Pishvaian Michael J, Biankin Andrew V, Bailey Peter, Chang David K, Laheru Daniel, Wolfgang Christopher L, Brody Jonathan R
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
Br J Cancer. 2017 Apr 11;116(8):1021-1026. doi: 10.1038/bjc.2017.40. Epub 2017 Mar 14.
Pancreatic cancer has become the third leading cause of cancer death with minimal improvements in outcome for over 40 years. Recent trials of therapies that target-defective DNA maintenance using poly (ADP-ribose) polymerase (PARP) inhibitors are showing promising results, yet invariably patients recur and succumb to disease. Mechanisms of resistance to platinum-based and PARP inhibitor therapy in other cancer types include secondary mutations, which restore the integrity of DNA repair through an increasing number of different mechanisms.
Here we present a case of a 63-year-old female patient with a germ line pathogenic BRCA2 mutation (6714 deletion) who developed pancreatic cancer and had an exceptional response to platinum and PARP inhibitor therapy. Through next-generation sequencing and clinical follow-up, we correlated tumour response and resistance to the BRCA2 mutational status in the tumour.
Initially, the patient had an exceptional response to platinum and PARP inhibitor therapy, most likely due to the BRCA2 mutation. However, the primary lesion recurred while on PARP inhibitor therapy and contained a secondary mutation in BRCA2, which mostly likely restored BRCA2 function in PARP inhibitor-resistant tumour cells.
To our knowledge, this is the first report of a BRCA2 reversion mutation that conferred resistance to PARP inhibitor-based therapy in a pancreatic ductal adenocarcinoma patient. Future studies are needed to understand this important mechanism of resistance and how it may impact the choice of therapy for patients with pancreatic cancer.
胰腺癌已成为癌症死亡的第三大主要原因，40多年来其治疗效果几乎没有改善。最近使用聚（ADP-核糖）聚合酶（PARP）抑制剂针对缺陷DNA维持的疗法试验显示出有希望的结果，但患者总是会复发并死于该疾病。其他癌症类型中对铂类和PARP抑制剂治疗产生耐药性的机制包括二次突变，这些突变通过越来越多不同的机制恢复DNA修复的完整性。
在此，我们报告一例63岁女性患者，其携带种系致病性BRCA2突变（6714缺失），患胰腺癌，对铂类和PARP抑制剂治疗有异常反应。通过下一代测序和临床随访，我们将肿瘤反应和耐药性与肿瘤中的BRCA2突变状态相关联。
最初，该患者对铂类和PARP抑制剂治疗有异常反应，很可能是由于BRCA2突变。然而，在接受PARP抑制剂治疗期间原发性病变复发，且BRCA2中存在二次突变，这很可能恢复了PARP抑制剂耐药肿瘤细胞中BRCA2的功能。
据我们所知，这是首例BRCA2回复突变赋予胰腺导管腺癌患者对基于PARP抑制剂的治疗产生耐药性的报告。需要进一步研究来了解这一重要的耐药机制及其可能如何影响胰腺癌患者的治疗选择。
