A survey study of women's responses to information about overdiagnosis in breast cancer screening in Britain

Background:

There is concern about public understanding of overdiagnosis in breast cancer screening, and uncertainty about the likely impact on screening participation.

Methods:

In a population-based survey of 2272 women, we assessed understanding of overdiagnosis and screening intentions before and after exposure to an explanation of overdiagnosis, and one of the three information formats providing an estimate of the rate of overdiagnosis based on the findings of the UK Independent Review.

Results:

Subjective and objective comprehension of overdiagnosis was moderate across information formats (64% and 57%, respectively). Following overdiagnosis information, 7% of women showed a decrease in screening intention, with a stronger effect among women below screening age (<47 years), and receiving the estimate of the rate of overdiagnosis in a simple ratio format (one life saved to three overdiagnoses).

Conclusions:

Brief written information on overdiagnosis was incompletely understood, but reduced breast screening intentions in a proportion of women, regardless of comprehension. Subjective comprehension was lower among women who had not yet reached screening age but the deterrent effect was higher.     

Complexities in the estimation of overdiagnosis in breast cancer screening

There is interest in estimating and attributing temporal changes in incidence of breast cancer in relation to the initiation of screening programmes, in particular to estimation of overdiagnosis of breast cancer as a result of screening. In this paper, we show how screening introduces complexities of analysis and interpretation of incidence data. For example, lead time brings forward time- and age-related increases in incidence. In addition, risk factors such as hormone replacement therapy use have been changing contemporaneously with the introduction of screening. Although we do not indicate exactly how such complexities should be corrected for, we use some simple informal adjustments to show how they may account for a substantial proportion of increased incidence, which might otherwise erroneously have been attributed to overdiagnosis. We illustrate this using an example of analysis of breast cancer incidence data from Sweden.     

Mean sojourn time, overdiagnosis, and reduction in advanced stage prostate cancer due to screening with PSA: implications of sojourn time on screening

This study aimed to assess the mean sojourn time (MST) of prostate cancer, to estimate the probability of overdiagnosis, and to predict the potential reduction in advanced stage disease due to screening with PSA. The MST of prostate cancer was derived from detection rates at PSA prevalence testing in 43 842 men, aged 50–69 years, as part of the ProtecT study, from the incidence of non-screen-detected cases obtained from the English population-based cancer registry database, and from PSA sensitivity obtained from the medical literature. The relative reduction in advanced stage disease was derived from the expected and observed incidences of advanced stage prostate cancer. The age-specific MST for men aged 50–59 and 60–69 years were 11.3 and 12.6 years, respectively. Overdiagnosis estimates increased with age; 10–31% of the PSA-detected cases were estimated to be overdiagnosed. An interscreening interval of 2 years was predicted to result in 37 and 63% reduction in advanced stage disease in men 65–69 and 50–54 years, respectively. If the overdiagnosed cases were excluded, the estimated reductions were 9 and 54%, respectively. Thus, the benefit of screening in reducing advanced stage disease is limited by overdiagnosis, which is greater in older men.     

Polygenic susceptibility to prostate and breast cancer: implications for personalised screening

Background:

We modelled the efficiency of a personalised approach to screening for prostate and breast cancer based on age and polygenic risk-profile compared with the standard approach based on age alone.

Methods:

We compared the number of cases potentially detectable by screening in a population undergoing personalised screening with a population undergoing screening based on age alone. Polygenic disease risk was assumed to have a log-normal relative risk distribution predicted for the currently known prostate or breast cancer susceptibility variants (N=31 and N=18, respectively).

Results:

Compared with screening men based on age alone (aged 55–79: 10-year absolute risk ⩾2%), personalised screening of men age 45–79 at the same risk threshold would result in 16% fewer men being eligible for screening at a cost of 3% fewer screen-detectable cases, but with added benefit of detecting additional cases in younger men at high risk. Similarly, compared with screening women based on age alone (aged 47–79: 10-year absolute risk ⩾2.5%), personalised screening of women age 35–79 at the same risk threshold would result in 24% fewer women being eligible for screening at a cost of 14% fewer screen-detectable cases.

