BACKGROUND: Medications may have direct effects on cancer risk (initiation) or promote growth of existing tumors. Measuring these effects on screen-detectable cancers is complex in settings in which receipt of cancer screening varies between treatment groups. CONCLUSIONS: This study illustrates the potential impact of a treat-ment's etiological mechanism on observed risk of screen-detectable cancers, and highlights the sensitivity of results to the level of screen-ing and its distribution in the population. The RR in particular is highly sensitive to the level of screening that occurs early in follow-up, when incidence is low.
OBJECTIVES: We sought to model cancer initiating and promoting treatment effects and their impacts on observed breast cancer incidence under differential and nondifferential screening scenarios.
METHODS: We used discrete event simulation to model lifetime risk ofbreast cancer initiation, tumor growth, detection via symptoms or screen-ing, and competing mortality in 1,000,000 women aged 20-84. Treatment receipt was modeled as a binary variable with initiation (or matched indexdate) occurring at age 50 to remove the impact of screening prior to treatment. Cancer initiating and promoting effects increased age-specific cancer rate and tumor size, respectively, by 1.2 times in all subsequent years. Two-year screening coverage among women aged 50-74 was var-ied between 0-100%. Cancer detection was modeled probabilistically as a function of tumor size and screening; in settings with differential screen-ing, treatment and screening were indirectly associated through an unobserved "access" parameter. We used Aalen-Johansen risk estimation to calculate cumulative incidence of breast cancer initiation and detection by treatment under each screening regimen, and computed risk differ-ences and ratios (RD, RR) at all time points.
RESULTS: In the nondifferential initiation setting, all screening-based esti-mates underestimated the true treatment effect, with the 100% screening estimates being least biased; lower screening coverage further attenuated the RD and RR. The largest promotion effects in the nondifferential screening setting were observed with 0% screening. In settings where screening varied by treatment group, 25% screening led to the greatest overestimation of the RD and RR relative to nondifferential screening. The25-year RDs for 25 vs. 0 and 100% screening were 0.018 vs. 0.012 and0.006, respectively, for initiation, and 0.010 vs. 0.004 and 0.001 for pro-motion. RRs were highest early in follow-up: 1-year RRs for 25 vs. 0 and100% screening in the initiation setting were 1.31 vs. 0.97 and 0.97,respectively; for promotion they were 1.61 vs. 1.37 and 1.07.
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