Outcomes of Active Surveillance for Ductal Carcinoma in Situ: A Computational Risk Analysis

Abstract

Background: Ductal carcinoma in situ (DCIS) is a noninvasive breast lesion with uncertain risk for invasive progression. Usual care (UC) for DCIS consists of treatment upon diagnosis, thus potentially overtreating patients with low propensity for progression. One strategy to reduce overtreatment is active surveillance (AS), whereby DCIS is treated only upon detection of invasive disease. Our goal was to perform a quantitative evaluation of outcomes following an AS strategy for DCIS.

Methods: Age-stratified, 10-year disease-specific cumulative mortality (DSCM) for AS was calculated using a computational risk projection model based upon published estimates for natural history parameters, and Surveillance, Epidemiology, and End Results data for outcomes. AS projections were compared with the DSCM for patients who received UC. To quantify the propagation of parameter uncertainty, a 95% projection range (PR) was computed, and sensitivity analyses were performed.

Results: Under the assumption that AS cannot outperform UC, the projected median differences in 10-year DSCM between AS and UC when diagnosed at ages 40, 55, and 70 years were 2.6% (PR = 1.4%-5.1%), 1.5% (PR = 0.5%-3.5%), and 0.6% (PR = 0.0%-2.4), respectively. Corresponding median numbers of patients needed to treat to avert one breast cancer death were 38.3 (PR = 19.7-69.9), 67.3 (PR = 28.7-211.4), and 157.2 (PR = 41.1-3872.8), respectively. Sensitivity analyses showed that the parameter with greatest impact on DSCM was the probability of understaging invasive cancer at diagnosis.

Conclusion: AS could be a viable management strategy for carefully selected DCIS patients, particularly among older age groups and those with substantial competing mortality risks. The effectiveness of AS could be markedly improved by reducing the rate of understaging.

Figure 1.

Active surveillance strategy. 1) Ductal carcinoma in situ (DCIS) is diagnosed at time t=0 and is either understaged (with probability p_inv) or classified as true DCIS otherwise. 2a) If understaged, the lesion is already localized at t=0 and starts progressing according to the natural history model. 2b) If the lesion is a true DCIS, it progresses with probability p₀ (progressive type), or stays indolent/regresses otherwise. If it is of progressive type, it progresses after a random time T_p to become localized IDC and then progresses according to the natural history model. 3) IDC is diagnosed during a subsequent follow-up screen (screening interval of ∆t months); the screening sensitivity is denoted by p_sen. The stage distribution of the diagnosed IDC depends on the time since onset of localized disease. The competing risk of dying from a DCIS-unrelated cause of death before IDC diagnosis is incorporated into the model but not illustrated here. Details on model design and implementation are found in the Supplementary Methods (available online). DCIS = ductal carcinoma in situ; IDC = invasive ductal carcinoma.

Figure 2.

Cumulative mortality—active surveillance (AS) disease-specific projections vs usual care (UC) disease-specific and competing risks. The model-based, projected disease-specific cumulative mortality (DSCM) for the AS strategy (median: black line; 95% projection range: gray shading) is compared with the Surveillance, Epidemiology, and End Results (SEER)–based DSCM for UC (point estimate: red solid line; 95% confidence interval: red dotted lines) and the cumulative mortality because of competing risks (point estimate: blue solid line; 95% confidence interval: blue dotted lines) for two different control parameter sets. A) baseline control parameter set with understaging probability p_inv = 18.9%, screening sensitivity p_sen = 80%, and screening interval ∆t = 6 months. B) Improved control parameter set with p_inv = 10%, p_sen = 90%, and ∆t = 6 months.

Figure 3.

Control parameter sensitivity for age at diagnosis 55 years. Sensitivity of the 10-year disease-specific cumulative mortality (DSCM) to the control parameters ∆t (screening interval) and p_inv (probability of understaging invasive ductal carcinoma [IDC]) is illustrated. Both parameters were varied over their respective sensitivity ranges (Table 1), and the screening sensitivity was held constant at p_sen = 80%. The color scale indicates the projected mean 10-year DSCM (per 100 patients). Each estimate is based on N = 1200 Monte Carlo simulations. DSCM = disease-specific cumulative mortality.