Breast CancerAREOLA-BNCT05400954
Association of Silicone Breast Implants With Overall Wellbeingand Auto-immune Diseases
An observational study of Breast Cancer and Breast Implant; Complications, run by The Netherlands Cancer Institute at 7 sites in Netherlands.
Trial summary
Background: Implant-based breast reconstructions contribute considerably to the quality of life of breast cancer patients. A knowledge gap exists concerning the potential role of breast implants in the development of so called 'breast implant illness' and autoimmune diseases in breast cancer survivors with a silicone… Read more about this study
- Who is it for?
- Ages 18 to 80 years, women only
- Conditions the study is for
- Breast Cancer, Breast Implant; Complications, Autoimmune Diseases
- What is being tested?
- Breast reconstruction with silicone breast implant, Breast conserving surgery/Mastectomy/Autologous reconstruction and Breast Augmentation
- Type of treatment
- Injection or infusion, Surgery or procedure
- How many people
- 15,000 participants
- Where
- 7 sitesNetherlands
- Study dates
- 1 Jul 2022to 1 Jun 2025
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- Women only
- No healthy volunteers
- Adult, Older adult
Study population: Women who underwent surgery for first invasive breast cancer or ductal carcinoma in situ (DCIS) in the years 2000 to 2015 in the collaborating centres. Eligible for inclusion in the exposed group are all women who underwent (i) mastectomy followed by immediate implant-based reconstruction, (ii) mastectomy followed by implant-based reconstruction at a later stage and (iii) latissimus dorsi flap reconstruction with a silicone breast implant. Eligible for inclusion in the comparison group are women who underwent (i) simple mastectomy without reconstruction, (ii) autologous reconstruction and (iii) breast conserving surgery. From the latter group a frequency-matched sample will be selected based on age at breast cancer diagnosis and calendar year of diagnosis. Women who underwent cosmetic augmentation in the years 2000 to 2015 constitute a second comparison group. From this group a frequency-matched sample will be selected based on age and year of surgery.
Who may be able to join
- surgery for first invasive breast cancer or ductal carcinoma in situ (DCIS) in the years 2000 to 2015 in the collaborating centres
Who cannot join
- above the age of 60 at breast cancer diagnosis
- above the age of 80 years at time of inclusion
- Not residing in Netherlands
Trial locations and contacts
7 sites in 1 country.
7 sites in 1 country
Netherlands7 sites
Ziekenhuisgroep Twente
Almelo, Overijssel
Netherlands Cancer Institute Antoni van Leeuwenhoek
Amsterdam, North Holland
Medisch Spectrum Twente
Enschede, Overijssel
Zuyderland Medical Center
Heerlen, Limburg
Velthuis Kliniek
Hilversum, North Holland
Maastricht University Medical Center
Maastricht, Limburg
Erasmus MC University Medical Center
Rotterdam, South Holland
About this study
Official title: Association of Silicone Breast Implant Reconstruction and -Enlargement With Overall Wellbeing, Lymphoma and Auto-immune Disease - Breast Implant Illness
Background: Implant-based breast reconstructions contribute considerably to the quality of life of breast cancer patients. A knowledge gap exists concerning the potential role of breast implants in the development of so called 'breast implant illness' and autoimmune diseases in breast cancer survivors with a silicone breast implant-based reconstruction. Breast implant illness is a constellation of non-specific symptoms reported by a small group of women with silicone breast implants.
Methods/Design: The Areola study is a multi-centre historic cohort study with prospective follow-up aiming to assess the risk of 'breast implant illness' and autoimmune diseases in female breast cancer survivors with and without silicone breast implants. The cohort consists of breast cancer survivors who received surgical treatment with silicone implant-based reconstruction in six major hospitals across the Netherlands in the period between 2000 and 2015. As comparison group, a frequency-matched sample of breast cancer survivors without breast implants will be selected. An additional group of women who received breast augmentation surgery in the same years will be selected to compare their characteristics and health outcomes with those of breast cancer patients with implants. All women still alive will be invited to complete a web-based questionnaire covering various health related topics. The entire cohort including deceased women will be linked to the population based computerized databases of Statistics Netherlands. These databases include a registry of diagnostic codes, a pharmacotherapeutic prescriptions registry and a cause-of-death registry in which diagnoses of autoimmune diseases will be identified. Outcomes of interest are the prevalence and incidence of BII and the prevalence and incidence of autoimmune diseases. In addition, risk factors for the development of BII and autoimmune disorders will be assessed among women with implants.
