HLA y fenotipo clínico

Early detection of breast cancer is crucial to improve its outcomes and overall survival (Anderson et al., 2008). Even though various methods are being used for breast cancer screening including: BSE, clinical examinations by physician, ultrasound, mammography, magnetic resonance imaging (MRI), and DNA testing (Allen et al., 2010; Maria Skłodowska- Curie Memorial Cancer Centre and Institute of Oncology, 2006; Ekiert et al., 2011) opinions vary as to which combinations of screening techniques are the most effective for identifying breast cancer (Chiu, 2002; Thornton and Pillarisetti, 2008). None of the screening examinations have a sensitivity of 100% and especially BSE has been questioned as a method of breast cancer detection (Allen et al., 2010). It has been highlighted that women need to be clearly informed about the inadequacy of BSE as part of screening (Chiu, 2002; Thornton and Pillarisetti, 2008). Nonetheless, BSE is still frequently perceived and recommended as a tool raising breast cancer awareness through empowering women to take responsibility for their own health (Thornton and Pillarisetti, 2008; Allen et al., 2010; WHO, 2011b).

Mammography is the most common detection method used in organised mass breast cancer screening programmes and since the early years of screening there have been substantial improvements in screening methods (Blanks et al., 2002; Advisory Committee on Breast Cancer Screening, 2006). Mammographic screening sensitivity, in particular forsmall invasive cancers, was improved as a result of the increased use oftwo view mammography, higher film densities, and the increasing experience of radiologists (Blanks et al., 2002; Advisory Committee on Breast Cancer Screening, 2006). Mammographic screening is effective in decreasing breast cancer mortality by up to 30% in women over the 50 years old (Nystrom, 1993; Shapiro, 1998; IARC, 2002; IARC, 2008; Gotzsche and Nielsen, 2011; Tria Tirona, 2013) but its benefit versus potential harms has been extensively debated (Independent UK Panel on Breast Cancer Screening, 2012; Gotzsche and Nielsen, 2011). A Cochrane review by Gøtzsche and Nielsen (2011) reviewed randomised trials and concluded that due to differential cause of death misclassification breast cancer mortality was an unreliable outcome. Adequately randomised studies (N=3) failed to produce conclusive evidence of mortality reduction due to screening but the sub optimally randomised (N=4) produced significant

results of reduced mortality. Risk ratio for all of the trials was 0.81 (95% CI 0.74-0.87) and authors stated that it is likely to achieve breast cancer mortality reduction (15%) through screening. It was also noted that screening leads to over diagnosis in 30% and therefore it may result in over treatment (Gotzsche and Nielsen, 2011). Over diagnosis has been stipulated to be one of the most significant screening harms as it happens due to small cancers being detected early resulting in higher incidence being reported (Independent UK Panel on Breast Cancer Screening, 2012). If some of the smaller cancers are not found through the screening they might never progress substantially before the woman dying for another reason never knowing of the existence of her cancer. Various prospective randomized studies demonstrated the lack of a high benefit from screening women younger than 50 and several potentially harmful screening outcomes such as radiation exposure, over diagnosis, lead time, higher number of false positive results in younger women, and costs) (Jatoi and Miller, 2003; National Institute of Health (NIH) Consensus Statement, 1997; Primic-Zakelj, 1999; Nelson et al., 2009). Other studies also confirmed that 40 to 49 year old women have also more false- positive results than other age groups (Nelson et al., 2009; Gotzsche and Nielsen, 2011). Similarly the latest literature review by Kerlikowske (2012) pointed towards the fact that even though after a period of 10 years of regular participation in screening women aged 40-49 years old benefit from a 15% decrease of breast cancer risk, the absolute benefit is small and the potential harms do not outweigh the benefits (Kerlikowske, 2012).

Following these controversies an Independent UK Panel on Breast Cancer was assembled to conduct a meta-analysis using data from good quality international clinical trials and observational studies to summarise the available evidence on the benefits and harms of breast cancer screening. They estimated, that the RR of breast cancer mortality was 0·80 (95% CI 0·73—0·89) for women invited to screening, versus controls, meaning that the RR of mortality reduction was 20% (Independent UK Panel on Breast Cancer Screening, 2012). The Panel highlighted that it is not possible to assess the over diagnosis in each individual and in reality only approximately 1% of women aged 50-52 years that get invited for screening would have experience of an over diagnosis in the next 20 years (Independent UK Panel on Breast Cancer Screening, 2012).

