The benefits and harms of breast cancer screening in Australia

The introduction of screening mammography in Australia has been associated with an increase in the incidence of early-stage breast cancer. Concern is growing about the problems caused when women are diagnosed with breast cancer and undergo treatments that do not benefit them because their cancer would not progress, or would progress, but would not become symptomatic within the remaining lifetime of the patient. This is known as overdiagnosis. Screening mammography aims to decrease breast cancer morbidity and mortality by advancing in time the diagnosis and thereby increasing the chance of successful treatment. But overdiagnosis and the consequent overtreatment can cause serious lifelong harm and are therefore considered the major downsides of breast screening. Mounting evidence of the extent of overdiagnosis has led to the recognition that the benefits and harms of breast screening are finely balanced, and women need to know the magnitude of the trade-offs. The extent of overdiagnosis due to breast screening is contested, with published estimates ranging from 1% to 57%. There is a critical need for research investigating the harm to benefit ratio in Australia and quantification of the effects of screening mammography on the incidence of stage-specific breast cancer and overdiagnosis. Individual women require information about the impact of regularly attending screening mammography on breast cancer mortality and overdiagnosis to make informed decisions. A challenge to estimating this in a randomised controlled trial is nonadherence to the trial protocol. Previous systematic reviews have provided estimates of the effect of receiving an invitation to screening on the risk of dying due to breast cancer. Chapter 2 presents a meta-analysis of the screening mammography trials using a simple adjustment that estimates the probability of a reduction in breast cancer mortality and risk of overdiagnosis due to the effect of receiving screening by regularly participating in a breast screening program. Adjustment for nonadherence increased the size of the size of the effect by up to 50%. The prevented fraction of breast cancer mortality at 13-year follow-up increased from 0.22 to 0.30 with deattenuation. The percentage risk of overdiagnosis during the screening period in women invited to screening increased from 19.0% to 29.7%. From 2013 through 2017, the Australian national breast cancer screening programme gradually invited women aged 70 to 74 years to attend screening, following a policy decision to extend invitations to older women. Yet no formal evaluation of the effects of the change in policy on outcomes for women was undertaken. Building on my meta-analysis, in Chapter 3 I used a Markov model and applied the breast cancer mortality reduction and overdiagnosis estimates reported in Chapter 2 to Australian breast cancer incidence and mortality data to estimate the benefits and harms of the new package of biennial screening from age 50 to 74 compared with the previous programme of screening from age 50 to 69. I found that the extra five years of screening results in approximately seven more overdiagnosed cancers to avert one more breast cancer death. Thus extending screening mammography in Australia to older women results in a less favourable harm to benefit ratio than stopping at age 69. To identify temporal trends in stage-specific breast cancer in Australia, I used an observational study design to analyse data on women who received a diagnosis of breast cancer from 1972 to 2012 as recorded in the New South Wales Cancer Registry (Chapter 4). I explored trends in stage-specific incidence before screening and compared them to periods after screening began. I found that screening was not associated with lower incidence of late-stage breast cancer at diagnosis and incidence for all stages remained higher than prescreening levels. In women aged 50 to 69 years, the incidence of carcinoma in situ, localised and regional breast cancer has more than doubled compared to the prescreening era. The data presented in Chapter 4 indicate that excess detection of breast cancer is a problem in New South Wales. Thus I designed an ecological study to quantify overdiagnosis. I estimated the background trend of increasing incidence using two approaches, the first based on the prescreening trend in women of screening age (50 years and older), and the second based on the contemporary trend in women too young to be screened (40 to 44 years of age). From these trends, I estimated the expected age-standardised incidence of breast cancer, by stage at diagnosis, in the absence of screening, for women aged 50 years and over in the years since the national screening mammography program, BreastScreen, was introduced (1988 to 2012). I then calculated the difference in observed and expected incidence rates to determine the excess incidence of early-stage breast cancer and reduction in the incidence of late-stage disease. I found that screening mammography has resulted in overdiagnosis of early-stage and regional breast cancer. I estimate that around six additional cases of early and regional breast cancer are detected for every distant metastatic breast cancer prevented. Due to the substantial increase in detection of carcinoma in situ of the breast observed in Chapter 4, I explored sub-types and causes of this. Chapter 6 presents a descriptive analysis of temporal trends in the incidence of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) in women who received a diagnosis from 1972 to 2012, recorded in the NSW Cancer Registry. Carcinoma in situ as a proportion of all breast cancer increased dramatically, and incidence of DCIS across all ages rose from 0.15 per 100,000 during 1972 to 1983 to 16.81 per 100,000 over 2006 to 2012, with the greatest increase seen among women in the target age group for screening (50 to 69 years). DCIS incidence has not stabilized despite screening being well established for over 20 years, and participation rates in the target age range remaining stable. Our observational estimate of overdiagnosis from Chapter 5 is different to those from meta-analyses of randomised controlled trials of screening mammography and some other observational studies. Thus the final paper in this thesis presents a Cochrane Protocol on Overdiagnosis due to screening mammography for women aged 40 years and older (Chapter 7). We present methodology to identify and evaluate all primary epidemiological studies that have quantified overdiagnosis resulting from screening mammography and provide estimates of its frequency (including randomised and observational studies). An approach to assessing the risk of bias due to lead time is also discussed. Trying to quantify the benefits and harms of screening mammography and present them to women using natural frequencies should better enable informed choice, and is consistent with the international shift towards promoting and supporting shared decision making for screening. This thesis provides valuable new evidence about the trade-offs of screening mammography in Australia. The finding that risk of harm is greater than the chance of benefit is consistent with international studies of breast screening and demonstrates the importance of continuing this work to better quantify overdiagnosis for women, clinicians, and policymakers

