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Research Articles

Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium

Anna Morra, Audrey Y. Jung, Sabine Behrens, Renske Keeman, Thomas U. Ahearn, Hoda Anton-Culver, Volker Arndt, Annelie Augustinsson, Päivi K. Auvinen, Laura E. Beane Freeman, Heiko Becher, Matthias W. Beckmann, Carl Blomqvist, Stig E. Bojesen, Manjeet K. Bolla, Hermann Brenner, Ignacio Briceno, Sara Y. Brucker, Nicola J. Camp, Daniele Campa, Federico Canzian, Jose E. Castelao, Stephen J. Chanock, Ji-Yeob Choi, Christine L. Clarke; for the ABCTB Investigators, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Douglas F. Easton, Diana M. Eccles, Kathleen M. Egan, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Manuela Gago-Dominguez, Susan M. Gapstur, José A. García-Sáenz, Mia M. Gaudet, Graham G. Giles, Mervi Grip, Pascal Guénel, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Sileny N. Han, Steven N. Hart, Mikael Hartman, Jane S. Heyworth, Reiner Hoppe, John L. Hopper, David J. Hunter, Hidemi Ito, Agnes Jager, Milena Jakimovska, Anna Jakubowska, Wolfgang Janni, Rudolf Kaaks, Daehee Kang, Pooja Middha Kapoor, Cari M. Kitahara, Stella Koutros, Peter Kraft, Vessela N. Kristensen; for the NBCS Collaborators, James V. Lacey, Diether Lambrechts, Loic Le Marchand, Jingmei Li, Annika Lindblom, Jan Lubiński, Michael Lush, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Shivaani Mariapun, Keitaro Matsuo, Dimitrios Mavroudis, Roger L. Milne, Taru A. Muranen, William G. Newman, Dong-Young Noh, Børge G. Nordestgaard, Nadia Obi, Andrew F. Olshan, Håkan Olsson, Tjoung-Won Park-Simon, Christos Petridis, Paul D.P. Pharoah, Dijana Plaseska-Karanfilska, Nadege Presneau, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Emmanouil Saloustros, Elinor J. Sawyer, Andreas Schneeweiss, Lukas Schwentner, Christopher Scott, Mitul Shah, Chen-Yang Shen, Xiao-Ou Shu, Melissa C. Southey, Daniel O. Stram, Rulla M. Tamimi, William Tapper, Rob A.E.M. Tollenaar, Ian Tomlinson, Diana Torres, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Qin Wang, Sophia S. Wang, Justin A. Williams, Robert Winqvist, Alicja Wolk, Anna H. Wu, Keun-Young Yoo, Jyh-Cherng Yu, Wei Zheng, Argyrios Ziogas, Xiaohong R. Yang, A. Heather Eliassen, Michelle D. Holmes, Montserrat García-Closas, Soo Hwang Teo, Marjanka K. Schmidt and Jenny Chang-Claude
DOI: 10.1158/1055-9965.EPI-20-0924 Published April 2021

Article Figures & Data

Tables

  • Table 1.

    Characteristics of the breast cancer population based on data from 67 population-based and hospital-based studies.

