1Education Level Was Missing for 155 (21%) of Individuals

Supplementary Table 1: Characteristics of patients with and without missing data on physical activity in the Seattle Colon Cancer Family Registry, restricted to those with local and regional disease

Participant characteristics Non-missing Missing p-value (n = 1309) (n = 737) Age at diagnosis (years), Mean (SD) 55.7 (12) 60.4 (10) <0.001 Males, n(%) 710 (54) 301 (41) <0.001 BMI (kg/m2), Mean (SD) 27.6 (6) 28.6 (6) 0.0005 Smoking history, n(%) 0.05 Never 566 (43) 281 (38) Former 532 (41) 314 (43) Current 211 (16) 141 (19) Education level1, n (%) <0.001

CRC Colorectal cancer 1Education level was missing for 155 (21%) of individuals 2671 (32.8%) individuals did not have BRAF-KRAS mutation status evaluated, n = 6 mutated on both BRAF & KRAS dropped 5457 (22.3%) individuals did not undergo testing for MSI status

1 Supplementary Table 2: Overall and colon cancer-specific survival across categories of prediagnostic physical activity levels (average MET-hours per week) among patients with local and regional disease who had data on at least one tumor molecular characteristica (n=1043)

Physical activity* Deaths/ Unadjusted Adjusted Model 11 Adjusted Model 22 (MET-h /week) CRC HR (95% CI) HR (95% CI) HR (95% CI) Overall survival <3.5 100/227 REF REF REF 3.5-<8.75 51/204 0.48 (0.34,0.67) 0.53 (0.37,0.74) 0.53 (0.38,0.74) 8.75-<17.5 69/226 0.60 (0.44,0.81) 0.67 (0.49,0.91) 0.65 (0.47,0.88) 17.5-<35 61/216 0.54 (0.39,0.74) 0.61 (0.44,0.84) 0.60 (0.44,0.83) >=35 48/170 0.54 (0.39,0.77) 0.60 (0.42,0.85) 0.59 (0.42,0.84) 3 p-trendoverall 0.001 0.006 0.004 3 p-trendactive 0.70 0.66 0.69

CRC-specific survival <3.5 56/227 REF REF REF 3.5-<8.75 30/204 0.52 (0.34,0.82) 0.57 (0.36,0.89) 0.58 (0.37,0.90) 8.75-<17.5 34/226 0.55 (0.36,0.83) 0.59 (0.39,0.92) 0.56 (0.37,0.87) 17.5-<35 30/216 0.50 (0.32,0.78) 0.54 (0.35,0.85) 0.53 (0.34,0.84) >=35 22/170 0.47 (0.29,0.77) 0.47 (0.28,0.77) 0.46 (0.28,0.76) 3 p-trendoverall 0.001 0.002 0.001 3 p-trendactive 0.65 0.48 0.43

CRC Colorectal cancer; MSI Microsatellite instability; HR Hazard ratio; CI Confidence intervals aOf the 1043, 3 had missing data on MSI status and 94 had missing data on BRAF/KRAS status *MET hours per week translated into time equivalent spent walking per week: 3.5 = 1 hour; 8.75 = 2.5 hours; 17.5 = 5 hours; 35 = 10 hours; Topmost percentile of physical activity was excluded 1Adjusted for age at CRC diagnosis, sex, body mass index, smoking status, education and diagnosis year 2Adjusted for age at CRC diagnosis, sex, body mass index, smoking status, education, diagnosis year and stage at diagnosis 3Tests for trend were based on the likelihood-ratio test associated with addition of the categorical physical activity variable in its continuous form (p- trendoverall). We also computed a separate trend test only among those that were physically active (p-trendactive).