CANCER INCIDENCE, MORTALITY, BREAST CANCER DETECTION AND SURVIVAL AMONG CANADIAN WOMEN WITH BILATERAL COSMETIC BREAST AUGMENTATION

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1 ÉRIC LAVIGNE CANCER INCIDENCE, MORTALITY, BREAST CANCER DETECTION AND SURVIVAL AMONG CANADIAN WOMEN WITH BILATERAL COSMETIC BREAST AUGMENTATION Thèse présentée à la Faculté des études supérieures et postdoctorales de l Université Laval dans le cadre du programme de doctorat en épidémiologie pour l obtention du grade de Philosophiae Doctor (Ph.D.) DÉPARTEMENT MÉDECINE SOCIALE ET PRÉVENTIVE FACULTÉ DE MÉDECINE UNIVERSITÉ LAVAL QUÉBEC 2012 Éric Lavigne, 2012

2 ii Résumé Objectifs : La popularité des implants mammaires pour fins esthétiques a rapidement augmentée dans les dernières décennies. Les objectifs de cette thèse étaient d évaluer l incidence de cancer, la mortalité, la détection du cancer du sein ainsi que la survie au cancer du sein chez les femmes avec des implants mammaires pour fins esthétiques. Méthodes : Cette thèse porte sur la deuxième phase d une étude de cohorte rétrospective de femmes ayant reçu des implants mammaires pour fins esthétiques dans les provinces de l Ontario et du Québec entre 1974 et Ces femmes ont été comparées à un groupe de femmes ayant reçu une autre chirurgie esthétique (n = ) ainsi qu à des femmes de la population générale. Résultats : Au cours d un suivi moyen de 24,5 ans, des taux plus élevés de suicide ont été observés chez les femmes avec une augmentation mammaire comparativement aux femmes de la population générale (Rapport Standardisé de Mortalité (RSM) = 2,00, Intervalle de confiance (IC) à 95% = 1,66-2,41) ainsi qu aux femmes avec une autre chirurgie esthétique (Rapport de taux (RT) de mortalité = 1,43, IC à 95% = 1,02-1,99). Les implants mammaires en position rétro-glandulaire étaient associés à un taux réduit de cancer du sein comparativement aux implants en position rétro-pectorale (RT d incidence = 0,78, IC à 95% = 0,63-0,96). Un taux 7 fois plus élevé de cancer du sein a été observé (RT d incidence = 7,36, IC à 95% = 1,86-29,12) dans les cinq premières années après la chirurgie pour les femmes ayant des implants en position rétro-glandulaire avec enveloppe au polyuréthane comparativement aux autres femmes ayant des implants en position rétroglandulaire sans enveloppe au polyuréthane, mais le RT d incidence diminuait par la suite (valeur p de tendance = 0,02). Les femmes avec des implants mammaires avaient un risque plus élevé d avoir un stade avancé au diagnostique du cancer du sein (Rapport de Cote (RC) = 1,51, IC à 95% = 1,18-1,92) ainsi qu une réduction de la survie spécifique au cancer du sein (RT de mortalité spécifique au cancer du sein = 1.38, IC à 95% = ). Conclusion : Les implants mammaires pour fins esthétiques sont associés à des risques pour la santé qui doivent être pris en considération. Davantage d investigations sont nécessaires pour clarifier le risque de cancer associé aux implants au polyuréthane ainsi que par rapport au diagnostique et pronostic du cancer du sein chez ces femmes.

3 iii Abstract Objectives: The popularity for cosmetic breast implants has been rapidly increasing in the past decades. The objectives of this thesis were to evaluate cancer incidence, mortality, breast cancer detection and survival following breast cancer diagnosis among women with cosmetic breast implants. Methods: This thesis is the second phase (follow-up) of a large Canadian retrospective cohort study of 24,558 women who received cosmetic breast implants between 1974 and 1989 in the provinces of Ontario and Quebec. These women were compared to other cosmetic surgery women (n = 15,893) and the general female population. Results: Over an average 24.5 years of follow-up, augmented women have been shown to have elevated rates of suicide relative to women in the general population (Standardized Mortality Ratio (SMR) = 2.00, 95% CI = ) and compared to women seeking other cosmetic surgery (mortality Rate Ratio (RR) = 1.43, 95% CI = ). Subglandular implants were associated to a reduced rate of breast cancer compared to submuscular implants (Incidence Rate Ratio (IRR) = 0.78, 95% CI = ). We observed a 7-fold increased rate (IRR = 7.36, 95% CI = ) of breast cancer in the first five years after the date of surgery for polyurethane-coated subglandular implant women compared to other women with subglandular implants without polyurethane coating, but this IRR decreased progressively over time (p value for trend = 0.02). Women who received cosmetic breast implants were also more likely to have an advanced stage at breast cancer diagnosis (Odds ratio = 1.51, 95 % CI = ) and to have poorer breast cancerspecific survival (Overall breast cancer-specific mortality hazard ratio: 1.38, 95 % CI = ). Conclusion: Cosmetic breast implants are associated with health risks that need to be acknowledged. Further investigations are needed for clarifying the cancer risk associated with polyurethane implants and for pursuing investigations on breast cancer diagnosis and prognosis among these women.