    CharacteristicsOverallER+ER−Luminal A–likeLuminal B HER2-negative–likeLuminal B HER2–likeHER2-enriched–likeTriple negative
    Number of womena, n121,43581,88522,25733,6338,9157,9764,0258,856
    Number of overall deaths, n16,8909,9414,5873,0391,4901,1278491,858
    Number of breast cancer–specific deaths, n8,5544,6542,5111,256792613458978
    Clinical risk factors
    Age at diagnosis, y, median (IQR)57 (48–65)58 (49–66)53 (44–62)59 (50–67)56 (46–65)54 (45–64)54 (46–62)53 (44–63)
    Missing, n56
    Year of diagnosis, n (%)
     1961–1975264 (0.2)98 (0.1)105 (0.5)24 (0.1)3 (0.0)16 (0.2)19 (0.5)59 (0.7)
     1976–19904,271 (3.6)1,707 (2.2)931 (4.3)725 (2.2)273 (3.1)144 (1.8)188 (4.7)433 (5)
     1991–200568,872 (58.8)44,075 (55.6)13,425 (61.4)13,776 (41.8)3,559 (40.7)3,694 (47.4)2,029 (51.1)4,351 (49.8)
     2006–201943,725 (37.3)33,414 (42.1)7,406 (33.9)18,465 (56.0)4,905 (56.1)3,943 (50.6)1,734 (43.7)3,898 (44.6)
     Missing, n4,303
    Ethnicity, n (%)
     European91,981 (84)62,984 (84.7)15,479 (75.4)26,087 (85.8)6,534 (82.5)5,773 (77.2)2,617 (68.3)6,078 (76.7)
     Hispanic American866 (0.8)554 (0.7)179 (0.9)225 (0.7)46 (0.6)78 (1.0)26 (0.7)104 (1.3)
     African1,015 (0.9)461 (0.6)435 (2.1)135 (0.4)52 (0.7)58 (0.8)52 (1.4)261 (3.3)
     Asian13,139 (12.0)8,397 (11.3)3,991 (19.5)3,033 (10.0)1,090 (13.8)1,416 (18.9)1,061 (27.7)1,263 (15.9)
     Other2,516 (2.3)1,929 (2.6)433 (2.1)936 (3.1)198 (2.5)157 (2.1)77 (2.0)217 (2.7)
     Missing, n11,918
    Tumor size, n (%)
     ≤2 cm49,887 (61.5)36,848 (63.2)7,746 (50.3)17,873 (65.5)3,339 (46.0)3,055 (52.2)1,305 (44.6)3,147 (48.2)
     >2 and ≤5 cm27,665 (34.1)19,024 (32.7)6,706 (43.5)8,358 (30.6)3,449 (47.5)2,478 (42.4)1,374 (47.0)3,016 (46.2)
     >5 cm3,603 (4.4)2,388 (4.1)948 (6.2)1,067 (3.9)472 (6.5)317 (5.4)245 (8.4)371 (5.7)
     Missing, n40,280
    Nodal status, n (%)
     Negative59,569 (62.1)43,212 (62.0)11,156 (59.6)20,203 (63.5)4,352 (51.4)3,930 (54.6)1,795 (50.5)4,874 (62.7)
     Positive36,395 (37.9)26,476 (38.0)7,551 (40.4)11,609 (36.5)4,112 (48.6)3,264 (45.4)1,759 (49.5)2,905 (37.3)
     Missing, n25,471
    Tumor stage, n (%)
     I34,157 (44.5)25,351 (45.9)5,147 (34.6)12,222 (47.7)1,903 (29.4)2,209 (37.5)839 (28.0)2,143 (34.6)
     II34,696 (45.2)24,498 (44.3)7,663 (51.5)11,154 (43.5)3,567 (55.2)2,838 (48.1)1,561 (52.1)3,314 (53.5)
     III7,990 (10.4)5,411 (9.8)2,056 (13.8)2,243 (8.8)997 (15.4)850 (14.4)597 (19.9)742 (12)
     Missing, n44,592
    Grade, n (%)
     Grade 117,919 (19.2)15,546 (22.6)800 (4.5)10,130 (30.1)–672 (9.3)62 (1.8)279 (3.7)
     Grade 245,065 (48.3)37,347 (54.3)4,614 (26.1)23,503 (69.9)–3,397 (47.0)918 (26.4)1,709 (22.4)
     Grade 330,231 (32.4)15,852 (23.1)12,253 (69.4)–8,915 (100)3,151 (43.6)2,498 (71.8)5,651 (74)
     Missing, n28,220
    Surgery, n (%)
     No surgery1,160 (1.6)437 (0.8)152 (1.1)108 (0.4)26 (0.4)37 (0.7)22 (0.8)35 (0.6)
     Breast conserving surgery29,530 (40.9)22,923 (44.4)4,971 (36.8)11,551 (47.5)2,371 (36.7)2,188 (40.3)775 (28.9)2,168 (38.8)
     Mastectomy22,785 (31.6)16,032 (31.1)5,237 (38.7)6,730 (27.7)2,156 (33.4)2,092 (38.5)1,378 (51.3)1,821 (32.6)
     Type unknown18,677 (25.9)12,187 (23.6)3,155 (23.3)5,942 (24.4)1,907 (29.5)1,111 (20.5)510 (19.0)1,561 (27.9)
     Missing, n49,283
    Radiotherapy, n (%)
     No18,563 (27.6)12,525 (26.3)3,684 (28.8)5,268 (25.7)1,250 (22.8)1,353 (26.1)801 (30.8)1,217 (25.7)
     Yes48,616 (72.4)35,037 (73.7)9,111 (71.2)15,241 (74.3)4,243 (77.2)3,826 (73.9)1,797 (69.2)3,510 (74.3)
     Missing, n54,256
    Chemotherapy, n (%)
     No27,667 (41.0)21,895 (45.9)2,310 (16.5)11,812 (53.0)1,632 (25.3)1,203 (21.9)328 (11.3)864 (15.2)
     Yes39,815 (59.0)25,796 (54.1)11,729 (83.5)10,465 (47.0)4,820 (74.7)4,294 (78.1)2,584 (88.7)4,816 (84.8)
     Missing, n53,953
    Endocrine therapy, n (%)
     No19,688 (28.6)7,869 (15.6)9,232 (77.4)3,629 (15.5)781 (13.1)978 (17.2)2,209 (88.0)3,907 (84.5)
     Yes49,163 (71.4)42,682 (84.4)2,689 (22.6)19,859 (84.5)5,175 (86.9)4,702 (82.8)302 (12.0)717 (15.5)
     Missing, n52,584
    Trastuzumab, n (%)
     No50,545 (95.1)33,531 (95.4)10,337 (91.6)16,909 (99.7)4,849 (99.4)2,341 (60.9)1,306 (61.9)5,104 (99.6)
     Yes2,598 (4.9)1,607 (4.6)952 (8.4)53 (0.3)30 (0.6)1,505 (39.1)805 (38.1)18 (0.4)
     Missing, n68,292
    Reproductive and lifestyle risk factors
    Age at menarche, median (IQR)13 (12–14)
     Missing, n35,35513 (12–14)13 (12–14)13 (12–14)13 (12–14)13 (12–14)13 (12–14)13 (12–14)
     Parity, median (IQR)2 (1–3)2 (1–3)2 (1–3)2 (1–3)2 (1–3)2 (1–3)2 (1–3)2 (1–3)
