Overlap of high-risk individuals across family history, genetic & non-genetic breast cancer risk models: Analysis of 180,398 women from European & Asian ancestries

ABCTB Investigators

doi:10.1101/2025.02.27.25323002

Overlap of high-risk individuals across family history, genetic & non-genetic breast cancer risk models: Analysis of 180,398 women from European & Asian ancestries

ABCTB Investigators

Research output: Preprint/Working paper › Preprint

Abstract

BACKGROUND: Breast cancer is multifactorial. Focusing on limited risk factors may miss high-risk individuals.

METHODS: We assessed the performance and overlap of various risk factors in identifying high-risk individuals for invasive breast cancer (BrCa) and ductal carcinoma in situ (DCIS) in 161,849 European-ancestry and 18,549 Asian-ancestry women. Discriminatory ability was evaluated using the area under the receiver operating characteristic curve (AUC). High-risk criteria included: 5-year absolute risk ≥1·66% by the Gail model [GAIL binary]; first-degree family history of breast cancer [FH binary]; 5-year absolute risk ≥1·66% by a 313-variants polygenic risk score [PRS binary]; and carriers of pathogenic variants in breast cancer predisposition genes [PTV binary].

FINDINGS: The 5-year absolute risk by PRS outperformed the Gail model in predicting BrCa (Europeans vs controls: AUC PRS=0·635 [0·632-0·638] vs AUC Gail=0·492 [0·489-0·495]; Asians vs controls: AUC PRS=0·564 [0·556-0·573] vs AUC Gail=0·506 [0·497-0·514]). PRS binary and GAIL binary identified more high-risk European than Asia individuals. High-risk proportions were higher among BrCa (16-26%) and DCIS (20-33%) compared to controls (9-15%) among young Europeans and all Asians. Fewer than 7% of BrCa, 10% of DCIS, and 3% of controls were classified as high-risk by multiple risk classifiers. Overlap between PRS binary and PTV binary was minimal (<0·65% Europeans, <0·15% Asians) compared to the proportion at high risk using PTV binary alone (Europeans: 4·6%, Asians: 4·4%) and PRS binary alone (Europeans: 13·9%, Asians: 8·5%). PRS binary and FH binary uniquely identified 5-6% and 9-11% of young BrCa, respectively.

INTERPRETATION: The incomplete overlap between high-risk individuals identified by PRS binary, GAIL binary, FH binary, and PTV binary highlights the need for a comprehensive approach to breast cancer risk prediction.

Original language	English
Publisher	Cold Spring Harbor Laboratory Press
DOIs	https://doi.org/10.1101/2025.02.27.25323002
Publication status	Published - 3 Mar 2025

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Name	medRxiv
Publisher	Cold Spring Harbor Laboratory Press

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10.1101/2025.02.27.25323002Licence: CC BY-NC-ND

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@techreport{7d68451428724b0f952b1aad5d6747e3,

title = "Overlap of high-risk individuals across family history, genetic & non-genetic breast cancer risk models: Analysis of 180,398 women from European & Asian ancestries",

abstract = "BACKGROUND: Breast cancer is multifactorial. Focusing on limited risk factors may miss high-risk individuals.METHODS: We assessed the performance and overlap of various risk factors in identifying high-risk individuals for invasive breast cancer (BrCa) and ductal carcinoma in situ (DCIS) in 161,849 European-ancestry and 18,549 Asian-ancestry women. Discriminatory ability was evaluated using the area under the receiver operating characteristic curve (AUC). High-risk criteria included: 5-year absolute risk ≥1·66% by the Gail model [GAIL binary]; first-degree family history of breast cancer [FH binary]; 5-year absolute risk ≥1·66% by a 313-variants polygenic risk score [PRS binary]; and carriers of pathogenic variants in breast cancer predisposition genes [PTV binary]. FINDINGS: The 5-year absolute risk by PRS outperformed the Gail model in predicting BrCa (Europeans vs controls: AUC PRS=0·635 [0·632-0·638] vs AUC Gail=0·492 [0·489-0·495]; Asians vs controls: AUC PRS=0·564 [0·556-0·573] vs AUC Gail=0·506 [0·497-0·514]). PRS binary and GAIL binary identified more high-risk European than Asia individuals. High-risk proportions were higher among BrCa (16-26%) and DCIS (20-33%) compared to controls (9-15%) among young Europeans and all Asians. Fewer than 7% of BrCa, 10% of DCIS, and 3% of controls were classified as high-risk by multiple risk classifiers. Overlap between PRS binary and PTV binary was minimal (<0·65% Europeans, <0·15% Asians) compared to the proportion at high risk using PTV binary alone (Europeans: 4·6%, Asians: 4·4%) and PRS binary alone (Europeans: 13·9%, Asians: 8·5%). PRS binary and FH binary uniquely identified 5-6% and 9-11% of young BrCa, respectively. INTERPRETATION: The incomplete overlap between high-risk individuals identified by PRS binary, GAIL binary, FH binary, and PTV binary highlights the need for a comprehensive approach to breast cancer risk prediction. ",

