Medical Imaging, Techniques, Reflection and Evaluation



Breast Cancer Screening in Women with a Familial or Genetic Predisposition The role of MRI Borstkanker screening bij vrouwen met een familiaire of genetische predispositie De rol van MRI Cover painting: Heleen Vriesendorp Layout / cover design: Philip de Bruin Printed by: Optima Grafische Communicatie, Rotterdam ISBN: 90-8559-210-0 The studies described in this thesis were supported by grants from the Dutch Health Insurance Council (OG-9803) and Zon MW (6200. 005), and were performed at the department of Medical Oncology, Erasmus MCDaniel den Hoed Cancer Center, Rotterdam in collaboration with the Departments of Radiology, Surgical Oncology, Clinical Genetics and Public Health of the Erasmus MC Rotterdam, the Netherlands Cancer Institute, Amsterdam, the Leiden University Medical Center, the University Medical Center Nijmegen, the University Medical Center, University of Groningen, the VU University Medical Center, Amsterdam. Publication of this thesis was financially supported by: GlaxoSmithKline, Amgen B. V. Breda, Roche Nederland B. V. , Siemens Nederland B. V. AstraZeneca © Mieke Kriege 2006 No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the author. Breast Cancer Screening in Women with a Familial or Genetic Predisposition The role of MRI Borstkanker screening bij vrouwen met een familiaire of genetische predispositie De rol van MRI Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van rector magnificus Prof. dr. S. W. J. Lamberts en volgens besluit van het College voor Promoties.

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De openbare verdediging zal plaatsvinden op woensdag 15 november 2006 om 9. 45 uur door Annemieke Germa Kriege geboren te Wassenaar Promotiecommissie Promotor Prof. dr. J. G. M. Klijn Overige Leden Dr. H. J. de Koning Prof. dr. G. P. Krestin Prof. dr. M. F. Niermeijer Copromotor Dr. C. T. M. Brekelmans CONTENTS CHAPTER 1 CHAPTER 2 Introduction MRI screening for breast cancer in women with a familial or genetic predisposition 7 23 Imaging Decisions, 9: 11-18 (2005) CHAPTER 3 MRI screening for breast cancer in women with a familial or genetic predisposition: design of the Dutch national study (MRISC) 37

Familial Cancer, 1: 163-168 (2001) CHAPTER 4 Efficacy of MRI and mammography for breast cancer screening in women with a familial or genetic predisposition 47 New England Journal of Medicine, 351: 427-437 (2004) CHAPTER 5 Differences between first and subsequent rounds of the MRISC breast cancer screening program for women with a familial or genetic predisposition 63 Cancer, 106: 2318-26 (2006) CHAPTER 6 Tumor characteristics and detection method in the MRISC screening program for the early detection of hereditary breast cancer 77

Breast Cancer Research and Treatment (2006), in press CHAPTER 7 Factors affecting sensitivity and specificity of screening mammography and MRI in women with an inherited risk for breast cancer 87 Breast Cancer Research and Treatment (2006), in press CHAPTER 8 Hereditary breast cancer growth rates and its impact on screening policy 103 European Journal of Cancer, 41: 1610-1617 (2005) CHAPTER 9 Discussion and concluding remarks Summary/Samenvatting Dankwoord Curriculum Vitae List of publications 117 129 137 139 141 CHAPTER 1 Introduction Introduction 9 INTRODUCTION Breast cancer is the most common cancer in females. Worldwide more than 1 million new cases are diagnosed each year and nearly 600,000 women die from breast cancer. 1 The incidence varies over the world and is highest in the USA, followed by northern Europe. Between 1997 and 2001, each year, in the USA there were diagnosed on average 135 breast cancers per 100,000 women and 27 breast cancer-related deaths per 100,000 women occurred. In total 13% (1:8) of the women in the USA will be diagnosed with breast cancer in their life. In the Netherlands, the incidence is 124 per 100,000 women each year, which means 11,700 new cases in 2002, accounting for almost one third of all cancers in females in the Netherlands.

The cumulative lifetime risk of breast cancer in the Netherlands is currently 11% (1:9) and 4% to 5% of Dutch women die from breast cancer. 3 Several risk factors for breast cancer are known. The most important risk factors are a female gender, a higher age, a mutation in one of the genes with a high susceptibility for breast cancer and a strong family history of breast cancer. Another important risk factor is mammographic breast density. Breast cancer risk is about 5 times higher in women with a dense structure in >75% of the breast compared with women with little or no dense structure. 5 Several hormonal factors are associated with an increased breast cancer risk, such as a young age at menarche, a high age of menopause, nulliparity, a decreasing number of children, a high age at first birth, no breast feeding, oral contraceptive use and hormone replacement (HRT) use. 6 Also exposure of the mammary gland to high-dose ionizing radiation increases the risk of breast cancer. Nutrition plays an undefined role despite of many studies investigating its elements, such as fatty acids, meat, dairy products, fish, and fruit and vegetables. Alcohol intake slightly increases the risk of breast cancer. Obesity and possible decreasing physical activity are associated with an increased risk for breast cancer. These both risk factors are associated with a change in hormonal factors. 7 A strong family history of breast and ovarian cancer combined with young ages at diagnosis of affected family members is a very important risk factor for breast cancer.