4 iv Avant-propos Cette thèse de doctorat en épidémiologie s inscrit à l intérieur d un grand projet de recherche portant sur les effets à long terme des implants mammaires sur la santé mis sur pied par le Dr. Jacques Brisson en collaboration avec le Dr. Eric J. Holowaty et le Dr. Yang Mao. Il s'agit d'un projet ayant été subventionné par l Agence de la santé publique du Canada. De plus, un support financier m a été accordé par l Unité de recherche en santé des populations (URESP), Action cancer Ontario et l Agence de la santé publique du Canada afin que je puisse poursuivre mes études doctorales. Cette thèse de doctorat représente la deuxième phase (suivi) d une étude de cohorte rétrospective portant sur des femmes ayant reçus des implants mammaires pour fins esthétiques entre les années 1974 et 1989 dans les provinces de l Ontario et de Québec. La première phase portait sur l évaluation de l incidence du cancer, de la mortalité, de la détection du cancer du sein ainsi que la survie au cancer du sein chez ces femmes. Cette deuxième phase porte sur un suivi additionnel de 10 ans. J ai eu un rôle de premier plan dans les étapes suivantes pour cette deuxième phase de ce projet de recherche : développement du protocole de recherche incluant la revue de la littérature, le développement des questions de recherche et le plan méthodologique, la collecte des données, l analyse des données, l interprétation des résultats ainsi que la rédaction des articles scientifiques. D ailleurs, quatre articles sont issus de cette thèse de doctorat. Ces articles sont les suivants : 1. Pan SY, Lavigne E, Holowaty EJ, Villeneuve PJ, Xie L, Morrison H, et al. Canadian breast implant cohort: Extended follow-up of cancer incidence. Int J Cancer 2012 Oct 1;131(7):E Holowaty EJ, Lavigne E, Pan SY, Villeneuve PJ, Xie L, Morrison H, Brisson J. Cosmetic breast augmentation and mortality: an update of a Canadian cohort (Cet article sera soumis pour publication). 3. Lavigne E, Holowaty EJ, Pan SY, Xie L, Villeneuve PJ, Morrison H, et al. Do breast implants adversely affect prognosis among those subsequently diagnosed with breast cancer? Findings from an extended follow-up of a Canadian cohort. Cancer Epidemiol Biomarkers Prev 2012 Oct;21(10): Lavigne E, Holowaty EJ, Pan SY, Villeneuve PJ, Morrison H, Brisson J. Breast cancer detection and survival among women with cosmetic breast implants: a

5 systematic review and meta-analysis of observational studies (Cet article sera soumis pour publicaiton au British Medical Journal). v

6 vi Aknowledgements I would first like to thank my research director, Dr. Jacques Brisson, for his support, his advices, his availability and his help throughout this scientific journey. He has been a mentor for me by communicating his knowledge and experience for which I will be forever grateful. Finally, I would also like to thank him for providing me the skills and knowledge to accomplish myself either professionally than personally. This project was made possible because of the dedicated work of several collaborators. I would like to thank Drs Yang Mao and Eric J. Holowaty for their devoted contribution to this project and for their advices and help throughout my studies. I would also like to thank Drs Sai Yi Pan, Howard Morrison, Paul J. Villeneuve, Mrs. Lin Xie and Drs Ken C. Johnson and Dean Fergusson for their scientific contribution and for their collaboration in the writing of the different manuscripts included in this thesis. I am also thankful to Sylvie Bérubé and Caty Blanchette from Quebec and Gemma Lee and Susitha Wanigaratne from Ontario, for their help in the design and conduct of this study. My sincere thanks go also to all the people who have supported me throughout these years. First, I would like to thank all my friends for their great support and encouraging comments. Thanks for your friendship and for being there for me. I am also grateful for the unconditional love that my parents, Murielle and Michel, have giving me throughout my life. Thank you for supporting me every day and for making me who I am today. I give thanks with all my heart to family members who have been there for me in the good and not so good times. Thanks to Françoise and Michel, my parents-in-law, for their supporting comments and for being in my life. Finally, I would like to thank my beloved Myriam for her unconditional support, her useful advices, her love and for making me a better person every day. I love you with all my heart.

7 vii Table of contents Résumé... ii Abstract... iii Avant-propos... iv Aknowledgements... vi Table of contents... vii List of tables... ix List of figures... xi Chapter 1: General introduction...12 Introduction...13 State of knowledge...17 Objectives...27 Material and Methods...28 Chapter 2: Canadian Breast Implant Cohort: extended follow-up of cancer incidence...51 Résumé...52 Abstract...53 Introduction...54 Material and methods...56 Results...60 Discussion...63 Acknowledgements...68 References...69 Chapter 3: Cosmetic breast augmentation and mortality: an update of a Canadian cohort...79 Résumé...80 Abstract...81 Introduction...82 Methods...83 Results...86 Discussion...87 References...94 Chapter 4: Do breast implants adversely affect prognosis among those subsequently diagnosed with breast cancer? Findings from an extended follow-up of a Canadian cohort Résumé Abstract Introduction Methods Results Discussion...112

8 Acknowledgements References Chapter 5: Breast cancer detection and survival among women with cosmetic breast implants: a systematic review and meta-analysis of observational studies Résumé Abstract Introduction Materials and methods Results Discussion References Appendix Conclusion References viii