Read more
Discussion: The Areola study will contribute to the availability of reliable information on the risks of breast implant illness and autoimmune diseases in Dutch breast cancer survivors with silicone breast implants. This will inform breast cancer survivors and aid future breast cancer patients and their treating physicians to make informed decisions about reconstructive strategies after mastectomy.
Keywords: Silicone breast implants, Breast reconstruction, Breast cancer, Breast Implant Illness, Autoimmune disease
Read the detailed description
There are various indications for implantation of a silicone breast implant. Most frequently, silicone breast implants are used in breast augmentation procedures for cosmetic reasons. In the field of oncology, breast implants are used for reconstructive purposes after mastectomy in the context of breast cancer treatment or prevention. A small percentage of breast reconstructions are performed in women with a hereditary predisposition for breast cancer who undergo bilateral prophylactic mastectomy. In the Netherlands, every year approximately 20,000-30,000 silicone breast implants are inserted for cosmetic (70%) and reconstructive purposes (30%)
From the 1990s onwards, there has been discussion in the scientific community about possible health risks associated with silicone breast implants. It was hypothesised that silicone breast implants could be the cause of breast cancer and sarcoma due to induction of pre-neoplastic fibrotic scar tissue. Furthermore, a variety of auto-immune-, auto-inflammatory- and neurological disorders have been attributed to silicone breast implants. The debate has generated significant research into potential cancer risks from silicone breast implants. Already in the 1990s, results from this research led to rejection of the hypothesis about associations between silicone breast implants and carcinoma or sarcoma of the breast. Most of the other alleged associations between silicone breast implants and various diseases were also discarded due to a lack of evidence after multiple epidemiologic investigations with long-term follow-up. A number of high-powered studies did suggest evidence for an association between silicone breast implants and autoimmune diseases.. However, these studies suffered from a number of methodological shortcomings such as failure to control for confounders, relying solely on unconfirmed patient-reported data, uncertainty as to which participants had silicone implants and high loss to follow-up. These caveats made their conclusions ultimately unconvincing. A strong causal association with silicone breast implants has only been established for Anaplastic Large Cell Lymphoma of the breast, an extremely rare T-cell lymphoma that can develop in the implant capsule.
In contrast to expectations based on the current body of scientific evidence, a number of women reports various health issues following placement of a silicone breast implant. These complaints are generally nonspecific and not attributable to one organ system. Reported symptoms include among others: numbness and tingling of the extremities, joint pain, myalgia, hair loss, cognitive problems, sicca complaints, chronic fatigue, rashes and hives, food intolerances and excessive sweating. The interval between placement of silicone breast implants and the onset of symptoms varies greatly from patient to patient. 'Autoimmune Syndrome Induced by Adjuvants' (ASIA) and 'Silicone Implant Incompatibility Syndrome' are two of the different names that have been coined to describe this constellation of symptoms. Lately, use of the term 'Breast Implant Illness' (BII) has become more commonplace among patients and patient advocates22. In line with difficulty in defining the diagnosis of this entity, its aetiology is unclear. The idea has been postulated that in susceptible individuals, silicone micro-particles that are shed from the implant set into motion a complex mechanism of immune dysregulation via receptor and cytokine pathways. However, so far an exact biochemical mechanism has not been described. With regard to the treatment of BII, suggestive evidence exists that explantation of the implant leads to an improvement of symptoms in at least part of affected women. However, two small observational studies from the Netherlands and the United States did not observe a statistically significant difference in the prevalence of BII-associated symptoms between women with cosmetic silicone breast implants and appropriate comparison groups. These results cast doubts with regard to an association between silicone breast implants and complaints ascribed to BII. In the absence of proof of proportionate organic abnormalities in patients with BII complaints, explanations from a behavioural science perspective have also been put forward, considering the role that psychological and social mechanisms can play in amplification of functional somatic symptoms 28. Striking similarities exist between the typical symptoms ascribed to BII and disorders like chronic fatigue syndrome and fibromyalgia.
