Cell-free DNA sequencing sheds additional insights on BRCA-altered metastatic castration-resistant prostate cancer.
Cell-free DNA sequencing sheds additional insights on BRCA-altered metastatic castration-resistant prostate cancer.
复制标题
DOI：
10.1016/j.ebiom.2023.104756
复制
发表时间：
2023-09
期刊：
影响因子：
11.1
通讯作者：
Tran PT
中科院分区：
文献类型：
--
作者：
Bazyar S;Sutera P;Deek MP;Marshall CH;Tran PT
前列腺癌是美国男性最常见的癌症。尽管在诊断和管理方面取得了进展，但在美国每年仍有超过34，000名男性死于前列腺癌。1自哈金斯和霍奇斯首次提出雄激素依赖的概念以来，雄激素剥夺疗法（ADT）一直是晚期或转移性前列腺癌初始治疗的标准治疗方法。然而，在长期ADT后，不可避免地会进展为转移性去势抵抗性前列腺癌（mCRPC）。mCRPC的治疗已取得巨大进展，其形式为延长生命的获批疗法，其中包括紫杉烷类和雄激素受体途径抑制剂（ARPI）。2重要的是，mCRPC的基因组研究已经确定了潜在的可操作的复发性基因组畸变。在超过20-25%的病例中观察到DNA损伤反应（DDR）基因的功能丧失改变，最常见的是BRCA基因和其他同源重组介导的DNA损伤反应（HR-DDR）基因的缺陷。32020年，FDA批准了两种PARP抑制剂（PARPi）药物olaparib和rucaparib，用于治疗患有影响HR-DDR的遗传异常的mCRPC患者，这些患者在随机临床试验中获得了积极的肿瘤学结果。因此，PARPi治疗的分子选择目前是mCRPC的标准治疗，但对这些基因突变在非PARPi治疗方案后的临床结局中的作用知之甚少。最近的临床研究还表明，与PARPi单药治疗相比，PARPi联合ARPI在一线治疗中可改善结局，尤其是在BRCA突变患者中，导致FDA批准该联合治疗用于HRDDR分子亚群的mCRPC一线治疗。6因此，现在，轻松识别mCRPC中的BRCA缺陷和其他潜在的靶向共存基因组改变非常重要。Fettke及其同事在本期eBioMedicine中提供了一些关于mCRPC中DDR缺陷的其他见解，他们使用CLIA认证的PredicineCARE™无细胞DNA（cfDNA）分析了来自美国和澳大利亚的375名男性的液体活检和生殖系样本。靶向152个癌症驱动基因（包括27个个体DDR基因）测序的面板测定。[7]与其他研究一致，在34%的表现出DDR改变的总队列中，最常见的改变基因是BRCA 2（17%）。也与BRCA 2突变mCRPC的一些既往报告一致，发现ARPI治疗的临床结局（包括PSA缓解、PFS和OS）较差。3，6这项以cfDNA为主的回顾性研究中最有趣的发现是，进一步的基因组分析表明，cfDNA中任何致病性异常而不是特定BRCA 2接合性状态（单等位基因或双等位基因改变）的鉴定表明临床结局较差。这是有趣的，因为先前的数据表明，双等位基因BRCA改变的mCRPC患者，特别是纯合子或双等位基因BRCA 2缺失的患者，表现出PARPi的最大临床获益。相比之下，先前的研究已经证明，PARPi反应很少在HRDRR基因中没有双等位基因失活改变的患者中观察到。4，8，9这种差异是否仅仅是预后和预测生物标志物关联之间的差异，还是一些更有趣的基础生物学差异仍有待确定。此外，显然需要进行更多的研究，以了解...