9 ix List of tables Chapter 1 Table 1. Least Significant Relative Risk (LSRR) comparing cancer incidence (overall and site-specific) between cosmetic breast implant women and the female general population applying the methods proposed by Walter...42 Table 2. Least Significant Relative Risk (LSRR) for mortality (overall and cause specific) between cosmetic breast implants and female general population applying the methods proposed by Walter...43 Table 3. Least Significant Relative Risk (LSRR) for cancer incidence (overall and sitespecific) among breast implant women vs. other cosmetic surgery women applying the methods proposed by Signorini for Poisson regression models...44 Table 4. Least Significant Relative Risk (LSRR) for mortality (overall and cause specific) among breast implant women vs. other cosmetic surgery women applying the methods proposed by Signorini for Poisson regression models...45 Table 5. Least Significant Relative Risk (LSRR) for breast cancer incidence among cosmetic breast implant women according to specific implant characteristics applying the methods proposed by Signorini for Poisson regression models...46 Table 6. Least significant odds ratio (LSOR) for stage of breast cancer at diagnosis among cosmetic breast implant women vs. other cosmetic surgery women applying the methods proposed by Hsieh for logistic regression models...47 Table 7. Least significant odds ratio (LSOR) for stage of breast cancer at diagnosis among cosmetic breast implant women according to specific implant characteristics applying the methods proposed by Hsieh for logistic regression models...48 Table 8. Least significant hazard ratio (LSHR) to investigate whether there is a differential breast cancer-specific survival between the implant women and other plastic surgery women applying the methods proposed by Hsieh and Lavori and Shoenfeld for Cox Proportional Hazards regression models...49 Table 9. Least significant hazard ratio (LSHR) to investigate whether there is a differential breast cancer-specific survival among cosmetic breast implant women according to specific implant characteristics when applying the methods proposed by Hsieh and Lavori and Shoenfeld for Cox Proportional Hazards regression models...50 Chapter 2 Table 1. Frequency distribution for selected characteristics of women who received breast implants and women who received other cosmetic surgeries, Canadian Breast Implant Cohort Study.73 Table 2. Standardized incidence ratios (SIRs) for selected cancers based on general population cancer incidence rates ( ) among breast implant and other cosmetic surgery women with comparisons with previous follow-up.74 Table 3. Incidence rate ratios (IRRs) for selected cancers between breast implant and other cosmetic surgery women with comparisons with previous analysis.75 Table 4. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) of breast cancer for selected breast implant characteristics among implant women...76

10 x Chapter 3 Table 1. Frequency distribution for selected characteristics of women who received breast implants and women who received other cosmetic surgeries, Canadian Breast Implant Cohort Study.98 Table 2. Standardized mortality ratios (SMRs) for selected causes of death based on general female population mortality rates ( ) among breast implant and other cosmetic surgery women, compared with previous analysis 99 Table 3. Mortality rate ratios (RRs) for selected causes of death between breast implant and other cosmetic surgery women with comparisons with previous analysis.100 Table 4. Standardized mortality ratios (SMRs) for suicide death based on general female population mortality rates ( ) among breast implant and other cosmetic surgery women, and incidence rate ratios (RRs) of suicide death for breast implant vs. other cosmetic surgery women by selected surgery characteristics.101 Chapter 4 Table 1. Frequency distribution for selected characteristics of women diagnosed with breast cancer who received breast implants and other cosmetic surgeries, Canadian Breast Implant Cohort Study..123 Table 2. Odds ratios (ORs) and 95% confidence intervals (CIs) for selected characteristics of incident cases of breast cancer comparing breast implant women to other cosmetic surgery women 125 Table 3. Odds ratios (ORs) and 95% confidence intervals (CIs) for stage distribution of breast cancer for selected breast implant characteristics.126 Chapter 5 Table 1. Characteristics of 12 studies selected for quantitative analysis to evaluate the association between cosmetic breast implants and stage distribution of breast cancer Table 2. Random effects overall odds ratio for the association between cosmetic breast implants and stage distribution of breast cancer stratified by variables potentially related to study quality 154 Table 3. Characteristics of 5 studies selected for quantitative analysis to evaluate the association between cosmetic breast implants and breast cancer-specific survival following breast cancer diagnosis...155

11 xi List of figures Chapter 2 Figure 1. Cumulative breast cancer incidence curves for time since index surgery comparing breast implant with other cosmetic surgery women 77 Figure 2. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) to evaluate the trend in breast cancer risk for women who received subglandular polyurethane coated breast implants relative to other women who received subglandular implants, by time since surgery...78 Chapter 4 Figure 1. Breast cancer-specific survival curves comparing breast implant with other cosmetic surgery women.126 Chapter 5 Figure 1. Flowchart of the meta-analysis search strategy and process of selecting scientific articles on the association between cosmetic breast implants and stage distribution of breast cancer and the association between cosmetic breast implants and survival following breast cancer diagnosis Figure 2. Forest plot with study-specific and random effects overall odds ratio (OR) for the association between cosmetic breast implants and stage distribution of breast cancer Figure 3. Forest plot with study-specific and random effects overall hazard ratio (HR) for the association between cosmetic breast implants and breast cancer-specific survival...158

