Authors' Affiliations: The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton; Edinburgh Cancer Research UK Center, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh; The Cancer Research UK Gene Function Laboratory; Breakthrough Breast Cancer Research Center; Tumour Profiling Unit, The Institute of Cancer Research, London, United Kingdom; University of California San Francisco, San Francisco, California; Department of Medical Oncology, Prince of Wales Clinical School, Prince of Wales Hospital, Sydney, Australia; The Chaim Sheba Medical Center, Tel Hashomer, Israel; Princess Margaret Hospital, Toronto, Canada; Oncologisch Centrum Vrije Universiteit Brussel, Brussels, Belgium; and Dana Farber Cancer Center, Boston, Massachusetts.
Clin Cancer Res. 2013 Oct 1;19(19):5485-93. doi: 10.1158/1078-0432.CCR-13-1262. Epub 2013 Aug 6.
Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.
We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing.
Data were collected from 89 patients who received a median of 3 (range 1-11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13-21] and 34 weeks (95% CI, 26-42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15-29) and OS of 45 weeks (95% CI, 15-75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0-0.375)].
Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC.
临床前数据表明，BRCA1/2 突变携带者卵巢癌（PBMCOC）患者在接受 PARP 抑制剂（PARPi）治疗后，可能会因获得继发性 BRCA1/2 突变而影响后续化疗（尤其是铂类为基础的化疗方案）的获益。因此，研究了 PARPi 耐药患者中化疗的疗效。
我们对至少接受了 200 毫克，每日两次，持续一个月或更长时间奥拉帕利治疗后疾病进展的 PBMCOC 患者进行了回顾性研究。在可行的情况下，在奥拉帕利治疗后采集肿瘤样本，并通过大规模平行测序进行分析。
共收集了 89 例患者的数据，这些患者在接受奥拉帕利治疗前接受了中位数为 3 （范围 1-11）线化疗。根据实体瘤反应评价标准（RECIST），奥拉帕利治疗后化疗的总客观缓解率（ORR）为 36%（67 例患者中的 24 例），根据 RECIST 和/或妇科癌症协作组（GCIG）CA125 标准为 45%（78 例患者中的 35 例），中位无进展生存期（PFS）和总生存期（OS）分别为 17 周（95%CI，13-21）和 34 周（95%CI，26-42）。对于接受铂类化疗的患者，ORR 分别为 40%（48 例患者中的 19 例）和 49%（53 例患者中的 26 例），中位 PFS 为 22 周（95%CI，15-29），OS 为 45 周（95%CI，15-75）。在奥拉帕利治疗后铂类药物中，增加铂类药物间隔与 OS 延长和对后续铂类药物治疗的反应可能性增加相关。在 6 例 PARPi 耐药患者的肿瘤样本中未检测到继发性 BRCA1/2 突变的证据（根据样本量调整此类突变的估计频率：0.125（95%CI：0-0.375））。
对 PARPi 耐药的大量预处理 PBMCOC 患者仍有可能对后续化疗（包括铂类药物）产生反应。这些数据支持在 PBMCOC 中进一步开发 PARPi。
