Clinical significance of homologous recombination deficiency score testing in endometrial Cancer.
Clinical significance of homologous recombination deficiency score testing in endometrial Cancer.
复制标题
子宫内膜癌同源重组缺陷评分检测的临床意义。
DOI：
10.1016/j.ygyno.2020.12.010
复制
发表时间：
2021-03
影响因子：
4.7
通讯作者：
Sood AK
中科院分区：
文献类型：
--
作者：
Siedel JH;Ring KL;Hu W;Dood RL;Wang Y;Baggerly K;Darcy KM;Conrads TP;Gallagher S;Tshiaba P;Neff C;Timms KM;Mangala S;Westin SN;Broaddus R;Lopez-Berestein G;Lu KH;Coleman RL;Maxwell GL;Sood AK
同源重组缺陷（HRD）评分与某些癌症的化疗反应有关，但其在子宫内膜癌中的作用尚不清楚。我们确定了子宫内膜癌 HR 通路改变的频率和临床意义。使用 Myriad HRD 测定对来自两个独立队列（发现和复制）的 253 个子宫内膜样子宫内膜腺癌 (EEA) 样本进行了 HRD 评分，并使用新一代测序测定对微卫星不稳定性 (MSI) 和肿瘤突变负荷 (TMB) 进行了测试。还对子宫内膜癌细胞系生成了 HRD 评分，并评估了奥拉帕尼的体内反应。采用 ROC 曲线来确定与子宫内膜癌生存影响相关的 HRD 最佳截止值，并使用发现队列建议 DFS 的 HRD ≥ 4 截止值。与 HRD 评分 <4 的患者相比，来自两个独立队列的 HRD 评分≥ 4 的患者的生存率趋于较差。根据分子亚型（TMB 阳性；MSI 阳性；HRD 阳性；所有其他），这两个队列进一步分为四组。当按分子亚型分组时，在初始 (p = 0.0024) 和复制 (p = 0.042) 队列中使用 HRD ≥ 4 截止值的组之间存在显着差异。 Hec1a 模型（HRD 评分 = 19）在体外和体内实验中对奥拉帕尼高度敏感。在我们的患者队列中，高 HRD 评分与较差的 DFS 相关。这些发现表明 HRD 评分可能对晚期或复发性子宫内膜癌患者具有临床实用性。
Homologous recombination deficiency (HRD) score is related to chemotherapy response in some cancers, but its role in endometrial cancer in not known. We determined frequency and clinical significance of alterations in the HR pathway in endometrial cancer. 253 endometrioid endometrial adenocarcinoma (EEA) samples from two independent cohorts (discovery and replication) were tested for HRD score using the Myriad HRD assay, microsatellite instability (MSI) and tumor mutation burden (TMB) using a next generation sequencing assay. HRD scores were also generated on endometrial cancer cell lines and in vivo response to olaparib was assessed. ROC curves were employed to determine optimal cutoffs of HRD in relation to survival impact in endometrial cancer and a cutoff of HRD ≥ 4 was suggested for DFS using discovery cohort. Patients from two independent cohorts with HRD score ≥ 4 trended toward worse survival as compared to those with HRD score <4. Both cohorts were further separated into four groups according to molecular subtypes (TMB positive; MSI positive; HRD positive; all others). When grouped by molecular subtype, there was a significant difference between groups using an HRD ≥4 cutoff in the initial (p= 0.0024) and replication (p = 0.042) cohorts. The Hec1a model (HRD score = 19) was highly sensitive to olaparib in in vitro and in vivo experiments. High HRD score was associated with worse DFS in our patient cohort. These findings suggest that HRD score may have clinical utility in patients with advanced or recurrent endometrial cancer.
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影响因子：
4.3
作者：
Liu FW;Tewari KS
通讯作者：
Tewari KS
影响因子：
56.9
作者：
Celeste, A;Petersen, S;Nussenzweig, A
通讯作者：
Nussenzweig, A
影响因子：
28.2
作者：
Birkbak NJ;Wang ZC;Kim JY;Eklund AC;Li Q;Tian R;Bowman-Colin C;Li Y;Greene-Colozzi A;Iglehart JD;Tung N;Ryan PD;Garber JE;Silver DP;Szallasi Z;Richardson AL
通讯作者：
Richardson AL
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.1
作者：
Muñoz-Gámez, JA;Martín-Oliva, D;Oliver, FJ
通讯作者：
Oliver, FJ