Conclusion:

Personalised screening approach could improve the efficiency of screening programmes. This has potential implications on informing public health policy on cancer screening.     

Overdiagnosis of prostate carcinoma by screening: An estimate based on the results of the Florence Screening Pilot Study

Objectives: To estimate overdiagnosis (detection of latent carcinomas) as a consequence of screening for prostate cancer.Design: Based on actual screen (first or repeat) detected and interval prostate cancer rates observed in the Florence screening pilot study, a scenario was simulated where males aged 60 years (or 65) had six biennal screens and were followed up for four years. Overdiagnosis was determined as the proportional excess of cancers detected by screening with respect to that expected in its absence.Setting: City of Florence, Italy, from 1992 through 1995.Population: 2,740 resident males, aged 60 to 74 years.Results: Overdiagnosis was estimated to be 51% (95% confidence limits: 44%–55%) or 93% (85%–101%) for age 60 or 65 at entry. Comparison with other screening experiences obtaining higher detection rates suggests that a more aggressive screening approach could be associated with overdiagnosis estimates as big as 200%–250%.Conclusions: Screening for prostate cancer is associated with a relevant risk of overdioagnosis. As latent carcinomas can not be presently identified, this would lead to overtreatment in most overdiagnosed cases. The negative consequences of overdiagnosis (knowledge of having a cancer) and of overtreatment (impotence, incontinence, perioperatory death) may be extremely serious. In absence of any scientific evidence of screening benefits (if any) screening should not be recommended as a current practice, but should be limited to prospective controlled studies designed to assess its cost-effectiveness.     

Association of screening status,polygenic risk score and environmental risk factors with colorectal cancer incidence and mortality risks

Whether screening can attenuate the influence of genetic risk and environmental risk factors for colorectal cancer (CRC) mortality risk remains unknown. Our study is to investigate the association of the screening history, genetic risk and environmental risk factors with CRC incidence and mortality risks using UK Biobank data. Screening history was associated with lower CRC incidence (hazard ratio [HR]: 0.63, 95% confidence interval [CI]: 0.58-0.69) and mortality risk (HR: 0.56, 95% CI: 0.49-0.63). Compared to the HRs of participants with a low genetic risk, low environmental risk and no screening history, the HRs of participants with a high genetic risk, high environmental risk and no screening history were 3.42 (95% CI: 2.76-4.24) for CRC incidence and 3.36 (95% CI: 2.48-4.56) for CRC mortality. In contrast, the HRs of participants with a high genetic risk and no screening history, but a low environmental risk, were 1.92 (95% CI: 1.55-2.36) for CRC incidence and 1.88 (95% CI: 1.39-2.53) for CRC mortality. Furthermore, the HRs of participants with a high genetic risk and a low environmental risk, but a screening history were 1.62 (95% CI: 1.15-2.28) for CRC incidence and 1.77 (95% CI: 1.08-2.89) for CRC mortality. Participants benefited more substantially from screenings for CRC mortality than for CRC incidence risk. A higher environmental risk was associated with higher risk of CRC incidence and mortality within each category of genetic risk. These findings emphasize the importance of CRC screening and identifying environmental factors to reduce CRC incidence and mortality risks.     

