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

乳房植入体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， 在纹理乳房植入体附近出现液体聚集或团块。淋巴瘤通常局限于液体中 植入物周围或囊，植入物周围的纤维组织，但在10-20%的情况下， 可以扩散到淋巴结或表现为浸润性肿块。使用植入物成功治疗BIA-ALCL 大多数患者需要切除和囊切除术，但约20%的患者需要化疗和/或放疗。 自1997年首次描述BIA-ALCL以来，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，并最终召回 2019年最受欢迎的制造商之一生产的纹理植入物市场。全球意识 因此，这种疾病的发病率有所增加，从而改善了病例的识别和报告， 迫切需要对植入植入物的妇女进行风险预测，目前估计有1000万人 国际吧尽管一些女性选择移除植入物，但暴露于植入物中导致BIA-ALCL的风险 与毛面植入物的相关性较低，可能与在很大程度上仍未知的特定变量有关。我们 纪念斯隆-凯特琳癌症中心（MSKCC）的一个合作小组报告了 在超过3500名植入毛面乳房植入体的女性队列中进行的BIA-ALCL，术后长期随访 乳腺癌（BC）在这个队列中，Cordeiro队列，在其性质上是独特的，11名患者发生了BIA， 暴露7-10年后发生ALCL。然而，这是迄今为止文献中描述的最高发生率， 无特定变量（与BC类型、化疗或放疗暴露、植入物填充相关 用生理盐水或硅胶）与淋巴瘤的高风险有关。我们的合作者来自荷兰癌症 研究所最近报告的初步数据表明，BRCA突变可能在BIA中更常见， ALCL病例比其他人群。在我们的3500名植入植入物的女性队列中， 长期以来，许多患者接受了BRCA突变检测和/或被纳入MSK-IMPACT研究，这是一项广泛的研究。 肿瘤靶向测序工作，包括正常DNA的分析，以过滤出生殖系突变， 肿瘤的结果。这种不寻常的和绝对独特的组合研究进行了这一人口可能 使我们能够确定BRCA和其他生殖系突变是否与淋巴瘤患者的淋巴瘤发生有关。 乳房植入体，以及生殖系突变女性发生BIA-ALCL的相对风险。这反过来将 为植入植入物的女性及其医生提供有关手术（如纹理植入物）的信息决策 乳腺切除术后的切除和重建对于淋巴瘤风险较高的女性。的识别 可能与淋巴瘤发生相关的生殖系突变将导致未来的拨款申请， 在其他淋巴瘤亚型中评估这些机制，因此代表了我们方法的里程碑 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.