Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab
Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab
复制标题
DOI：
10.1210/jc.2018-01347
复制
发表时间：
2018-10-01
影响因子：
5.8
通讯作者：
Geer, Eliza B.
中科院分区：
文献类型：
--
作者：
Lin, Andrew L.;Jonsson, Philip;Geer, Eliza B.
背景：垂体癌是一种罕见的侵袭性恶性肿瘤，预后较差，且缺乏有效的治疗选择。病例：一名35岁的女性出现了侵袭性促肾上腺皮质激素垂体腺瘤，在转移到肝脏之前，最初对替莫唑胺和卡培他滨有反应。在伊匹单抗和纳武单抗治疗后，优势肝转移的肿瘤体积减少了92%，复发性颅内疾病消退了59%。同时，她的血浆ACTH水平从45,550 pg/mL降至66 pg/mL。分子评价：采用Memorial Sloan Kettering-Integrated mutations Profiling of Actionable Cancer Targets进行前瞻性临床测序和回顾性全外显子组测序，以表征化疗后垂体腺瘤和替莫唑胺耐药肝转移的分子改变。肝转移具有与烷基化剂诱导的高突变一致的体细胞突变负担，这在未接受治疗的肿瘤中是不存在的。对替莫唑胺治疗的耐药性、获得新的致癌驱动因素以及随后对免疫治疗的敏感性可能归因于高突变。结论：伊匹单抗与纳武单抗联合治疗垂体癌可能是一种有效的治疗方法。常规化疗后复发的垂体肿瘤的临床测序可以确定治疗诱导的体细胞超突变的发展，这可能与免疫治疗的治疗反应有关。
Context: Pituitary carcinoma is a rare and aggressive malignancy with a poor prognosis and few effective treatment options.Case: A 35-year-old woman presented with an aggressive ACTH-secreting pituitary adenoma that initially responded to concurrent temozolomide and capecitabine prior to metastasizing to the liver. Following treatment with ipilimumab and nivolumab, the tumor volume of the dominant liver metastasis reduced by 92%, and the recurrent intracranial disease regressed by 59%. Simultaneously, her plasma ACTH level decreased from 45,550 pg/mL to 66 pg/mL.Molecular Evaluation: Both prospective clinical sequencing with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and retrospective whole-exome sequencing were performed to characterize the molecular alterations in the chemotherapynaive pituitary adenoma and the temozolomide-resistant liver metastasis. The liver metastasis harbored a somatic mutational burden consistent with alkylator-induced hypermutation that was absent from the treatment-naive tumor. Resistance to temozolomide treatment, acquisition of new oncogenic drivers, and subsequent sensitivity to immunotherapy may be attributed to hypermutation.Conclusion: Combination treatment with ipilimumab and nivolumab may be an effective treatment in pituitary carcinoma. Clinical sequencing of pituitary tumors that have relapsed following treatment with conventional chemotherapy may identify the development of therapy-induced somatic hypermutation, which may be associated with treatment response to immunotherapy.