With increasing evidence demonstrating the positive impact of breast-contour preserving surgical strategies on quality of life, a growing group of breast cancer patients undergo implant-based breast reconstructions after mastectomy. International data show an upsurge in immediate breast reconstruction over the past decade with rates now reaching around 50% in both The United States and England. Most breast cancer patients undergoing mastectomy are candidates for reconstruction. Although patient preference increasingly plays a role in the choice for a specific reconstructive strategy, factors such as patient's BMI, smoking, comorbidities or available surgical expertise may limit the options. In the Netherlands, the vast majority (83,4%) of immediate breast reconstructions are implant-based with the proportion of autologous reconstructions being around 11% 37. International trends also indicate a shift towards implant based reconstructions.
The current position of the U.S. Food and Drug Administration is that silicone breast implants are safe and reliable devices when used as labelled. Although the purported association between silicone breast implants and autoimmune diseases has been investigated many times, this issue has not been definitively resolved. Large epidemiologic studies investigating the potential association between silicone breast implants and the controversial new entity referred to as BII are lacking. Elucidating the role of implants in autoimmune disease and BII is of great importance to breast cancer patients who often have to make decisions about undergoing an implant-based reconstruction in a short timeframe. Uncertainty fuelled by lay reports on unsubstantiated side effects of silicone breast implants can complicate the decision-making process for patients as well as healthcare professionals. Possibly, this may lead to patients opting for more technically and physically demanding alternatives such as autologous reconstructions which entail longer recovery times, a higher risk of complications and higher expenses 40.
The Areola study is a Dutch prospective cohort study aiming to assess the risk of BII and autoimmune diseases in female breast cancer survivors with and without silicone breast implants. Focussing on sound epidemiological method, it attempts to overcome limitations that hampered previous studies. An additional goal is to identify risk factors for the development of BII and autoimmune disorders among women with implants. The Areola study was set up to meet the demand for reliable information about the role of silicone breast implants on long-term health outcomes in breast cancer survivors.
- Being tested
- Breast reconstruction with silicone breast implant, Breast conserving surgery/Mastectomy/Autologous reconstruction, Breast Augmentation
- Keywords
- Silicone Breast Implant, Breast Reconstruction, Breast Cancer, Breast Implant Illness, Autoimmune disease
- Medical subject headings
- Breast Neoplasms, Autoimmune Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Breast reconstruction with silicone breast implantProcedure or surgery
Also called Breast Reconstruction
(i) mastectomy followed by immediate implant-based reconstruction, (ii) mastectomy followed by implant-based reconstruction at a later stage and (iii) latissimus dorsi flap reconstruction with a silicone breast implant.
Breast conserving surgery/Mastectomy/Autologous reconstructionProcedure or surgery
(iv) simple mastectomy without reconstruction, (v) autologous reconstruction and (vi) breast conserving surgery,
Breast AugmentationProcedure or surgery
(vii) cosmetic augmentation with silicone breast implants
| Study group | Role | What they receive |
|---|---|---|
| Reconstruction with silicone breast implant | The cohort will be composed of women who underwent surgery for first invasive breast cancer or ductal carcinoma in situ (DCIS) in the years 2000 to 2015 in the collaborating centres. Eligible for inclusion in the exposed group are all women who underwent (i) mastectomy followed by immediate implant-based reconstruction, (ii) mastectomy followed by implant-based reconstruction at a later stage and (iii) latissimus dorsi flap reconstruction with a silicone breast implant Receives: Procedure: Breast reconstruction with silicone breast implant | |
| Breast cancer surgery without silicone breast implant | . Eligible for inclusion in the comparison group are women who underwent (i) simple mastectomy without reconstruction, (ii) autologous reconstruction and (iii) breast conserving surgery. From the latter group a frequency-matched sample will be selected based on age at breast cancer diagnosis and calendar year of diagnosis. Receives: Procedure: Breast conserving surgery/Mastectomy/Autologous reconstruction | |
| cosmetic breast augmentation | . Women who underwent cosmetic augmentation in the years 2000 to 2015 constitute a second comparison group. From this group a frequency-matched sample will be selected based on age and year of surgery. Receives: Procedure: Breast Augmentation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Breast Implant Illness
Relative risk (RR) of experiencing the following complaints in exposed and comparison groups:
Cognitive impairment joint pain myalgia anxiety feeling depressed skin rashes weakness sleeping problems headache hair loss food intolerances and allergies numbness/tingling in upper and lower limbs dry eyes morning stiffness night sweats heart palpitations shoulder pain
Measured: 20years
Autoimmune disease
Relative risk (RR) and Incidence rate (IR) for the following illnesses in exposed group and comparison group:
Sjögren's Syndrome (SjS) Rheumatoid Arthritis (RA) Systemic Lupus Erythematosus (SLE) Systemic Sclerosis (SSc), Mixed Connective Tissue Disease (MCTD) Antiphospholipid Syndrome (APS) Ankylosing Spondylitis Sarcoidosis Multiple Sclerosis (MS) hypothyroidism hyperthyroidism psoriatic disease inflammatory bowel disease fibromyalgia chronic fatigue syndrome irritable bowel syndrome
Measured: 20years
Relative risk to develop autoimmune diseases and BII complaints associated with certain risk factors:
RR for BII and autoimmune diseases will be assessed associated with riskfactors in the domains of demographics, lifestyle, reproductive history, medical- and treatment history and family history. Furthermore the influence of psychosocial factors like satisfaction with the breasts and self-esteem on BII risk are evaluated.
