Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom.
MRC Clinical Trials Unit, University College London, London, United Kingdom.
Clin Cancer Res. 2021 Jan 1;27(1):288-300. doi: 10.1158/1078-0432.CCR-20-3237. Epub 2020 Oct 7.
The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer.
Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial ( = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial ( = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer.
Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer.
DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status.
基于同源重组和范可尼贫血途径缺陷相关的生物学特征，在乳腺癌中开发了 DNA 损伤免疫反应 (DDIR) 检测。阳性的 DDIR 检测结果提示患者可能对乳腺癌和食管癌的铂类化疗有反应。在结直肠癌中，目前尚无预测奥沙利铂反应的生物标志物。我们检测了 DDIR 检测对结直肠癌奥沙利铂为基础化疗的反应预测能力，并对 DDIR 阳性结直肠癌的生物学特征进行了研究。
根据 FOCUS 试验（n = 361，IV 期）中接受氟尿嘧啶（5-FU）或 5-FUFA（氟尿嘧啶+亚叶酸钙，推注和输注）联合奥沙利铂（FOLFOX）或 FOxTROT 试验（n = 97，II/III 期）新辅助 FOLFOX 的患者的 DDIR 状态，评估这些样本的患者样本和临床数据。这些样本的全转录组、突变和免疫组化数据用于研究结直肠癌中 DDIR 的生物学特征。
与我们的假设相反，与 DDIR 阳性患者相比，DDIR 阴性患者接受奥沙利铂为基础的化疗后显示出改善的趋势。DDIR 阳性与微卫星不稳定（MSI）和结直肠癌分子亚型 1 相关。基于 DDIR 阳性与结直肠癌和乳腺癌队列中 IFN 相关趋化因子信号重叠的相关性，对 DDIR 特征进行细化，进一步证实 DDIR 检测对结直肠癌的奥沙利铂为基础化疗没有预测价值。
DDIR 阳性不能预测结直肠癌奥沙利铂治疗后的反应改善。然而，这里提供的数据表明，DDIR 检测在识别免疫丰富的肿瘤方面具有潜力，这些肿瘤可能受益于免疫检查点阻断，超出目前 MSI 状态的应用。
