Breast cancer: When to screen, if at all?
Breast cancer screening and the optimal age for offering mammography remain matters of debate. A randomized, controlled trial in over 150,000 women in the UK has found that yearly mammography before the age of 50 years, commencing at 40 or 41 years of age, is associated with a relative reduction in breast cancer mortality.
UK Age trial: Results after 23 years of follow-up
Between 1990 and 1997, a total of 160,921 women aged 39–41 years were randomly assigned in a 1:2 ratio to undergo yearly mammographic screening from the year of inclusion in the trial until the age of 49 years (intervention group), or standard care with no screening until the invitation to their first National Health Service (NHS) screen at approximately 50 years of age (control group). Between randomization and 2017, women were followed up for a median of 22.8 years. [Lancet Oncol 2020;21:1165-1172]
In the total follow-up period, there were 10,439 deaths, 683 (7 percent) of which were from breast cancer diagnosed during the intervention period. The primary endpoint of mortality from breast cancer diagnosed during the 10-year intervention period before the participant's first NHS screen was significantly lower in the intervention vs control group at 10 years of follow-up (83 vs 219 deaths; relative rate [RR], 0.75; 95 percent confidence interval [CI], 0.58 to 0.97; p=0.029). “[This represents] a substantial and significant reduction in breast cancer mortality, of the order of 25 percent, associated with the invitation to yearly mammography between age 40 and 49 years in the first 10 years,” wrote the researchers.
However, this effect was attenuated thereafter, with little or no effect of the intervention on breast cancer deaths occurring ≥10 years after randomization between the intervention and control groups (RR, 0.98; 95 percent CI, 0.79 to 1.22; p=0.86). “This reflects that the breast cancer deaths prevented by the intervention were in the first 10 years after randomization. However, there were no compensatory additional breast cancer deaths after 10 years of follow-up, and therefore the absolute benefit from the intervention remains the same in the long term,” commented the researchers.
There was a substantial reduction in mortality in the intervention group from grade 1 and 2 breast cancer, which can progress more rapidly in younger women. However, no difference was seen in mortality from grade 3 breast cancer. At an earlier analysis conducted after 17 years of follow-up, the researchers speculated that the absence of effect after 10 years could be due to a lesser effect of the intervention on mortality from grade 3 tumours, whereby some breast cancer deaths were postponed rather than prevented. [Lancet Oncol 2015;16:1123-1132] However, at 23 years of follow-up, the absolute reduction in breast cancer mortality was shown to remain approximately constant in the long term, confirming prevention as the main cause for this reduction.
The absolute difference in breast cancer mortality between the intervention and control groups was −0.6 deaths per 1,000 women invited for screening (95 percent CI, −1.3 to 0.1). “This corresponds to 1,667 women needing to be invited and, given the 69 percent average participation rate, needing to screen 1,150 women aged 40–49 years to prevent one breast cancer death,” reported the researchers.
Limitations and other considerations
One limitation of the study was that during the intervention period of the 1990s and early 2000s, considerable changes in diagnosis, screening, and therapy took place. “Since therapies have changed substantially in recent decades, there might be less scope for screening to reduce mortality in our current era,” the researchers wrote. “On the other hand, recent results suggest that even with effective adjuvant systemic therapies, there is still a substantial survival advantage from diagnosis and treatment at an early stage. Further evaluation of screening in women younger than 50 years, with modern screening and treatment protocols, is warranted.” [BMJ 2015;351h4901; Cancer 2019;125:515-523]
The average nonparticipation rate in the UK Age trial was 31 percent, and three out of 23 centres had to cease screening early because of capacity problems. [Lancet Oncol 2015;16:1123-1132; J Med Screen 2010;17:37-43] “These factors suggest that the mortality benefit observed in the trial is conservative,” pointed out the researchers.