Measured: 20years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jun 2022
- Study start1 Jul 2022
- Primary completion1 Jun 2024 (estimated)
- Study completion1 Jun 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by The Netherlands Cancer InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 15,000 participants (estimated)
Sponsor and investigators
- Lead sponsor
- The Netherlands Cancer Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Erasmus Medical Center, Maastricht University Medical Center, Zuyderland Medical Centre, Medisch Spectrum Twente, Ziekenhuisgroep Twente, Velthuis Kliniek
- Responsible party
- Principal investigator, Sanne Schagen, The Netherlands Cancer Institute
- Investigators
- Floor van Leeuwen, PhD, Principal investigator, The Netherlands Cancer InstituteMarie-Jeanne Vrancken Peeters, PhD, Principal investigator, The Netherlands Cancer InstituteEveline Bleiker, Principal investigator, The Netherlands Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05400954
- Sponsor's protocol ID
- M21REO
- Acronym
- AREOLA-B
- Status last verified
- Apr 2023
- First submitted
- 27 May 2022
- Last updated
- 28 Apr 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Spoor J, de Jong D, van Leeuwen FE. [Silicone breast implants: the importance of nuanced reporting]. Ned Tijdschr Geneeskd. 2022 Mar 21;166:D6515. Dutch.
PubMed 35499539Spoor J, de Jong D, van Leeuwen FE. Silicone Particle Migration: A Misleading Report. Aesthet Surg J. 2022 Mar 15;42(4):NP261-NP262. doi: 10.1093/asj/sjab377. No abstract available.
PubMed 34695179Spoor J, Mureau MAM, de Jong D, Tissier RLM, Vis M, Rakhorst H, Hommes J, de Boer M, Oldenburg HSA, Heuts EM, Vissers YLJ, Dassen AE, Evers DJ, Koppert LB, Zaal LH, van der Hulst RRWJ, Vrancken Peeters MTFD, Bleiker EMA, van Leeuwen FE. Risk of autoimmune and rheumatic diseases in breast cancer patients with silicone breast implants. J Natl Cancer Inst. 2026 Apr 19:djag115. doi: 10.1093/jnci/djag115. Online ahead of print.
PubMed 42001600Spoor J, van Leeuwen FE, de Jong D, Zaal LH, Rakhorst H, de Boer M, Vissers YLJ, Bleiker EMA, Vrancken Peeters MTFD, Mureau MAM; AREOLA Collaboration. A comparison of Breast Implant Illness-related symptoms between breast cancer survivors and breast augmentation recipients. Plast Reconstr Surg. 2026 Mar 27. doi: 10.1097/PRS.0000000000013061. Online ahead of print.
PubMed 41891787Spoor J, Mureau MAM, Tissier RLM, Hommes J, Rakhorst H, de Boer M, Oldenburg HSA, Heuts EM, Vissers YLJ, Dassen AE, Evers DJ, Koppert LB, Zaal LH, Linn SC, de Jong D, van der Hulst RRWJ, Vrancken Peeters MTFD, Bleiker EMA, van Leeuwen FE. Breast implant illness after reconstruction with silicone breast implants. J Natl Cancer Inst. 2025 Aug 1;117(8):1717-1728. doi: 10.1093/jnci/djaf136.