     Nulliparous, n (%)12,932 (14.0)8,971 (14.2)2,066 (12.9)3,633 (14.1)934 (15.0)870 (15.0)384 (13.5)787 (12.8)
     Parous, n (%)79,415 (86.0)54,292 (85.8)13,955 (87.1)22,162 (85.9)5,291 (85.0)4,928 (85.0)2,456 (86.5)5,376 (87.2)
     Missing, n29,088
    Age at first full-term pregnancyb, median (IQR)25 (22–28)
     Missing, n50,96525 (22–28)24 (21–28)24 (21–28)25 (22–28)25 (22–29)25 (22–28)24 (21–27)
    Breastfeeding, n (%)
     Never24,906 (39.5)16,660 (38.4)4,476 (39.9)7,039 (39.2)1,754 (41.9)1,716 (40.2)831 (41.3)1,796 (42.5)
     Ever38,195 (60.5)26,730 (61.6)6,734 (60.1)10,912 (60.8)2,435 (58.1)2,555 (59.8)1,181 (58.7)2,433 (57.5)
     Missing, n58,334
     Duration in moc, median (IQR)7 (3–15)7 (3–15)7 (3–16)7 (3–15)7 (3–15)7 (3–15)8 (3–17)6 (3–15)
     Missing, n68,870
    Time since last full-term birthb,,† n (%)
     ≥10 y29,200 (64.2)18,626 (63.3)5,795 (65.7)7,901 (65.5)1,822 (62.0)1,986 (63.0)1,096 (67.8)2,303 (67.3)
     5–10 y1,926 (4.2)1,115 (3.8)466 (5.3)362 (3.0)103 (3.5)177 (5.6)65 (4.0)163 (4.8)
     0–5 y1,179 (2.6)601 (2.0)393 (4.5)161 (1.3)70 (2.4)101 (3.2)51 (3.2)130 (3.8)
     Missing, n75,975
    Oral contraceptives, n (%)
     Never use29,677 (44.5)20,263 (45.0)5,090 (43.4)8,398 (46.4)1,967 (45.1)2,018 (43.6)1,096 (48.6)1,923 (43.2)
     Ever use37,070 (55.5)24,799 (55.0)6,629 (56.6)9,701 (53.6)2,395 (54.9)2,608 (56.4)1,159 (51.4)2,533 (56.8)
     Missing, n54,688
    MHT‡, n (%)
     Never use, postmenopausal28,534 (37.1)20,062 (38.3)5,088 (37.1)9,129 (41.4)2,315 (42.8)2,044 (39.0)1,108 (43.3)2,115 (39.0)
      Formere use estrogen therapy1,394 (1.8)1,041 (2.0)195 (1.4)397 (1.8)81 (1.5)77 (1.5)40 (1.6)91 (1.7)
      Formere use estrogen+progestin1,414 (1.8)1,035 (2.0)246 (1.8)490 (2.2)91 (1.7)94 (1.8)49 (1.9)124 (2.3)
      Formere use (unknown type)5,972 (7.8)4,366 (8.3)912 (6.7)1,960 (8.9)481 (8.9)291 (5.6)164 (6.4)405 (7.5)
      Currentf use estrogen therapy2,175 (2.8)1,456 (2.8)272 (2.0)562 (2.5)103 (1.9)129 (2.5)48 (1.9)119 (2.2)
      Currentf use estrogen+progestin3,755 (4.9)2,689 (5.1)458 (3.3)1,251 (5.7)181 (3.3)287 (5.5)79 (3.1)205 (3.8)
      Currentf use (unknown type)5,854 (7.6)4,398 (8.4)647 (4.7)1,896 (8.6)300 (5.5)247 (4.7)102 (4.0)236 (4.4)
     Missing, n44,547
    BMId, median (IQR)25 (23–28)25 (23–29)25 (22–28)25 (23–29)26 (23–29)25 (22–28)25 (22–28)25 (23–29)
     18.5–25 kg/m2, n (%)43,302 (47.4)29,382 (46.9)7,716 (47.9)11,545 (44.2)2,813 (42.8)2,962 (49.4)1,428 (49.4)2,925 (45.8)
     <18.5 kg/m2, n (%)1,657 (1.8)1,103 (1.8)355 (2.2)405 (1.6)117 (1.8)143 (2.4)72 (2.5)132 (2.1)
     25–30 kg/m2, n (%)29,960 (32.8)20,776 (33.2)5,134 (31.9)8,939 (34.2)2,210 (33.6)1,857 (31.0)933 (32.3)2,041 (32.0)
     >=30 kg/m2, n (%)16,435 (18.0)11,353 (18.1)2,891 (18.0)5,228 (20.0)1,430 (21.8)1,034 (17.2)459 (15.9)1,284 (20.1)
     Missing, n30,081
     Adult height, median (IQR)163 (158–168)163 (159–168)163 (158–168)163 (159–168)163 (158–168)163 (158–168)162 (157–167)163 (158–168)
     Missing, n33,481
    Smoking, n (%)
     Never39,512 (59.0)27,175 (59.3)7,352 (63.3)11,767 (60.1)2,795 (62.4)2,961 (64.3)1,581 (68.7)2,856 (64.0)
     Formerg17,407 (26.0)12,082 (26.3)2,424 (20.9)4,954 (25.3)1,093 (24.4)1,069 (23.2)387 (16.8)903 (20.2)
     Currenth10,073 (15.0)6,605 (14.4)1,840 (15.8)2,850 (14.6)589 (13.2)575 (12.5)332 (14.4)701 (15.7)
     Missing, n54,443
     Pack-years of smoking
      Former smokersg, median (IQR)0.8 (0.3–1.8)0.8 (0.3–1.8)0.7 (0.2–1.6)0.9 (0.3–1.9)0.8 (0.2–1.8)0.7 (0.2–1.8)0.6 (0.2–1.7)0.7 (0.2–1.6)
      Current smokersh, median (IQR)1.9 (0.9–3.1)1.9 (1.0–3.1)1.5 (0.7–2.6)2.0 (0.9–3.2)2.0 (1.0–3.1)1.6 (0.7–2.5)1.6 (0.8–2.7)1.5 (0.6–2.6)
     Missing, n62,214
    Alcohol consumptionh
     g/wk, median (IQR)14.7 (0.0–57.3)16.0 (0.0–59.5)10.8 (0.0–50.7)12.0 (0.0–51.8)12.0 (0.0–49.7)15.0 (0.0–60.0)6.0 (0.0–48.3)6.0 (0.0–45.0)
     Missing, n100,522
    Cumulative alcohol consumption
     g/d, median (IQR)1.9 (0.0–7.9)2.0 (0.0–8.2)1.1 (0.0–6.1)2.0 (0.0–8.4)1.7 (0.0–7.0)2.1 (0.0–7.8)0.8 (0.0–5.6)1.0 (0.0–5.7)
     Missing, n102,451
    Physical activityh,i, median (IQR)3 (1–8)3 (1–9)3 (1–8)5 (1–11)4 (2–11)4 (1–9)4 (1–9)4 (1–10)
     <1.8 hours/wk, n (%)7,103 (33.3)4,643 (31.6)1,043 (31.1)1,564 (27.1)305 (24.6)437 (28.2)222 (29.1)418 (31.0)
     ≥1.8 – <5.5 hours/wk, n (%)7,063 (33.1)4,679 (31.9)1,106 (33.0)1,545 (26.8)424 (34.2)491 (31.7)231 (30.4)382 (28.3)
     ≥5.5 hours/wk, n (%)7,154 (33.6)5,363 (36.5)1,205 (35.9)2,656 (46.1)510 (41.2)619 (40.1)308 (40.5)549 (40.7)
     Missing, n100,115

