[MUSIC] Hello, I'm Jean-Luc Bulliard. Welcome to this lecture dedicated to breast cancer screening. In this lecture, I will present the burden and risk factors of breast cancer. I will then discuss evidence about mammography screening effectiveness, efficacy, and harms. Finally, I will address other screening methods for breast cancer, and some important challenges and issues for the near future. Breast cancer is an important public health problem. It is the most common cancer in women in about 140 countries, and the main cause of cancer deaths in over 100 countries. Each year, 1.7 million women are diagnosed with breast cancer in the world, which represent one cancer in four in the female population. And over half a million women die of breast cancer. Established risk factors for breast cancer, can be grouped in three categories, as shown in the table. Host or personal factors. Hormonal and reproductive factors. And factors associated with lifestyle. Host factors include age, density of breast tissue, family and personal history of breast cancer. Genetic predisposition, for example BRCA1 or BRCA2 gene carriers, having a previous breast biopsy or benign breast disease, and height. All the factors can be endogenous, such as an early menarche, that is early onset of puberty, or late menopause. Or can be exogenous, such as intake of estrogen or progestogen as oral contraceptives, or as hormone-replacement therapy. Lifestyle or environmental factors, include alcohol and tobacco consumption, being overweight after the menopause, and exposure to ionising radiation. Only few of the known risk factors, can be modified by primary prevention. Age and breast density are probably the single largest risk factors, with the risk increasing with age and relative density of the breast tissue. Most breast cancers occurs after 50 years of age, and after menopause. So primary prevention mainly focuses on general health promotion. The five individual action against breast cancer, recommended in the fourth edition of the European Code against Cancer in 2015, are to breastfeed your baby, to be physically active in everyday life. To not smoke or use any form of tobacco. To limit your alcohol consumption, and to limit the use of hormone replacement therapy. The health benefits of this prevention actions, clearly extend beyond breast cancer avoidance. The main reason why breast cancer is the first cause of cancer death in many countries, particularly in low and middle-income countries, is because a high proportion of women present with advanced disease, which leads to poor prognosis. In this context, it was a limited potential of primary prevention, screening through early detection in asymptomatic women, has been the main prevention tool used to reduce mortality from breast cancer, as well as the morbidity associated with advanced disease. Mammography is the most common method of screening for breast cancer. Indeed, mammography screening has become an established part of women's healthcare, and is available, to a great extent, in many high-income countries, through either opportunistic or organized programs. Mammography has been one of the most investigated cancer screening methods. So with abundant evidence, efficacy, and the effectiveness of mammography screening, no less than 11 randomized controlled trials, have been conducted involving more than 650,000 women. These trials indicated overall an average reduction in breast cancer mortality of about 20%, with regular invitation to mammography screening for women age 50 to 69 years. The multitude of this over benefit, has been questioned by some. Notably, due to true differences and uneven quality, across these randomized controlled trials, potential residual biases in some trials, and differences in the benefit estimated by these trials. But since an independent panel in England concluded in the meta analysis in 2013, that 20% reductions was still the most reasonable estimate of the effect of randomized control trials, on breast cancer mortality. There is a general agreement about this order of magnitude. It was also nicely demonstrated that in each individual trial, each person decreased in the incidence of advanced breast cancer, corresponded to an equal decrease in breast cancer mortality. However, all randomized controlled trials, were conducted at least 20 to 30 years ago. And the relevance of these old trials is now being questioned. Major improvements have occurred since. In mammographic tests, there's been the advent of digital mammography, and a requirement for higher quality standards of radiologists and radiographers, involved in the screening process. Treatment of breast cancer has also substantially improved, notably with therapies. Recent estimates of the effectiveness of breast cancer screening, come from observational studies and ongoing programs. But women participating in mammography screening programs, are likely to have a different background risk, than non-participant, which would often over-estimate the mortality reduction. Many question and some simply refute, evidence coming from studies where the comparability between screened and unscreened women, cannot be ensured. These particular points have been discussed in another lecture. In the handbook on breast cancer screening released in 2016, the International Agency for Research on Cancer has been the first to also include in their review, evidence from high quality, non-randomized studies with long follow-up periods. Inclusion of the latest evidence based on nonrandomized studies, did not influence much the magnitude of the benefit from regular mammography screening. The handbook working group concluded that women invited to a mammography screening, had on average, a 23% reduction in the risk of dying from breast cancer. The strength of evidence was deemed sufficient, not only for the age of 50 to 69, but also for women aged 70 to 74. For women aged 40 to 49, the benefit of mammography screening is less, with evidence still considered to be limited. For women who choose to regularly attend mammography screening, the expected benefit is of course larger, with an estimated 40% reduction in risk of deaths from breast cancer. Expressed in absolute risk, these multidirection means that out of 100 women invited to bi-annual mammography screening over 20 years, one death from breast cancer will be prevented. Two deaths are prevented, if we focus on 100 women regularly attending screening. Recent evaluations of mammography screening have also quantified the harms of screening. The two most important recognized harms associated with mammography screening, are currently false-positive results and overdiagnosis. At