The best way of detection of and screening for breast cancer in women with genetic or hereditary risk

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1 The best way of detection of and screening for breast cancer in women with genetic or hereditary risk Ingrid Vogelaar Introduction Each year almost 1.2 million women are diagnosed with breast cancer worldwide. 1 Breast cancer is the most common type of cancer among women in Western countries; one in nine women will develop breast cancer at any point in their life. This gives a cumulative risk of 10% with a ten year mortality of about 40 percent percent of breast cancer cases are diagnosed at an age above 50, which means that 25 percent of the patients are diagnosed with breast cancer before they have reached an age of 50 years. Among younger women, aged 35 to 50, breast cancer is the leading cause of death. Five to ten percent of breast cancer cases are familial 3, which means the disease runs in the family. Approximately six percent of breast cancers in younger women are genetic. These cancers are due to mutations in the breast and ovarian cancer susceptible genes BRCA1 and BRCA2. 4 Women with a high risk of developing breast cancer include women who are genetically predisposed, like carriers of mutations in BRCA1, BRCA2 and TP53, women who have a family history of breast and ovarian cancer and women exposed to chest radiation for treatment of Hodgkin s disease before they were 30 years old. Women who carry a mutation in either BRCA1 or BRCA2 have a cumulative lifetime risk of developing breast cancer of about percent before reaching the age of 50 years. 5 These women are recommended to do a monthly breast self examination from the age of years, semi-annual clinical breast examination starting from the age of 20 and annual mammography beginning from years. 6 Prophylactic mastectomy 7 or oophorectomy 8 (or both) can significantly reduce the risk of developing breast cancer. These procedures are very radical and have great impact on the lives of women, which makes it an unacceptable option for some of them. Although prophylactic mastectomy is the most effective risk-reducing therapy, many carriers would prefer extra surveillance instead, to give them a feeling of confidence that a possible cancer is detected early. 9 Mammography is a quite sensitive test for screening of postmenopausal women, but it is less sensitive for screening of younger women and those with a genetic predisposition 10 to breast cancer. This is due to increased mammographic density in younger, pre-menopausal women, which makes it difficult to distinguish normal breast tissue from malignant tissue, because radiological features are blurred by dense breast tissue. And even if a tumor is recognized on the mammogram it often appears benign while it is actually malignant. This has been suggested for tumors caused by BRCA mutations. 11 Therefore special screening in young, pre-menopausal women is very important, also because breast cancer in young women is suggested to have a more aggressive phenotype. 12 In the Netherlands a special screening program for breast cancer is executed. Every two years women between age 50 and 75 are invited to participate in the screening program. The screening program uses mammography, which is a technique that applies X-ray for visualizing breast tissue.

2 Because mammography and clinical surveillance only have a limited efficacy, other imaging techniques are required to properly screen for breast cancer in women at high risk of developing cancer. Most important candidates for screening are high-frequency breast ultrasound and magnetic resonance imaging (MRI). 13 Materials and Methods For this literature study we searched the internet database op PubMed for articles. We used different search terms and different combinations. We searched for genetic breast cancer and x-ray mammography and we also searched for detection genetic breast cancer MRI. We also searched for screening breast cancer mammography MRI In the articles that PubMed found, we first looked for titles that seemed appropriate to use for our review article. After that, we read the abstracts to see if the information of the article was suitable. Finally, we read the entire article to find the information we needed. After reading the abstracts, there is an option in PubMed to find related articles. We used this option for amongst others the cost-effectiveness of the different screening methods. For the data on the mortality declines on screening with mammography, we used an article that we already found during our initial research. 14 In this article, a very good reference was mentioned. 15 Using this reference, we found another article 16, which we will also discuss. We also used information from websites other than PubMed. They are listed in our references (see below). Search Results During our search we found enough articles to write this review. It was difficult to make a proper selection, since there was so much information online. During the writing process, we came to the conclusion that we found the right articles to come with enough insights to draw a careful conclusion. Discussion Comparison of different techniques In the detection of and screening for breast cancer there are a lot of different techniques that can be used. At this moment, mammography and ultrasound are the ones most commonly used in the clinic. Also, women are advised to do a regular breast self examination (BSE) at home, to check for abnormalities. A relatively new technique is magnetic resonance imaging, MRI. We found studies that compare MRI to mammography plus ultrasound and with or without breast self examination (BSE). Kuhl 12 and colleagues found that mammography and a combination of mammography with breast ultrasound is not sufficient for early diagnosis in women who carry the BRCA1 or BRCA2 mutation. They also found that when MRI was added, the diagnosis was achieved with a higher sensitivity and that the cancer was detected in a more favourable stage. 12 Warner et al 17 found that, in a group of 196 women that carry BRCA1 or BRCA2 mutations or have a strong family history of breast cancer, MRI was the most sensitive technique for screening. MRI detected all the six invasive breast cancers that developed in this group. In comparison, only three invasive cancers were detected by ultrasound. Two of the cancers were seen on mammography and two by breast self examination. This led to the conclusion that MRI is better in detecting cancers than are mammography and ultrasound. 17 In another article of Warner 18, the conclusion was drawn as well that MRI is more sensitive for detecting breast cancers than mammography, ultrasound and CBR alone.