PubMed 40605595Spoor J, Mureau MAM, Hommes J, Rakhorst H, Dassen AE, Oldenburg HSA, Vissers YLJ, Heuts EM, Koppert LB, Zaal LH, van der Hulst RRWJ, Vrancken Peeters MTFD, Bleiker EMA, van Leeuwen FE; AREOLA Collaboration. The Areola study: design and rationale of a cohort study on long-term health outcomes in women with implant-based breast reconstructions. Ann Epidemiol. 2023 Jun;82:16-25. doi: 10.1016/j.annepidem.2023.04.001. Epub 2023 Apr 6.
PubMed 37028614
Study at a glance
From the registry record, last updated by the sponsor on 28 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Association of Silicone Breast Implant Reconstruction and -Enlargement With Overall Wellbeing, Lymphoma and Auto-immune Disease - Breast Implant Illness
- ClinicalTrials.gov ID
- NCT05400954
- Acronym / sponsor ID
- AREOLA-B / M21REO
- Keywords
- Silicone Breast Implant, Breast Reconstruction, Breast Cancer, Breast Implant Illness, Autoimmune disease
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 15,000 participants (estimated)
- Lead sponsor
- The Netherlands Cancer InstituteUniversity, hospital or other
- Collaborators
- Erasmus Medical Center, Maastricht University Medical Center, Zuyderland Medical Centre, Medisch Spectrum Twente, Ziekenhuisgroep Twente, Velthuis Kliniek
- Study start
- 1 Jul 2022 (actual)
- Primary completion
- 1 Jun 2024 (estimated)
- Study completion
- 1 Jun 2025 (estimated)
- First posted
- 2 Jun 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background: Implant-based breast reconstructions contribute considerably to the quality of life of breast cancer patients. A knowledge gap exists concerning the potential role of breast implants in the development of so called 'breast implant illness' and autoimmune diseases in breast cancer survivors with a silicone breast implant-based reconstruction. Breast implant illness is a constellation of non-specific symptoms reported by a small group of women with silicone breast implants.
Methods/Design: The Areola study is a multi-centre historic cohort study with prospective follow-up aiming to assess the risk of 'breast implant illness' and autoimmune diseases in female breast cancer survivors with and without silicone breast implants. The cohort consists of breast cancer survivors who received surgical treatment with silicone implant-based reconstruction in six major hospitals across the Netherlands in the period between 2000 and 2015. As comparison group, a frequency-matched sample of breast cancer survivors without breast implants will be selected. An additional group of women who received breast augmentation surgery in the same years will be selected to compare their characteristics and health outcomes with those of breast cancer patients with implants. All women still alive will be invited to complete a web-based questionnaire covering various health related topics. The entire cohort including deceased women will be linked to the population based computerized databases of Statistics Netherlands. These databases include a registry of diagnostic codes, a pharmacotherapeutic prescriptions registry and a cause-of-death registry in which diagnoses of autoimmune diseases will be identified. Outcomes of interest are the prevalence and incidence of BII and the prevalence and incidence of autoimmune diseases. In addition, risk factors for the development of BII and autoimmune disorders will be assessed among women with implants.
Discussion: The Areola study will contribute to the availability of reliable information on the risks of breast implant illness and autoimmune diseases in Dutch breast cancer survivors with silicone breast implants. This will inform breast cancer survivors and aid future breast cancer patients and their treating physicians to make informed decisions about reconstructive strategies after mastectomy.
