Clinicopathologic and genomic characterization of PD-L1-positive uterine cervical carcinoma
Clinicopathologic and genomic characterization of PD-L1-positive uterine cervical carcinoma
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DOI：
10.1038/s41379-021-00780-3
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发表时间：
2021-02-26
期刊：
影响因子：
7.5
通讯作者：
Lin, Douglas, I
中科院分区：
文献类型：
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作者：
Huang, Richard S. P.;Haberberger, James;Lin, Douglas, I
阳性程序死亡配体1 （PD-L1）免疫组织化学（IHC）是一种被批准的伴随诊断，指导在宫颈癌（CXC）中使用免疫检查点抑制剂。PD-L1阳性（PD-L1（阳性））CXC的临床和基因组特征此前未被描述。我们回顾了647例CXC病例的临床病理和分子特征，这些病例在临床护理过程中使用DAKO 22C3 PD-L1免疫组化和全面的基因组图谱进行了检测。PD-L1（阳性）病例通过>= 1的联合阳性评分来定义。PD-L1（阳性）（n = 548）和PD-L1（阴性）疾病亚群的年龄、遗传血统和HPV状态均无差异。PD-L1阳性率因CXC的组织学亚型而异，鳞状细胞癌（SCC）的PD-L1阳性率为91%(397/437)，普通型腺癌的PD-L1阳性率为60%（35/58）。此外，PD-L1阳性率因肿瘤部位的不同而不同，宫颈标本中PD-L1阳性率为89.1%(261/293)，而脑转移标本中PD-L1阳性率为25%（2/8）。PD-L1（阳性）和PD-L1（阴性）CXC亚群在肿瘤突变负荷（TMB）、微卫星不稳定性和CD274（编码PD-L1）扩增方面无显著差异。通过将TMB与PD-L1联合使用，与单独使用PD-L1相比，又有17名患者有资格接受派姆单抗治疗。在PD-L1（阳性）CXC SCC中，TERT启动子改变和APOBEC突变特征富集（p = 0.011, p = 0.004）。我们的研究揭示了CXC非scc中PD-L1阳性的重要流行数据，并表明有必要对这些组织学亚型进行进一步研究。此外，我们还提供了一个关键框架来指导标本选择和宫颈癌患者免疫治疗反应预测因素的未来研究。最后，TERT启动子改变和APOBEC突变特征可能是PD-L1（阳性）CXC SCC的生物学独特子集。
Positive program death-ligand 1 (PD-L1) immunohistochemistry (IHC) is an approved companion diagnostic guiding the use of immune checkpoint inhibitors in uterine cervical carcinoma (CXC). The clinical and genomic features of PD-L1-positive (PD-L1(positive)) CXC have not been previously described. We reviewed the clinicopathologic and molecular features of 647 CXC cases that were tested using DAKO 22C3 PD-L1 IHC and comprehensive genomic profiling during the course of clinical care. PD-L1(positive) cases were defined via a combined positive score of >= 1. No differences were found in age, genetic ancestry, and HPV status of the PD-L1(positive) (n = 548) and PD-L1(negative) disease subset. The PD-L1 positivity rate varied by histologic subtype of CXC with squamous cell carcinoma (SCC) having a PD-L1 positivity rate of 91% (397/437) and usual-type adenocarcinoma's PD-L1 positivity rate being 60% (35/58). In addition, the PD-L1 positivity rate varied depending on site of the specimen with 89.1% (261/293) positivity rate observed in cervix specimens compared to 25% (2/8) in brain metastases specimens. No significant difference in tumor mutational burden (TMB), microsatellite instability, and CD274 (encoding PD-L1) amplification was observed between PD-L1(positive) and PD-L1(negative) CXC subsets. By combining TMB with PD-L1, an additional 17 patients are eligible for pembrolizumab when compared to PD-L1 testing alone. TERT promoter alterations and APOBEC mutational signature were enriched in the PD-L1(positive) CXC SCC (p = 0.011, and p = 0.004, respectively). Our study reveals important prevalence data on PD-L1 positivity in CXC non-SCC and suggests that further studies in these histologic subtypes are warranted. In addition, we also provide a key framework to guide both specimen selection and future investigations of predictors of immunotherapy response in cervical cancer patients. Lastly, TERT promoter alterations and APOBEC mutational signature may be a biologically unique subset of PD-L1(positive) CXC SCC.