    • Note: Percentages shown in the table might not sum up to 100% due to rounding.

    • ↵aNumbers for subtypes do not add to total due to missing.

    • ↵bFor parous women only.

    • ↵cFor women who breastfed only.

    • ↵dBMI at interview.

    • ↵eMore than 6 mo before diagnosis.

    • ↵fAt diagnosis or within 6 mo before diagnosis.

    • ↵gMore than 1 year before diagnosis.

    • ↵hAt diagnosis or within 1 year before diagnosis.

    • ↵iCategories based on the tertiles of the observed distribution of the variable.

    • †Numbers are given for parous women, excluding those who had a post-diagnosis last full-term birth, while percentages are computed based on all women with non-missing values, including nulliparous and women who had a post-diagnosis full-term birth.

    • ‡Numbers are given for postmenopausal women, while percentages are computed based on all women with non-missing values, including pre-perimenopausal women.

  • Table 2.

    Associations between individual risk factors and 10-year all-cause mortality by ER status and intrinsic-like subtype based on the imputed datasets.

    OverallER+ER−Luminal A–likeLuminal B HER2-negative–likeLuminal B HER2-positive-likeHER2-enriched–likeTriple negative
    Risk factorP HR (95% CI)P HR (95% CI)P HR (95% CI)P HR (95% CI)P HR (95% CI)P HR (95% CI)P HR (95% CI)P HR (95% CI)
    Age at menarche, per 1 year increase2.3E-015.9E-018.0E-029.1E-016.9E-012.3E-012.4E-012.2E-01
    1.02 (1.00–1.04)1.01 (0.99–1.03)1.03 (1.00–1.06)1.00 (0.98–1.03)1.01 (0.98–1.04)1.03 (0.99–1.07)1.04 (0.99–1.09)1.03 (0.99–1.07)
    Parity1.4E-031.3E-041.5E-017.6E-041.4E-016.2E-019.1E-015.6E-02
     0Ref.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
     10.87 (0.79–0.96)0.87 (0.79–0.97)0.85 (0.73–0.98)0.86 (0.75–0.99)0.88 (0.76–1.02)0.91 (0.75–1.11)0.87 (0.66–1.15)0.80 (0.67–0.96)
     20.86 (0.77–0.96)0.83 (0.74–0.93)0.92 (0.80–1.06)0.81 (0.70–0.93)0.86 (0.73–1.01)0.87 (0.71–1.06)1.00 (0.76–1.31)0.84 (0.71–1.00)
     30.90 (0.82–1.00)0.88 (0.79–0.98)0.92 (0.79–1.06)0.86 (0.76–0.98)0.90 (0.77–1.06)0.92 (0.74–1.14)0.97 (0.75–1.25)0.86 (0.71–1.05)
     4+0.97 (0.88–1.06)0.92 (0.83–1.02)1.05 (0.90–1.23)0.89 (0.78–1.02)0.94 (0.79–1.12)1.01 (0.80–1.29)1.06 (0.80–1.41)0.99 (0.80–1.24)
    Age at FFTPa, y1.9E-142.5E-111.5E-024.3E-072.6E-024.3E-035.7E-013.9E-02
     <20Ref.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
     20–<250.88 (0.83–0.94)0.86 (0.80–0.93)0.93 (0.83–1.04)0.84 (0.76–0.93)0.92 (0.80–1.07)0.83 (0.69–1.00)0.94 (0.71–1.23)0.91 (0.79–1.04)
     25–<300.82 (0.76–0.87)0.80 (0.73–0.86)0.87 (0.77–0.99)0.78 (0.70–0.87)0.82 (0.71–0.95)0.79 (0.65–0.97)0.89 (0.67–1.17)0.86 (0.73–1.01)
     ≥300.79 (0.73–0.86)0.78 (0.71–0.87)0.82 (0.71–0.96)0.79 (0.68–0.91)0.83 (0.70–1.00)0.73 (0.58–0.91)0.80 (0.58–1.10)0.82 (0.69–0.98)
    Time since last full-term birtha, y9.5E-024.5E-047.5E-018.8E-037.6E-012.0E-018.1E-016.4E-01
     ≥10Ref.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
     ≥5–<101.07 (0.96–1.19)1.15 (1.01–1.33)0.95 (0.81–1.12)1.16 (0.98–1.38)1.10 (0.83–1.45)1.17 (0.92–1.50)0.99 (0.73–1.34)0.88 (0.70–1.10)
     >0–<51.21 (1.03–1.41)1.36 (1.12–1.65)1.02 (0.82–1.26)1.55 (1.08–2.24)1.11 (0.83–1.48)1.28 (0.86–1.91)1.07 (0.76–1.51)0.93 (0.68–1.27)
    Breastfeedinga
    2.4E-015.4E-011.2E-014.7E-017.2E-014.1E-016.7E-011.1E-01
     Per 6 mo increase1.02 (0.99–1.04)1.01 (0.99–1.04)1.03 (1.00–1.06)1.01 (0.99–1.04)1.01 (0.97–1.06)1.02 (0.99–1.06)1.01 (0.97–1.05)1.03 (1.00–1.06)
    7.5E-016.2E-019.1E-015.1E-019.1E-017.3E-019.5E-019.0E-01
     Ever vs. never0.97 (0.85–1.10)0.95 (0.84–1.08)1.01 (0.84–1.23)0.93 (0.81–1.08)0.99 (0.83–1.17)0.94 (0.76–1.17)0.99 (0.75–1.31)1.02 (0.85–1.22)
    BMI, kg/m2
     All women2.2E-025.9E-032.8E-015.9E-031.4E-011.6E-016.4E-013.2E-01
      18.5–<25Ref.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
      <18.51.34 (0.96–1.87)1.41 (1.03–1.95)1.24 (0.82–1.87)1.56 (1.12–2.18)1.32 (0.80–2.18)1.17 (0.71–1.94)1.22 (0.69–2.14)1.20 (0.78–1.83)
      25–<301.05 (0.92–1.21)1.06 (0.94–1.20)1.03 (0.86–1.24)1.03 (0.90–1.18)1.07 (0.92–1.26)1.13 (0.96–1.33)0.98 (0.80–1.20)1.04 (0.86–1.27)
      ≥301.23 (1.09–1.40)1.24 (1.10–1.39)1.20 (1.01–1.43)1.24 (1.09–1.41)1.22 (1.04–1.42)1.23 (1.01–1.50)1.19 (0.92–1.55)1.21 (1.02–1.43)
     Postmenopausal women2.5E-073.4E-062.0E-021.2E-051.2E-012.4E-015.3E-011.2E-01
      18.5–<25Ref.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
      <18.51.53 (1.30–1.80)1.57 (1.30–1.89)1.46 (1.09–1.95)1.73 (1.41–2.12)1.45 (0.89–2.38)1.16 (0.67–2.00)1.42 (0.80–2.50)1.48 (1.03–2.13)
      25–<301.05 (0.97–1.12)1.06 (0.97–1.15)1.02 (0.92–1.12)1.02 (0.92–1.12)1.09 (0.94–1.26)1.16 (0.95–1.42)0.95 (0.75–1.20)1.02 (0.89–1.17)
      ≥301.20 (1.12–1.29)1.22 (1.12–1.33)1.15 (1.02–1.29)1.21 (1.09–1.35)1.20 (1.00–1.44)1.20 (0.97–1.48)1.19 (0.92–1.53)1.14 (0.98–1.33)
     Pre/perimenopausal women5.4E-015.3E-016.9E-016.4E-016.2E-016.2E-019.1E-016.7E-01
      18.5–<25Ref.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
      <18.51.08 (0.53–2.21)1.14 (0.54–2.41)1.03 (0.49–2.19)1.17 (0.49–2.80)1.17 (0.54–2.52)1.17 (0.46–2.95)1.02 (0.41–2.55)0.90 (0.36–2.22)
      25–<301.07 (0.76–1.49)1.06 (0.77–1.48)1.06 (0.72–1.57)1.08 (0.70–1.66)1.04 (0.76–1.41)1.06 (0.76–1.49)1.02 (0.71–1.47)1.09 (0.68–1.74)
      ≥301.32 (0.94–1.85)1.32 (0.96–1.82)1.30 (0.88–1.94)1.36 (0.87–2.12)1.28 (0.96–1.72)1.34 (0.94–1.92)1.18 (0.75–1.88)1.35 (0.90–2.04)
    Adult height, per 5 cm increase3.7E-014.6E-013.0E-014.1E-016.7E-016.4E-013.4E-014.4E-01
    0.97 (0.92–1.02)0.97 (0.91–1.03)0.97 (0.92–1.02)0.97 (0.91–1.03)0.98 (0.91–1.05)0.97 (0.90–1.05)0.95 (0.87–1.03)0.97 (0.92–1.03)
    Oral contraceptive use1.6E-047.8E-042.6E-028.9E-042.6E-011.5E-012.7E-015.9E-02
     Ever vs. never0.88 (0.84–0.93)0.89 (0.84–0.94)0.88 (0.80–0.96)0.87 (0.81–0.93)0.91 (0.81–1.03)0.89 (0.79–1.01)0.90 (0.77–1.04)0.88 (0.78–0.98)
    MHT0.0E+000.0E+003.0E-090.0E+006.2E-053.1E-043.9E-023.5E-03
     Never use, postmenopausalRef.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
     Formerb use of ET0.73 (0.64–0.84)0.75 (0.65–0.88)0.67 (0.48–0.93)0.78 (0.64–0.94)0.68 (0.49–0.94)0.75 (0.50–1.13)0.60 (0.27–1.31)0.71 (0.46–1.10)
     Formerb use of EPT0.81 (0.70–0.93)0.80 (0.67–0.95)0.89 (0.68–1.18)0.75 (0.57–0.99)0.86 (0.58–1.27)0.77 (0.49–1.19)0.97 (0.55–1.70)0.93 (0.64–1.35)
     Formerb use (unknown type)0.80 (0.75–0.85)0.79 (0.74–0.85)0.81 (0.71–0.94)0.78 (0.70–0.86)0.82 (0.68–1.01)0.79 (0.63–0.99)0.87 (0.66–1.15)0.80 (0.68–0.94)
     Currentc use of ET0.70 (0.61–0.79)0.68 (0.59–0.79)0.75 (0.58–0.97)0.73 (0.60–0.88)0.64 (0.42–0.97)0.64 (0.42–0.95)0.53 (0.29–0.99)0.83 (0.59–1.17)
     Currentc use of EPT0.58 (0.52–0.65)0.59 (0.52–0.67)0.56 (0.45–0.70)0.59 (0.50–0.70)0.57 (0.40–0.82)0.55 (0.40–0.76)0.53 (0.34–0.84)0.64 (0.48—0.85)
     Currentc use (unknown type)0.75 (0.69–0.82)0.72 (0.65–0.80)0.87 (0.71–1.06)0.72 (0.64–0.82)0.70 (0.56–0.88)0.72 (0.53–0.99)0.81 (0.54–1.23)0.96 (0.73–1.27)
    Smoking0.0E+000.0E+003.5E-030.0E+003.5E-033.0E-021.6E-014.8E-02
     NeverRef.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
     Formerd1.01 (0.97–1.05)1.04 (0.98–1.09)0.97 (0.88–1.06)1.05 (0.98–1.13)0.99 (0.89–1.12)1.00 (0.88–1.14)1.07 (0.86–1.33)0.94 (0.83–1.05)
     Currente1.38 (1.30–1.45)1.46 (1.37–1.56)1.20 (1.10–1.32)1.59 (1.48–1.71)1.31 (1.14–1.50)1.28 (1.09–1.50)1.28 (1.04–1.59)1.20 (1.04–1.37)
    No. of pack-years of smoking, per 101.2E-031.2E-033.0E-035.0E-042.2E-021.9E-022.2E-022.2E-02
    units increase1.11 (1.06–1.15)1.12 (1.07–1.17)1.08 (1.04–1.12)1.13 (1.08–1.18)1.10 (1.03–1.16)1.09 (1.03–1.15)1.10 (1.03–1.17)1.07 (1.03–1.12)
    Alcohol consumptione, per 10 g/wk8.8E-019.0E-018.8E-019.9E-018.4E-017.5E-019.1E-018.1E-01
    1.01 (0.99–1.01)1.00 (0.99–1.01)1.00 (0.99–1.01)1.00 (0.99–1.01)1.00 (0.99–1.01)1.00 (0.98–1.01)1.00 (0.99–1.02)1.00 (0.98–1.01)
    Cumulative alcohol consumption,8.0E-017.8E-018.7E-017.5E-019.0E-019.1E-016.9E-019.1E-01
    per 10 g/d1.01 (0.96–1.06)1.01 (0.96–1.06)1.01 (0.96–1.06)1.01 (0.96–1.07)1.01 (0.94–1.08)1.01 (0.95–1.06)1.02 (0.96–1.08)1.00 (0.94–1.07)
    Physical activitye,f, hours/wk8.3E-029.6E-028.2E-021.1E-012.1E-018.4E-036.1E-021.4E-01
     <1.8Ref.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
     ≥ 1.8–<5.50.80 (0.38–1.68)0.80 (0.38–1.70)0.79 (0.38–1.65)0.77 (0.33–1.80)0.85 (0.40–1.81)0.84 (0.55–1.28)0.87 (0.52–1.46)0.76 (0.29–1.97)
     ≥5.50.42 (0.21–0.85)0.42 (0.20–0.88)0.42 (0.20–0.85)0.40 (0.18–0.89)0.47 (0.21–1.06)0.44 (0.27–0.71)0.46 (0.25–0.87)0.40 (0.18–0.90)

    • Note: All the analyses were stratified by study and adjusted for lymph nodes status, tumor size, tumor grade and (neo)adjuvant systemic treatment. Age of the patients was used as time scale. Reported P values (P) are from likelihood ratio tests comparing a model with and without a particular risk factor and are adjusted for multiple testing using the Benjamini-Hochberg method for false discovery rate (FDR) control on 136 tests. Heterogeneity test by subtype is shown in Table 3. Numbers of patients and events included in the corresponding complete-case analyses are shown in Supplementary Figs. S1 (overall), S3 (ER+), S5 (ER−), S7 (Luminal A–like), S9 (Luminal B-HER2-negative–like), S11 (Luminal B-HER2-positive-like), S13 (HER2-enriched), and S15 (triple negative).