12 Chapter 1: General introduction 12

13 13 Introduction The demand for cosmetic breast implants among women has been rapidly increasing since the first mammary prosthesis was inserted in a woman s breasts in the early 1960 s (1). For instance, in the US, cosmetic breast augmentation was the most commonly performed surgical cosmetic procedure in 2010 with 296,000 surgeries performed (2), an increase of approximately 800 % compared with the early 90 s and an increase of about 50 % compared with the year 2000 (3). It is estimated that 100,000 to 200,000 women have breast implants in Canada (4). Although very popular, there remains considerable controversy about the long-term health effects of breast implants. Cosmetic breast augmentation has been the subject of numerous investigations in the past two decades. Concerns have been raised concerning the possible carcinogenic effect of cosmetic breast implants, specifically for breast cancer (5). Most of the epidemiological studies published have shown no carcinogenic effect of breast augmentation on breast cancer (6-32) and even showing for some a lower than expected incidence of breast cancer (9;14;16;22). In recent years, the concern of the carcinogenic effect of breast implants has focused on the fact that breast cancer development might be affected by specific implant characteristics: type of implant (saline and silicone-gel-filled implants (SGFIs)), implant placement (submuscular and subglandular), implant fill volume and implant envelope (polyurethane coated or not). For the latter characteristic, it has been reported that polyurethane could degrade into significant quantities of 2,4- and 2,6-toluene-diisocyanate diamines (TDA s) which has been shown to cause cancer in laboratory animals and is recognized by the International Agency for Research on Cancer as an animal carcinogen (33;34). However, very few studies to date have been able to investigate breast cancer incidence by implant characteristics. For the studies that investigated this issue, results have been inconclusive due either to their small number of cancer incident cases and insufficient amount of follow-up time (9;12;14;18;28;35). Extended follow-up time is particularly relevant given that immunologic changes and deterioration of the implant capsule may only occur over an extended period of time (36;37). Moreover, the existing literature suggests

14 14 that the expected latency period between first exposure to carcinogenic agents and solid tumor development is lengthy (38). In this thesis, we aim to evaluate if breast cancer risk is affected by specific implant characteristics, especially for implants with polyurethane coated envelope. Furthermore, some studies have evaluated the relationship between breast implants and the incidence of cancers at sites other than the breast (8;9;16;18;22;26;27;29;30;39). The findings from these studies have been largely negative, though excesses have been inconsistently reported for some types of cancers including the brain (25), lung (22;25;26), vulva (16) and cervix (39). Although these excesses appear largely attributable to life style characteristics rather than the presence of the implant itself, taken as a whole, the epidemiological evidence for risk of cancer at body sites other than the breast needs to be further clarified. Moreover, a recent report by the FDA as well as review articles recommended that the risk of hematopoietic malignancies among women who have cosmetic breast implants be further investigated (39-41). One of the aims of this thesis is to examine non-breast cancer risk among breast implant women. In addition to the question of cancer risks, some investigations reported lower breast cancer and overall mortality rates among implant women (15;42-45) while others have shown increased risks of overall mortality (46-48) compared to women in the general population or to women with other cosmetic surgeries. Furthermore, a number of studies have shown higher deaths from suicide relative to the general female population (42-49). Some studies have also suggested that the excess in suicide risk may change with length of time since surgery (42;46) and age at which surgery was performed (42;43;46). A number of studies have also reported higher deaths related to respiratory diseases (46-48), lung cancer deaths (46;48) and deaths from motor vehicle accidents (42) and several other types of injuries (44;46-48) among cosmetic breast implant women relative to the general female population. However, these reports have been severely limited by a small number of deaths for these causes which makes it difficult to draw any solid conclusions. In this thesis, we will assess mortality experience, specifically deaths from suicide, among cosmetic breast implant women.

15 15 Another concern is that breast augmentation may be associated with an advanced stage of breast cancer at diagnosis. It s been reported that cosmetic breast implants, especially implants placed under the breast glands (subglandular placement), are radiopaque and may obscure the visualization of breast tissue with mammography which may delay the detection of breast cancer and affect prognosis of the disease (50-53). While a few studies have performed such evaluations, their findings have been mixed with some reporting that women with breast augmentation may be more likely to be diagnosed with advanced cancers (51;54-56) while others have reported no such difference (7;8;12;14;17;18;20;30;32;57-65). These conflicting results may be explained by the small number of incident breast cancer cases in these studies, especially among women with breast implants, which could have limited statistical power to clearly evaluate this question. In particular, across studies, the number of incident breast cancer cases among implant subjects varies from 7 to 182 (7;8;12;14;17;18;20;30;32;51;54-65). In addition to the concern of possible advanced stage of breast cancers among augmented women, breast cancer related survival has been of interest (56;58-61;64). If diagnosis of breast cancer is associated with more advanced tumors among augmented women, this could translate into poorer survival. To date, all published studies reported no statistically significant differences in breast cancer-specific survival when comparing augmented women with breast cancer to non-augmented women with breast cancer (56;58-61;64). However, the small numbers of incident breast cancer cases and insufficient follow-up time after diagnosis in these studies may have limited the statistical power necessary to detect a difference in survival. Additionally, no study has evaluated breast cancer survival according to implant characteristics. In this thesis, we will examine whether cosmetic breast implants can impair the ability to identify breast cancer at an early stage and affect prognosis of the disease. We will also examine whether the stage distribution and prognostic factors of breast cancer among women with implants are affected by implant characteristics and examine survival rate patterns among breast implant women who develop breast cancer. This thesis is the second phase (follow-up) of a large Canadian retrospective cohort study evaluating long term health effects of women who received cosmetic breast implants between 1974 and 1989 in the provinces of Ontario and Quebec. This project is conducted