author = "{ABCTB Investigators} and Ho, {Peh Joo} and Loo, {Christine Kim Yan} and Goh, {Meng Huang} and Mustapha Abubakar and Ahearn, {Thomas U} and Andrulis, {Irene L} and Antonenkova, {Natalia N} and Aronson, {Kristan J} and Annelie Augustinsson and Sabine Behrens and Clara Bodelon and Bogdanova, {Natalia V} and Bolla, {Manjeet K} and Kristen Brantley and Hermann Brenner and Helen Byers and Camp, {Nicola J} and Castelao, {Jose E} and Cessna, {Melissa H} and Jenny Chang-Claude and Chanock, {Stephen J} and Georgia Chenevix-Trench and Ji-Yeob Choi and Colonna, {Sarah V} and Kamila Czene and Daly, {Mary B} and Francoise Derouane and Thilo D{\"o}rk and Eliassen, {A Heather} and Christoph Engel and Mikael Eriksson and Evans, {D Gareth} and Olivia Fletcher and Lin Fritschi and Manuela Gago-Dominguez and Genkinger, {Jeanine M} and Geurts-Giele, {Willemina R R} and Gord Glendon and Per Hall and Ute Hamann and Ho, {Cecilia Y S} and Weang-Kee Ho and Hooning, {Maartje J} and Reiner Hoppe and Anthony Howell and Keith Humphreys and Artitaya Lophatananon and Kenneth Muir and Patel, {Alpa V} and Scott, {Christopher G}",

year = "2025",

month = mar,

day = "3",

doi = "10.1101/2025.02.27.25323002",

language = "English",

series = "medRxiv",

publisher = "Cold Spring Harbor Laboratory Press",

address = "United States",

type = "WorkingPaper",

institution = "Cold Spring Harbor Laboratory Press",

}

TY - UNPB

T1 - Overlap of high-risk individuals across family history, genetic & non-genetic breast cancer risk models

T2 - Analysis of 180,398 women from European & Asian ancestries

AU - ABCTB Investigators

AU - Ho, Peh Joo

AU - Loo, Christine Kim Yan

AU - Goh, Meng Huang

AU - Abubakar, Mustapha

AU - Ahearn, Thomas U

AU - Andrulis, Irene L

AU - Antonenkova, Natalia N

AU - Aronson, Kristan J

AU - Augustinsson, Annelie

AU - Behrens, Sabine

AU - Bodelon, Clara

AU - Bogdanova, Natalia V

AU - Bolla, Manjeet K

AU - Brantley, Kristen

AU - Brenner, Hermann

AU - Byers, Helen

AU - Camp, Nicola J

AU - Castelao, Jose E

AU - Cessna, Melissa H

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J

AU - Chenevix-Trench, Georgia

AU - Choi, Ji-Yeob

AU - Colonna, Sarah V

AU - Czene, Kamila

AU - Daly, Mary B

AU - Derouane, Francoise

AU - Dörk, Thilo

AU - Eliassen, A Heather

AU - Engel, Christoph

AU - Eriksson, Mikael

AU - Evans, D Gareth

AU - Fletcher, Olivia

AU - Fritschi, Lin

AU - Gago-Dominguez, Manuela

AU - Genkinger, Jeanine M

AU - Geurts-Giele, Willemina R R

AU - Glendon, Gord

AU - Hall, Per

AU - Hamann, Ute

AU - Ho, Cecilia Y S

AU - Ho, Weang-Kee

AU - Hooning, Maartje J

AU - Hoppe, Reiner

AU - Howell, Anthony

AU - Humphreys, Keith

AU - Lophatananon, Artitaya

AU - Muir, Kenneth

AU - Patel, Alpa V

AU - Scott, Christopher G

PY - 2025/3/3

Y1 - 2025/3/3

N2 - BACKGROUND: Breast cancer is multifactorial. Focusing on limited risk factors may miss high-risk individuals.METHODS: We assessed the performance and overlap of various risk factors in identifying high-risk individuals for invasive breast cancer (BrCa) and ductal carcinoma in situ (DCIS) in 161,849 European-ancestry and 18,549 Asian-ancestry women. Discriminatory ability was evaluated using the area under the receiver operating characteristic curve (AUC). High-risk criteria included: 5-year absolute risk ≥1·66% by the Gail model [GAIL binary]; first-degree family history of breast cancer [FH binary]; 5-year absolute risk ≥1·66% by a 313-variants polygenic risk score [PRS binary]; and carriers of pathogenic variants in breast cancer predisposition genes [PTV binary]. FINDINGS: The 5-year absolute risk by PRS outperformed the Gail model in predicting BrCa (Europeans vs controls: AUC PRS=0·635 [0·632-0·638] vs AUC Gail=0·492 [0·489-0·495]; Asians vs controls: AUC PRS=0·564 [0·556-0·573] vs AUC Gail=0·506 [0·497-0·514]). PRS binary and GAIL binary identified more high-risk European than Asia individuals. High-risk proportions were higher among BrCa (16-26%) and DCIS (20-33%) compared to controls (9-15%) among young Europeans and all Asians. Fewer than 7% of BrCa, 10% of DCIS, and 3% of controls were classified as high-risk by multiple risk classifiers. Overlap between PRS binary and PTV binary was minimal (<0·65% Europeans, <0·15% Asians) compared to the proportion at high risk using PTV binary alone (Europeans: 4·6%, Asians: 4·4%) and PRS binary alone (Europeans: 13·9%, Asians: 8·5%). PRS binary and FH binary uniquely identified 5-6% and 9-11% of young BrCa, respectively. INTERPRETATION: The incomplete overlap between high-risk individuals identified by PRS binary, GAIL binary, FH binary, and PTV binary highlights the need for a comprehensive approach to breast cancer risk prediction.

AB - BACKGROUND: Breast cancer is multifactorial. Focusing on limited risk factors may miss high-risk individuals.METHODS: We assessed the performance and overlap of various risk factors in identifying high-risk individuals for invasive breast cancer (BrCa) and ductal carcinoma in situ (DCIS) in 161,849 European-ancestry and 18,549 Asian-ancestry women. Discriminatory ability was evaluated using the area under the receiver operating characteristic curve (AUC). High-risk criteria included: 5-year absolute risk ≥1·66% by the Gail model [GAIL binary]; first-degree family history of breast cancer [FH binary]; 5-year absolute risk ≥1·66% by a 313-variants polygenic risk score [PRS binary]; and carriers of pathogenic variants in breast cancer predisposition genes [PTV binary]. FINDINGS: The 5-year absolute risk by PRS outperformed the Gail model in predicting BrCa (Europeans vs controls: AUC PRS=0·635 [0·632-0·638] vs AUC Gail=0·492 [0·489-0·495]; Asians vs controls: AUC PRS=0·564 [0·556-0·573] vs AUC Gail=0·506 [0·497-0·514]). PRS binary and GAIL binary identified more high-risk European than Asia individuals. High-risk proportions were higher among BrCa (16-26%) and DCIS (20-33%) compared to controls (9-15%) among young Europeans and all Asians. Fewer than 7% of BrCa, 10% of DCIS, and 3% of controls were classified as high-risk by multiple risk classifiers. Overlap between PRS binary and PTV binary was minimal (<0·65% Europeans, <0·15% Asians) compared to the proportion at high risk using PTV binary alone (Europeans: 4·6%, Asians: 4·4%) and PRS binary alone (Europeans: 13·9%, Asians: 8·5%). PRS binary and FH binary uniquely identified 5-6% and 9-11% of young BrCa, respectively. INTERPRETATION: The incomplete overlap between high-risk individuals identified by PRS binary, GAIL binary, FH binary, and PTV binary highlights the need for a comprehensive approach to breast cancer risk prediction.

U2 - 10.1101/2025.02.27.25323002

DO - 10.1101/2025.02.27.25323002

M3 - Preprint

C2 - 40093266

T3 - medRxiv

BT - Overlap of high-risk individuals across family history, genetic & non-genetic breast cancer risk models

PB - Cold Spring Harbor Laboratory Press

ER -

Overlap of high-risk individuals across family history, genetic & non-genetic breast cancer risk models: Analysis of 180,398 women from European & Asian ancestries

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