As you like it: How the same data can support manifold views of overdiagnosis in breast cancer screening

Overdiagnosis estimates have varied substantially, causing confusion. The discussions have been complicated by the fact that population and study design have varied substantially between studies. To help assess the impact of study design choices on the estimates, we compared them on a single population. A cohort study from Funen County, Denmark, recently suggested little (∼1%) overdiagnosis. It followed previously screened women for up to 14 years after screening had ended. Using publically available data from Funen, we recreated the designs from five high‐estimate, highly cited studies from various countries. Selected studies estimated overdiagnosis to be 25–54%. Their designs were adapted only to the extent that they reflect the start of screening in Funen in 1993. The reanalysis of the Funen data resulted in overdiagnosis estimates that were remarkably similar to those from the original high‐estimate age‐period studies, 21–55%. In additional analyses, undertaken to elucidate the effect of the individual components of the study designs, overdiagnosis estimates were more than halved after the most likely changes in the background risk were accounted for and decreased additionally when never‐screened birth cohorts were excluded from the analysis. The same data give both low and high estimates of overdiagnosis, it all depends on the study design. This stresses the need for a careful scrutiny of the validity of the assumptions underpinning the estimates. Age‐period analyses of breast cancer overdiagnosis suggesting very high frequencies of overdiagnosis rested on unmet assumptions. This study showed that overdiagnosis estimates should in the future be requested to adequately control for the background risk and include an informative selection of the studied population to achieve valid and comparable estimates of overdiagnosis.     

Overestimated lead times in cancer screening has led to substantial underestimation of overdiagnosis

Background:

Published lead time estimates in breast cancer screening vary from 1 to 7 years and the percentages of overdiagnosis vary from 0 to 75%. The differences are usually explained as random variations. We study how much can be explained by using different definitions and methods.

Methods:

We estimated the clinically relevant lead time based on the observed incidence reduction after attending the last screening round in the Norwegian mammography screening programme. We compared this estimate with estimates based on models that do not take overdiagnosis into account (model-based lead times), for varying levels of overdiagnosis. Finally, we calculated overdiagnosis adjusted for clinical and model-based lead times and compared results.

Results:

Clinical lead time was about one year based on the reduction in incidence in women previously offered screening. When overdiagnosed tumours were included, the estimates increased to 4–9 years, depending on the age at which screening begins and the level of overdiagnosis. Including all breast cancers detected in women long after the end of the screening programme dilutes the level of overdiagnosis by a factor of 2–3.

Conclusion:

When overdiagnosis is not taken into account, lead time is substantially overestimated. Overdiagnosis adjusted for model-based lead time is a function tending to zero, with no simple interpretation. Furthermore, the estimates are not in general comparable, because they depend on both the duration of screening and duration of follow-up. In contrast, overdiagnosis adjusted for clinically relevant tumours is a point estimate (and interpreted as percentage), which we find is the most reasonable method.     

The effect of study arm on prostate cancer treatment in the large screening trial ERSPC

Prostate cancer (PC) mortality is the most valid end‐point in screening trials, but could be influenced by the choice of initial treatment if treatment has an effect on mortality. In this study, PC treatment was compared between the screening and control arms in a screening trial. Data were collected from the European Randomized Study of Screening for Prostate Cancer (ERSPC). The characteristics and initial treatment of PC cases detected in the screening and the control arm were compared. Polytomous logistic regression analysis was used to assess the influence of study arm on treatment, adjusting for potential confounders and with statistical imputation of missing values. A total of 8,389 PC cases were detected, 5,422 in the screening arm and 3,145 in the control arm. Polytomous regression showed that trial arm was associated with treatment choice after correction for missing values, especially in men with high‐risk PC. A control subject with high‐risk PC was more likely than a screen subject to receive radiotherapy (OR: 1.43, 95% CI: 1.01–2.05, p = 0.047), expectant management (OR: 2.92, 95% CI: 1.33–6.42, p = 0.007) or hormonal treatment (OR: 1.77, 95% CI: 1.07–2.94, p = 0.026) instead of radical prostatectomy. However, trial arm had only a minor role in treatment choice compared to other variables. In conclusion, a small effect of trial arm on treatment choice was seen, particularly in men with high‐risk PC. Therefore, differences in treatment between arms are unlikely to play a major role in the interpretation of the results of the ERSPC.     

