A Novel HRD Signature Is Predictive of FOLFIRINOX Benefit in Metastatic Pancreatic Cancer.
A Novel HRD Signature Is Predictive of FOLFIRINOX Benefit in Metastatic Pancreatic Cancer.
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DOI：
10.1093/oncolo/oyad178
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发表时间：
2023-08-03
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胰腺癌 (PC) 是一种侵袭性疾病，在一线治疗中中位总生存期 (OS) 不足 1 年。 FOLFIRINOX 以及吉西他滨和紫杉醇 (GP) 是这些患者的标准治疗选择；然而，最佳治疗选择具有挑战性。对 8358 名 PC 患者进行了全面的基因组分析。 1149 名接受 1L FOLFIRINOX 或 GP 治疗的转移性 PC 患者的结果可用。基于疤痕的 HRD 测量被称为使用基于机器学习的算法，结合了拷贝数和插入缺失特征。在 9% 的患者中发现了基于疤痕的 HRD 特征 (HRDsig)。 HRDsig 与 BRCA1/2、PALB2、BARD1 和 RAD51C/D 中的双等位基因改变显着同时发生，但涵盖的群体比 BRCA1/BRCA2/PALB2 定义的群体更大（9% 对 6%）。 HRDsig 预测 1L FOLFIRNOX 化疗获益，相对于吉西他滨和紫杉醇 (GP)，OS 增加一倍（rwOS aHR 0.37 [0.22-0.62]），包括在真实世界患者队列中 25% 的人群具有长期（2 年以上）生存。在 HRDsig(−) 人群中观察到 FOLFIRINOX 的益处较少。 BRCA1/2/PALB2 突变体和野生型群体均具有预测价值，这表明突变分析具有附加价值。在相当一部分 PC 患者中发现了基于疤痕的 HRD 生物标志物，并且可以预测 FOLFIRINOX 的益处。结合 HRDsig 等生物标志物可以识别适合铂类化疗的患者，并有可能将 FOLFIRINOX 的使用量减少 40% 以上，从而最大限度地减少毒性，同时获得相似的生存结果。应进行验证性研究。胰腺癌患者一线治疗的选择具有挑战性。本文报道了一种基于疤痕的同源重组缺陷生物标志物，该标志物可预测一线 FOLFIRINOX 的获益，相对于吉西他滨和紫杉醇，中位总生存期增加一倍。
Pancreatic cancer (PC) represents an aggressive disease with median overall survival (OS) of less than 1 year in the front-line setting. FOLFIRINOX and gemcitabine and paclitaxel (GP) are standard of care options for these patients; however, optimal selection of therapy is challenging. Comprehensive genomic profiling was performed on 8358 PC patients. Outcomes were available for 1149 metastatic PC patients treated with 1L FOLFIRINOX or GP. A scar-based measure of HRD was called using a machine learning-based algorithm incorporating copy number and indel features. A scar-based HRD signature (HRDsig) was identified in 9% of patients. HRDsig significantly co-occurred with biallelic alterations in BRCA1/2, PALB2, BARD1, and RAD51C/D, but encompassed a larger population than that defined by BRCA1/BRCA2/PALB2 (9% vs. 6%). HRDsig was predictive of 1L FOLFIRNOX chemotherapy benefit with doubled OS relative to gemcitabine and paclitaxel (GP) (rwOS aHR 0.37 [0.22-0.62]), including 25% of the population with long-term (2 year+) survival in a real-world cohort of patients. Less benefit from FOLFIRINOX was observed in the HRDsig(−) population. Predictive value was seen in both the BRCA1/2/PALB2 mutant and wildtype populations, suggesting additional value to mutational profiling. A scar-based HRD biomarker was identified in a significant fraction of PC patients and is predictive of FOLFIRINOX benefit. Incorporating a biomarker like HRDsig could identify the right patients for platinum chemotherapy and potentially reduce FOLFIRINOX use by over 40%, minimizing toxicities with similar survival outcomes. Confirmatory studies should be performed. Selection of first-line therapy for patients with pancreatic cancer is challenging. This article reports a scar-based biomarker of homologous recombination deficiency that was predictive of benefit from first-line FOLFIRINOX with a doubled median overall survival relative to gemcitabine and paclitaxel.
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影响因子：
8.8
作者：
Wattenberg, Max M.;Asch, Daniella;Reiss, Kim A.
通讯作者：
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通讯作者：
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