16 16 by Laval University s Population Health Research Unit (URESP), Cancer Care Ontario and the Public Health Agency of Canada for which three scientific papers were previously published based on the results of the first phase (9;43;56). This first phase identified incident cancers and deaths through linkage to Canadian registries up to December 31, The second phase of this project is based on an additional 10 years of follow-up for cancer incidence, mortality and survival analyses by identifying incident cancers and deaths through linkage to provincial registries (Quebec and Ontario). With the largest cohort to date evaluating long term health effects of cosmetic breast implants, the additional followup time is expected to substantially increase statistical power as more cancer cases and deaths will be identified. I have been involved in all stages of the second phase of this cohort study, namely the literature review, development of the research questions, the writing of the research protocol, the data collection, the data analyses and the writing of the manuscripts.

17 17 State of knowledge Cosmetic breast implants Breast implants have been a popular type of cosmetic surgery since the early 1960s (66). Cosmetic breast implants were first used in the United States in 1962 (67), and in Canada in 1969 (66). Also known as augmentation mammaplasty, breast implant surgery is an elective surgical procedure to enhance the size of a woman s breast by insertion of a mammary prosthesis behind each breast (68). They are the most common cosmetic procedure in the Unites-States (69;70). They are principally used for cosmetic purposes among women who have dissatisfaction with breast size and/or shape (71), but also used for breast reconstruction in the case of a mastectomy. There are mainly two types of cosmetic breast implants; silicone gel-filled implants (SGFIs) and saline-filled implants. SGFIs are composed of a silicone elastomer shell of varying thickness that encases different volumes of silicone gel and oil. Saline-filled implants consist of a single lumen enclosed by a silicone elastomer envelope. These implants are inflated with sterile saline via a self-sealing valve through a closed system into the recipient (68;72). Implants vary in size (implant fill volume), shape, and external surfaces (i.e. smooth, textured, polyurethane foam-covered), and can be inserted either superficial to the muscles, on top of the pectoralis muscle and directly under the breast glands (subglandular placement), covering the chest wall or under the pectoralis major muscle (submuscular placement) (68;73). Implants placed under the breast glands (subglandular placement) are considered to be less painful postsurgery as only the skin and fat are cut, with a quicker recovery (74). Subglandular implant placement is considered in the case of a breast with adequate body fat to minimize the palpability of the implant, a breast with good skin elasticity and when the elimination of any pectoralis muscle incision is requested (68). Implants placed under the pectoralis major muscle (submuscular placement) are considered to be more painful post surgery as the skin, fat and muscle are cut and the muscle is stretched, with a slightly longer recovery (75). Although the recovery is longer, submuscular implant placement has certain benefits; implants are less palpable, there is a possibility of less capsular contracture and easier imaging of the breast

18 18 tissue with mammography (68). The site of implantation, which is usually decided by the plastic surgeon in collaboration with the recipient, depends on the body type, the thickness of the breast tissue and its ability to adequately cover the breast implant and the patient s preferences (68). Implants covered with polyurethane foam became popular in 1981 (66) since they reduced the incidence of capsular contracture so frequently encountered with smooth or textured SGFIs (52;76-79). However, polyurethane foam-covered (PU) breast implants were withdrawn from the market in April, 1991 when the United States FDA found that polyurethane could degrade into significant quantities of 2,4- and 2,6-toluene-diisocyanate diamines (TDAs) (33) which has been shown to cause cancer in laboratory animals and is recognized by the International Agency for Research on Cancer as an animal carcinogen (33;34). Since their first use in the 1960 s, cosmetic breast implants, particularly silicone gel-filled implants (SGFIs), have been subject to controversies. Concern over silicone as a potential carcinogen largely began when the results of a 2-year toxicity and carcinogenicity study by Dow Corning Corporation (1987) of medical-grade silicone gel found that 23% of rats developed sarcomas at the implant site, most of which were fibrosarcomas (80). On January 6, 1992, Health Canada asked manufacturers to stop the sale of silicone gel-filled implants (SGFIs) in Canada until further studies could be done (81). A similar decision was made in the United States, and silicone gel-filled breast implants were removed from general sale (81). However, because of the lack of studies showing carcinogenic effect of silicone, between the year 2000 and October 2006, silicone implants had been available again in Canada through special approval by Health Canada (82). Finally, on October 20 th 2006, Health Canada reapproved silicone gel-filled breast implants for general cosmetic use in Canada (83). Characteristics of women with cosmetic breast implants Certain studies have been able to characterize the reasons why women have cosmetic breast surgery. Motivations for cosmetic breast surgery include improving self-esteem due to dissatisfaction with body image and with breast size and/or shape and increasing sexual attractiveness and responsiveness (71;84;85). Studies have also shown that between 3% and

