High frequency of radiological differential responses with poly(ADP-Ribose) polymerase (PARP) inhibitor therapy.
High frequency of radiological differential responses with poly(ADP-Ribose) polymerase (PARP) inhibitor therapy.
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DOI：
10.18632/oncotarget.22303
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发表时间：
2017-11-28
期刊：
影响因子：
--
通讯作者：
Yap TA
中科院分区：
文献类型：
--
作者：
Perez-Lopez R;Roda D;Jimenez B;Brown J;Mateo J;Carreira S;Lopez J;Banerji U;Molife LR;Koh DM;Kaye SB;de Bono JS;Tunariu N;Yap TA
尽管对生殖系BRCA 1和BRCA 2（BRCA 1/2）突变型癌症患者的临床活性令人印象深刻，但对聚（ADP-核糖）聚合酶（PARP）抑制剂的抗肿瘤反应是可变的。我们着手评估患者对PARP抑制剂的放射学差异反应（RDR）率，其与患者结局的相关性，以及与RDR相关的因素的识别。我们回顾性分析了5项早期PARP抑制剂单药治疗试验中的所有晚期癌症患者。113例患者（卵巢癌57.5%;乳腺癌23.9%）纳入本回顾性研究; 46例（40.7%）患者在PARP抑制剂单药治疗后发生RDR。我们确定了两种RDR模式：69.6%的患者出现早期RDR（第一次或第二次治疗扫描），30.4%的患者出现晚期RDR（倒数第二次或最后一次扫描）。早期RDR与较短的疾病进展时间（TTP）（225 vs 367天，HR：0.59，95%CI 0.36-0.98; p=0.04）和总生存期（OS）（499 vs 857天; HR：0.47，95%CI 0.27-0.82，p=0.006）相关。79例（69.9%）患者存在已知的生殖系BRCA 1/2突变; 49.4%的BRCA 1/2突变携带者发生RDR，而20.6%的BRCA 1/2状态未知或野生型患者发生RDR。携带生殖系BRCA 1/2突变可独立预测RDR（RR：2.93，95% CI 1.08-7.90，p=0.03）。生殖系BRCA 1突变患者的TTP和OS比BRCA 2突变携带者差（212 vs 406天，HR：0.58，95% CI 0.36-0.94，p=0.023和515 vs 937天; HR：0.49，95% CI 0.29-0.83; p=0.007）。PARP抑制剂的RDR很常见，特别是在生殖系BRCA 1/2突变携带者中。这些发现对患者的预后具有临床意义，并可能反映了潜在的患者内基因组异质性。
Despite impressive clinical activity in patients with germline BRCA1 and BRCA2 (BRCA1/2) mutant cancers, antitumor responses to poly(ADP-Ribose) polymerase (PARP) inhibitors are variable. We set out to assess the rate of intrapatient radiological differential responses (RDR) to PARP inhibitors, its correlation with patient outcomes, and the identification of factors associated with RDR. We retrospectively reviewed all patients with advanced cancers from five early phase PARP inhibitor monotherapy trials. 113 patients (ovarian cancers 57.5%; breast cancers 23.9%) were included in this retrospective study; 46 (40.7%) patients developed RDR on PARP inhibitor monotherapy. We identified two patterns of RDR: early RDR (1st or 2nd on-treatment scans) in 69.6% of patients, and late RDR (penultimate or final scans) in 30.4% of patients. Early RDR was associated with shorter time to progression (TTP) (225 vs 367 days, HR:0.59, 95%CI 0.36-0.98; p=0.04) and overall survival (OS) (499 vs 857 days; HR:0.47, 95%CI 0.27-0.82, p=0.006). Seventy-nine (69.9%) patients had known germline BRCA1/2 mutations; 49.4% of these BRCA1/2 mutation carriers developed RDR versus 20.6% of patients with unknown or wildtype BRCA1/2 status. Harboring germline BRCA1/2 mutations was independently predictive for RDR (RR:2.93, 95% CI 1.08-7.90, p=0.03). Patients with germline BRCA1 mutations had worse TTP and OS than BRCA2 mutation carriers (212 vs 406 days, HR:0.58, 95% CI 0.36-0.94, p=0.023 and 515 vs 937 days; HR:0.49, 95% CI 0.29-0.83; p=0.007). RDR with PARP inhibitors are frequent, particularly in germline BRCA1/2 mutation carriers. These findings have clinical implications for patient outcomes and may reflect underlying intrapatient genomic heterogeneity.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
28.2
作者：
Goodall J;Mateo J;Yuan W;Mossop H;Porta N;Miranda S;Perez-Lopez R;Dolling D;Robinson DR;Sandhu S;Fowler G;Ebbs B;Flohr P;Seed G;Rodrigues DN;Boysen G;Bertan C;Atkin M;Clarke M;Crespo M;Figueiredo I;Riisnaes R;Sumanasuriya S;Rescigno P;Zafeiriou Z;Sharp A;Tunariu N;Bianchini D;Gillman A;Lord CJ;Hall E;Chinnaiyan AM;Carreira S;de Bono JS;TOPARP-A investigators
通讯作者：
TOPARP-A investigators
DOI：
10.1158/1078-0432.ccr-16-2174
发表时间：
2017-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Afghahi A;Timms KM;Vinayak S;Jensen KC;Kurian AW;Carlson RW;Chang PJ;Schackmann E;Hartman AR;Ford JM;Telli ML
通讯作者：
Telli ML
影响因子：
45.3
作者：
Choi, Haesun;Charnsangavej, Chuslip;Benjamin, Robert S.
通讯作者：
Benjamin, Robert S.
影响因子：
6.2
作者：
Azer, Mary W. F.;Menzies, Alexander M.;Long, Georgina V.
通讯作者：
Long, Georgina V.