To date, mutations in two genes, BRCA1 and BRCA2, are identified with a high risk for breast and ovarian cancer. 8,9 Recently, also a low-penetrance susceptibility gene for breast cancer became identified: Chek2. 10 Apart from these genes, also germline mutations of the high risk cancer genes TP53, PTEN and STK11/LKB1 are associated with breast cancer. 11,12 The remaining cases of hereditary and familial breast cancer are possibly caused by multiple gene mutations with a low-penetrance for breast cancer, environmental factors or a combination of both. 13-15

HEREDITARY CANCER: RISKS OF BREAST AND OTHER CANCERS The BRCA1 gene located on chromosome 17q2116 was identified in 1994. 8 A year later the BRCA2 gene located on chromosome 13q12-13 was identified. 9 BRCA1 and BRCA2 are both tumor suppressor genes that play a role in DNA repair. The BRCA1 gene plays also a 10 | Chapter 1 role in checkpoint control. Mutations in either genes are associated with an autosomal dominant inherited form of breast and/or ovarian cancer. 17,18 The prevalence of BRCA1/2 mutations is estimated as 0. 23% in the general Caucasian population and on average 2-3% in breast cancer patients.

This percentage is higher in younger breast cancer patients. 19 Early family-based studies found that mutations in the BRCA1 and BRCA2 genes are associated with high cumulative lifetime risks of breast cancer: for BRCA1 gene mutation carriers the cumulative breast cancer risk is 20% by age 40, 50% by age 50 and 87% by age 70; for BRCA2 this is 12% by age 40, 28% by age 50 and 84% by age 70. 20,21 But the later (population-based) studies found lower percentages: a cumulative lifetime risk of 45-65% for BRCA1 and 40-45% for BRCA2 at age 70 (Table 1). 14,22,23 Table 1.

Cumulative risk of breast cancer in BRCA1 and BRCA2 gene mutation carriers. Ford et al 21 Struewing et al (BRCA1 and 2) Population based % 104 King et al 14 Antoniou et al Population based % 22 Chen 23 Multiple case families % BRCA1 Age 40 50 60 70 BRCA2 Age 40 50 60 70 12 28 48 84 19 51 54 85 Population based % Multiple case families and population based % 33 56 21 39 58 69 12 37 52 65 14 28 41 46 33 56 17 34 48 74 8 18 32 45 11 23 39 43 In addition to an early onset of breast cancer, bilateral breast cancer commonly occurred in BRCA1 and BRCA2 mutation carriers. 4-28 Studies investigating the risk of ipsilateral breast cancer in BRCA1 and BRCA2 mutation carriers show inconsistent results, some found a higher (especially on the long-term) and others a comparable risk compared to sporadic breast cancer patients. 27-30 The cumulative risk of ovarian cancer was in the early family based studies for BRCA1 mutation carriers 23% by age 50 and 63% by age 70; for BRCA2 mutation carriers 0. 4% by age 50 and 27% by age 70. 20,21 Also these risk percentages were some lower in later (population based) studies (Table 2).

4,23,31 If no gene mutation is detected or no gene mutation analysis performed, models exist that can estimate the cumulative lifetime risk and age-specific risk of breast cancer based on the family history and sometimes also on hormonal factors and benign breast disease. 32,33 In addition to breast and ovarian cancer a BRCA1 or BRCA2 mutation can increase the risk of other cancer sites. BRCA1 mutations are associated with higher risk of pancreatic cancer and cancer of uterine body, cervix cancer and prostate cancer in men younger than 65 years. 4 In BRCA2 mutation carriers, increased risks of prostate cancer, pancreatic cancer, gallbladder and bill duct cancer, stomach cancer and malignant melanoma are reported. 35,36 Introduction | 11 HEREDITARY BREAST CANCER: PATHOLOGY AND SURVIVAL Hereditary breast cancer differs from sporadic cancer in various clinical and pathological features. BRCA1-related tumors are found to have more frequent a highly poor grade (grade 3), because of higher scores for mitosis, a high pleomorphism and less tubule formation. 7-39 These tumors have also a very high frequency of p53 mutations, are more likely to be estrogen receptor (ER), progesterone receptor (PgR) and HER-2neu negative24,40,41 and are more frequently of the medullary histology type and a basal-like phenotype than sporadic breast cancers.

37,42,43 When only invasive ductal carcinomas are compared with those of sporadic controls, BRCA1-related tumors have more frequently a prominent lymphocytic infiltrate and pushing margins. 8 Despite the evidence of unfavorable pathologic features in BRCA1-related tumors, results of survival studies in BRCA1 mutation carriers compared with sporadic breast cancer patients are inconsistent. Some studies found no difference in survival between women with BRCA1related breast cancers and women with sporadic breast cancer with comparable age. 24,27,44,45 Table 2. Cumulative risk of ovarian cancer in BRCA1 and BRCA2 gene mutation carriers. Ford et al21 Multiple case families % BRCA1 Age 40 50 60 70 BRCA2 Age 40 50 60 70


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