Stephanie Lheureux, Jeff P. Bruce, Julia V. Burnier, Katherine Karakasis, S.Y. Cindy Yang, Rene Quevedo, Tiantian Li, Mark Dowar, Valerie Bowering, Trevor J. Pugh, and Amit M. Oza, Princess Margaret Cancer Centre; Stephanie Lheureux, Patricia A. Shaw, Blaise A. Clarke, S.Y. Cindy Yang, Rene Quevedo, Trevor J. Pugh, and Amit M. Oza, University of Toronto; Patricia A. Shaw and Blaise A. Clarke, University Health Network, Toronto, Canada.
J Clin Oncol. 2017 Apr 10;35(11):1240-1249. doi: 10.1200/JCO.2016.71.3677. Epub 2017 Feb 21.
Purpose Durable and long-term responses to the poly (ADP-ribose) polymerase inhibitor olaparib are observed in patients without BRCA1/2 mutations. However, beyond BRCA1/2 mutations, there are no approved biomarkers for olaparib in high-grade serous ovarian cancer (HGSOC). To determine mechanisms of durable response and resistance to olaparib therapy, we performed an analysis of HGSOC tumors from three patients without germline BRCA1/2 mutations who experienced exceptional responses to olaparib. Patients and Methods We performed integrated exome, low-pass genome, and RNA sequence analysis of tumors at diagnosis and upon relapse from patients with platinum-sensitive HGSOC recurrence who were treated > 5 years with olaparib therapy as a single agent. Results We observed somatic disruption of BRCA1/2 in all three patients at diagnosis, followed by subsequent BRCA recovery upon progression by copy number gain and/or upregulation of the remaining functional allele in two patients. The third patient with ongoing response (> 7 years) had a tumor at diagnosis with biallelic somatic deletion and loss-of-function mutation, thereby lacking a functional allele for recovery of BRCA1 activity and indicating a potential cure. Conclusion Olaparib has durable benefit for patients with ovarian cancer beyond germline BRCA1/2 carriers. These data suggest that biallelic loss of BRCA1/2 in cancer cells may be a potential marker of long-term response to poly (ADP-ribose) polymerase inhibition and that restoration of homologous repair function may be a mechanism of disease resistance.
目的
在没有 BRCA1/2 突变的患者中，观察到聚（ADP-核糖）聚合酶抑制剂奥拉帕利的持久和长期反应。然而，除了 BRCA1/2 突变之外，在高级别浆液性卵巢癌（HGSOC）中，没有批准用于奥拉帕利的生物标志物。为了确定对奥拉帕利治疗有持久反应和耐药的机制，我们对来自三名没有种系 BRCA1/2 突变的患者的 HGSOC 肿瘤进行了分析，这些患者对奥拉帕利有异常反应。
患者和方法
我们对接受奥拉帕利单药治疗> 5 年的铂敏感 HGSOC 复发患者的肿瘤进行了综合外显子组、低通基因组和 RNA 序列分析。
结果
我们在所有三名患者的诊断时均观察到 BRCA1/2 的体细胞失活，随后在两名患者中通过拷贝数增加和/或剩余功能等位基因的上调，在进展时恢复了 BRCA。第三例持续反应（> 7 年）的患者在诊断时肿瘤具有双等位基因体细胞缺失和功能丧失突变，因此缺乏恢复 BRCA1 活性的功能性等位基因，表明可能治愈。
结论
奥拉帕利对除种系 BRCA1/2 携带者以外的卵巢癌患者具有持久的益处。这些数据表明，癌细胞中 BRCA1/2 的双等位基因缺失可能是聚（ADP-核糖）聚合酶抑制的长期反应的潜在标志物，同源修复功能的恢复可能是耐药的机制。