3 We will discuss the sensitivity and specificity of the different techniques in the section below, because this requires some additional explanation. Study design One very important factor that needs to be considered is the study design used to draw conclusions on the data that were obtained during the study. Therefore we point out some of the studies here to compare their design to see if that could influence conclusions they draw. We particularly look at the way a high risk (of developing cancer) is defined. Rubinstein et al. performed a prospective study in which 30 high-risk women with an age of were followed in time. 4 High risk was defined as a calculated risk of 3.5 or more percent for 5 years by assessment with the Gail and BRCAPRO model. The effect of adding MRI to conventional screening (with mammography) was studied. In the study of Kriege et al 14, women with a cumulative lifetime risk of 15 percent or more (owing to genetic or familial predisposition) were screened every half year with clinical breast examination and annually with mammography and MRI with independent readings. Data found in these groups were compared with two independent control groups of the same age. The median follow up time was 2.9 years. One other study performed by Kriege et al. 3 included 1700 women with a lifetime risk of 15 percent or more for developing breast cancer and BRCA1/2 mutation carriers. They performed a prospective observational study which was performed by six different medical centres across the Netherlands. A distinction is made for the risk of women in the study. Group I include women who carry a BRCA mutation (with a cumulative lifetime risk of 60 percent or more for breast cancer). Group 2 are women with a high risk (cumulative lifetime risk of percent). Group 3 includes women with a moderate risk (15 percent). Cumulative lifetime risk was determined with a decision tree. The women included in this study were screened with mammography and MRI once a year. 3 Warner et al. 18 performed a surveillance study in which 236 Canadian BRCA 1 or BRCA 2 mutation carriers, with an age between 25 and 65, were screened 1-3 times a year. The examination screenings included ultrasound, mammography and MRI. This study was performed in a single hospital. 18 Another study was performed by Warner et al. 17 to compare mammography, MRI and ultrasound for surveillance of women, aged 26-59, at high risk for hereditary breast cancer. 196 women at high risk, defined as carriers of BRCA1 or BRCA 2 or individuals with a strong family history of breast cancer, were included in this study. On one day the subjects were examined by mammography, MRI, ultrasound and clinical breast examination. 17 All these study designs were follow up studies. To find out what the best technique is for screening on breast cancer you ideally would want to perform a randomised controlled trial. In this randomised controlled trial you would assign one high risk group to MRI, one to mammography, one to breast ultrasound and one to clinical breast examination. This type of study design would allow you to compare the groups in the best way. Unfortunately, this design would also bring unethical aspects along, because the women that need to be studied are at high risk of developing breast cancer. Therefore the prospective observational study is the best alternative to compare the techniques for screening.

4 The studies described above all investigate a population at high risk of developing breast cancer. All studies defined this high risk as a cumulative lifetime risk of 15 percent or more. All studies described used prospective observational follow up studies. Because the study designs are almost equal, we can easily compare the results of these studies in the remaining part of our review. Sensitivity and specificity: test accuracy There are a lot of differences in sensitivity and specificity of MRI, mammography, ultrasound and clinical breast examination between the different studies that are performed. The studies report incremental sensitivity, which is the probability of a positive test result in subjects with breast cancer. Also specificity was reported, this is the probability that a test gives a negative result in subjects without breast cancer. Different values were found for the estimated specificity of MRI combined with conventional testing (mammography, ultrasound and in some studies clinical breast examination) across the different studies (ranging from 77 to 96 percent. 19 Sensitivity and specificity are different for pre-menopausal women as compared to postmenopausal women. 3 The study by Rubinstein 4 confirmed this and found that for mammography the sensitivity in pre-menopausal women, aged under 50, was lower than the sensitivity in post-menopausal women, aged above 50. Sensitivity in pre-menopausal women was percent as compared to the sensitivity in post-menopausal women was percent. 3 This is a strong argument that mammography is not sufficient for screening in premenopausal women. In the study of Warner et al. 17 sensitivity and specificity were compared for clinical breast examination, mammography, ultrasound and MRI. Sensitivity and specificity are the same for mammography and clinical breast examination, with sensitivity being 33 percent and specificity being 99.5 percent. Sensitivity and specificity of ultrasound are 60 percent and 93 percent, respectively. MRI has a high sensitivity (100 percent) but a specificity that is lower than for ultrasound, mammography and clinical breast examination (91.5 percent compared to respectively, 93 and 99.5 percent. These studies point out that MRI is a more sensitive technique than mammography and ultrasound but when screening with MRI, more false-positives are diagnosed. Some studies reported on the rates of recalling subjects for further examination of false positive results and rates of biopsies, which gave benign results, for mammography, MRI and breast ultrasound. 12,20 The images made by MRI of these women suggested that there was a malignancy, while there was in fact nothing wrong. Other studies showed that MRI combined with mammography gave rise to more benign biopsies and more surgical biopsies. From these findings can be concluded that the risk to be recalled for thorough investigation (for example biopsy), while there is no malignancy, is higher for subjects examined by MRI combined with mammography as compared to subjects examined by mammography alone. According to these articles it was estimated that there were extra false positives per 1000 screening rounds. 19 The women undergo a biopsy which is not necessary and this causes unneeded commotion and stress and brings along unnecessary costs. Although these findings seem to be negative, because there are extra false positives when screening with MRI, we think this is not true. Women at high risk of developing breast cancer seem to prefer to be recalled more often for thorough examination and monitoring. This is

