Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial.
Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial.
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DOI：
10.1158/2159-8290.cd-21-0007
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发表时间：
2021-11
期刊：
影响因子：
28.2
通讯作者：
de Bono, Johann S.
中科院分区：
文献类型：
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作者：
Carreira, Suzanne;Porta, Nuria;Arce-Gallego, Sara;Seed, George;Llop-Guevara, Alba;Bianchini, Diletta;Rescigno, Pasquale;Paschalis, Alec;Bertan, Claudia;Baker, Chloe;Goodall, Jane;Miranda, Susana;Riisnaes, Ruth;Figueiredo, Ines;Ferreira, Ana;Pereira, Rita;Crespo, Mateus;Gurel, Bora;Rodrigues, Daniel Nava;Pettitt, Stephen J.;Yuan, Wei;Serra, Violeta;Rekowski, Jan;Lord, Christopher J.;Hall, Emma;Mateo, Joaquin;de Bono, Johann S.
从PARP抑制中获益最多的前列腺癌有BRCA2改变，BRCA2纯合子缺失与获益最长的相关；PALB2和ATM双等位基因缺失也对PARP抑制敏感。PARP抑制剂被批准用于治疗具有各种缺陷DNA修复基因的晚期前列腺癌（APC）；然而，需要进一步的临床研究来确定预测性生物标志物的资格。在此，我们分析了TOPARP-B II期临床试验样本，评估了全外显子组和低通全基因组测序，以及评估ATM和RAD51病灶的IHC和IF分析（测试同源重组修复功能）。BRCA1/2种系和体细胞致病性突变与奥拉帕尼的相似获益相关；纯合子BRCA2缺失观察到更大的益处。双等位基因，而非单等位基因，PALB2有害改变与临床获益相关。在ATM队列中，IHC导致的ATM蛋白丢失与更好的预后相关。RAD51病灶缺失鉴定了双等位基因BRCA和PALB2改变的肿瘤，而大多数ATM和cdk12改变的apc具有较高的RAD51病灶水平。总的来说，纯合子BRCA2缺失的apc是特殊的应答者；PALB2双等位基因缺失和ATM IHC表达缺失与临床获益相关。并非所有具有DNA修复缺陷的apc都能从PARP抑制中获得类似的益处。在BRCA2纯合缺失、PALB2双等位基因缺失和ATM蛋白缺失的患者中，获益最多。评估同源重组修复功能的RAD51病灶缺失主要在具有BRCA1/2和PALB2双等位基因改变的肿瘤中发现。这篇文章在本期专题中特别突出，
Prostate cancers that benefit most from PARP inhibition have BRCA2 alterations, with BRCA2 homozygous loss associating with the longest benefit; biallelic loss of PALB2 and ATM can also sensitize to PARP inhibition. PARP inhibitors are approved for treating advanced prostate cancers (APC) with various defective DNA repair genes; however, further studies to clinically qualify predictive biomarkers are warranted. Herein we analyzed TOPARP-B phase II clinical trial samples, evaluating whole-exome and low-pass whole-genome sequencing and IHC and IF assays evaluating ATM and RAD51 foci (testing homologous recombination repair function). BRCA1/2 germline and somatic pathogenic mutations associated with similar benefit from olaparib; greater benefit was observed with homozygous BRCA2 deletion. Biallelic, but not monoallelic, PALB2 deleterious alterations were associated with clinical benefit. In the ATM cohort, loss of ATM protein by IHC was associated with a better outcome. RAD51 foci loss identified tumors with biallelic BRCA and PALB2 alterations while most ATM- and CDK12-altered APCs had higher RAD51 foci levels. Overall, APCs with homozygous BRCA2 deletion are exceptional responders; PALB2 biallelic loss and loss of ATM IHC expression associated with clinical benefit. Not all APCs with DNA repair defects derive similar benefit from PARP inhibition. Most benefit was seen among patients with BRCA2 homozygous deletions, biallelic loss of PALB2, and loss of ATM protein. Loss of RAD51 foci, evaluating homologous recombination repair function, was found primarily in tumors with biallelic BRCA1/2 and PALB2 alterations. This article is highlighted in the In This Issue feature,