    • Abbreviations: ET: estrogen therapy; EPT: combined estrogen and progestin therapy.

    • ↵aAssociation estimated in parous women.

    • ↵bMore than 6 mo before diagnosis.

    • ↵cAt diagnosis or within 6 mo before diagnosis.

    • ↵dMore than 1 year before diagnosis.

    • ↵eAt diagnosis or within 1 year before diagnosis.

    • ↵fCategories based on the tertiles of the observed distribution of the variable.

  • Table 3.

    Heterogeneity tests of the associations between risk factors and outcomes (10-year all-cause mortality and breast cancer–specific mortality), by ER status and by intrinsic-like subtype.

    All-cause mortalityBreast cancer–specific mortality
    ER statusIntrinsic-like subtypeeER statusIntrinsic-like subtypee
    Risk factorPPPP
    Age at menarche6.7E-018.6E-017.2E-011.0E+00
    Parity8.1E-011.0E+007.2E-011.0E+00
    Age at FFTPa6.7E-011.0E+007.2E-011.0E+00
    Time since last full-term birtha8.5E-011.0E+005.4E-013.3E-01
    Breastfeedinga7.8E-019.7E-011.0E+001.0E+00
    Duration of breastfeedinga7.8E-011.0E+001.0E+001.0E+00
    BMI (all women)1.0E+001.0E+001.0E+001.0E+00
    BMI (postmenopausal women)1.0E+001.0E+001.0E+001.0E+00
    BMI (pre/perimenopausal women)1.0E+001.0E+001.0E+001.0E+00
    Height1.0E+001.0E+001.0E+001.0E+00
    Oral contraceptive use6.7E-016.7E-017.2E-011.0E+00
    MHTb,c1.0E+008.1E-011.0E+001.0E+00
    Smoking6.7E-016.7E-011.0E+001.0E+00
    No. of pack-years of smoking6.7E-016.7E-011.0E+001.0E+00
    Alcohol consumptiond1.0E+001.0E+001.0E+001.0E+00
    Cumulative alcohol consumption1.0E+001.0E+001.0E+001.0E+00
    Physical activityd1.0E+001.0E+001.0E+001.0E+00

    • Note: Reported P values come from a likelihood ratio test comparing a model including the ER status/subtype variable and an interaction term between such variable and a specific risk factor, with a model without the interaction term. ER negative was used as the reference category for ER status and luminal A as the reference category for the subtype variable. P values are adjusted for multiple testing using the Benjamini–Hochberg method for false discovery rate (FDR) control on 34 tests for each endpoint of interest (all-cause and breast cancer–specific mortality). All models have been stratified by study and adjusted for lymph nodes status, tumor size, tumor grade, and (neo)adjuvant systemic treatment. Age of the patients was used as time scale.

    • ↵aAssociation estimated in parous women.

    • ↵bFormer use of MHT was more than 6 mo before diagnosis.

    • ↵cCurrent use of MHT was at diagnosis or within 6 mo before diagnosis.

    • ↵dAt diagnosis or within 1 year before diagnosis.

    • ↵eDefinition of intrinsic-like subtype follows Goldhirsch et al. 2011 as in Tables 2 and 4.

  • Table 4.

    Associations between individual risk factors and 10-year breast cancer–specific mortality by ER status and intrinsic-like subtype based on the imputed datasets.