Keywords: Silicone breast implants, Breast reconstruction, Breast cancer, Breast Implant Illness, Autoimmune disease
Detailed description
There are various indications for implantation of a silicone breast implant. Most frequently, silicone breast implants are used in breast augmentation procedures for cosmetic reasons. In the field of oncology, breast implants are used for reconstructive purposes after mastectomy in the context of breast cancer treatment or prevention. A small percentage of breast reconstructions are performed in women with a hereditary predisposition for breast cancer who undergo bilateral prophylactic mastectomy. In the Netherlands, every year approximately 20,000-30,000 silicone breast implants are inserted for cosmetic (70%) and reconstructive purposes (30%)
From the 1990s onwards, there has been discussion in the scientific community about possible health risks associated with silicone breast implants. It was hypothesised that silicone breast implants could be the cause of breast cancer and sarcoma due to induction of pre-neoplastic fibrotic scar tissue. Furthermore, a variety of auto-immune-, auto-inflammatory- and neurological disorders have been attributed to silicone breast implants. The debate has generated significant research into potential cancer risks from silicone breast implants. Already in the 1990s, results from this research led to rejection of the hypothesis about associations between silicone breast implants and carcinoma or sarcoma of the breast. Most of the other alleged associations between silicone breast implants and various diseases were also discarded due to a lack of evidence after multiple epidemiologic investigations with long-term follow-up. A number of high-powered studies did suggest evidence for an association between silicone breast implants and autoimmune diseases.. However, these studies suffered from a number of methodological shortcomings such as failure to control for confounders, relying solely on unconfirmed patient-reported data, uncertainty as to which participants had silicone implants and high loss to follow-up. These caveats made their conclusions ultimately unconvincing. A strong causal association with silicone breast implants has only been established for Anaplastic Large Cell Lymphoma of the breast, an extremely rare T-cell lymphoma that can develop in the implant capsule.
In contrast to expectations based on the current body of scientific evidence, a number of women reports various health issues following placement of a silicone breast implant. These complaints are generally nonspecific and not attributable to one organ system. Reported symptoms include among others: numbness and tingling of the extremities, joint pain, myalgia, hair loss, cognitive problems, sicca complaints, chronic fatigue, rashes and hives, food intolerances and excessive sweating. The interval between placement of silicone breast implants and the onset of symptoms varies greatly from patient to patient. 'Autoimmune Syndrome Induced by Adjuvants' (ASIA) and 'Silicone Implant Incompatibility Syndrome' are two of the different names that have been coined to describe this constellation of symptoms. Lately, use of the term 'Breast Implant Illness' (BII) has become more commonplace among patients and patient advocates22. In line with difficulty in defining the diagnosis of this entity, its aetiology is unclear. The idea has been postulated that in susceptible individuals, silicone micro-particles that are shed from the implant set into motion a complex mechanism of immune dysregulation via receptor and cytokine pathways. However, so far an exact biochemical mechanism has not been described. With regard to the treatment of BII, suggestive evidence exists that explantation of the implant leads to an improvement of symptoms in at least part of affected women. However, two small observational studies from the Netherlands and the United States did not observe a statistically significant difference in the prevalence of BII-associated symptoms between women with cosmetic silicone breast implants and appropriate comparison groups. These results cast doubts with regard to an association between silicone breast implants and complaints ascribed to BII. In the absence of proof of proportionate organic abnormalities in patients with BII complaints, explanations from a behavioural science perspective have also been put forward, considering the role that psychological and social mechanisms can play in amplification of functional somatic symptoms 28. Striking similarities exist between the typical symptoms ascribed to BII and disorders like chronic fatigue syndrome and fibromyalgia.
With increasing evidence demonstrating the positive impact of breast-contour preserving surgical strategies on quality of life, a growing group of breast cancer patients undergo implant-based breast reconstructions after mastectomy. International data show an upsurge in immediate breast reconstruction over the past decade with rates now reaching around 50% in both The United States and England. Most breast cancer patients undergoing mastectomy are candidates for reconstruction. Although patient preference increasingly plays a role in the choice for a specific reconstructive strategy, factors such as patient's BMI, smoking, comorbidities or available surgical expertise may limit the options. In the Netherlands, the vast majority (83,4%) of immediate breast reconstructions are implant-based with the proportion of autologous reconstructions being around 11% 37. International trends also indicate a shift towards implant based reconstructions.
The current position of the U.S. Food and Drug Administration is that silicone breast implants are safe and reliable devices when used as labelled. Although the purported association between silicone breast implants and autoimmune diseases has been investigated many times, this issue has not been definitively resolved. Large epidemiologic studies investigating the potential association between silicone breast implants and the controversial new entity referred to as BII are lacking. Elucidating the role of implants in autoimmune disease and BII is of great importance to breast cancer patients who often have to make decisions about undergoing an implant-based reconstruction in a short timeframe. Uncertainty fuelled by lay reports on unsubstantiated side effects of silicone breast implants can complicate the decision-making process for patients as well as healthcare professionals. Possibly, this may lead to patients opting for more technically and physically demanding alternatives such as autologous reconstructions which entail longer recovery times, a higher risk of complications and higher expenses 40.