Identifying and characterizing "escapes"-men who develop metastases or die from prostate cancer despite screening (ERSPC, section Rotterdam)

We aim to identify and characterize "escapes," men who developed metastasis and/or died from prostate cancer (PCa) despite screening, in the framework of the novel international ESCAPE-project. With this knowledge, the ultimate goal is to improve screening strategy. In this article, we focus on the study cohort of the European Randomized Study of Screening for Prostate Cancer (ERSPC), section Rotterdam. In all, 21,210 men were randomized to the screening arm of whom 19,950 were actually screened. The screening interval was 4 years. Men with prostate-specific antigen ≥3.0 ng/ml were recommended to undergo lateralized sextant prostate biopsy. The follow-up was complete until January 1, 2009. Of 19,950 screened men, 2,317 were diagnosed with PCa. Of these cancers 1,946 were detected in a screening round and 371 during an interval. The median follow-up was 11.1 years for the whole cohort and 7.3 years for men diagnosed with PCa. In total, we identified 168 escapes among 2,317 cancers (7.3%) within our screening cohort of 19,950 men (0.8%). More than half of these escapes were found in the initial screening round (94 of 168). Possible mechanisms behind escaping are nonattending, inadequate screening tests, the relative long screening interval, the age cut-off at 75 years, and undertreatment. International cooperation is crucial to compare the escapes of our cohort with other study groups participating in the ESCAPE-project which have different, more aggressive screening strategies. Subsequently, we can achieve improvements of the current screening algorithm, which hopefully will further decrease PCa-specific mortality without increasing overdiagnosis and overtreatment.     

The impact of overdiagnosis on the selection of efficient lung cancer screening strategies

The U.S. Preventive Services Task Force (USPSTF) recently updated their national lung screening guidelines and recommended low‐dose computed tomography (LDCT) for lung cancer (LC) screening through age 80. However, the risk of overdiagnosis among older populations is a concern. Using four comparative models from the Cancer Intervention and Surveillance Modeling Network, we evaluate the overdiagnosis of the screening program recommended by USPSTF in the U.S. 1950 birth cohort. We estimate the number of LC deaths averted by screening (D) per overdiagnosed case (O), yielding the ratio D/O, to quantify the trade‐off between the harms and benefits of LDCT. We analyze 576 hypothetical screening strategies that vary by age, smoking, and screening frequency and evaluate efficient screening strategies that maximize the D/O ratio and other metrics including D and life‐years gained (LYG) per overdiagnosed case. The estimated D/O ratio for the USPSTF screening program is 2.85 (model range: 1.5–4.5) in the 1950 birth cohort, implying LDCT can prevent ～3 LC deaths per overdiagnosed case. This D/O ratio increases by 22% when the program stops screening at an earlier age 75 instead of 80. Efficiency frontier analysis shows that while the most efficient screening strategies that maximize the mortality reduction (D) irrespective of overdiagnosis screen through age 80, screening strategies that stop at age 75 versus 80 produce greater efficiency in increasing life‐years gained per overdiagnosed case. Given the risk of overdiagnosis with LC screening, the stopping age of screening merits further consideration when balancing benefits and harms.     

Estimating breast cancer mortality reduction and overdiagnosis due to screening for different strategies in the United Kingdom

Background:

The benefits and harms of population-wide mammography screening have been long debated. This study evaluated the impact of screening frequency and age range on breast cancer mortality reduction and overdiagnosis.

Methods:

We developed a Markov simulation model for the evaluation of mammography screening in a cohort of British women born in 1935–40.

Results:

For triennial screening in women aged 47–73, breast cancer mortality reduction and overdiagnosis was 18.1% (95% confidence interval: 17.3%, 19.0%) and 5.6% (5.1%, 6.1%), of all breast cancer deaths and diagnoses, respectively, from age 40 to 85 years. For annual screening in the same age range, estimates for both outcomes increased considerably to 35.0% (34.2%, 35.7%) and 7.6% (7.1%, 8.1%), respectively. For the age extension of triennial screening from 50–70 to 47–73, we estimated 5 (3, 7) incremental breast cancer deaths avoided and 14 (9, 19) incremental cases overdiagnosed per 10 000 women invited for screening.

