Elvin Julia A, Gay Laurie M, Ort Rita, Shuluk Joseph, Long Jennifer, Shelley Lauren, Lee Ronald, Chalmers Zachary R, Frampton Garrett M, Ali Siraj M, Schrock Alexa B, Miller Vincent A, Stephens Philip J, Ross Jeffrey S, Frank Richard
Pathology Department, Foundation Medicine Inc., Cambridge, Massachusetts, USA.
Hematology and Oncology, Norwalk Hospital, Western Connecticut Health Network, Norwalk, Connecticut, USA.
Oncologist. 2017 Apr;22(4):416-421. doi: 10.1634/theoncologist.2016-0310. Epub 2017 Mar 10.
Uterine leiomyosarcoma (uLMS) responds poorly to conventional chemotherapeutic agents, and personalized therapies have yet to be systematically explored. Comprehensive genomic profiling (CGP) can identify therapeutic targets and provide insight into the biology of this highly aggressive tumor. We report a case of uLMS treated with the CGP-matched therapy palbociclib, a CDK4/6 inhibitor, with sustained clinical benefit in this rare and deadly malignancy.
This study analyzed 279 clinically advanced/recurrent uLMS samples. Median patient age was 54 years (range, 23-83 years). DNA was extracted from 40 µm of formalin-fixed, paraffin-embedded sections, and CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 405 cancer-related genes plus introns from up to 31 genes frequently rearranged in cancer. Sequencing data were analyzed for base pair substitutions, insertions/deletions, copy number alterations, and rearrangements.
CGP shows that 97.1% of uLMS harbor at least one alteration, and approximately 57% harbor alterations in one or more therapeutically targetable pathways. mutations that inactivate p16INK4a were identified in 11% of uLMS. We report the first demonstration of clinical benefit in response to palbociclib treatment for a uLMS patient with a mutation, resulting in disease stabilization and significant symptom reduction.
A patient with uLMS harboring a mutation experienced clinical benefit from treatment with palbociclib, and genomic analysis of 279 uLMS samples revealed that 19% of patients had mutations affecting the cyclin-dependent kinase (CDK) pathway. These observations provide a rationale for a clinical trial investigating treatment with CDK pathway inhibitors for uLMS harboring relevant genomic alterations. 2017;22:416-421 Comprehensive genomic profiling (CGP) of individuals with uterine leiomyosarcoma (uLMS) indicates that nearly 20% of patients may harbor a mutation affecting the cyclin-dependent kinase (CDK) pathway. The case presented demonstrates that a CDK inhibitory drug may provide clinical benefit to such individuals. Given the lack of curative therapies for uLMS, CGP could be performed on all cases of advanced uLMS and a CDK inhibitor could be recommended (preferably as part of a clinical trial) for individuals harboring a mutation in the CDK pathway.
子宫平滑肌肉瘤（uLMS）对传统化疗药物反应不佳，个性化治疗尚未得到系统探索。全面基因组分析（CGP）可以识别治疗靶点，并深入了解这种高度侵袭性肿瘤的生物学特性。我们报告了一例uLMS患者接受与CGP匹配的疗法哌柏西利（一种CDK4/6抑制剂）治疗，在这种罕见且致命的恶性肿瘤中获得了持续的临床益处。
本研究分析了279例临床晚期/复发性uLMS样本。患者中位年龄为54岁（范围23 - 83岁）。从40微米福尔马林固定、石蜡包埋切片中提取DNA，并对杂交捕获、基于衔接子连接的文库进行CGP，检测多达405个癌症相关基因以及多达31个在癌症中频繁重排基因的内含子。对测序数据进行碱基对替换、插入/缺失、拷贝数改变和重排分析。
CGP显示97.1%的uLMS至少存在一种改变，约57%的uLMS在一个或多个可治疗靶点途径中存在改变。11%的uLMS中鉴定出使p16INK4a失活的突变。我们报告了首例携带 突变的uLMS患者接受哌柏西利治疗获得临床益处的病例，导致疾病稳定且症状显著减轻。
一名携带 突变的uLMS患者接受哌柏西利治疗获得了临床益处，对279例uLMS样本的基因组分析显示19%的患者存在影响细胞周期蛋白依赖性激酶（CDK）途径的突变。这些观察结果为一项临床试验提供了理论依据，该试验旨在研究针对携带相关基因组改变的uLMS患者使用CDK途径抑制剂进行治疗。2017年；22:416 - 421 对子宫平滑肌肉瘤（uLMS）患者进行的全面基因组分析（CGP）表明，近20%的患者可能携带影响细胞周期蛋白依赖性激酶（CDK）途径的突变。所呈现的病例表明，一种CDK抑制药物可能为此类患者带来临床益处。鉴于uLMS缺乏治愈性疗法，对于所有晚期uLMS病例均可进行CGP，并可为携带CDK途径突变的个体推荐使用CDK抑制剂（最好作为临床试验的一部分）。