19 19 15% of patients undergoing cosmetic surgery may also suffer from excessive dissatisfaction with body image consistent with the psychiatric diagnosis of body dysmorphic disorder (86) which would also be a reason to have breast augmentation (71). Literature has also been able to describe inherent characteristics of women having cosmetic breast implants. It is suggested that women with implants are more likely to have had more sexual partners, be middle to upper middle socioeconomic status, be younger at their first pregnancy, use oral contraceptives, have a history of terminated pregnancies, be more frequent users of alcohol and tobacco, have higher divorce rate and be below average body weight (68;84). In the epidemiological studies assessing the health effects of breast implants, women with implants were compared either to general population estimates or to a control group consisting of women who received other elective cosmetic surgery. These other surgeries include chemical peel or dermabrasion, coronal brow lift (eyebrow and forehead lift), otoplasty (ear surgery), rhinoplasty (nose surgery), rhytidectomy (face lift) or blepharoplasty (eyelid surgery). Studies using other cosmetic surgery women as a control group have supported the notion that these patients are a more appropriate comparison group than women in the general population to study the health effects associated with breast implants because women in the control group tend to be more similar in terms of sociodemographic and lifestyle factors than women in the general population (87;88). Understanding this, it is then important to specify when reporting statistically significant results of health effects associated with cosmetic breast implants the comparison group used because there could be discrepancy between the ones using general population estimates and the ones using a more comparable comparison group. Cancer incidence among augmented women Understanding that cosmetic breast augmentation has been subject to controversies regarding their possible carcinogenic effect (72;89-93), numerous investigations in the past two decades have been conducted. No epidemiological study to date was able to establish that cosmetic breast implants are associated with increased breast cancer incidence (6-32). However, some studies have found statistically significant lower than expected breast

20 20 cancer risk among women with breast implants when compared with general population estimates (9;14;16;22) or women having other cosmetic surgeries (9). Possible biological mechanisms have been suggested in the literature to explain this finding. It seems that the presence of breast implants could enhance the immune system, whereby carcinogens and transformed cells would be more easily destroyed (14). The weight and volume of breast implants is suggested to compress the glandular tissue resulting in a decreased blood supply that may reduce the rate of cell proliferation (14;94). It is also important to mention that the decreased risk of breast cancer incidence among augmented women reported in the literature could also be due to the fact that these women have smaller breasts prior to augmentation which could make them less likely to develop breast cancer. Nonetheless, in recent years, breast cancer incidence among augmented women has continued to be studied in an attempt to clearly evaluate variations of breast cancer risk, if any exist, according to specific implant characteristics. Common implant characteristics include the type of implant (saline and silicone-gel-filled implants (SGFIs)), the placement of the implant (submuscular and subglandular), the implant fill volume and the implant envelope (polyurethane coated or not). Polyurethane foam-covered breast implants is of particular interest here because of their potential carcinogenic effect (33;91-93). However, most of the epidemiological investigations reporting on breast implants and breast cancer risk have not been able to conduct subgroup analyses due principally to their inability to collect specific implant characteristics. For the studies that did report subgroup analyses, results have been deemed inconclusive due to important limitations such as their relatively small sample sizes and their limited number of breast cancer cases which lacked the statistical power needed to conduct subgroup analyses by specific implant characteristics (9;12;14;18;28;35). Another identified shortcoming of past studies include an insufficient amount of follow-up time as most studies followed women for less than 30 years and only a few had a follow-up time over 30 years (18;22;26). Considering that immunologic changes and deterioration of the implant capsule may only occur over an extended period of time (36;37), and that the expected latency period between first

21 exposure to carcinogenic agents and solid tumor development is lengthy, it is of great importance to have an extended follow-up period (9;38). 21 To our knowledge, only one scientific article, Brisson et al., which was one of the scientific papers published from the first phase of this project, was able to report a statistically significant 2 fold increase of breast cancer risk among women whose implants were inserted subglandularly with a polyurethane envelope compared to women with the same site of implantation without such envelope (9). However, no other statistically significant associations were reported for breast cancer risk according to implant characteristics in the first phase of this project. Moreover, to date, there is no other study that has been able to report convincing subgroup analyses due to the reasons mentioned above to compare breast cancer risk between saline implants and SGFI s, subglandular and submuscular implant placement, between different fill volumes of implants and between polyurethane coated implants and non-coated implants. It is then still uncertain whether there are variations in breast cancer risk according to specific implant characteristics due to the lack of scientific evidence. Given that a certain number of women received breast implants at a young age, continued follow-up is important to examine associations between breast implants and the incidence of breast cancer up to postmenopausal years when breast cancer incidence is greater. In this thesis, we propose to examine with a large cohort adding 10 more years of follow-up for cancer incidence whether cancer risk among cosmetic breast implant women is affected by the following implant characteristics: implant type (saline and silicone-gelfilled implants (SGFIs)), implant placement (submuscular and subglandular), implant envelope (polyurethane coated or not) and fill volume. A certain number of epidemiological investigations have been able to evaluate the relationship between breast implants and the incidence of non-breast cancers (8;9;16;18;22;26;27;29;30;39). The findings from these studies have been largely negative when women with implants are compared to other women that had cosmetic surgery (8;9;18) or to general population estimates (9;16;18;30). However, statistically significant increased risk for some types of cancer including the brain (25), lung (22;25;26), vulva (16) and cervix (39) have been inconsistently reported among women with cosmetic breast