Conclusions:

Estimates of mortality reduction and overdiagnosis were highly dependent on screening frequency, age range, and uptake, which may explain differences between some previous estimates obtained from randomised trials and from service screening.     

Effect of the correction for noncompliance and contamination on the estimated reduction of metastatic prostate cancer within a randomized screening trial (ERSPC section Rotterdam)

The European Randomized study of Screening for Prostate Cancer (ERSPC) has recently reported a 20% reduction in death from prostate cancer in a population‐based prostate cancer screening (core age group: 55–69 years of age). The effect of screening may be diluted by noncompliance in the screening arm and contamination by PSA testing in the control arm. The purpose is to analyze the effect of prostate cancer screening on the incidence of metastatic prostate cancer, both with and without adjustment for noncompliance and contamination. We analyzed the occurrence of metastases in 42,376 men aged 55–75 years who were randomized in the Rotterdam section of the ERSPC between 1993 and 1999. Contamination adjustment was based on follow‐up findings and questionnaire data from all men in the control group who developed prostate cancer and from a random sample of 291 men without cancer who had a PSA test. Prostate cancer screening significantly reduced the occurrence of metastatic prostate cancer in the intention‐to‐screen analysis [RR 0.75, 95% CI 0.59–0.95, p = 0.02] and more so in adjusted analyses; contamination adjusted RR 0.73, 95% CI 0.56–0.96; noncompliance adjusted RR 0.72, 95% CI 0.55–0.95 and fully adjusted analysis RR 0.68, 95% CI 0.49–0.94, p = 0.02. In the population of ERSPC Rotterdam (N = 42,376 men), screening reduces the risk to be diagnosed with metastatic prostate cancer considerably on population level, an effect which is even more pronounced in men who are in fact screened.     

Excess cases of prostate cancer and estimated overdiagnosis associated with PSA testing in East Anglia

This study aimed to estimate the extent of 'overdiagnosis' of prostate cancer attributable to prostate-specific antigen (PSA) testing in the Cambridge area between 1996 and 2002. Overdiagnosis was defined conceptually as detection of prostate cancer through PSA testing that otherwise would not have been diagnosed within the patient's lifetime. Records of PSA tests in Addenbrookes Hospital were linked to prostate cancer registrations by NHS number. Differences in prostate cancer registration rates between those receiving and not receiving prediagnosis PSA tests were calculated. The proportion of men aged 40 years or over with a prediagnosis PSA test increased from 1.4 to 5.2% from 1996 to 2002. The rate of diagnosis of prostate cancer was 45% higher (rate ratios (RR)=1.45, 95% confidence intervals (CI) 1.02-2.07) in men with a history of prediagnosis PSA testing. Assuming average lead times of 5-10 years, 40-98% [corrected] of the PSA-detected cases were estimated to be overdiagnosed. In East Anglia, from 1996 to 2000, a 1.6% excess of cases was associated with PSA testing (around a quarter of the 5.3% excess incidence cases observed in East Anglia from 1996 to 2000). Further quantification of the overdiagnosis will result from continued surveillance and from linkage of incidence to testing in other hospitals.     