The Areola study is a Dutch prospective cohort study aiming to assess the risk of BII and autoimmune diseases in female breast cancer survivors with and without silicone breast implants. Focussing on sound epidemiological method, it attempts to overcome limitations that hampered previous studies. An additional goal is to identify risk factors for the development of BII and autoimmune disorders among women with implants. The Areola study was set up to meet the demand for reliable information about the role of silicone breast implants on long-term health outcomes in breast cancer survivors.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Reconstruction with silicone breast implant | – | Procedure: Breast reconstruction with silicone breast implantThe cohort will be composed of women who underwent surgery for first invasive breast cancer or ductal carcinoma in situ (DCIS) in the years 2000 to 2015 in the collaborating centres. Eligible for inclusion in the exposed group are all women who underwent (i) mastectomy followed by immediate implant-based reconstruction, (ii) mastectomy followed by implant-based reconstruction at a later stage and (iii) latissimus dorsi flap reconstruction with a silicone breast implant |
| Breast cancer surgery without silicone breast implant | – | Procedure: Breast conserving surgery/Mastectomy/Autologous reconstruction. Eligible for inclusion in the comparison group are women who underwent (i) simple mastectomy without reconstruction, (ii) autologous reconstruction and (iii) breast conserving surgery. From the latter group a frequency-matched sample will be selected based on age at breast cancer diagnosis and calendar year of diagnosis. |
| cosmetic breast augmentation | – | Procedure: Breast Augmentation. Women who underwent cosmetic augmentation in the years 2000 to 2015 constitute a second comparison group. From this group a frequency-matched sample will be selected based on age and year of surgery. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Women who underwent surgery for first invasive breast cancer or ductal carcinoma in situ (DCIS) in the years 2000 to 2015 in the collaborating centres. Eligible for inclusion in the exposed group are all women who underwent (i) mastectomy followed by immediate implant-based reconstruction, (ii) mastectomy followed by implant-based reconstruction at a later stage and (iii) latissimus dorsi flap reconstruction with a silicone breast implant. Eligible for inclusion in the comparison group are women who underwent (i) simple mastectomy without reconstruction, (ii) autologous reconstruction and (iii) breast conserving surgery. From the latter group a frequency-matched sample will be selected based on age at breast cancer diagnosis and calendar year of diagnosis. Women who underwent cosmetic augmentation in the years 2000 to 2015 constitute a second comparison group. From this group a frequency-matched sample will be selected based on age and year of surgery.
Key inclusion criteria (1 listed)
- surgery for first invasive breast cancer or ductal carcinoma in situ (DCIS) in the years 2000 to 2015 in the collaborating centres
Key exclusion criteria (3 listed)
- above the age of 60 at breast cancer diagnosis
- above the age of 80 years at time of inclusion
- Not residing in Netherlands
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Breast reconstruction with silicone breast implantAlso: Breast Reconstruction(i) mastectomy followed by immediate implant-based reconstruction, (ii) mastectomy followed by implant-based reconstruction at a later stage and (iii) latissimus dorsi flap reconstruction with a silicone breast implant. | Procedure or surgery | Reconstruction with silicone breast implant |
| Breast conserving surgery/Mastectomy/Autologous reconstruction(iv) simple mastectomy without reconstruction, (v) autologous reconstruction and (vi) breast conserving surgery, | Procedure or surgery | Breast cancer surgery without silicone breast implant |
| Breast Augmentation(vii) cosmetic augmentation with silicone breast implants | Procedure or surgery | cosmetic breast augmentation |
Primary outcome
Breast Implant Illness
Time frame: 20years
Relative risk (RR) of experiencing the following complaints in exposed and comparison groups: Cognitive impairment joint pain myalgia anxiety feeling depressed skin rashes weakness sleeping problems headache hair loss food intolerances and allergies numbness/tingling in upper and lower limbs dry eyes morning stiffness night sweats heart palpitations shoulder pain
Autoimmune disease
Time frame: 20years
Relative risk (RR) and Incidence rate (IR) for the following illnesses in exposed group and comparison group: Sjögren's Syndrome (SjS) Rheumatoid Arthritis (RA) Systemic Lupus Erythematosus (SLE) Systemic Sclerosis (SSc), Mixed Connective Tissue Disease (MCTD) Antiphospholipid Syndrome (APS) Ankylosing Spondylitis Sarcoidosis Multiple Sclerosis (MS) hypothyroidism hyperthyroidism psoriatic disease inflammatory bowel disease fibromyalgia chronic fatigue syndrome irritable bowel syndrome
Relative risk to develop autoimmune diseases and BII complaints associated with certain risk factors:
Time frame: 20years
RR for BII and autoimmune diseases will be assessed associated with riskfactors in the domains of demographics, lifestyle, reproductive history, medical- and treatment history and family history. Furthermore the influence of psychosocial factors like satisfaction with the breasts and self-esteem on BII risk are evaluated.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Apr 2023.
