Friedlander Michael L, Russell Kenneth, Millis Sherri, Gatalica Zoran, Bender Ryan, Voss Andreas
Prince of Wales Hospital, Prince of Wales Clinical School UNSW, Sydney, New South Wales, Australia.
Int J Gynecol Cancer. 2016 May;26(4):648-54. doi: 10.1097/IGC.0000000000000677.
Advanced stage/recurrent clear cell ovarian cancers (CCOCs) are characterized by a low response to chemotherapy and a poor prognosis. There is growing interest in investigating novel/molecular targeted therapies in patients with CCOC in histotype-specific trials. However, CCOCs are not a uniform entity and comprise a number of molecular subtypes and it is unlikely that a single approach to treatment will be appropriate for all patients. The aim of this study was to analyze the results of a multiplatform profiling panel in CCOCs to identify potential therapeutic targets.
Tumor profiling was performed on 521 CCOCs. They were grouped into pure (n = 422) and mixed (n = 99) CCOC for analysis. Testing included a combination of DNA sequencing (including next-generation sequencing) using a 46-gene panel, immunohistochemistry, fluorescent or chromogenic in situ hybridization, and RNA fragment analysis.
The most common findings were in the PIK3CA/Akt/mTOR pathway, with 61% of all CCOCs showing a molecular alteration in one of these pathway components. Next-generation sequencing revealed PIK3CA mutations in 50% of pure CCOCs. Significant differences were observed between pure and mixed CCOCs with respect to hormone receptor expression (9% vs 34.7% for ER, 13.45 vs 26.4% for PR), cMET (24.1% vs 11.6%), PD-1 tumor infiltrating lymphocytes (48.1% vs 100%), expression of PD-L1 (7.4% vs 25%), and TOPO1 (41% vs 27.1%) on immunohistochemistry, whereas next-generation sequencing revealed significant differences in mutation frequency in PIK3CA (50% vs 18.5%), TP53 (18.1% vs 57.7%), KRAS (12.4% vs 3.7%), and cMET (1.9% vs 11.1%).
This large study confirms that the PIK3CA/Akt/mTOR pathway is commonly altered in CCOCs, and highlights the significant differences between pure and mixed CCOCs. Clear cell ovarian cancers are molecularly heterogeneous and there are a number of potential therapeutic targets which could be tested in clinical trials.
晚期/复发性透明细胞卵巢癌（CCOC）的特点是对化疗反应低且预后差。在组织学类型特异性试验中，对CCOC患者进行新型/分子靶向治疗的研究兴趣日益浓厚。然而，CCOC并非一个统一的实体，而是包含多种分子亚型，单一的治疗方法不太可能适用于所有患者。本研究的目的是分析CCOC多平台分析 panel 的结果，以确定潜在的治疗靶点。
对521例CCOC进行肿瘤分析。将它们分为纯合型（n = 422）和混合型（n = 99）CCOC进行分析。检测包括使用46基因 panel 的DNA测序（包括二代测序）、免疫组化、荧光或显色原位杂交以及RNA片段分析的组合。
最常见的发现存在于PIK3CA/Akt/mTOR通路，所有CCOC中有61%在这些通路成分之一中显示分子改变。二代测序显示50%的纯合型CCOC存在PIK3CA突变。在激素受体表达方面（雌激素受体为9%对34.7%，孕激素受体为13.4%对26.4%）、cMET（24.1%对11.6%）、PD - 1肿瘤浸润淋巴细胞（48.1%对100%）、免疫组化检测的PD - L1表达（7.4%对25%）以及TOPO1（41%对27.1%）方面，纯合型和混合型CCOC之间观察到显著差异，而二代测序显示PIK3CA（50%对18.5%）、TP53（18.1%对57.7%）、KRAS（12.4%对3.7%）和cMET（1.9%对11.1%）的突变频率存在显著差异。
这项大型研究证实PIK3CA/Akt/mTOR通路在CCOC中普遍改变，并突出了纯合型和混合型CCOC之间的显著差异。透明细胞卵巢癌在分子水平上具有异质性，存在许多潜在的治疗靶点，可在临床试验中进行测试。