Prostate cancer mortality reduction by screening: power and time frame with complete enrollment in the European Randomised Screening for Prostate Cancer (ERSPC) trial

From 1992-2001, 7 countries in Europe gradually recruited men for the European Randomised Screening for Prostate Cancer (ERSPC) trial. Centres recruit different age groups and have different designs for recruiting and countries have different underlying risks for prostate cancer. Recruitment has reached 163,126 men aged 55-69 at entry now. Our purpose was to calculate the power of the trial and at what point in time can statistically significant differences in prostate cancer mortality be expected. Recruitment data were collected from the screening centres. We calculated the expected number of prostate cancer deaths in each follow-up year, based on national statistics and expected rate in trial entrants. The power was calculated using different assumptions on intervention effect and contamination rate and also if the ERSPC trial would cooperate with other trials. With an assumed 25% intervention effect in men actually screened and a 20% contamination rate, the trial will reach a power of 0.86 in 2008. With an assumed intervention effect of 40%, the power reaches 0.90 in 2003-2004. Pooling data with those of the Prostate, Lung, Colorectal and Ovary (PLCO) trial early is expected to improve the power to 79% (20% intervention effect) to 92% (40% intervention effect PLCO). Adding more centres with compliance rates lower than 45% decreases the power of the trial. The ERSPC trial has sufficient power to detect a significant difference in prostate cancer mortality between the 2 arms if the true reduction in mortality by screening is 25% or more or if contamination remains limited to 10% if the true effect is 20% or more. If early detection and treatment turns out to have a stronger effect as may be suggested by observational data, the ERSPC trial is likely to conclusively show that within the next 5 years.     

Overdiagnosis due to breast cancer screening: updated estimates of the Helsinki service study in Finland

Background:

Overdiagnosis is the most important adverse event of breast cancer screening with the estimates ranging from 0% to 40–50% depending on invitational age and methods. We updated the estimates of overdiagnosis in Helsinki service screening study in Finland by comparing the observed and expected cumulative incidence of all breast carcinomas and invasive breast carcinomas.

Methods:

Women aged 50–59 years have been invited to Helsinki service screening since 1986. The incidence of breast carcinoma in the first invited birth cohorts born in 1935–1939 was compared with older, non-invited cohorts. The minimum follow-up time of the invitees after the last screening round was 14 years. Expected cumulative incidence rates were estimated with two alternative approaches.

Results:

For both any breast carcinoma and invasive breast carcinoma, the estimates of overdiagnosis varied from 5% (95% CI=−1, 11%) to 7% (95% CI=1, 13%) depending on the approach.

Conclusions:

Our estimates of overdiagnosis are of the same magnitude than other plausible estimates in Europe. Both alternative approaches produced similar estimates for the expected cumulative incidence, which increased the confidence in the estimates of overdiagnosis.     

Screening for prostate cancer in the US? Reduce the harms and keep the benefit

While the benefit of prostate‐specific antigen (PSA) based screening is uncertain, a significant proportion of screen‐detected cases is overdiagnosed. In order to make screening worthwhile, it is necessary to find policies that minimize overdiagnosis, without significantly increasing prostate cancer mortality (PCM). Using a microsimulation model (MISCAN) we project the outcomes of 83 screening policies in the US population, with different start and stop ages, screening frequencies, strategies where the PSA value changes the screening frequency, and strategies in which the PSA threshold (PSAt) increases with age. In the basecase strategy, yearly screening 50–74 with a PSAt of 3, the lifetime risk of PCM and overdiagnosis equals, respectively, 2.4 and 3.8%. The policies that reduce overdiagnosis the most (for maximum PCM increases relative to basecase of 1%, 3%, and 5%, respectively) are with a PSAt of 3, (1) yearly screening 50–74 where, if PSA <1 at age 65 or older, frequency becomes 4 years, with 3.6% (5.9% reduction), (2) 2‐year screening 50–72, with 2.9% (24.3% reduction), and (3) yearly screening 50–70 (PSAt of 4 after age 66), with 2.2% (43.4% reduction). Stopping screening at age 70 is a reasonable way to reduce the harms and keep the benefit. Decreasing the stopping age has a larger effect on overdiagnosis reduction than reducing the screen frequency. Screening policies where the frequency of screening depends on PSA result or in which the PSAt changes with age did not substantially improve the balance of harms and benefits relative to simple yearly screening.     

African‐specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross‐validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10‐fold cross‐validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross‐validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47‐4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65‐0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.