Supplementary Material for: Sustained clinical response to Olaparib in a patient with metastatic pancreatic cancer and somatic ATM-Mutation R2034Ter: a case report

Background
Pancreatic cancer remains a lethal disease with limited therapeutic options. The field of targeted therapies is still growing. Treatment with PARP inhibitors has been successfully described mainly in patients with germline mutation in in BRCA1/2. The efficacy of PARP inhibitors in patients with alterations in other genes in the homologous repair pathway is under discussion.
Case Presentation
A 77-year-old male patient with metastatic pancreatic ductal adenocarcinoma (PDAC) was initially treated with 5-fluoruracil, oxaliplatin and irinotecan, followed by 5-floururacil and irinotecan over the course of one year, leading to sustained partial remission. Molecular genetic analysis of the tumor revealed an inactivating R2034Ter mutation in the Ataxia telangiectasia serine/threonine kinase gene (ATM), being part of a homologous DNA damage repair pathway eventually involving BRCA1 and BRCA2. After discussion in the Molecular Tumor Board (MTB), the patient was started on off-label Olaparib maintenance therapy, under which he has shown stable disease over a period of eighteen months. After developing one new liver metastasis at 21 months on Olaparib, he received conventional therapy with Gemcitabine/Cisplatin to which he responded.
Conclusion
This is the first case of a R2034Ter ATM mutant PDAC with sustained clinical response under Olaparib maintenance therapy reported. In select cases, ATM, a member of the BRCA pathway, might be a druggable target in pancreatic cancer.

背景
胰腺癌仍是一种致死性疾病，治疗选择十分有限。靶向治疗领域仍在不断发展。PARP抑制剂（PARP inhibitor）治疗已被证实主要对携带BRCA1/2生殖系突变的患者有效，但针对同源重组修复通路中其他基因发生变异的患者，PARP抑制剂的疗效仍存在争议。
病例介绍
本例为1例77岁男性转移性胰腺导管腺癌（PDAC, Pancreatic ductal adenocarcinoma）患者，初始接受5-氟尿嘧啶（5-fluoruracil）、奥沙利铂（oxaliplatin）及伊立替康（irinotecan）治疗，后续一年内序贯予以5-氟尿嘧啶联合伊立替康治疗，获得持续部分缓解。肿瘤分子遗传学分析显示，共济失调毛细血管扩张症丝氨酸/苏氨酸激酶基因（ATM, Ataxia telangiectasia serine/threonine kinase gene）存在失活性R2034Ter突变，该基因属于最终涉及BRCA1与BRCA2的同源DNA损伤修复通路。经分子肿瘤委员会（MTB, Molecular Tumor Board）讨论后，患者接受超说明书奥拉帕利（Olaparib）维持治疗，治疗18个月期间疾病保持稳定。在奥拉帕利治疗21个月后，患者出现1处新发肝转移，遂接受吉西他滨/顺铂（Gemcitabine/Cisplatin）常规治疗并获得临床应答。
结论
本研究为首例报道的携带R2034Ter ATM突变的胰腺导管腺癌患者，在奥拉帕利维持治疗下获得持续临床应答的病例。在经过筛选的特定病例中，作为BRCA通路成员的ATM基因或可成为胰腺癌的可靶向治疗靶点。