22 22 implants when compared with general populations estimates. Nonetheless, these increases in risk, appear largely attributable to life style characteristics rather than the implant itself (39). For instance, studies reporting these results have not used women with other cosmetic surgeries as control group which would have been more appropriate according to the rationale given above. In one of our previous papers, results showed that women with implants were not at an increased risk of these types of cancers compared to a more comparable control group (9). Moreover, a recent report by the FDA as well as review articles recommended that the risk of hematopoietic malignancies, especially for anaplastic large T cell lymphomas, among women who have cosmetic breast implants be further investigated (39-41). Taken as a whole, the epidemiological evidence for risk of cancer at body sites other than the breast needs to be further clarified (39). One of the aims of this thesis is to clarify the question of non-breast cancer risk among breast implant women using as recommended a comparison group of women with other cosmetic surgeries. Mortality and women with cosmetic breast implants Assessment of mortality experience among cosmetic breast implant women has been investigated in past years. Conflicting results have been reported for overall mortality because some studies reported a statistically significant reduction in overall mortality compared with general population estimates (42;43;45), others reported statistically significant increased risk of overall mortality compared to general population estimates (46-48) and one study showed no difference (44). However, among studies that used a control group that consisted of women who received other plastic surgery, no difference of overall mortality risk has been reported (42;43;45-47). Breast cancer mortality has also been studied when we consider that the implants might induce carcinogenic activity in the breast and result in death. Studies have consistently reported that women with cosmetic breast implants are not at an increased risk of breast cancer deaths compared to women in the general population or women with other cosmetic surgeries (42-48).

23 23 Another cause of death that has been of concern among women with implants is death related to respiratory diseases such as lung cancer, chronic obstructive pulmonary diseases or pneumonia. In fact, three studies have shown that women with implants have a higher statistically significant risk of death from respiratory diseases than women in the general population (46-48) while two others have shown a trend towards higher risk of death from respiratory diseases without being significant (42;43). Here again, studies that have used a more comparable control group in parallel or not to the comparisons with general population estimates showed no difference of risk of deaths by respiratory diseases (42;43;45-47). Psychological considerations concerning women who have cosmetic breast implants have been of interest when several cohort studies reported 2 to 3-fold higher suicide rates among women with implants compared with general population estimates (42-49). Despite the consistency of these findings, some studies have been severely limited by small sample sizes and the fact that they did not use a more comparable comparison group. For example, the small sample sizes make it difficult to characterize suicide risk by age group and time since surgery was performed and the comparison with general population estimates is affected by residual confounding due to the fact that women with implants are not similar in terms of sociodemographic and lifestyle factors to women in the general population. However, no studies using a comparison group of women who have had other cosmetic surgeries reported this association (42;43;45;47). As mentioned earlier, it is suggested that women with implants may suffer from excessive dissatisfaction consistent with the psychiatric diagnosis of body dysmorphic disorder (95;96). Understanding this, it would not be the implant itself that would cause suicide, but rather psychological disorders prior to breast augmentation. It is then recommended that women interested in having breast augmentation undergo mental health evaluations before getting the surgery. In this thesis, we aim at clarifying mortality patterns among women with cosmetic breast implants.

24 24 Detection of breast cancer and survival among augmented women There has been some concern that cosmetic breast implants may delay the detection of breast cancer and impair the ability to identify breast cancer at an early stage (50-53). The diagnosis of more advanced cancers can lead to poorer prognosis and consequently poorer survival post-breast cancer diagnosis. It is reported that cosmetic breast implants are radiopaque which may obscure the visualization of breast tissue with mammography and result in a delayed detection of breast cancer (50-53). In fact, the amount of parenchymal breast tissue obscured at mammography by the implant is known to be between 22 and 83 % (97). Consequently, breast implants will hinder visualization of breast tissue and affect mammography detection of breast cancers (31). Insufficient compression of the breast to visualize the parenchyma and the production of implant-related artifacts on the film can also make it difficult to interpret mammographic exams in women with augmented breasts (52;98). There has been a few reports that showed that the presence of breast implants increases the false-negative rate (poorer sensitivity) of mammograms compared with non-augmented breasts (32;51;54;64), but does not increase the false-positive rate (poorer specificity) (62). While specialized radiographic techniques have been developed for women with breast implants to improve visualization which involve displacing the implant posteriorly against the chest wall and pulling breast tissue over and in front of the implant (53;99-101), there is still one-third of the breast that is not adequately visualized leading to an increase of false-negative mammograms (52). Most of the studies that evaluated the detection of breast cancer among women with cosmetic breast implants have compared the stage distribution of breast cancer at diagnosis to a control group that consisted of women with other types of cosmetic surgery with breast cancer (8;17;18;56) or to other non-augmented women with breast cancer (7;12;14;20;30;32;51;54;55;57-65). Results have been mixed with some reporting that women with breast augmentation may have up to a 3-fold increased risk to be diagnosed

