Clinical trial NCT05400954: Association of Silicone Breast Implants With Overall Wellbeingand Auto-immune Diseases
Official title: Association of Silicone Breast Implant Reconstruction and -Enlargement With Overall Wellbeing, Lymphoma and Auto-immune Disease - Breast Implant Illness
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Breast Cancer
Breast Implant; Complications
Autoimmune Diseases
Keywords: Silicone Breast Implant
Breast Reconstruction
Breast Cancer
Breast Implant Illness
Autoimmune disease
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
Collaborators: name: Erasmus Medical Center
name: Maastricht University Medical Center
name: Zuyderland Medical Centre
name: Medisch Spectrum Twente
name: Ziekenhuisgroep Twente
name: Velthuis Kliniek
First posted: 2022-06-02
Enrollment: 15000
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
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.

Brief 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 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.

Eligibility criteria: Inclusion Criteria:

* surgery for first invasive breast cancer or ductal carcinoma in situ (DCIS) in the years 2000 to 2015 in the collaborating centres

Exclusion Criteria:

* above the age of 60 at breast cancer diagnosis
* above the age of 80 years at time of inclusion
* Not residing in Netherlands

Primary outcomes:
measure: Breast Implant Illness
timeFrame: 20years
measure: Autoimmune disease
timeFrame: 20years
measure: Relative risk to develop autoimmune diseases and BII complaints associated with certain risk factors:
timeFrame: 20years
Secondary outcomes:
Other outcomes:
Locations:
city: Heerlen
country: Netherlands
facility: Zuyderland Medical Center
state: Limburg
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
state: Limburg
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute Antoni van Leeuwenhoek
state: Noord-Holland
city: Hilversum
country: Netherlands
facility: Velthuis Kliniek
state: Noord-Holland
city: Almelo
country: Netherlands
facility: Ziekenhuisgroep Twente
state: Overijssel
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
state: Overijssel
city: Rotterdam
country: Netherlands
facility: Erasmus MC University Medical Center
state: Zuid-Holland
Study officials:
affiliation: The Netherlands Cancer Institute
name: Floor van Leeuwen, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Netherlands Cancer Institute
name: Marie-Jeanne Vrancken Peeters, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Netherlands Cancer Institute
name: Eveline Bleiker
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Spoor 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.