    OverallER+ER−Luminal A–likeLuminal B HER2-negative–likeLuminal B HER2–likeHER2-enriched–likeTriple negative
    Risk factorP HR (95% CI)P HR (95% CI)P HR (95% CI)P HR (95% CI)P HR (95% CI)P HR (95% CI)P HR (95% CI)P HR (95% CI)
    Age at menarche, per 1 year increase2.0E-016.1E-018.0E-026.7E-019.2E-014.8E-012.8E-014.8E-01
    1.02 (1.00–1.05)1.01 (0.99–1.04)1.04 (1.01–1.08)1.02 (0.98–1.05)1.00 (0.96—1.04)1.04 (0.99–1.09)1.06 (1.00–1.11)1.03 (0.99–1.08)
    Parity6.3E-013.3E-017.1E-017.8E-015.4E-011.0E+009.6E-018.7E-01
     0Ref.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
     10.95 (0.87–1.04)0.94 (0.85–1.05)0.95 (0.80–1.12)0.96 (0.82–1.13)0.87 (0.73–1.04)1.04 (0.78–1.39)0.92 (0.68–1.23)0.92 (0.73–1.16)
     20.93 (0.86–1.02)0.88 (0.80–0.97)1.03 (0.88–1.21)0.89 (0.76–1.03)0.87 (0.74–1.03)0.96 (0.75–1.22)1.04 (0.77–1.40)0.98 (0.80–1.20)
     30.98 (0.89–1.07)0.96 (0.86–1.06)1.00 (0.83–1.19)0.97 (0.83–1.14)0.90 (0.75–1.08)1.02 (0.78–1.34)1.05 (0.78–1.41)0.95 (0.75–1.19)
     4+1.06 (0.95–1.19)0.98 (0.86–1.11)1.21 (1.01–1.46)1.01 (0.85–1.21)0.96 (0.76–1.22)1.01 (0.73–1.40)1.17 (0.79–1.74)1.17 (0.90–1.52)
    Age at FFTPa, y5.0E-052.8E-035.2E-012.0E-012.6E-016.1E-017.2E-017.6E-01
     <20Ref.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
     20–<250.90 (0.82–0.98)0.88 (0.78–0.98)0.95 (0.82–1.08)0.87 (0.75–1.01)0.89 (0.73–1.08)0.88 (0.67–1.15)0.92 (0.67–1.26)0.95 (0.80–1.13)
     25–<300.86 (0.79–0.94)0.85 (0.76–0.96)0.91 (0.79–1.05)0.87 (0.73–1.04)0.81 (0.66–0.99)0.86 (0.65–1.12)0.85 (0.63–1.14)0.91 (0.76–1.10)
     ≥300.83 (0.76–0.91)0.82 (0.72–0.93)0.87 (0.74–1.03)0.83 (0.68–1.00)0.82 (0.65–1.03)0.81 (0.59–1.10)0.81 (0.55–1.18)0.88 (0.70–1.11)
    Time since last full-term birtha, y4.6E-022.2E-047.7E-015.5E-036.7E-014.1E-018.7E-016.5E-01
     ≥10Ref.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
     ≥5–<101.10 (0.96–1.27)1.24 (1.07–1.44)0.92 (0.73–1.18)1.25 (1.03–1.53)1.16 (0.90–1.51)1.23 (0.91–1.66)1.05 (0.67–1.65)0.82 (0.59–1.14)
     >0–< 51.28 (1.11–1.49)1.49 (1.22–1.81)1.03 (0.83–1.29)1.79 (1.27–2.51)1.21 (0.85–1.70)1.37 (0.95–1.99)1.14 (0.75–1.74)0.90 (0.65–1.24)
    Breastfeedinga
    4.6E-015.4E-014.1E-014.6E-017.2E-017.2E-016.8E-014.8E-01
     Per 6 mo increase1.03 (0.99–1.06)1.02 (0.99–1.05)1.03 (1.00–1.07)1.03 (0.99–1.06)1.02 (0.97–1.07)1.02 (0.97–1.07)1.03 (0.96–1.11)1.03 (0.99–1.07)
    9.2E-019.7E-018.7E-019.7E-019.7E-018.7E-019.2E-017.2E-01
     Ever vs. Never1.02 (0.85–1.22)1.01 (0.84–1.20)1.05 (0.83–1.32)0.99 (0.80–1.23)0.99 (0.81–1.22)0.95 (0.71–1.26)1.04 (0.70–1.55)1.09 (0.89–1.34)
    BMI, kg/m2
      All women3.0E-012.6E-016.4E-014.8E-017.2E-014.6E-018.7E-017.8E-01
      18.5–<25Ref.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
      <18.51.12 (0.78–1.60)1.13 (0.76–1.66)1.11 (0.73–1.68)1.04 (0.66–1.65)1.27 (0.74–2.17)1.20 (0.65–2.23)1.10 (0.52,2.31)0.99 (0.56,1.73)
      25–<301.07 (0.92–1.23)1.09 (0.95–1.25)1.03 (0.87–1.23)1.07 (0.90–1.29)1.06 (0.90–1.25)1.16 (0.93–1.44)0.96 (0.74–1.25)1.05 (0.86–1.28)
      ≥301.19 (1.05–1.34)1.19 (1.04–1.37)1.16 (1.01–1.34)1.21 (1.03–1.43)1.12 (0.95–1.31)1.27 (0.99–1.63)1.19 (0.91–1.55)1.15 (0.96–1.38)
     Postmenopausal women5.7E-021.2E-014.8E-015.4E-018.7E-014.8E-017.8E-017.8E-01
      18.5–<25Ref.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
      <18.51.25 (0.98–1.59)1.14 (0.84–1.56)1.43 (0.99–2.06)1.11 (0.66–1.84)1.12 (0.46–2.68)1.19 (0.52–2.71)1.40 (0.64–3.07)1.38 (0.79–2.39)
      25–<301.08 (0.98–1.20)1.12 (0.99–1.26)1.02 (0.89–1.18)1.08 (0.92–1.26)1.10 (0.91–1.34)1.25 (0.99–1.57)0.93 (0.67–1.29)1.05 (0.87–1.28)
      ≥301.15 (1.04–1.27)1.17 (1.02–1.33)1.12 (0.97–1.30)1.18 (1.00–1.40)1.08 (0.83–1.40)1.22 (0.91–1.65)1.21 (0.89–1.65)1.08 (0.88–1.34)
     Pre/perimenopausal women6.3E-016.1E-017.8E-017.2E-017.4E-017.1E-019.7E-017.7E-01
      18.5–<25Ref.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
      <18.50.97 (0.52–1.83)1.07 (0.55–2.10)0.87 (0.42–1.81)0.89 (0.39–2.01)1.42 (0.74–2.71)1.20 (0.45–3.22)0.82 (0.28–2.42)0.63 (0.20–2.02)
      25–<301.04 (0.80–1.35)1.04 (0.80–1.35)1.05 (0.76–1.46)1.07 (0.74–1.57)1.00 (0.77–1.29)1.04 (0.74–1.46)1.00 (0.69–1.46)1.06 (0.72–1.55)
      ≥301.27 (1.01–1.59)1.28 (1.02–1.63)1.23 (0.92–1.64)1.32 (0.94–1.85)1.19 (0.91–1.56)1.39 (0.94–2.05)1.14 (0.74–1.76)1.27 (0.93–1.73)
    Adult height, per 5 cm increase9.6E-018.8E-019.0E-018.7E-011.0E+001.0E+008.7E-018.7E-01
    1.00 (0.95–1.05)0.99 (0.94–1.05)1.01 (0.95–1.07)0.99 (0.93–1.05)1.00 (0.94–1.06)1.00 (0.93–1.07)0.98 (0.90–1.08)1.02 (0.95,1.09)
    Oral contraceptive use3.3E-015.9E-013.3E-016.1E-018.7E-016.1E-017.2E-014.1E-01
     Ever vs. never0.93 (0.86–1.00)0.94 (0.87–1.03)0.89 (0.79–1.00)0.94 (0.83–1.05)0.96 (0.80–1.16)0.91 (0.77–1.07)0.92 (0.76–1.12)0.87 (0.75–1.02)
    MHT1.1E-104.3E-075.6E-031.9E-021.9E-015.2E-018.3E-014.6E-01
     Never use, postmenopausalRef.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
     Formerb use of ET0.82 (0.66–1.02)0.79 (0.61–1.03)0.95 (0.65–1.38)0.73 (0.47–1.15)0.80 (0.49–1.30)1.10 (0.61–1.99)0.91 (0.40–2.10)0.92 (0.57–1.50)
     Formerb use of EPT1.06 (0.87–1.30)1.01 (0.79–1.30)1.20 (0.85,1.69)0.96 (0.67–1.38)1.11 (0.64–1.93)0.97 (0.55–1.71)1.16 (0.57–2.38)1.24 (0.79–1.97)
     Formerb use (unknown type)0.87 (0.79–0.96)0.87 (0.78–0.96)0.91 (0.76–1.08)0.85 (0.72–1.01)0.87 (0.66–1.14)0.83 (0.59–1.16)0.93 (0.66–1.31)0.90 (0.73–1.12)
     Currentc use of ET0.69 (0.55–0.86)0.69 (0.54–0.88)0.69 (0.48–1.00)0.71 (0.50–1.01)0.59 (0.33–1.07)0.68 (0.42–1.12)0.63 (0.27–1.50)0.78 (0.49–1.26)
     Currentc use of EPT0.60 (0.51–0.72)0.61 (0.49–0.75)0.59 (0.44–0.79)0.63 (0.48–0.83)0.59 (0.37–0.93)0.58 (0.38–0.87)0.60 (0.31–1.14)0.63 (0.42–0.95)
     Currentc use (unknown type)0.83 (0.73–0.94)0.80 (0.69–0.93)0.94 (0.74–1.20)0.81 (0.66–0.98)0.75 (0.53–1.06)0.81 (0.51–1.30)0.89 (0.53–1.50)1.02 (0.73–1.42)
    Smoking5.7E-021.2E-016.3E-012.0E-016.5E-018.7E-018.7E-016.7E-01
     NeverRef.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
     Formerd0.93 (0.87–0.99)0.94 (0.86–1.03)0.91 (0.81–1.03)0.93 (0.83–1.05)0.91 (0.80–1.04)0.94 (0.78–1.13)1.04 (0.81–1.34)0.89 (0.75–1.05)
     Currente1.11 (1.02–1.21)1.14 (1.04–1.26)1.04 (0.90–1.21)1.19 (1.03—1.36)1.09 (0.89–1.32)1.06 (0.84–1.33)1.12 (0.81–1.55)1.07 (0.87–1.33)
    No. of pack-years of smoking, per 106.7E-016.7E-017.8E-016.7E-018.4E-018.0E-016.1E-019.2E-01
    units increase1.02 (0.98–1.07)1.02 (0.97–1.08)1.01 (0.97–1.06)1.03 (0.97–1.09)1.02 (0.94–1.10)1.02 (0.95–1.09)1.05 (0.97–1.13)1.01 (0.94–1.07)
    Alcohol consumptione, per 10 g/wk9.0E-019.6E-018.7E-019.8E-018.7E-018.5E-018.8E-018.7E-01
    1.00 (0.99–1.01)1.00 (0.99–1.01)1.00 (0.99–1.01)1.00 (0.99–1.01)1.00 (0.99–1.01)1.00 (0.98–1.01)1.00 (0.99–1.01)1.00 (0.98–1.01)
    Cumulative alcohol consumption, per7.8E-017.8E-018.7E-017.3E-019.2E-017.2E-019.7E-018.7E-01
    10 g/d0.98 (0.91–1.05)0.97 (0.89–1.07)0.99 (0.93–1.05)0.96 (0.87–1.07)0.99 (0.89–1.10)0.96 (0.88–1.06)1.01 (0.90–1.12)0.99 (0.92–1.06)
    Physical activitye,f, hours/wk5.2E-015.4E-015.2E-016.0E-016.5E-012.8E-015.2E-015.9E-01
     <1.8Ref.Ref.Ref.Ref.Ref.Ref.Ref.Ref.
     ≥1.8–< 5.50.76 (0.21–2.73)0.77 (0.21–2.81)0.75 (0.21–2.67)0.78 (0.19–3.22)0.79 (0.20–3.07)0.72 (0.28–1.85)0.82 (0.28–2.42)0.72 (0.17–3.15)
     ≥5.50.39 (0.13–1.17)0.40 (0.13–1.19)0.38 (0.12–1.21)0.39 (0.12–1.26)0.44 (0.13–1.49)0.38 (0.16–0.88)0.42 (0.15–1.12)0.38 (0.11–1.31)