Overdiagnosis due to screening mammography for women aged 40 years and over

This is a protocol for a Cochrane Review. The objective was to assess the effect of screening mammography for breast cancer on overdiagnosis in women aged 40 years and older at average risk of breast cancer

Overdetection in breast cancer screening: Development and preliminary evaluation of a decision aid

Objective: To develop, pilot and refine a decision aid (ahead of a randomised trial evaluation) for women around age 50 facing their initial decision about whether to undergo mammography screening. Design: Two-stage mixed-method pilot study including qualitative interviews (n=15) and a randomised comparison using a quantitative survey (n=34). Setting: New South Wales, Australia. Participants: Women aged 43–59 years with no personal history of breast cancer. Interventions: The decision aid provides evidence-based information about important outcomes of mammography screening over 20 years (breast cancer mortality reduction, overdetection and false positives) compared with no screening. The information is presented in a short booklet for women, combining text and visual formats. A control version produced for the purposes of comparison omits the overdetection-related content. Outcomes: Comprehension of key decision aid content and acceptability of the materials. Results: Most women considered the decision aid clear and helpful and would recommend it to others. Nonetheless, the piloting process raised important issues that we tried to address in iterative revisions. Some participants found it hard to understand overdetection and why it is of concern, while there was often confusion about the distinction between overdetection and false positives. In a screening context, encountering balanced information rather than persuasion appears to be contrary to people’s expectations, but women appreciated the opportunity to become better informed. Conclusions: The concept of overdetection is complex and new to the public. This study highlights some key challenges for communicating about this issue. It is important to clarify that overdetection differs from false positives in terms of its more serious consequences (overtreatment and associated harms). Screening decision aids also must clearly explain their purpose of facilitating informed choice. A staged approach to development and piloting of decision aids is recommended to further improve understanding of overdetection and support informed decision-making about screening.National Health and Medical Research Counci

How information about overdetection changes breast cancer screening decisions: a mediation analysis within a randomised controlled trial

