Innocenti Federico, Jiang Chen, Sibley Alexander B, Denning Stefanie, Etheridge Amy S, Watson Dorothy, Niedzwiecki Donna, Hatch Ace J, Hurwitz Herbert I, Nixon Andrew B, Furukawa Yoichi, Kubo Michiaki, Crona Daniel J, Kindler Hedy L, McLeod Howard L, Ratain Mark J, Owzar Kouros
UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill.
Duke Cancer Institute.
Pharmacogenet Genomics. 2019 Aug;29(6):123-131. doi: 10.1097/FPC.0000000000000375.
One of the standard of care regimens for advanced pancreatic cancer is gemcitabine-based chemotherapy. The efficacy of gemcitabine is limited by dose-limiting hematologic toxicities especially neutropenia. Uncovering the variability of these toxicities attributed to germline DNA variation is of great importance.
CALGB 80303 was a randomized study in advanced pancreatic cancer patients treated with gemcitabine with or without bevacizumab. The study protocol included genotyping of genes of gemcitabine disposition (CDA, DCTD, SLC29A1, SLC28A1, and SLC29A2), as well as a genome-wide analysis. The clinical phenotype was time to early high-grade neutropenia event accounting for progression or death or other treatment-terminating adverse events as competing for informative events. The inference was carried out on the basis of the association between genotype and cause-specific hazard of a neutropenic event.
The primary analyses were carried out on the basis of 294 genetically estimated European pancreatic cancer patients. For CDA rs2072671 (A>C), AC and CC patients had a lower risk of neutropenia than AA patients (P=0.01, hazard ratio: 0.61, 95% confidence interval: 0.41-0.89). For SLC28A1 rs3825876 (G>A), AA patients have a higher risk of neutropenia than GA and GG patients (P=0.02, hazard ratio: 1.51, 95% confidence interval: 1.06-2.16). CDA rs2072671 was associated with increased mRNA expression in whole blood in three studies (P=2.7e-14, 6.61e-62, and 9.70e-65). In the genome-wide analysis, variants in TGFB2 were among the top hits (lowest P=1.62e-06) but had no effect in luciferase assays.
This is the first genetic analysis of gemcitabine-induced neutropenia using a competing risk model in a prospective randomized clinical study has proposed a potentially novel mechanism of the protective effect of the CDA rs2072671 variant. Further confirmation is needed.
晚期胰腺癌的标准治疗方案之一是以吉西他滨为基础的化疗。吉西他滨的疗效受到剂量限制性血液学毒性尤其是中性粒细胞减少的限制。揭示这些毒性因种系DNA变异而产生的变异性非常重要。
CALGB 80303是一项针对晚期胰腺癌患者的随机研究，这些患者接受了吉西他滨治疗，部分患者联合贝伐单抗。研究方案包括对吉西他滨处置相关基因（CDA、DCTD、SLC29A1、SLC28A1和SLC29A2）进行基因分型，以及全基因组分析。临床表型为早期重度中性粒细胞减少事件发生时间，将疾病进展或死亡或其他导致治疗终止的不良事件作为竞争信息事件。基于基因型与中性粒细胞减少事件的病因特异性风险之间的关联进行推断。
主要分析基于294例经基因评估的欧洲胰腺癌患者进行。对于CDA rs2072671（A>C），AC和CC患者发生中性粒细胞减少的风险低于AA患者（P=0.01，风险比：0.61，95%置信区间：0.41-0.89）。对于SLC28A1 rs3825876（G>A），AA患者发生中性粒细胞减少的风险高于GA和GG患者（P=0.02，风险比：1.51，95%置信区间：1.06-2.16）。在三项研究中，CDA rs2072671与全血中mRNA表达增加相关（P=2.7e-14、6.61e-62和9.70e-65）。在全基因组分析中，TGFB2中的变异位列最显著结果之中（最低P=1.62e-06），但在荧光素酶测定中无作用。
这是在一项前瞻性随机临床研究中首次使用竞争风险模型对吉西他滨诱导的中性粒细胞减少进行基因分析，提出了CDA rs2072671变异具有保护作用的潜在新机制。尚需进一步证实。