5 because more tests will lead to detection of more cancers and probably detection at a less advanced stage. Cost effectiveness In our search for articles, we found one study that performed a cost-effectiveness analysis in which mammography was compared to MRI. In the review of Lord et al. 19 we found another analysis as well, on an internet website. 21 On this website The National Collaborating Centre for Primary Care of the UK comes with an interpretation of the results of the MARIBS study that was published. They both used a different approach to get to their conclusions. Plevritis and her colleagues used a computer model that simulated the life history of the individual BRCA1 and BRCA2 carriers, in which they incorporated the effects of mammography and MRI screening. 22 The National Collaborating Centre for Primary Care used the results on test accuracy and the costs of mammography and MRI from the MARIBS study. They used these results to come to a conclusion of the 5-year survival of early versus late detection. 21 Although these are two very different approaches, they did lead to the same conclusions. Plevritis and colleagues found that the screening for BRCA1 and BRCA2 mutation carriers for breast cancer with both annual mammography and annual MRI can be cost-effective at selected ages. There is a great variation between different age groups. For BRCA1, MRI is cost-effective for women aged and for BRCA2, MRI is cost-effective in the same age group. 22 The authors also concluded that if MRI would become cheaper, it would become more cost-effective for a larger group. The authors also found that MRI is more important in the screening of BRCA1 carries, because they have a greater risk of developing breast cancer that BRCA2 carries. Their cancers are also more aggressive. Even between BRCA1 carriers there is a lot of variation in the cost-effectiveness. Annual MRI was found not to be cost-effective in younger women because this group has a lower cancer incidence. In the group of women above 55 years of age annual MRI was also not cost-effective because the chance that they die from other diseases increases. 22 What is striking in these articles is that both of the research groups did not include ultrasound in their research. One might expect that if ultrasound is added, more tumours will be detected by a combination of mammography and ultrasound. This would mean that the costeffectiveness of MRI would go down. Mortality Until today, many studies have been performed to try to find a relationship between MRI scanning and a decreased mortality from breast cancer. However, there is no evidence on the effects of early detection of breast cancer with MRI on mortality. This is mainly due to the barriers that come with a randomized controlled trial, for example large sample size, length of follow-up and the ethic arguments against this kind of study. 23 Although there is no evidence about MRI, there is a lot of evidence that mammography decreases mortality. There are various studies performed that support this conclusion. Nystrom and colleagues 15 performed a trial in which they included women, divided in an invited (women were invited for a mammography) and a control group. The study had a median follow-up of 15.8 years (with a range of years) and concluded from this study was that the invited group had a significant reduction of 21 percent in breast cancer mortality. There was a large variation in age groups, with the largest effect in the oldest

6 group. These results were supported by the group of Tabar et al. 16 They found a 63 percent decline in mortality of breast cancer in a group of women at the age of 40 to 69 years during the screening period ( ) compared to a time period where there was no screening available ( ). These are women who actually underwent screening, so who accepted the invitation. When they included the women who did not attend the screening as well, the decline in mortality was still 50 percent. These two studies both provide enough evidence for the impact that breast cancer screening with mammography has. Although these articles do not concern women with a high risk of developing breast cancer, they are still applicable. The effect of the biannual mammography is proven here. Women with a high risk of developing cancer get a mammogram made every year so that will compromise for the increased risk they have for a positive mammogram. Ultrasound is found to be a good adjunct to mammography to detect additional cancers 23, but no articles were found on a possible mortality decline of ultrasound alone. At the end of this review, we would like to give a short overview and come to a recommendation on a screening and detection regimen for women with a high risk of developing breast cancer. A lot of studies found that the sensitivity is very high for MRI and specificity of MRI varied among the different studies but was lower than the specificity of mammography. So, with MRI a lot of lesions can be detected but a great number of these lesions are benign, which induces additional costs. Therefore, MRI seems a cost-ineffective technique, but this is actually not true, as proven by the study of Plevritis. They found that MRI is cost effective from age 35. Also needs to be taken into account that MRI detects more cancers and at a less advantaged stage as compared to mammography. This is important for women at high risk, which are likely to develop breast cancer during their life, even so at a very young age with there whole life ahead. We suspect that mortality of these younger, premenopausal women will decrease; we expect the life expectancy to increase. We therefore recommend additional MRI screening every year in women at high risk, defined as carriers of mutations in breast cancer susceptible genes of with a strong family history, at least from age 35 until they reach an age of 50. References 1. Fucito A, 2007, Genetic and epigenetic alterations in breast cancer: What are the perspectives for clinical practice? Int. J. Biochem Cell Biol Oct 23 [Epub ahead of print]. 2. Visser, 2000, Incidence of cancer in The Netherlands Utrecht: The Netherlands Cancer Registry Coebergh JWW, Cancer incidence and survival in the southeast of The Netherlands Eindhoven: The Eindhoven Cancer Registery, Kriege M, 2001, MRI screening for breast cancer in women with familial or genetic predisposition: design of the Dutch National Study (MRISC), Familial Cancer 1: , Rubinstein WS, 2006, Prospective screening study of 0.5 Tesla dedicated magnetic resonance imaging for the detection of breast cancer in young,high-risk women, BMC Women's Health 2006, 6:10 doi: / Antoniou A, 2003, Average risk of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies, Am J Hum Genet 2003;72:

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