Leichman Lawrence, Groshen Susan, O'Neil Bert H, Messersmith Wells, Berlin Jordan, Chan Emily, Leichman Cynthia G, Cohen Steven J, Cohen Deirdre, Lenz Heinz-Josef, Gold Philip, Boman Bruce, Fielding Anitra, Locker Gershon, Cason Ronald C, Hamilton Stan R, Hochster Howard S
New York University, Perlmutter Cancer Center, New York, New York, USA
University of Southern California, Norris Cancer Center, Los Angeles, California, USA.
Oncologist. 2016 Feb;21(2):172-7. doi: 10.1634/theoncologist.2015-0319. Epub 2016 Jan 19.
Effective new agents for patients with colorectal cancer (CRC) with disease progression during standard therapy regimens are needed. We hypothesized that poly ADP ribose polymerase (PARP) inhibitor therapy in patients with CRC and inefficient tumor DNA repair mechanisms, such as those with high-level microsatellite instability (MSI-H), would result in synthetic lethality.
This was an open-label phase II trial testing olaparib 400 mg p.o. b.i.d. for patients with disseminated, measurable CRC failing standard therapies with centrally confirmed tumor MSI status. The primary endpoint was the tumor response, assessed by RECIST, version 1.0. The secondary endpoints were safety/toxicity, progression-free survival (PFS), and overall survival (OS).
Thirty-three patients (20 microsatellite stable [MSS], 13 MSI-H) were enrolled. The median age for all patients was 57 years and for MSS and MSI-H patients was 51 and 61 years, respectively. All patients received at least one 28-day cycle of olaparib. No patient had a complete or partial response. Nausea (48%), fatigue (36%), and vomiting (33%) were the most commonly reported treatment-related adverse events. The median PFS for all patients was 1.84 months. No statistically significant differences were found in the median PFS or OS for the MSS group compared with the MSI-H group.
Single-agent olaparib delivered after failure of standard systemic therapy did not demonstrate activity for CRC patients, regardless of microsatellite status. Future trials, testing PARP inhibitors in patients with CRC should focus on the use of DNA-damaging chemotherapy and/or radiation therapy, combined with PARP inhibitors, remembering the toxicity reported in the present study.
Microsatellite instability (MSI-H) colorectal tumors exhibit hypermethylation in tumor mismatch repair genes, or have mutations in one or more of these genes resulting from a germ-line defect (Lynch syndrome). PARP inhibitors such as olaparib are most effective in tumors associated with inability to repair DNA damage. However, in this trial, single agent olaparib failed to elicit responses in patients with MSI-H colorectal tumors, and in those with microsatellite-stable tumors. It is possible that by adding olaparib to radiation therapy, or to a systemic DNA damaging agent, tumor lethality could be obtained. However, the price would be increased toxicity.
对于在标准治疗方案期间疾病进展的结直肠癌（CRC）患者，需要有效的新型药物。我们假设，在CRC患者中，使用聚ADP核糖聚合酶（PARP）抑制剂进行治疗，对于肿瘤DNA修复机制低效的患者，如那些具有高水平微卫星不稳定性（MSI-H）的患者，会导致合成致死效应。
这是一项开放标签的II期试验，对400mg口服，每日两次的奥拉帕尼进行测试，受试对象为经中心确认肿瘤MSI状态且标准治疗失败的播散性、可测量的CRC患者。主要终点是根据RECIST 1.0版评估的肿瘤反应。次要终点是安全性/毒性、无进展生存期（PFS）和总生存期（OS）。
共纳入33例患者（20例微卫星稳定[MSS]，13例MSI-H）。所有患者的中位年龄为57岁，MSS和MSI-H患者的中位年龄分别为51岁和61岁。所有患者均接受了至少一个28天周期的奥拉帕尼治疗。没有患者出现完全或部分缓解。恶心（48%）、疲劳（36%）和呕吐（33%）是最常报告的与治疗相关的不良事件。所有患者的中位PFS为1.84个月。MSS组与MSI-H组在中位PFS或OS方面未发现统计学上的显著差异。
在标准全身治疗失败后给予单药奥拉帕尼，无论微卫星状态如何，均未显示对CRC患者有活性。未来在CRC患者中测试PARP抑制剂的试验应侧重于将DNA损伤化疗和/或放射治疗与PARP抑制剂联合使用，同时要记住本研究中报告的毒性。
微卫星不稳定性（MSI-H）结直肠肿瘤在肿瘤错配修复基因中表现出高甲基化，或由于种系缺陷（林奇综合征）导致这些基因中的一个或多个发生突变。PARP抑制剂如奥拉帕尼在与无法修复DNA损伤相关的肿瘤中最有效。然而，在本试验中，单药奥拉帕尼未能在MSI-H结直肠肿瘤患者和微卫星稳定肿瘤患者中引发反应。通过将奥拉帕尼添加到放射治疗或全身DNA损伤剂中，有可能获得肿瘤致死效应。然而，代价将是毒性增加。
