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 - 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 - Colonna, Sarah V.

AU - Couch, Fergus J.

AU - Cox, Angela

AU - Cross, Simon S.

AU - Czene, Kamila

AU - Daly, Mary B.

AU - Dennis, Joe

AU - Dörk, Thilo

AU - Dossus, Laure

AU - Dunning, Alison M.

AU - Dwek, Miriam

AU - Eccles, Diana M.

AU - Ekici, Arif B.

AU - Eliassen, A. Heather

AU - Eriksson, Mikael

AU - Evans, D. Gareth

AU - Fasching, Peter A.

AU - Flyger, Henrik

AU - Fritschi, Lin

AU - Gago-Dominguez, Manuela

AU - Nielsen, Sune F.

AU - Nordestgaard, Børge G.

AU - NBCS Collaborators

AU - ABCTB Investigators

AU - kConFab Investigators

N1 - Publisher Copyright: © 2021. The Author(s).

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 cancer-specific survival

KW - Common germline genetic variants

KW - Patient subgroups

KW - Systemic treatment

KW - Tumor biology

U2 - 10.1186/s13058-021-01450-7

DO - 10.1186/s13058-021-01450-7

M3 - Journal article

C2 - 34407845

AN - SCOPUS:85114653695

VL - 23

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 1

M1 - 86

ER -