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

乳房植入相关间变性大细胞淋巴瘤(BIA-ALCL)是T细胞淋巴瘤的一种亚型 出现在有纹理的乳房植入物附近的液体集合或肿块。淋巴瘤通常局限于液体中。 植入物周围或包膜周围有纤维组织，但在10%-20%的情况下，它 可扩散至淋巴结或呈浸润性肿块。BIA-ALCL植入治疗成功 大多数患者需要摘除和切除囊膜，但约20%需要化疗和/或放射治疗。 自1997年首次描述BIA-ALCL以来，总共报告了733例独特病例，其中36例患者 死亡，导致FDA在2011年和2016年发出警告通知，最终导致从 2019年最受欢迎的制造商之一生产的纹理植入物的市场。全球意识 因此，这种疾病的发病率增加了，从而改善了病例的识别和报告，以及 迫切需要对安装了植入物的妇女进行风险预测，目前估计有1000万人 全世界。尽管一些女性选择移除植入物，但接触BIA-ALCL的风险 质地植入物的风险很低，可能与在很大程度上仍不清楚的特定变量有关。我们的 合作小组通过纪念斯隆·凯特琳癌症中心(MSKCC)报告了 BIA-ALCL在3500多名接受质地乳房假体植入的女性中进行了术后长期随访 用于乳腺癌(BC)。在这个队列中，Cordeiro队列的性质是独一无二的，11名患者发生了BIA- ALCL暴露7-10年后。然而，这是迄今为止文献中描述的最高发病率。 没有特定的变量(与BC的类型、化疗或放射治疗的暴露、植入物的填充有关 使用生理盐水或硅胶)与患淋巴瘤的风险更高有关。我们来自荷兰癌症的合作者 研究所最近报告的初步数据表明，BRCA突变可能在BIA- ALCL病例多于其他人群。在我们的3500名接受植入物的女性队列中，Long 长期，许多患者接受了BRCA突变测试和/或包括在MSK影响研究中，这是一个广泛的 肿瘤靶向测序工作，包括对正常DNA的分析，以筛选出来自 肿瘤的结果。这种对这一人群进行的不同寻常和绝对独特的研究组合可能 允许我们确定BRCA和其他生殖系突变是否与淋巴肿大有关 乳房植入，以及生殖系突变女性患BIA-ALCL的相对风险。这反过来又会 为接受植入物的妇女及其医生提供有关纹理植入物等程序的决策信息 淋巴瘤风险较高的女性乳房切除后的切除和重建。身份的鉴定 可能与淋巴肿大有关的种系突变将导致未来的拨款申请和 在其他淋巴瘤亚型中对这些机制的评估，因此是我们方法的一个里程碑 对疾病的影响。

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.