least one 50-year-old woman in 5, screened 10 times over 20 years, as is practiced in most screening programs, experiences a false-positive result at least once. But only about 1 in 20 false-positive screens requires an invasive procedure. Strong evidence indicates that false-positive results generate short-term negative psychological consequences, such as anxiety and health care costs. Overdiagnosis is difficult to measure and the optimal method for estimation is an ongoing debate and research topic. Therefore, there are few reliable sources of data to quantify this harm. I'll remind you that overdiagnosis was not a primary end point in any of the randomized controlled trials. The most reliable estimates of overdiagnosis, indicate that between 6 and 11% of cancers diagnosed in women invited to screening, constitutes overdiagnosis. But estimates vary hugely across studies. It ranges from near 0 to about 50%. Putting together benefit and overdiagnosis, the current best evidence suggests that women are at least three times more likely to be overdiagnosed, than to have their life saved by screening. Is this balance of benefit and harm acceptable? Well, it depends on societal and individual values and choices. This balance for breast cancer, is more favorable than for prostate and lung cancer screening. According to the handbook from the International Agency for Research on Cancer, the strength of evidence is sufficient to conclude that organized mammary screening, yields a net benefit from inviting women age 50 to 69. And can be cost effective in countries with a high incidence of breast cancer. The net benefit tends to increase with age, and is larger in women aged 60 to 69 than in women aged 50 to 59. The risk of radiation-induced breast cancer, has strongly decreased with improvements in mammographic equipment. Currently, more than 100 lives are saved by mammography screening for one radio-induced breast cancer. Radiation is therefore not considered anymore as a major hub of mammography screening, albeit every effort should be made to minimize radiation exposure of the breast tissue. I should remind you here that to achieve the greatest benefit from screening, early access to effective diagnostic and treatment services is essential. In parallel, it is also essential to have a comprehensive quality assurance to minimize harms of screening. What about other screening tests? Several imaging techniques, initially developed for diagnosis, are under investigation for population screening. Tomosynthesis, ultrasonography, magnetic resonance imaging. Positron-emission tomography, and positron-emission mammography, have been, or are being, investigated for their value as supplementary methods for screening. Digital breast tomosynthesis is a technique that derives from digital mammography. It enables a reconstruction of quasi 3-dimensional images, from a series of 2-dimensional projection images, which reduces the effect of tissue superimposition. And can improve mammography interpretation. Tomosynthesis, used as an adjunct to digital mammography, does increase the detection rate of breast cancer, and may also reduce false positive results. But robust evidence for reduction in breast cancer mortality is lacking. The cost of this technique is rather high, and the radiation dose delivered is roughly doubled, compared to mammography alone. Research trials are under way in some screening programs, to assess this technology for routine use. Clinical breast examination is a simple, inexpensive screening technique, which takes on importance in low and middle-income countries, where mammography is not feasible or not affordable. It enables a favorable shift in a stage distribution of cancers, and may slightly increase the detection rate, when used as an adjunct to mammography, as compared to mammography alone. But again, these positive effects have not yet led to reduction in breast cancer mortality. Breast self-examination, whether taught or practiced competently and regularly, does not yield any mortality benefit. The use of ultrasonography as an adjunct to mammography in women with dense breast and negative results on mammography, may increase the detection rate. But at the expense of more false-positive screening outcomes. In summary, screening methods other than mammography for the population, used loan or as an adjunct to mammography, have some proven beneficial effects. But none, has yet provided sufficient evidence of a significant reduction in breast cancer mortality. Breast cancer screening is a dynamic and active field. Among the many challenges and important issues to face in the near future, I would like to mention two in conclusion. The first is individualized screening. Who should be screened and how often? Population screening will likely move from an age-based to a more nuanced risk-based program. According to the individual risk, women could be screened less frequently or more intensively. The obvious advantage is to target resources for women most likely to benefit from screening, while at the same time, reducing screening interventions, and potential harm, for women at lower risk. The net benefit of screening will increase. Several individual risk models are currently being investigated. Challenges of a change to individualized screening programs, include the organizational aspects, the professional acceptability, the public tolerability. Notwithstanding, ethical, legal and societal consideration. For instance, in US, laws have recently been passed that requires clinicians to tell women when they have dense breasts, and inform them of the increased risk of breast cancer. And have additional screening tests available for the situation, such as ultrasound, and magnetic resonance imaging. The second challenge is to determine which breast cancers need to be treated. Some tumors detected by screening, are unlikely to cause trouble if left alone. Research is actively trying to identify genetic and molecular biomarkers, that could help to predict the cause of an individual tumor. Breast radiomics, an emerging field, they offer great promise for reducing overdiagnosis, by identifying image-based biomarkers, strongly associated with tumor biology. The potential gain is huge. A therapy could focus on cancer, which is pose a real threat, while saving women from harmful over treatment. Two prospective randomized trials, comparing standard surgery and therapy, versus the safety of active monitoring for low risk ductal carcinoma in situ, are ongoing. Results, in terms of the incidents of ipsilateral invasive breast cancer after ten years, will be available in a few years. Thank you for watching this video. [MUSIC]