Objectives: In a randomised controlled trial, we found that informing women about overdetection changed their breast screening decisions. We now present a mediation analysis exploring the psychological pathways through which study participants who received the intervention processed information about overdetection and how this influenced their decision-making. We examined a series of potential mediators in the causal chain between exposure to overdetection information and women’s subsequently reported breast screening intentions. Design: Serial multiple mediation analysis within a randomised controlled trial. Setting: New South Wales, Australia. Participants: 811 women aged 48–50 years with no personal history of breast cancer. Interventions: Two versions of a decision aid giving women information about breast cancer deaths averted and false positives from mammography screening, either with (intervention) or without (control) information on overdetection. Main outcome: Intentions to undergo breast cancer screening in the next 2–3 years. Mediators: Knowledge about overdetection, worry about breast cancer, attitudes towards breast screening and anticipated regret. Results: The effect of information about overdetection on women’s breast screening intentions was mediated through multiple cognitive and affective processes. In particular, the information led to substantial improvements in women’s understanding of overdetection, and it influenced—both directly and indirectly via its effect on knowledge—their attitudes towards having screening. Mediation analysis showed that the mechanisms involving knowledge and attitudes were particularly important in determining women’s intentions about screening participation. Conclusions: Even in this emotive context, new information influenced women’s decision-making by changing their understanding of possible consequences of screening and their attitudes towards undergoing it. These findings emphasise the need to provide good-quality information on screening outcomes and to communicate this information effectively, so that women can make well-informed decisions. Trial registration number: This study was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12613001035718) on 17 September 2013.This work was supported by the National Health and Medical Research Council of Australia through project grant number 1062389

Meta-analysis of breast cancer mortality benefit and overdiagnosis adjusted for adherence: improving information on the effects of attending screening mammography

Background: Women require information about the impact of regularly attending screening mammography on breast cancer mortality and overdiagnosis to make informed decisions. To provide this information we aimed to meta-analyse randomised controlled trials adjusted for adherence to the trial protocol. Methods: Nine screening mammography trials used in the Independent UK Breast Screening Report were selected. Extending an existing approach to adjust intention-to-treat (ITT) estimates for less than 100% adherence rates, we conducted a random-effects meta-analysis. This produced a combined deattenuated prevented fraction and a combined deattenuated percentage risk of overdiagnosis. Results: In women aged 39–75 years invited to screen, the prevented fraction of breast cancer mortality at 13-year follow-up was 0.22 (95% CI 0.15–0.28) and it increased to 0.30 (95% CI 0.18–0.42) with deattenuation. In women aged 40–69 years invited to screen, the ITT percentage risk of overdiagnosis during the screening period was 19.0% (95% CI 15.2–22.7%), deattenuation increased this to 29.7% (95% CI 17.8–41.5%). Conclusions: Adjustment for nonadherence increased the size of the mortality benefit and risk of overdiagnosis by up to 50%. These estimates are more appropriate when developing quantitative information to support individual decisions about attending screening mammography

Characterizing Prostate Cancer Risk Through Multi-Ancestry Genome-Wide Discovery of 187 Novel Risk Variants

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups

A Comparative Risk Assessment Of Burden Of Disease And Injury Attributable To 67 Risk Factors And Risk Factor Clusters In 21 Regions, 1990–2010: A Systematic Analysis For The Global Burden Of Disease Study 2010

Background Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time

Demonstration of Classic Screening Biases, Not Additional Benefit of Annual Over Biennial Screening.

Letter to edito

Screening for cervical, prostate, and breast cancer: Interpreting the evidence

Cancer screening is an important component of prevention and early detection in public health and clinical medicine. The evidence for cancer screening, however, is often contentious. A description and explanation of disagreements over the evidence for cervical, breast, and prostate screening may assist physicians, policymakers, and citizens faced with screening decisions and suggest directions for future screening research. There are particular issues to be aware of in the evidence base for each form of screening, which are summarized in this paper. Five tensions explain existing conflicts over the evidence: (1) data from differing contexts may not be comparable; (2) screening technologies affect evidence quality, and thus evidence must evolve with changing technologies; (3) the quality of evidence of benefit varies, and the implications are contested; (4) evidence about harm is relatively new, there are gaps in that evidence, and there is disagreement over what it means; and (5) evidence about outcomes is often poorly communicated. The following principles will assist people to evaluate and use the evidence: (1) attend closely to transferability; (2) consider the influence of technologies on the evidence base; (3) query the design of meta-analyses; (4) ensure harms are defined and measured; and (5) improve risk communication practices. More fundamentally, there is a need to question the purpose of cancer screening and the values that inform that purpose, recognizing that different stakeholders may value different things. If implemented, these strategies will improve the production and interpretation of the methodologically challenging and always-growing evidence for and against cancer screening