Church David N, Stelloo Ellen, Nout Remi A, Valtcheva Nadejda, Depreeuw Jeroen, ter Haar Natalja, Noske Aurelia, Amant Frederic, Tomlinson Ian P M, Wild Peter J, Lambrechts Diether, Jürgenliemk-Schulz Ina M, Jobsen Jan J, Smit Vincent T H B M, Creutzberg Carien L, Bosse Tjalling
Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (DNC, IPMT); Oxford Cancer Centre, Churchill Hospital, Oxford, UK (DNC); Department of Pathology (ES, NtH, VTHBMS, TB) and Department of Clinical Oncology (RAN, CLC), Leiden University Medical Center, Leiden, the Netherlands; Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland (NV, AN, PJW); Vesalius Research Center (VRC), VIB, Leuven, Belgium (JD, DL); Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Belgium (FA, DL); Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium (FA); Genomic Medicine Theme, Oxford Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK (IPMT); Department of Radiation Oncology, University Medical Centrum Utrecht, the Netherlands (IMJS); Department of Radiation Oncology, Medisch Spectrum Twente, Enschede, the Netherlands (JJJ).
J Natl Cancer Inst. 2014 Dec 12;107(1):402. doi: 10.1093/jnci/dju402. Print 2015 Jan.
Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis.
We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided.
POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P < .001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06).
POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC.
目前子宫内膜癌（EC）的风险分层导致辅助治疗经常过度使用和使用不足，新型生物标志物可能会改善这种情况。我们研究了最近报道的约7%的EC中存在的POLE校对突变是否能预测预后。
我们对PORTEC-1和-2试验中的EC进行了靶向POLE测序（n = 788），并根据POLE状态分析临床结局。我们通过荟萃分析将这些结果与另外三个系列（n = 628）的结果相结合，以生成POLE突变型EC无复发生存期（RFS）和癌症特异性生存期（CSS）的多变量调整合并风险比（HR）。所有统计检验均为双侧检验。
在PORTEC-1和-2的788例EC中，有48例（6.1%）检测到POLE突变，且与高肿瘤分级相关（P <.001）。POLE突变型EC的女性复发较少（6.2%对14.1%），EC死亡也较少（2.3%对9.7%），不过，在整个PORTEC队列中，RFS和CSS的差异无统计学意义（多变量调整HR = 0.43，95%CI = 0.13至1.37，P =.15；HR = 0.19，95%CI = 0.03至1.44，P =.11）。然而，在109例3级肿瘤中，15例POLE突变型EC无复发，而94例（30.9%）POLE野生型癌症中有29例复发；这反映在RFS有统计学显著差异（多变量调整HR = 0.11，95%CI = 0.001至0.84，P =.03）。在另外的系列中，33例POLE突变型EC中无一例发生与EC相关的事件，导致RFS的多变量调整合并HR为0.33（95%CI = 0.12至0.91，P =.03），CSS的多变量调整合并HR为0.26（95%CI = 0.06至1.08，P =.06）。
POLE校对突变可独立于其他临床病理变量预测EC的良好预后，在高级别肿瘤中效果最为明显。这种新型生物标志物可能有助于减少EC的过度治疗。
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