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+ERLuminal 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.