - 23

SP - 86

JO - Breast Cancer Research

JF - Breast Cancer Research

IS - 1

M1 - 86

ER -

Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Abstract

UN SDGs

Keywords

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