    • Note: All analyses were stratified by study and adjusted for lymph nodes status, tumor size, tumor grade, and (neo)adjuvant systemic treatment. Age of the patients was used as time scale. Reported P values (P) are from likelihood ratio tests comparing a model with and without a particular risk factor and are adjusted for multiple testing using the Benjamini–Hochberg method for false discovery rate (FDR) control on 136 tests. Heterogeneity test by subtype is shown in Table 3. Numbers of patients and events included in the corresponding complete-case analyses are shown in Supplementary Figs. S2 (overall), S4 (ER+), S6 (ER−), S8 (Luminal A–like), S10 (Luminal B HER2-negative–like), S12 (Luminal B HER2-positive–like), S14 (HER2-enriched–like), and S16 (TN).

    • Abbreviations: ET, estrogen therapy; EPT, combined estrogen and progestin therapy.

    • ↵aAssociation estimated in parous women.

    • ↵bMore than 6 mo before diagnosis.

    • ↵cAt diagnosis or within 6 mo before diagnosis.

    • ↵dMore than 1 year before diagnosis.

    • ↵eAt diagnosis or within 1 year before diagnosis.

    • ↵fCategories based on the tertiles of the observed distribution of the variable.

  • Table 5.

    Multivariable Cox regression model on the imputed datasets including all risk factors simultaneously with 10-year all-cause mortality as endpoint.

    Risk factorHR (95% CI)P
    Age at menarche1.02 (1.00–1.04)6.8E-02
    Parity
     0Ref.
     11.02 (0.91–1.15)7.4E-01
     20.99 (0.86–1.15)9.0E-01
     31.01 (0.86–1.18)9.4E-01
     4+1.01 (0.86–1.18)9.2E-01
    Age at FFTP, y
     <20Ref.
     20–<250.90 (0.84–0.96)1.9E-03
     25–<300.84 (0.78–0.90)2.8E-06
     ≥300.79 (0.72–0.86)2.0E-07
    Time since last full-term birth, y
     ≥10Ref.
     ≥5–<101.13 (1.01–1.28)3.2E-02
     >0–<51.31 (1.11–1.55)1.1E-03
    Breastfeeding
     Ever vs. never0.94 (0.82–1.06)2.7E-01
     Duration of breastfeeding, per 6 mo1.02 (1.00–1.04)6.9E-02
    BMI, kg/m2
     18.5–<25Ref.
     <18.51.31 (0.96–1.77)5.6E-02
     25–<301.04 (0.92–1.18)4.4E-01
     ≥301.19 (1.06–1.34)1.1E-03
    Adult height, per 5 cm0.98 (0.93–1.03)2.8E-01
    Oral contraceptive use
     Ever vs. never0.91 (0.87–0.96)9.4E-05
    MHT
     Never use, postmenopausalRef.
     Formera use of ET0.75 (0.65–0.86)2.9E-05
     Formera use of EPT0.85 (0.73–0.98)3.0E-02
     Formera use (unknown type)0.81 (0.76–0.86)1.1E-11
     Currentb use of ET0.72 (0.64–0.82)8.3E-07
     Currentb use of EPT0.61 (0.54–0.69)3.8E-15
     Currentb use (unknown type)0.78 (0.72–0.85)4.9E-08
    Smoking
     NeverRef.
     Formerc1.03 (0.98–1.07)2.3E-01
     Currentd1.37 (1.27–1.47)0.0E+00
    Alcohol consumptiond, per 10 g/wk1.00 (0.99–1.01)6.6E-01
    Cumulative alcohol consumption, per 10 g/d1.00 (0.96–1.05)9.3E-01
    Physical activityd,e, hours/wk
     <1.8Ref.
     ≥1.8–<5.50.81 (0.39–1.68)5.2E-01
     ≥5.50.43 (0.21–0.86)6.3E-03

    • Note: The Cox model was stratified by study and adjusted for lymph nodes status, tumor size, tumor grade, ER status, PR status, HER2 status, and (neo)adjuvant systemic treatment. Age of the patients was used as time scale. All the risk factors were simultaneously included in the model. Corresponding complete-case analysis was based on 1,264 cases and 158 deaths from all causes. A comparison between results from imputed data analysis and corresponding complete-case analysis are shown in Supplementary Fig. S23.

    • Abbreviations: ET, estrogen therapy; EPT, combined estrogen and progestin therapy.

    • ↵aMore than 6 mo before diagnosis.

    • ↵bAt diagnosis or within 6 mo before diagnosis.

    • ↵cMore than 1 year before diagnosis.

    • ↵dAt diagnosis or within a year before diagnosis.

    • ↵eCategories based on the tertiles of the observed distribution of the variable.

  • Table 6.

    Multivariable Cox regression model on the imputed datasets including all risk factors simultaneously, with 10-year breast cancer–specific mortality as endpoint.

    Risk factorHR (95% CI)P
    Age at menarche1.03 (1.00–1.05)1.4E-02
    Parity
     0Ref.
     11.04 (0.90–1.21)5.5E-01
     21.00 (0.83–1.20)1.0E+00
     31.00 (0.81–1.24)1.0E+00
     4+1.01 (0.81–1.25)9.4E-01
    Age at FFTP, y
     <20Ref.
     20–<250.90 (0.82–0.99)2.7E-02
     25–<300.87 (0.79–0.95)2.8E-03
     ≥300.80 (0.72–0.89)4.4E-05
    Time since last full-term birth, y
     ≥10Ref.
     ≥5–< 101.16 (1.01–1.34)2.9E-02
     >0–< 51.36 (1.15–1.61)2.4E-04
    Breastfeeding
     Ever vs. never0.98 (0.81–1.18)8.2E-01
     Duration of breastfeeding, per 6 mo1.02 (1.00–1.05)7.2E-02
    BMI, kg/m2
     18.5–<25Ref.
     <18.51.10 (0.79–1.53)5.6E-01
     25–<301.06 (0.93–1.20)3.6E-01
     ≥301.16 (1.04–1.29)4.7E-03
    Adult height, per 5 cm1.00 (0.95–1.06)8.7E-01
    Oral contraceptive use
     Ever vs. never0.96 (0.89–1.03)2.5E-01
    MHT
     Never use, postmenopausalRef.
     Formera use of ET0.82 (0.66–1.03)8.2E-02
     Formera use of EPT1.11 (0.91–1.35)3.2E-01
     Formera use (unknown type)0.88 (0.80–0.97)1.0E-02
     Currentb use of ET0.71 (0.57–0.89)2.6E-03
     Currentb use of EPT0.64 (0.54–0.76)2.3E-07
     Currentb use (unknown type)0.86 (0.76–0.97)1.3E-02
    Smoking
     NeverRef.
     Formerc0.94 (0.88–1.01)7.2E-02
     Currentd1.11 (1.02–1.21)1.1E-02
    Alcohol consumptiond, per 10 g/wk1.00 (0.99–1.01)8.4E-01
    Cumulative alcohol consumption, per 10 g/d0.98 (0.91–1.06)5.2E-01
    Physical activityd,e, hours/wk
     <1.8Ref.
     ≥1.8–<5.50.77 (0.22–2.73)6.4E-01
     ≥5.50.40 (0.13–1.19)5.7E-02

    • Note: The Cox model is stratified by and adjusted for lymph nodes status, tumor size, tumor grade, ER status, PR status, HER2 status, and (neo)adjuvant systemic treatment. Age of the patient was used as time scale. All risk factors were simultaneously included in the model. Corresponding complete-case analysis was based on 1,264 cases and 114 deaths from breast cancer. A comparison between results from imputed data analysis and corresponding complete-case analysis are shown in Supplementary Fig. S24.