Public health experts who question the value of breast cancer screening note that while mammograms save lives, for each breast cancer death prevented, several women are overdiagnosed. However, results of the UK Age trial suggest a modest overdiagnosis at worst when compared with the breast cancer incidence among women aged 40–49 years. “Any overdiagnosed cancers would otherwise be diagnosed at NHS screening from age 50 years onwards, and screening in the age group of 40–49 years does not appear to add to overdiagnosed cases from screening at age ≥50 years,” wrote the researchers.
Furthermore, a false-positive result on mammography is associated with increased medical costs from follow-up with more than one doctor, additional tests and procedures including a possible biopsy, as well as potential complications of follow-up procedures and psychological distress. [Hong Kong Med J 2007;13:106-113] In the UK Age trial, there were 2,134 (4.9 percent) false positives among 43,709 results at first intervention screen, and 7,041 (3.2 percent) false positives among 216,930 results at subsequent intervention screens. Of those attending screening during the intervention period, 7,893 (18.1 percent) of 43,709 women had ≥1 false-positive result. [Cancer Epidemiol Biomarkers Prev 2010;19:2758-2764]
Another way of evaluating value of cancer screening is estimating years of life lost to cancer in the intervention and control groups. In a post-hoc analysis, there were 8,442.5 (95 percent CI, 7766.2 to 9118.7) vs 3,632.4 (95 percent CI, 3201.1 to 4063.6) years of life lost to breast cancer in the control vs intervention group – equivalent to 78.9 vs 67.4 years per 1,000 women, respectively. “Thus, 11.5 [95 percent CI, 1.0 to 22.0] years of life were saved per 1,000 women invited [p=0.031], or 620 years of life saved in total,” reported the researchers.
Application in Hong Kong
In 2016, approximately a third of all breast cancers in Hong Kong occurred in women aged ≤50 years. While the incidence rate is increasing it remains lower than that in some Western countries (eg, UK or Australia). [Hong Kong Med J 2018;24:298-306]
In spite of the rising number of new cases and deaths of female breast cancer over the past three decades, and the fact that breast cancer accounted for 12.2 percent of female cancer deaths in Hong Kong in 2016, the Cancer Expert Working Group on Cancer Prevention and Screening’s (CEWG) latest guidance does not recommend population-based breast cancer screening. [Centre for Health Protection. Recommendations on Prevention and Screening for Breast Cancer. Available from: https://www.chp.gov.hk/files/pdf/breast_cancer_professional_hp.pdf] Instead, the CEWG recommends that all women adopt primary preventive measures, such as avoiding alcohol, maintaining a healthy body weight, undertaking moderate-intensity or equivalent aerobic physical activity for ≥150 minutes per week, bearing children at an earlier age, breastfeeding for a longer duration, and seeking timely medical attention in case of any suspicious symptoms.
For women at high risk, including BRCA1/2 deleterious mutation carriers (who account for approximately 8 percent of Hong Kong’s breast cancer patients), women with relevant family history of breast cancer, and recipients of radiation therapy to the chest at an early age, the CEWG recommends commencing screening at the age of 35 years or 10 years prior to the age at diagnosis of the youngest-affected relative. [Hong Kong Med J 2018;24:S4-S6] The recommendation for women at moderate risk (ie, those with family history of only one first-degree female relative diagnosed with breast cancer at ≤50 years of age or two first-degree female relatives diagnosed at >50 years of age) is to consider mammography every 2 to 3 years, after discussing with their doctor. [Hong Kong Med J 2018;24:298-306]
The lack of a recommendation for population-wide screening of average-risk women, which was last reaffirmed by CEWG in 2017, is informed by multiple reviews and long-term randomized screening studies from Western countries, some of which have highlighted unfavourable cost-effectiveness, reflective of the overdiagnosis and false-positive rates associated with screening. Furthermore, local modelling studies have shown that population-based mammography screening is not a cost-effective public health intervention in Hong Kong compared with other strategies to prevent and control breast cancer. [Hong Kong Med J 2010;16:38-41; Cancer 2012;118:4394-403]
It remains to be seen how the breast cancer screening research published in the last 3 years, including the UK Age trial, will impact Hong Kong’s public health policy.