Breast Implant Associated-Anaplastic Large Cell Lymphoma (BIA-ALCL): The Lymphoma Study Association (LYSA) Registry Data
Authors: Le Bras Fabien , Gaulard Philippe , Andre Marc , Haioun Corinne , Bosc Romain , Laurent Camille , Tortelano Lionel , Dao Thua-Ha , Itti Emmanuel , Malhaire Caroline , Jean Marc Schiano de Colella , Bannier Marie , Bachy Emmanuel , Slama Borhane , Fornecker Luc Mathieu , Oberic Lucie , Traverse-Glehen Alexandra , Croix Manon , Bonnefoy Julie , Fogarty Patrick , Bouabbas Feriel , Amara Nadia , Fataccioli Virginie , Ricci Romain , Cassubie-Mercier Tania , Kirova Youlia , Reyal Fabien , Tilly Herve , Nicolas-Virelizier Emmanuelle , Xerri Luc , Bonnet Christophe 
Published: November 2019

Background: BIA-ALCL is a rare subtype of T cell lymphomas associated with textured breast implants which has recently been recognized. The pathogenesis of this entity remains elusive even if mutations in the JAK/STAT pathway have been identified. Little is known about the causes, prognostic factors of this disease, and treatment outcome.
Methods: since 2016, a WebEx national multidisciplinary meeting has been implemented by the French Cancer Agency in order to better define therapeutic strategies for newly diagnosed cases after histologic confirmation. In the same time, BIA-ALCL registry was funded by LYSA in order to collect ambispectively, in France and Belgium, patient clinical data including reasons for breast implantation (breast augmentation, reconstruction), implant manufacturer, treatments and outcome. A biological program aiming molecular characterization of this T-cell lymphoma subtype has been set in coordination with the registry.
Results: Fifty-eight patients (pts) have been analyzed so far among the 88 (67 in France and 21 in Belgium) identified from 2009 to 2019. Median age was 58 years (range 29-82) at diagnosis. In 29 out of the 58 pts (50%) the first implant followed a mastectomy for breast cancer. In this analysis, only implants in the breast(s) where the lymphoma occurred have been considered. Four pts (6.9%) had bilateral lymphoma and 54 pts had unilateral lymphoma (50% left side and 50% right side), 25 pts were implanted once (43.1%), 24 twice (41.4%) and 9 pts (15.5%) 3 times or more. The median delay between first implant and BIA-ALCL diagnosis was 11.9 years (range 4.1-37), and median delay from last implant to diagnosis was 6.5 years (range 0.2-25.4). The two clinical presentations i.e. seroma (n = 43, 74.1%) and breast tumor mass with or without seroma (n = 12, 20.7%) were most often correlated with the two distinct histological subtypes (in situ /mixed (n=41) or infiltrative (n=17). Three pts were diagnosed without any mass or seroma (1 lymph node involvement, 2 in the context of systematic implant removal). The majority of pts were stage I-II (n=45, 77.6%), and 13 (22.4%) pts were stage IV. One hundred and five implants have been used on lymphoma associated breast for these 58 patients. Considering available information regarding the type of implants, almost all patients had at least one silicone-filled (n=51) and at least one textured implant (n=49) with Biocell texturation (n=40, 69%). No patient had only smooth implant. Implant removal with total capsulectomy was performed in 49 patients and 17 underwent chemotherapy based mostly on CHOP or CHOP-like chemotherapy regimens (n=12) and brentuximab vedotin CHP (n=3). After 21 months of median follow-up, 52 pts are alive and free of evolutive disease and one was lost to follow up. Five pts have died, either from lymphoma progression alone (n=2), or associated with concomitant active breast cancer (n=2) and one due to another disease. All had an infiltrative histology, and the 2 patients who died from lymphoma were stage IV. All but one received systemic chemotherapy and one received palliative care only due to concomitant active breast cancer. One of these patients early relapsed after a first complete remission.
After the BIA-ALCL diagnosis, breast reconstruction was performed in in 23 pts (39.7%), 17 with a new implant, lipofilling in 4 pts, with a flap in 4 pts, and one benefit from combined approaches. Whole exome sequencing and/or targeted deep sequencing was performed in 29 of these patients. Recurrent mutation of epigenetic modifiers were seen in 22 pts (76%) involving notably KMT2C (28%), CM2D (14%) and CREBBP (14%). Eighteen pts (62%) showed mutations in at least one member of JAK STAT signaling pathway including STAT3 (38%) and JAK1(21%).
Conclusions: We here confirm that in situ BIA-ALCLs have an indolent clinical course and remain in complete remission mainly after implant removal. Infiltrative histological subtype which have a more aggressive clinical course should be precisely identified at baseline. In our series, most BIA-ALCL cases were associated with macrotextured implants with Biocell texturation observed in 69% of the cases.
The molecular characterization of these cases highlights the key role of the JAK/STAT pathway, and the importance of epigenomics. Such observation provide basis to develop novel targeted therapies for patients with aggressive disease.

Disclosures
Le Bras: Takeda: Research Funding; Pfizer: Other: Travel grant; Jansen: Other: Travel grant. Haioun:novartis: Honoraria; celgene: Honoraria; roche: Consultancy; celgene: Consultancy; gilead: Consultancy; takeda: Consultancy; janssen cilag: Consultancy; amgen: Honoraria; servier: Honoraria. Bachy:Janssen Cilag: Honoraria; Janssen Cilag: Other: Travel, accomodation, Expense; Roche: Honoraria; Amgen: Honoraria; Roche: Consultancy; Gilead Science: Honoraria. Oberic:Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Tilly:Roche: Consultancy; roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Astra-Zeneca: Consultancy; Celgene: Consultancy, Research Funding.