功能性丧失定义了平滑肌肉瘤的一个可靶向亚群。
Functional Loss Defines a Targetable Subset in Leiomyosarcoma.
机构信息
Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
出版信息
Oncologist. 2019 Jul;24(7):973-979. doi: 10.1634/theoncologist.2018-0448. Epub 2018 Dec 12.
BACKGROUND
Soft-tissue sarcomas (STS) describe a heterogeneous group of mesenchymal tumors with limited treatment options. Targeted therapies exist for gene alterations, but their prevalence and role have not been fully described in STS. Here, we present the largest effort to characterize the frequency of homologous recombination (HR) DNA repair pathway alterations in STS subtypes and highlight the unique nature of leiomyosarcoma (LMS).
MATERIALS AND METHODS
DNA sequencing data were analyzed for HR pathway alterations for 1,236 patients with STS. DNA sequencing data from an additional 1,312 patients were used to confirm the prevalence of HR pathway alterations in LMS. Four uterine LMS (uLMS) patients with functional loss were evaluated for response to poly (ADP-ribose) polymerase (PARP) inhibition.
RESULTS
In an unselected STS study population, alterations were identified in 15 (1%) patients, and homozygous loss was detected in 9 (<1%). However, subset analysis revealed that these alterations were concentrated in uLMS as compared with any other STS subtype. Notably, 10% of uLMS tumors had a alteration. We further report that PARP inhibitors had demonstrated durable clinical benefit in four uLMS patients with loss.
CONCLUSION
HR pathway alterations are rare in most STS. However, we identify uLMS to be enriched for loss and report the positive outcomes of a series of patients treated with PARP inhibitors. Our data suggest that patients with uLMS should be considered for somatic profiling. Prospective trials are necessary to confirm the efficacy of PARP inhibition in uLMS.
IMPLICATIONS FOR PRACTICE
Soft-tissue sarcomas are a highly morbid, diverse set of tumors with limited treatment options. This study identifies an increased prevalence of functional loss in patients with uterine leiomyosarcoma (uLMS). It also presents four patients with uLMS and loss who achieved durable clinical benefit from poly (ADP-ribose) polymerase inhibition. These data suggest that patients with uLMS in particular should be screened for alterations and may benefit from treatment targeted to these alterations.
背景
软组织肉瘤（STS）描述了一组具有有限治疗选择的异质性间充质肿瘤。针对基因突变存在靶向治疗，但它们在 STS 中的普遍性和作用尚未得到充分描述。在这里，我们进行了迄今为止最大的努力来描述 STS 亚型中同源重组（HR）DNA 修复途径改变的频率，并强调了平滑肌肉瘤（LMS）的独特性质。
材料和方法
对 1236 名 STS 患者的 HR 途径改变进行了 DNA 测序数据分析。另外 1312 名患者的 DNA 测序数据用于确认 LMS 中 HR 途径改变的普遍性。对 4 名具有功能性缺失的子宫平滑肌肉瘤（uLMS）患者进行了聚（ADP-核糖）聚合酶（PARP）抑制的反应评估。
结果
在未选择的 STS 研究人群中，在 15 名（1%）患者中发现了改变，在 9 名（<1%）患者中检测到纯合性缺失。然而，亚组分析显示，与任何其他 STS 亚型相比，这些改变集中在 uLMS 中。值得注意的是，10%的 uLMS 肿瘤存在 改变。我们进一步报告称，PARP 抑制剂在 4 名具有 缺失的 uLMS 患者中显示出持久的临床获益。
结论
HR 途径改变在大多数 STS 中很少见。然而，我们确定 uLMS 中富含 缺失，并报告了一系列接受 PARP 抑制剂治疗的患者的阳性结果。我们的数据表明，应考虑对 uLMS 患者进行体细胞 分析。有必要进行前瞻性试验以确认 PARP 抑制在 uLMS 中的疗效。
实践意义
软组织肉瘤是一组高度恶性、多样化的肿瘤，治疗选择有限。本研究确定了子宫平滑肌肉瘤（uLMS）患者中功能性 缺失的发生率增加。它还介绍了 4 名具有 uLMS 和 缺失的患者，他们从聚（ADP-核糖）聚合酶抑制中获得了持久的临床获益。这些数据表明，特别是 uLMS 患者应进行 改变筛查，并且可能受益于针对这些改变的治疗。
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