University of Groningen
Breast cancer screening in women at elevated risk
Phí, Xuân Anh
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Publication date: 2018
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Phí, X. A. (2018). Breast cancer screening in women at elevated risk: Comparative evaluation of screening modalities to inform practice. University of Groningen.
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CHAPTER 1
As an introduc on of the thesis, this chapter will briefly outline the ra onale and present the aims and structure of the thesis.
Ra onale
Breast cancer (BC) is the most frequent female cancer worldwide with an es mate of 1,67 million new cases in 2012 (25% of all cancers) and the leading cause of cancer-specific death in women (accoun ng for 14.3% of cancer deaths) (1). Among all diagnosed BCs, 10-15% are related to a gene c predisposi on and 5% of the BCs are related to a gene muta on (2,3). Among several gene muta ons related to BC risk, BRCA1 and BRCA2 are the most highly penetrant muta ons. Although the prevalence of these gene muta ons is low in the popula on (4,5), women carrying these muta ons are at very high risk of developing BC and ovarian cancer (6). In addi on, they are more likely to develop cancer at a younger age (7). Moreover, tumours occurring in these women have a faster tumour growth rate compared to sporadic BC (8,9). This poses a high burden of disease on predisposed women and represents a challenge for health-care providers to manage the risk of BC in this popula on of women and to improve outcomes in those affected.
Mammography is established as the standard screening modality for women at average risk in general popula on screening programs. However, due to the earlier age of onset of BC and the related increased tumour doubling me, general popula on screening programs which start screening women from age 50 are not an appropriate screening strategy for high risk popula ons. It is therefore recommended to screen high risk popula ons at younger age, more frequently and with addi onal imaging modali es to mammography. There are studies evalua ng intensive screening in women at substan ally increased risk for breast cancer including mammography and MRI, an approach now implemented in a hospital se ng in several countries using MRI and mammography (10,11). However, some uncertain es exists with regard to the op mal screening strategy, as reflected by the variability in interna onal guidelines (12-15). More in-depth evidence regarding screening in women at high risk according to their risk level and age is therefore needed, considering compara ve accuracy of mammography and MRI, to help re-evaluate and inform prac ce and policy makers on current guidelines.
Of relevance is the progressive improvement in mammography technology with the transi on from screen-film mammography to full film digital mammography, and more
recently the development and evalua on of digital breast tomosynthesis, so called '3D mammography', which has been studied for implementa on in prac ce. A key mo va on for this new technique is to overcome the disadvantage of 2D mammography in visualizing cancers in overlapping ssue and par cularly in mammographically dense breasts. Since women at increased BC risk tend to develop BC at a younger age (7) and the breasts are denser at a younger age, breast density is a factor to consider in the planning of screening more generally but par cularly in these women. Digital breast tomosynthesis (DBT or tomosynthesis) allows for reconstruc ons of a 3D representa on of the breast ssue in slices, unravelling parenchymal layers and overlapping dense ssue making it easier to visualize cancerous lesions. Further, the most recent DBT technology also allows for reconstruc on of high defini on synthe c 2D images of the breast (very similar to standard two-view mammography) which adds values in the diagnosis process (16). DBT is further thought to be a poten al alterna ve to mammography in screening women with mammographically dense breasts. However, most of the evidence so far has focused on screening accuracy in women at average risk and considered breast density as a confounder based on cohort studies (retrospec ve or prospec ve) with very short follow-up (17,18). More concrete evidence is thus needed on the value of DBT in women with dense breasts compared to standard mammography, to inform prac ce and further research in risk-tailored screening.
Aim of this thesis
This thesis firstly aims to inves gate screening accuracy and cost-effec veness of screening for high risk women using mammography and magne c resonance imaging (MRI) as an adjunct, according to their risk level and risk factors (type of BRCA muta on and age). The second aim is to summarize the evidence on the detec on capability of DBT in screening women with mammographically dense breasts compared to conven onal mammography. Structure of the thesis
Part 1 – An overview of screening women at high risk - current state of the art – consists of a published book chapter on screening women with known or suspected gene muta ons. In Chapter 2, the available evidence related to breast cancer screening in high risk popula ons is highlighted and discussed in detail, taking into account several aspects: gene c predisposi on to breast cancer, the penetrance and how it impacts the screening; benefits and harms of breast cancer screening in terms of cancer detec on, mortality reduc on, false
nega ves/posi ves, induced radia on risk and cost effec veness.
Part 2 – Evalua on of screening in high risk women – consists of three Individual pa ent data (IPD) meta-analyses and a cost-effec veness analysis, each addressing evidence gaps in this theme. An IPD meta-analysis is performed in chapter 3 and 4 on MRI and mammography screening in women with a BRCA1/2 muta on, repor ng compara ve screening accuracy in different age groups and different types of BRCA muta ons, aiming to provide evidence in terms of cancer detec on according to these strata. In chapter 5, using similar study methodology, screening accuracy in women without a known gene muta on but with a strong family history of BC is inves gated. Chapter 6, the last chapter of this part of the thesis, a cost-effec veness analysis is performed on intensive screening in women with a BRCA1/2 muta on a er age 60, comparing poten al screening strategies to the current guideline strategy.
Part 3 – Digital Breast Tomosynthesis – a poten al modality - consists of a systema c review and meta-analysis (Chapter 7) exploring the poten al of DBT in breast cancer screening in women with mammographically dense breasts. In this chapter, evidence from cohort studies either in screening or in the diagnos c se ng was synthesized considering screening accuracy of DBT compared to conven onal mammography.
The thesis concludes with a General discussion which summarizes the findings of all the chapters and discusses further on the methodology and the implica ons of the studies reported in this work. In addi on, future perspec ves will be discussed based on the evidence presented in this thesis.
Reference
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(2) Phelan CM, Lancaster JM, Tonin P, Gumbs C, Cochran C, Carter R, et al. Muta on analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet 1996 May;13(1):120-122.
(3) Claus EB, Risch N, Thompson WD. Gene c analysis of breast cancer in the cancer and steroid hormone study. Am J Hum Genet 1991 Feb;48(2):232-242.
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(10) Lord SJ, Lei W, Cra P, Cawson JN, Morris I, Walleser S, et al. A systema c review of the effec veness of magne c resonance imaging (MRI) as an addi on to mammography and ultrasound in screening young women at high risk of breast cancer. Eur J Cancer 2007 Sep;43(13):1905-1917.
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