Cancer of the prostate is the most common cancer occurring in men in the US. Despite advances in diagnosis and management, more than 34,000 men continue to die of prostate cancer each year in the United States. 1 Androgen deprivation therapy (ADT) has been the standard of care for initial management of advanced or metastatic prostate cancer since Huggins and Hodges first introduced the concept of androgendependence. However, progression to metastatic castration-resistant prostate cancer (mCRPC) inevitably occurs after prolonged ADT. Tremendous progress has been made in the treatment of mCRPC in the form of life prolonging approved therapies, among them, taxanes and androgen receptor pathway inhibitors (ARPIs). 2 Importantly, genomic studies of mCRPC have identified potentially actionable recurrent genomic aberrations. Loss-of-function alterations in DNA damage response (DDR) genes have been observed in greater than 20–25% of cases, most commonly defects in BRCA genes and other homologous recombination-mediated DNA damage response (HR-DDR) genes. 3 In 2020, the FDA authorized two PARP inhibitor (PARPi) agents, olaparib and rucaparib, for the treatment of individuals with mCRPC who harbor genetic abnormalities affecting HR-DDR, following positive oncological outcomes in randomized clinical trials. 4, 5 Thus, molecular selection for PARPi treatment is currently the standard of care for mCRPC but less is known about the role of these gene mutations in clinical outcomes following non-PARPi treatment regimens. Recent clinical studies have also revealed that PARPi in combination with ARPIs in the first line setting can improve outcomes compared to PARPi alone, particularly in BRCA-mutated patients, leading to FDA approval of this combination in the mCRPC first-line setting for HRDDR molecular subsets. 6 Thus, easily identifying BRCA-deficiency and other potential targetable cooccurring genomic alterations in mCRPC is now of great importance.Fettke and colleagues in this issue of eBioMedicine provide some additional insights into the landscape of DDR defects in mCRPC analyzing liquid biopsy and germline samples from a total of 375 men from the US and Australia using the CLIA-certified PredicineCARE™ cell-free DNA (cfDNA) panel assay which targets sequencing of 152 cancer driver genes including 27 individual DDR genes. 7 From the 34% of the total cohort that exhibited DDR alterations, consistent with other studies, the most common altered gene was BRCA2 (17%). Also consistent with some previous reports in BRCA2 mutated mCRPC, clinical outcomes including PSA response, PFS and OS were found to be inferior with ARPI treatments. 3, 6 The most interesting finding from this predominantly cfDNA retrospective study, was that further genomic analysis indicated that identification of any pathogenic anomaly rather than specific BRCA2 zygosity status (mono-or bi-allelic alterations) in cfDNA was indicative of poor clinical outcomes. This is interesting because previous data have suggested that bi-allelic BRCA altered mCRPC patients, particularly those with homozygous or bi-allelic BRCA2 deletion, exhibited the most clinical benefit from PARPi. In contradistinction, previous studies have demonstrated that PARPi responses are rarely observed in patients without bi-allelic inactivating alterations in HRDRR genes. 4, 8, 9 Whether this discrepancy is simply the difference between prognostic and predictive biomarker associations or some more interesting foundational biological difference remains to be determined. Also, more research clearly needs to be performed to understand the …
登录
查看更多内容
影响因子：
28.2
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.
通讯作者：
de Bono, Johann S.
影响因子：
4.7
作者：
通讯作者：
--
影响因子：
4.7
作者：
Kwan, Edmond M. M.;Wyatt, Alexander W. W.;Chi, Kim N. N.
通讯作者：
Chi, Kim N. N.
影响因子：
11.1
作者：
Fettke, Heidi;Dai, Chao;Kwan, Edmond M.;Zheng, Tiantian;Du, Pan;Ng, Nicole;Bukczynska, Patricia;Docanto, Maria;Kostos, Louise;Foroughi, Siavash;Brown, Stephen;Graham, Lisa-Jane K.;Mahon, Kate;Horvath, Lisa G.;Jia, Shidong;Kohli, Manish;Azad, Arun A.
通讯作者：
Azad, Arun A.
影响因子：
254.7
作者：
Siegel, Rebecca L.;Miller, Kimberly D.;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin