背景:POLE和POLD1校对缺陷(POLE/D1pd)定义了一种罕见的超突变转移性结直肠癌(mCRC;超过100mut/Mb)亚型。缺乏关于POLE/D1pdmCRC中免疫检查点抑制剂(ICIs)的活性和功效的疾病特异性数据,并且未知结果是否可能与用ICIs治疗的错配修复缺陷(dMMR)/微卫星不稳定性高(MSI-H)mCRC不同。
方法:在这项全球研究中,我们收集了27例mCRC患者,这些患者携带POLE/D1突变导致校对缺陷,并单独接受抗程序性细胞死亡配体1+/-抗细胞毒性T淋巴细胞抗原4药物治疗.我们收集了临床病理和基因组特征,回应,和POLE/D1pdmCRCICIs后的生存结局,并将其与接受ICIs治疗的610dMMR/MSI-HmCRC患者队列进行比较。在7241个CRC的独立队列中进行了进一步的基因组分析,以定义POLE和POLD1pd分子谱和突变特征。
结果:POLE/D1pd与年龄较小有关,男性,较少的RAS/BRAF驱动突变,和占主导地位的右侧结肠癌。与dMMR/MSI-HmCRC相比,POLE/D1pdmCRC患者的总体缓解率(ORR)明显更高(89%对54%;P=0.01)。中位随访24.9个月(四分位距:11.3-43.0个月)后,POLE/D1pd患者的无进展生存期(PFS)显著优于dMMR/MSI-HmCRC[风险比(HR)=0.24,95%置信区间(CI)0.08-0.74,P=0.01],且总生存期(OS)(HR=0.38,95%CI0.12-1.18,P=0.09).在包括DNA修复缺陷类型在内的多变量分析中,POLE/D1pd与显著改善PFS(HR=0.17,95%CI0.04-0.69,P=0.013)和OS(HR=0.24,95%CI0.06-0.98,P=0.047)相关。分子谱分析显示POLE/D1pd肿瘤具有较高的肿瘤突变负荷(TMB)。在两种亚型中均观察到反应,并与POLE/D1pd特征的强度相关。
结论:与dMMR/MSI-HmCRC相比,POLE/D1pdmCRC患者在肿瘤反应和生存率方面表现出更有利的结果。
BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs.
METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures.
RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature.
CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.