Association of silicone breast implant Reconstruction and -Enlargement with Overall wellbeing, Lymphoma and Auto-immune disease - Anaplastic large cell lymphoma of the breast

In the Netherlands, every year approximately 20,000 SBIs are inserted. Of
these, 70% are placed for cosmetic indications. Since the 1990s, there has been
discussion within the scientific community about possible health risks
associated with silicone breast implants. resulting in ample media coverage. It
was hypothesised that SBIs 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 were attributed to
SBIs. Most of the reported associations between SBIs and various diseases have
never been substantiated in thorough epidemiologic investigations and were
later discarded. There is, however, one exception: a strong and likely causal
association has been established between SBIs and Anaplastic Large Cell
Lymphoma of the breast.

In most countries, reporting of BIA-ALCL cases was not mandatory until very
recently. In the Netherlands, since 1989 all pathology reports have been filed
in the *nationwide network and registry of histo- and cytopathology* (PALGA).
This provides a population-based unbiased source for BIA-ALCL cases and
potential control populations. In a 2008 case-control study by the PIs,
comparing 11 confirmed BIA-ALCL patients with 35 patients with other types of
breast lymphoma, an odds ratio of 18.2 was found for ALCL associated with
breast implants. Based on all cases in this database registered between 1990
and 2016 (n=43) and an estimation of the breast implant prevalence,
incorporating data from the national breast cancer screening programme and
implant sales data, a new odds ratio of 421.8 (95% CI, 52.6-3385.2) was
calculated. Furthermore, the cumulative incidence was 82 cases per million for
breast ALCL in women with implants who reached the age of 70 years.

Until now, it is unknown to which extent external and intrinsic factors
predispose individual women with breast implants to develop BIA-ALCL. Most
likely, aetiology is based on a multifactorial process consisting of a
combination of specific implant types, the composition of a bacterial biofilm
surrounding the breast implant (possibly related to surgical procedures), other
factors maintaining a chronic low-grade inflammation and inherent genetic
features of the women affected. It is also unclear to which extent BIA-ALCL is
associated with demographic, reproductive and socio-behavioural patient factors
(obesity, smoking, childbirth after implantation) and postoperative sequelae,
such as capsular contractures and implant replacements.

1. To determine risk factors for BIA-ALCL in women with silicone breast
implants. The associations between demographic-, reproductive- and lifestyle
characteristics and BIA-ALCL risk among women with breast implants will be
investigated. Furthermore, the association between autoimmune disease, family
history of autoimmune disease, cancer, family history of cancer, sequelae to
breast surgery, implant replacements and BIA-ALCL risk among women with breast
implants will be investigated.
2. To assess the prevalence of nonspecific symptoms in the period that one or
two SBI(s) were in-situ in cases and controls.
3. To assess the effect of genetic factors on BIA-ALCL risk.

The AREOLA-A Study is a case-control study on risk factors for BIA-ALCL among
women with breast implants. This study does not aim to assess the relative risk
of ALCL associated with silicone breast implants as such a study has already
been performed. That study also included ALCL cases in the breast without a
history of implants (which is extremely rare; the large majority of breast ALCL
cases have implants). Breast ALCL cases without a history of implants will be
excluded in this study.
Cases with BIA-ALCL will be compared with matched controls; women who have
implants but no ALCL. Data from PALGA, hospital-based registries and
clinic-based patient files will be used to identify the cases and controls.
Patient reported questionnaires will provide data on demographic-,
reproductive- and lifestyle characteristics, medical history and nonspecific
symptoms. The role of genomic markers in BIA-ALCL risk will be assessed by
analysis of DNA isolated from a one-time blood sample and non-cancer germline
DNA isolated from Formalin-Fixed-Paraffin-Embedded (FFPE).

Burden consitis of filling out a one-time questionnaire of 30min and undergoing
a one-time blood sampling during which 6ml of blood is collected. The
possibility exist of finsing genetic predisposition for certain types of
cancer. This has implications for the patients health and possibly for the
patients family.