Assessing the Risk of Non-Colorectal Malignancy in Patients with a ``False Positive’’ Cologuard Result

Author

Lu Mao

Published

September 20, 2026

Statistical analysis

Categorical variables were summarized as counts and percentages, and continuous variables were summarized as medians and interquartile ranges (IQRs). Baseline characteristics were compared using the chi-square or Fisher’s exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables.

NCAM incidence rates were calculated as the number of patients developing NCAM divided by total person-years at risk. Follow-up began at Cologuard testing and ended at the first NCAM diagnosis, death, or last follow-up. Rates are reported per 1,000 person-years with exact Poisson 95% confidence intervals. Incidence rate ratios (IRRs) were estimated using Poisson regression with log person-years as an offset and negative Cologuard results as the reference. Adjusted models included age, sex, and race.

Kaplan–Meier plots and log-rank tests were used to compare cancer-free survival (CFS) and overall survival (OS) by Cologuard result. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of CFS and OS by Cologuard result adjusting for demographics. A two-sided p value < 0.05 was considered statistically significant. All statistical analyses were performed using R (version 4.3.1).

Results

Patient characteristics

The cohort consists of 48927 patients, including 45574 with negative and 3353 with false positive Cologuard results.

Baseline characteristics and cancer rates are summarized in Table 1 by Cologuard result.

Table 1: Characteristics of patients with negative vs. false positive cologuard results
Characteristic Negative
N = 45,5741		 False Positive
N = 3,3531		 p-value2
Age at Cologuard test (years) 58 (50, 65) 63 (56, 69) <0.001
Sex

0.4
    Female 27,350 (60%) 1,979 (59%)
    Male 18,195 (40%) 1,371 (41%)
    Uncertain/Unknown 29 (<0.1%) 3 (<0.1%)
Race

<0.001
    White 40,802 (90%) 3,169 (95%)
    Black Or African American 1,791 (3.9%) 77 (2.3%)
    Asian Or Pacific Islander 1,436 (3.2%) 42 (1.3%)
    American Indian Or Alaska Native 277 (0.6%) 12 (0.4%)
    Unknown 1,268 (2.8%) 53 (1.6%)
Ethnicity

<0.001
    Not Hispanic or Latino 42,224 (93%) 3,231 (96%)
    Hispanic/Latino 2,182 (4.8%) 70 (2.1%)
    Unknown 1,168 (2.6%) 52 (1.6%)
BMI 29 (25, 34) 29 (25, 35) 0.4
    Unknown 25,543 1,877
Any other cancer 669 (1.5%) 145 (4.3%) <0.001
    Unknown 2 0
Head and neck cancer 166 (0.4%) 21 (0.6%) 0.018
    Unknown 2 0
Lung cancer 227 (0.5%) 50 (1.5%) <0.001
    Unknown 2 0
Non-colorectal GI cancer 276 (0.6%) 74 (2.2%) <0.001
    Unknown 2 0
1 Median (Q1, Q3); n (%)
2 Wilcoxon rank sum test; Fisher’s exact test; Pearson’s Chi-squared test
  • Patients with false positive Cologuard results have higher incidences of non-colorectal cancers.

NCAM incidence rates

NCAM incidence rates were calculated as the number of patients developing NCAM divided by total person-years at risk. Follow-up began at Cologuard testing and ended at the first NCAM diagnosis, death, or last follow-up. Rates are reported per 1,000 person-years with exact Poisson 95% confidence intervals. Incidence rate ratios (IRRs) were estimated using Poisson regression with log person-years as an offset and negative Cologuard results as the reference. Adjusted models included age, sex, and race.

NCAM incidence rates and incidence rate ratios are summarized in Table 2.

Table 2: NCAM incidence rates and incidence rate ratios by Cologuard result
Cologuard result Patients NCAM events Person-years Rate per 1,000 person-years (95% CI) Unadjusted IRR (95% CI) Unadjusted p-value Adjusted IRR (95% CI) Adjusted p-value
Negative 45402 664 130,253.7 5.10 (4.72–5.50) Reference — Reference —
False positive 3342 135 10,260.5 13.16 (11.03–15.57) 2.58 (2.14–3.11) <0.001 2.23 (1.85–2.69) <0.001
No follow-up colonoscopy 2501 56 5,835.2 9.60 (7.25–12.46) 1.88 (1.43–2.47) <0.001 1.55 (1.18–2.04) 0.002

NCAM incidence by findings among false-positive patients

NCAM incidence rates among false-positive patients are summarized in Table 3.