- Background: PubMed 35499539Spoor J, de Jong D, van Leeuwen FE. [Silicone breast implants: the importance of nuanced reporting]. Ned Tijdschr Geneeskd. 2022 Mar 21;166:D6515. Dutch.
- Background: PubMed 34695179Spoor J, de Jong D, van Leeuwen FE. Silicone Particle Migration: A Misleading Report. Aesthet Surg J. 2022 Mar 15;42(4):NP261-NP262. doi: 10.1093/asj/sjab377. No abstract available.
- Derived from this study: PubMed 42001600Spoor J, Mureau MAM, de Jong D, Tissier RLM, Vis M, Rakhorst H, Hommes J, de Boer M, Oldenburg HSA, Heuts EM, Vissers YLJ, Dassen AE, Evers DJ, Koppert LB, Zaal LH, van der Hulst RRWJ, Vrancken Peeters MTFD, Bleiker EMA, van Leeuwen FE. Risk of autoimmune and rheumatic diseases in breast cancer patients with silicone breast implants. J Natl Cancer Inst. 2026 Apr 19:djag115. doi: 10.1093/jnci/djag115. Online ahead of print.
- Derived from this study: PubMed 41891787Spoor J, van Leeuwen FE, de Jong D, Zaal LH, Rakhorst H, de Boer M, Vissers YLJ, Bleiker EMA, Vrancken Peeters MTFD, Mureau MAM; AREOLA Collaboration. A comparison of Breast Implant Illness-related symptoms between breast cancer survivors and breast augmentation recipients. Plast Reconstr Surg. 2026 Mar 27. doi: 10.1097/PRS.0000000000013061. Online ahead of print.
- Derived from this study: PubMed 40605595Spoor J, Mureau MAM, Tissier RLM, Hommes J, Rakhorst H, de Boer M, Oldenburg HSA, Heuts EM, Vissers YLJ, Dassen AE, Evers DJ, Koppert LB, Zaal LH, Linn SC, de Jong D, van der Hulst RRWJ, Vrancken Peeters MTFD, Bleiker EMA, van Leeuwen FE. Breast implant illness after reconstruction with silicone breast implants. J Natl Cancer Inst. 2025 Aug 1;117(8):1717-1728. doi: 10.1093/jnci/djaf136.
- Derived from this study: PubMed 37028614Spoor J, Mureau MAM, Hommes J, Rakhorst H, Dassen AE, Oldenburg HSA, Vissers YLJ, Heuts EM, Koppert LB, Zaal LH, van der Hulst RRWJ, Vrancken Peeters MTFD, Bleiker EMA, van Leeuwen FE; AREOLA Collaboration. The Areola study: design and rationale of a cohort study on long-term health outcomes in women with implant-based breast reconstructions. Ann Epidemiol. 2023 Jun;82:16-25. doi: 10.1016/j.annepidem.2023.04.001. Epub 2023 Apr 6.
- Website RIVM: Onderzoeksprogramma vrouwen met een siliconen borstimplantaatLink provided by the sponsor.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Floor van Leeuwen, PhD principal investigator
The Netherlands Cancer Institute
Marie-Jeanne Vrancken Peeters, PhD principal investigator
The Netherlands Cancer Institute
Eveline Bleiker principal investigator
The Netherlands Cancer Institute
7 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Breast Cancer and Breast Implant; Complications, run by The Netherlands Cancer Institute at 7 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 28 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Breast Implant Illness (time frame: 20years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05400954, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Apr 2023.