In addition to, or instead of mammography an MRI may be proposed to women at high risk of breast cancer (carrying BRCA 1/2 mutations or having as strong family history of breast cancer) but it was highlighted that woman’s age should be considered when offering MRI (NCCPC, 2006) (for more information on BRCA 1/2 and family history please refer back to section 2.3.2.2). It was proposed that Polish women aged 20-49 years old who have BRCA1/2 mutation or TP53 mutation should be offered MRI annually (Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, 2006; Nienartowicz, 2011). Polish Union of Oncology summarised guidance on breast cancer screening stating that in addition to mammography (or ultrasound for women with higher density breast tissue) every 2 years for ages 50-69 and clinical breast examination every year for women over 40 years old, BSE is also recommended to be performed every month by women of all ages (Jassem et al., 2011).

The resources for routine screening mammography initiatives are often not available in low and middle income countries (such as Poland) and the disease is often diagnosed in its late stage (Tfayli et al., 2010; Yip et al., 2008). This was also the case for Poland prior to 2006 despite sporadic presence of breast screening activities that were conducted mostly spontaneously among various populations and by different governmental or private organisations (i.e. first opportunistic local cervical screening initiative started in 1970s in Białystok) (Łoś, 2006). It is therefore difficult to quantify the coverage of such campaigns and the only attempt can be made through conducting surveys, such as the one used in this thesis.

Currently, despite the ongoing screening programme the uptake numbers are still much below desirable levels (acceptable rate of screened women is >70% and desirable >75%) (Szewczyk, 2011) as only 31%-39.8% of Polish women are taking up mammography (Madej et al., 2010; Central Statistical Office of Poland, 2012c). Therefore many lessons can be learnt from countries where the world’s first national breast screening programmes were set up many years ago (i.e. UK). Success of the screening programme can be assessed not only by achieving high coverage but also by studying the mortality decrease which has been seen for many countries with ongoing mass screening initiatives (Shapiro et al., 1998; GLOBOCAN, 2008a; Advisory Committee on Breast Cancer Screening, 2006). Additionally the positive effect of screening can be also seen through an increase in incidence of early stage and in situ

breast cancers and a decrease in the incidence of late stage malignant neoplasms and therefore reduced mortality since women present with earlier, less aggressive tumours (McCann et al., 1998; Hakama et al., 1997; Tabar et al., 1992; Kricker et al., 1999; Autier et al., 2010). Evidence shows that between 1989 and 2006 mortality was reduced by more than 20% in 15 countries. For example England and Wales, Northern Ireland, and Scotland had the largest decreases in mortality (35%, 29%, and 30% respectively) in 1989 (Autier et al., 2010) and throughout the life of the UK programme (since 1988) over 100,000 cancers were found (100 cancers per week) (NHS, 2013; NHS Breast Screening Programmes, 2008). Conversely, in Central and Eastern Europe such a decline was not present (i.e. Poland), with some countries experiencing even an increase of deaths due to this cancer (i.e. Romania) (Autier et al., 2010).

Women who are entitled to free mammography in Poland are those who are 50-69 years old, who have not had a mammography done in the past 24 months or those who have been invited in writing after 12 months from the previous mammography (Narodowy Fundusz Zdrowia (NFZ), 2011b). Women can participate in this form of screening not only by invitation but they may choose to request a test from their physician who will assess their screening needs (Narodowy Fundusz Zdrowia (NFZ), 2011b).

Table 6 Comparison of the main features of breast screening programmes in Poland and United Kingdom Target screening population Screening location Screening procedures Screening

personnel Uptake rates Note

UK 50-70– screened every 3 years; or by doctor’s indication Patient's local clinic, hospital or mobile screening unit Mammogram, clinical breast examination & BSE as a part of breast awareness programme Physician/ specialist breast nurse 2010 - 77%† Programme is currently being extended to invite women in their late 40s and up to 73 years Poland 50-69 – screened every 2 years; younger, older or women from a higher risk group by doctor’s indication Patient's local clinic, hospital or mobile screening unit Mammogram, clinical breast examination & BSE Physician 2009 -31%‡ 2009 -39.8%¥ National rollout since 2006