Table 3: NCAM incidence rates by colonoscopy findings among false-positive patients
Colonoscopy finding Patients NCAM events Person-years Rate per 1,000 person-years (95% CI) Unadjusted IRR (95% CI) Unadjusted p-value Adjusted IRR (95% CI) Adjusted p-value
Negative 45402 664 130,253.7 5.10 (4.72–5.50) Reference — Reference —
FP: no colonoscopy findings 1457 76 4,385.9 17.33 (13.65–21.69) 3.40 (2.68–4.31) <0.001 3.04 (2.39–3.85) <0.001
FP: tubular adenoma 1235 52 3,812.2 13.64 (10.19–17.89) 2.68 (2.02–3.55) <0.001 2.20 (1.66–2.93) <0.001
FP: sessile serrated polyp 494 7 1,540.7 4.54 (1.83–9.36) 0.89 (0.42–1.88) 0.762 0.81 (0.38–1.70) 0.571
FP: diverticulosis 156 0 521.6 0.00 (0.00–7.07) Not estimable — Not estimable —

CFS and OS

Follow-up and crude event rates of cancer-free survival (primary endpoint) and overall survival are summarized in Table 4 by Cologuard result.

Table 4: Follow-up and event rates of cancer-free survival and overall survival
Characteristic Negative
N = 45,5741		 False Positive
N = 3,3531
CFS Follow-up (months) 32 (16, 51) 34 (17, 56)
Cancer-free survival event 1,469 (3.2%) 216 (6.4%)
OS Follow-up (months) 33 (16, 51) 36 (18, 57)
Deceased 898 (2.0%) 100 (3.0%)
1 Median (Q1, Q3); n (%)

Kaplan–Meier plots and log-rank tests of cancer-free survival (CFS) and overall survival (OS) by Cologuard result are shown in Figure 1. Patients with false positive Cologuard results have significantly worse CFS (p < 0.001) and OS (p=0.008).

Figure 1: Kaplan-Meier plots of cancer-free survival by Cologuard result

Survival estimates at 24, 48, and 72 months for CFS and OS survival by Cologuard result are summarized in Table 5.

Table 5: Survival estimates at 24, 48, and 72 months for cancer-free survival and overall survival by Cologuard result
Endpoint Month 24 Month 48 Month 72
CFS


    FP 96.0% (95.3%, 96.7%) 92.7% (91.6%, 93.9%) 87.0% (84.9%, 89.2%)
    Neg 98.2% (98.1%, 98.4%) 95.7% (95.5%, 96.0%) 92.0% (91.4%, 92.5%)
OS


    FP 98.3% (97.8%, 98.8%) 96.4% (95.6%, 97.2%) 93.7% (92.2%, 95.2%)
    Neg 99.1% (99.0%, 99.2%) 97.3% (97.1%, 97.5%) 94.9% (94.5%, 95.3%)

Cox regression analyses

Cox proportional hazards regression analyses of CFS and OS against Cologuard result adjusting for demographics are summarized in Table 6.

Table 6: Cox regression analyses of cancer-free survival and overall survival against Cologuard result adjusting for demographics
Characteristic
Cancer-free survival
Overall survival
HR 95% CI p-value HR 95% CI p-value
Cologuard result





    Negative — —
— —
    False Positive 1.52 1.31, 1.75 <0.001 1.09 0.89, 1.34 0.4
Age at Cologuard test (years) 1.06 1.06, 1.07 <0.001 1.08 1.07, 1.09 <0.001
Sex





    Female — —
— —
    Male 1.45 1.31, 1.59 <0.001 1.54 1.36, 1.75 <0.001
    Uncertain/Unknown 1.33 0.19, 9.45 0.8 0.00 0.00, Inf >0.9
Race





    White — —
— —
    Black Or African American 1.40 1.08, 1.82 0.010 1.49 1.07, 2.08 0.020
    Asian Or Pacific Islander 1.02 0.73, 1.42 >0.9 0.71 0.42, 1.20 0.2
    American Indian Or Alaska Native 1.30 0.68, 2.51 0.4 1.78 0.85, 3.74 0.13
    Unknown 0.65 0.43, 0.97 0.037 0.70 0.42, 1.16 0.2
Abbreviations: CI = Confidence Interval, HR = Hazard Ratio

(Ethnicity is non-significant after adjusting for race.)

  • After adjusting for demographics:
    • False positives have a significantly higher risk of non-colorectal cancer or death (CFS: HR 1.52, 95% CI 1.31–1.75, p < 0.001).
    • False positives also have a higher risk of death (p < 0.4)
      • Statistical nonsignificance may be due to adjustment of age (FP are older; see Table 1).
  • Factors significantly associated with worse CFS and/or OS:
    • Older age
    • Male vs female
    • Black or African American vs White