25 25 with advanced cancers compared with non-augmented women (51;54-56) while others have reported no such difference (7;8;12;14;17;18;20;30;32;57-65). These conflicting results can be explained by the small number of incident breast cancer cases in these studies which limit statistical power to clearly evaluate this association. It is of great importance to pursue this evaluation in order to give clear information to women who are interested in breast augmentation and who are at a high risk of developing breast cancer. In this thesis, we will examine whether breast implants impair the ability to identify breast cancer at an early stage. Furthermore, it has been suggested that specific breast implant characteristics might affect the detection of breast cancer (102). Specifically, implants placed under the breast glands (subglandular placement), because of their proximity with breast tissue, are suspected to obstruct mammographic visualization of the breast more so than submuscular placement (50;103). However, to date, no study has been able to report increased stage at diagnosis of breast cancer among women with subglandular implants compared with women whose implants are placed submuscularly. This can also be due to the small number of breast cancer incident cases which limits the capacity to perform subgroup analyses. In this thesis, we will examine whether the stage distribution of breast cancer among women with implants is affected by implant characteristics such as the placement of the implant. In addition to the concern of advanced stage at diagnosis of breast cancer among augmented women, breast cancer related survival subsequent to the diagnosis of breast cancer has been investigated in the past years (56;58-61;64). The idea is that the possible advanced stage of breast cancer in the augmented women could translate into poorer survival. However, all studies published to date reported no statistically significant differences in breast cancer survival when comparing augmented women with breast cancer to non-augmented women with breast cancer (56;58-61;64). The small numbers of incident breast cancer cases and insufficient amount of follow-up time in these studies are suspected to limit statistical power to clearly compare survival rate patterns among these two groups of women. To provide further insight about length of survival post-breast cancer diagnosis,

26 we will compare survival rates of augmented women with non-augmented women postbreast cancer diagnosis. 26 Survival rate patterns following breast cancer diagnosis according to breast implant characteristics are also of interest if any difference exists in terms of breast cancer stage at diagnosis among augmented women according to these characteristics. To our knowledge, no study to date, even the first phase of this project which is probably due to limited statistical power for these analyses, has evaluated this association. In this thesis, we will compare survival rates following breast cancer diagnosis among women with cosmetic breast implants by specific implant characteristics (e.g. survival rate post breast cancer diagnosis of submuscular vs. subglandular placement).

27 27 Objectives In order to investigate the above research gaps, this thesis seeks to fill critical voids in the current literature as several hypotheses regarding outcomes among cosmetic breast implant women have yet to be adequately examined. Specifically, the objectives of the proposed investigation are as follows: 1. To evaluate the association between cancer incidence, overall and site-specific, and cosmetic breast implants. 2. To examine whether breast cancer risk among cosmetic breast implant women is associated to the following implant characteristics: implant type (saline and silicone-gel-filled implants (SGFIs)), implant placement (submuscular and subglandular), implant envelope (polyurethane coated or not) and fill volume. 3. To assess the association of mortality, specifically deaths from suicide and other causes, with cosmetic breast implants. 4. To examine whether cosmetic breast implants are associated with more advanced stage at diagnosis of breast cancer. 5. To examine whether characteristics of cosmetic breast implants are associated with stage at breast cancer diagnosis focusing on implant type (saline and silicone-gelfilled implants (SGFIs)), implant placement (submuscular and subglandular), implant envelope (polyurethane coated or not) and fill volume. 6. To examine whether cosmetic breast implants are associated with poorer survival rates following breast cancer diagnosis. 7. To examine whether characteristics of cosmetic breast implants are associated with poorer survival rates following breast cancer diagnosis focusing on the effect of implant type (saline and silicone-gel-filled implants (SGFIs)), implant placement (submuscular and subglandular), implant envelope (polyurethane coated or not) and fill volume.

28 28 Material and Methods Study design, study population and selection criteria As mentioned earlier, this thesis is based on an extension of the largest retrospective cohort study carried-out to date to evaluate long term health effects among women with cosmetic breast implants (9;43;56). The study population consists of women, 18 years of age or older, who were residents of the province of Ontario or Quebec in Canada and who underwent bilateral cosmetic breast augmentation in their province of residence between January 1, 1974, and December 31, A control cohort (comparison group) was assembled consisting of women who received other common elective cosmetic surgeries. These women received other cosmetic surgeries, not billable to the publicly funded health insurance plans of Ontario or Quebec, which included the following: chemical peel or dermabrasion, coronal brow lift (eyebrow and forehead lift), otoplasty (ear surgery), rhinoplasty (nose surgery), rhytidectomy (facelift), or blepharoplasty (eyelid surgery). Controls were frequency matched to the breast implant recipients by year of entry into the cohort, province of residence and by surgeon. The matching ratio would be called a two-to-one (2:1) implant to other plastic surgery patient, but in practice, there was a slight departure from this ratio. This is due to the fact that recruitment was done based on a priori expected case numbers, and some women who received breast implants did not fulfill the requisite inclusion criteria. Eligible subjects in Ontario were identified through plastic surgeons that performed cosmetic breast implant surgeries in this province between January 1, 1974, and December 31, Investigations revealed that plastic surgeons that performed cosmetic breast implant surgeries also performed most of the other cosmetic surgeries. In total, 133 plastic surgeons ever performed augmentation mammaplasty during the study period where nearly 75 % of these procedures were performed by 24 plastic surgeons.