    • Abbreviations: ET, estrogen therapy; EPT, combined estrogen and progestin therapy.

    • ↵aMore than 6 mo before diagnosis.

    • ↵bAt diagnosis or within 6 mo before diagnosis.

    • ↵cMore than 1 year before diagnosis.

    • ↵dAt diagnosis or within a year before diagnosis.

    • ↵eCategories based on the tertiles of the observed distribution of the variable.

Additional Files

  • Supplementary Data

    • Supplementary Table S1 - Supplementary Table S1 shows an overview of the Breast Cancer Association Consortium (BCAC) studies.
    • Supplementary Materials and Methods. Supplementary Tables 2-7. Supplementary Figures 1-26 -

      The Supplementary Methods section includes details about: study population; multiple imputation of missing data; pooling of Western and Asian studies; correction for multiple testing; test for heterogeneity of associations between tumor subtypes; time-dependent ROC curve analysis. Supplementary Table S2 shows the list of imputed variables with corresponding percentage of missing values, by Western and Asian studies, imputation method and processing. Supplementary Table S3 shows the associations between individual risk factors and 10-year all-cause mortality by ER status and intrinsic-like subtype based on the complete-case dataset. Supplementary Table S4 shows the associations between individual risk factors and 10-year breast cancer-specific mortality by ER status and intrinsic-like subtype based on the complete-case dataset. Supplementary Table S5 shows the meta-analysis of the overall associations between individual risk factors and 10-year all-cause mortality in Western and Asian studies, performed on the imputed datasets. Supplementary Table S6 shows the meta-analysis of the overall associations between individual risk factors and 10-year breast cancer-specific mortality from Western and Asian studies, performed on the imputed datasets. Supplementary Table S7 shows the multivariable Cox regression model on the complete-case dataset including all risk factors simultaneously with 10-year all-cause mortality as endpoint. Supplementary Table S8 shows the multivariable Cox regression model on the complete-case dataset including all risk factors simultaneously, with 10-year breast cancer-specific mortality as endpoint. Supplementary Figures S1 to S16 display forest-like plots showing the comparison between the results from the imputed data analysis and complete-case analysis for the association between individual risk factors and 10-year all-cause mortality and breast cancer-specific mortality, based on: all patients (Supplementary Figures S1 and S2); by ER status (Supplementary Figures S3 to S6); and by intrinsic-like tumor subtype (Supplementary Figures S7 to S16). Supplementary Figures S17 and S18 display forest-like plots showing the comparison between the results from the imputed data analysis based on prospective studies only and corresponding complete-case analysis for the overall association between individual risk factors and 10-year all-cause mortality and breast cancer-specific mortality, respectively. Supplementary Figures S19 and S20 display forest-like plots showing the comparison between the results from the imputed data analysis based on prospective studies only and corresponding imputed data analysis based on all studies for the overall association between individual risk factors and 10-year all-cause mortality and breast cancer-specific mortality, respectively. Supplementary Figures S21 and S22 display forest-like plots showing the comparison between the results from the complete-case analysis based on prospective studies only and corresponding complete-case analysis based on all studies for the overall association between individual risk factors and 10-year all-cause mortality and breast cancer-specific mortality, respectively. Supplementary Figures S23 and S24 display forest-like plots showing the comparison between the results from the imputed data analysis (from Tables 5 and 6) and corresponding complete-case analysis (from Supplementary Tables S7 and S8) for the overall association between multiple risk factors and 10-year all-cause mortality (Table 5 and Supplementary Table S7) and breast cancer-specific mortality (Table 6 and Supplementary Table S8), respectively. Supplementary Figures S25 and S26 show the AUC of 10-year all-cause mortality and 10-year breast cancer-specific mortality, respectively, at varying ages, and the concordance index overall for two multivariable models: one model including and the other one excluding the risk factors investigated.
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Cancer Epidemiology Biomarkers & Prevention: 30 (4)
April 2021
Volume 30, Issue 4

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Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium
Anna Morra, Audrey Y. Jung, Sabine Behrens, Renske Keeman, Thomas U. Ahearn, Hoda Anton-Culver, Volker Arndt, Annelie Augustinsson, Päivi K. Auvinen, Laura E. Beane Freeman, Heiko Becher, Matthias W. Beckmann, Carl Blomqvist, Stig E. Bojesen, Manjeet K. Bolla, Hermann Brenner, Ignacio Briceno, Sara Y. Brucker, Nicola J. Camp, Daniele Campa, Federico Canzian, Jose E. Castelao, Stephen J. Chanock, Ji-Yeob Choi, Christine L. Clarke, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Douglas F. Easton, Diana M. Eccles, Kathleen M. Egan, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Manuela Gago-Dominguez, Susan M. Gapstur, José A. García-Sáenz, Mia M. Gaudet, Graham G. Giles, Mervi Grip, Pascal Guénel, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Sileny N. Han, Steven N. Hart, Mikael Hartman, Jane S. Heyworth, Reiner Hoppe, John L. Hopper, David J. Hunter, Hidemi Ito, Agnes Jager, Milena Jakimovska, Anna Jakubowska, Wolfgang Janni, Rudolf Kaaks, Daehee Kang, Pooja Middha Kapoor, Cari M. Kitahara, Stella Koutros, Peter Kraft, Vessela N. Kristensen, James V. Lacey, Diether Lambrechts, Loic Le Marchand, Jingmei Li, Annika Lindblom, Jan Lubiński, Michael Lush, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Shivaani Mariapun, Keitaro Matsuo, Dimitrios Mavroudis, Roger L. Milne, Taru A. Muranen, William G. Newman, Dong-Young Noh, Børge G. Nordestgaard, Nadia Obi, Andrew F. Olshan, Håkan Olsson, Tjoung-Won Park-Simon, Christos Petridis, Paul D.P. Pharoah, Dijana Plaseska-Karanfilska, Nadege Presneau, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Emmanouil Saloustros, Elinor J. Sawyer, Andreas Schneeweiss, Lukas Schwentner, Christopher Scott, Mitul Shah, Chen-Yang Shen, Xiao-Ou Shu, Melissa C. Southey, Daniel O. Stram, Rulla M. Tamimi, William Tapper, Rob A.E.M. Tollenaar, Ian Tomlinson, Diana Torres, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Qin Wang, Sophia S. Wang, Justin A. Williams, Robert Winqvist, Alicja Wolk, Anna H. Wu, Keun-Young Yoo, Jyh-Cherng Yu, Wei Zheng, Argyrios Ziogas, Xiaohong R. Yang, A. Heather Eliassen, Michelle D. Holmes, Montserrat García-Closas, Soo Hwang Teo, Marjanka K. Schmidt and Jenny Chang-Claude for the ABCTB Investigators, for the NBCS Collaborators
Cancer Epidemiol Biomarkers Prev April 1 2021 (30) (4) 623-642; DOI: 10.1158/1055-9965.EPI-20-0924
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