Monday, September 10, 2018

Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL): "Where we are, and aren’t"

By: Constantine Kaniklidis Medical Research (Cancer Knowledge network) & Director of No Surrender Breast Cancer Foundation (NSBCF)-- circa 2018, September

Here some reflections, and a plea for further, more systematized and coordinated action and consensus:

First, the just published LYSA Registry data from the French Cancer Agency [reported at ASCO 2018] has shed some further light on two prognostically distinct classes of BIA-ALCLs (based on effusion, breast tumor mass, and lymph node involvement), with in situ BIA-ALCLs exhibiting an indolent clinical course that enables complete remission typically after implant removal, in contrast to infiltrative BIA-ALCLs exhibiting a more aggressive clinical course, with in fact a prognosis virtually identical to systemic anaplastic large cell lymphoma (ALCL), despite real differences. Further clarification was provided in AU-NZ studies [especially Loch-Wilkinson, Plast Reconstr Surg. 2017 Oct], higher-surface-area (HAS) textured implants significantly increased the risk of BIA-ALCL (over 14 times higher with Biocell textured implants and almost 11 times higher with polyurethane (Silimed) textured implants compared with Siltex textured implants, so there clearly is a risk hierarchy at play here.

Second, being mindful of overtreatment (always a concern), nonetheless given that BIA-ALCL related death, although rare, is predominantly due to uncontrolled local disease progression, there is a role in patients with more advanced local disease – particularly in the minority of patients whose disease extends beyond the capsule – for chemotherapeutic intervention, and at this time the best evidenced first-line therapy apart from the strongly toxic CHOP family of regimens is the monoclonal antibody brentuximab vedotin (Adcetris) based on its role in refractory in ALCL, despite the limited but still positive data of its off-label use in BIA-ALCL; and I have seen some cases of patients progressing on CHOP therapy but achieving pathological complete response (pCR) with brentuximab vedotin in the second line. Given its comparatively favorable side effect profile and higher tolerability over traditional chemotherapies, it retains some considerable appeal.

Third, for myself, given that:
(1) the NF-kB) pathway is commonly deregulated in lymphomas, and that
(2) curcumin can inhibit growth of these cell lines and increase their chemosensitivity to cisplatin, and given also that
(3) it (curcumin) increases apoptosis and differentiation of vitamin D-treated tumor cells, with direct binding of curcumin to the vitamin D receptor (VDR), and that
(4) curcumin modulates the well-known overexpression of EZH2 in anaplastic lymphomas and can down-regulate the  JAK/STAT pathway that is also incriminated in BIA-ALCL, then I have (strictly ad hoc-ly and off-label) counseled the deployment, with provisional but promising success, of a regimen of high-penetrance curcuminoids (either phytosomal or nanoparticulate) and optimal-dosed Vitamin D3 (achieving 25(OH)D assay levels of at least 66 ng/ml and above), in the small number of BIA-ALCL cases I have consulted on, but clearly this requires validation in clinical trial. And Mark Clemens' recent findings suggesting that some BIA-ALCL are associated with a chronic allergic immune response to currently undetermined antigen(s) - with IL-13 activity (associated with allergic inflammation) as well as eosinophils and mast cells surrounding the BIA-ALCL tumors plus the presence of IgE – is tantalizing in this connection of anti-inflammatory interventions.

Going Forward, Work Still To Do:
1.     I am also looking to press for the expansion of the European Commission Medical Device Expert Group (VMDEC) Task Force with respect to collection and analysis of EU-based BIA-ALCL cases, but VMDEC registry data must be coordinated with other non-EU entities – like the PROFILE Registry maintained by the The Plastic Surgery Foundation here in the States, the Australian Breast Device Registry,  among many others – if we are to establish a larger and more comprehensive cross-boundary collaborative BIA-ALCL surveillance initiatives to advance our knowledge and better serve the many women affected (and often overlooked and sometimes misdiagnosed as Hodgkin lymphoma or other entities).

2.     It is disconcerting that we still, even in 2018, lack consistent standardization and reporting regarding pathological examination of mammary implants (most institutions often continue to recommend gross examination alone).

3.     Furthermore, we are not doing enough to educate patients and their health professionals on the importance of routine surveillance after implantation.

4.     And we must finally – long overdue -bring explicit consent issues to the fore to assure fairness to patients. It would appear that most breast-focused plastic surgeons in the U.S. and the UK fail to consistently include risk of BIA-ALCL and that uniform informed-consent documents lack widespread adoption and use, so a model BIA-ALCL informed consent is required and effective efforts made to assure that the patient is not simply “allowed” to read and decipher the information as it is found in the informed consent agreement as is all too commonly the case, but that health professionals first openly and candidly discuss not only the risk of BIA-ALCL but also the common presenting symptoms (a mass, breast swelling/pain, or delayed-presentation seroma / effusion) of BIA-ALCL the patient should be on guard for which would trigger a mandated evaluation. I call this the need for “informed discussion” in addition to mere “informed consent”, and that need was best put by the UK High Court (Judgement in Montgomery ‘v’ Lanarkshire Health Board) that stated that “risk shouldn't be a numbers game, it should be part of dialogue”.

Constantine Kaniklidis of
Director, Medical Research, No Surrender Breast Cancer Foundation (NSBCF)
Oncology Reviewer, Current Oncology
Member, Society for Integrative Oncology (SIO)
European Association for Cancer Research (EACR)

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