Impact of germline mutations on the development of breast-implant associated anaplastic large cell lymphoma (BIA-ALCL) in women with textured breast implants

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Breast implant-associated Anaplastic Large Cell Lymphoma (BIA-ALCL) is a subtype of T-cell lymphoma that arises as a fluid collection or mass near textured breast implants. The lymphoma is usually confined to the fluid surrounding the implants or to the capsule, a fibrous tissue around the implants, but in 10-20% of the cases, it can spread to lymph nodes or present as an infiltrating mass. BIA-ALCL is treated successfully with implant removal and capsulectomy in most patients, but ~20% require chemotherapy and/or radiotherapy. Since the first description of BIA-ALCL in 1997, 733 total unique cases have been reported, with 36 patient deaths, leading to warning communications from the FDA in 2011 and 2016, and ultimately, to the recall from the market of textured implants produced by one of the most popular manufacturers in 2019. Global awareness of this disease was thus increased, leading to improved identification and reporting of cases, as well as to an urgent need for risk prediction for women with implants in place, currently estimated to be 10s of millions worldwide. Although some women choose to remove the implants, the risk of getting BIA-ALCL from exposure to textured implants is low and could be related to specific variables that remain largely unknown. Our collaborative group through Memorial Sloan Kettering Cancer Center (MSKCC) has reported the incidence of BIA-ALCL in a cohort of more than 3500 women with textured breast implants followed long term after surgery for breast cancer (BC). In this cohort, the Cordeiro Cohort, unique in its nature, 11 patients developed BIA- ALCL after an exposure of 7-10 years. This is the highest incidence described so far in the literature, however no particular variable (related to the type of BC, exposure to chemo or radiation therapy, filling of the implants with saline or silicone) was related to higher risk of lymphoma. Our collaborators from the Netherlands Cancer Institute have recently reported preliminary data suggesting BRCA mutations might be more frequent in BIA- ALCL cases than in the rest of the population. Within our cohort of 3500 women with implants followed long term, many patients were tested for BRCA mutations and/or were included in the MSK-IMPACT study, a broad tumor targeted sequencing effort that included the analysis of normal DNA to filter out germline mutations from the tumor results. This unusual and absolutely unique combination of studies conducted on this population may allow us to determine if BRCA and other germline mutations are related to lymphomagenesis in people with breast implants, and the relative risk of women with germline mutations to develop BIA-ALCL. This in turn will inform decision making for women with implants and their physicians on procedures such as textured implant removal and reconstruction after mastectomy for women at higher risk of lymphoma. The identification of germline mutations that might be related to lymphomagenesis will lead to future grant submissions and evaluations of these mechanisms in other lymphoma subtypes, thus representing a milestone in our approach to the disease.