Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, 06520, USA.
Department of Immunobiology, Yale University School of Medicine, 333 Cedar Street, FMB307, New Haven, CT, 06520, USA.
J Cancer Res Clin Oncol. 2018 Dec;144(12):2449-2456. doi: 10.1007/s00432-018-2753-y. Epub 2018 Sep 25.
Hypersensitivity reactions (HSRs) to chemotherapy is an ongoing issue in cancer treatments. Strategies to induce tolerance and maximize chemotherapy efficacy include desensitization protocols. The precise impact of these protocols, however, in the long-term treatments remains unclear. We aim to compare overall survival (OS) in hypersensitive patients treated with carboplatin desensitization to patients without hypersensitivity reactions. We also sought to identify new risk factors for HSRs and reconfirm that the DNA repair enzyme, germline BRCA1/2 (gBRCA1/2), is a risk factor for hypersensitivity.
Retrospective study in patients with ovarian cancer tested for gBRCA1/2 mutations who received more than six infusions of carboplatin from August 2005 to November 2016. Two-sided Fisher exact, Student's t test and Gehan-Breslow-Wilcoxon test were used for statistical analysis. Univariate and multivariate analyses were completed to identify independent predictors of survival. Statistical significance was set with a two-sided p value of 0.05.
Ninety-one patients with gBRCA1/2 testing met inclusion. Forty patients (44%) were gBRCA1/2-deficient and 51 (56%) were gBRCA1/2-proficient. Patients with gBRCA1/2 deficiencies had a higher likelihood of developing carboplatin hypersensitivity, HR 6.433 (95% CI: 1.868-22.149). None of the patients with carboplatin hypersensitivity were given PARP inhibitors prior to the development of HSRs. The patients with recurrent advanced stage (III-IV) ovarian cancer had a higher likelihood of developing carboplatin hypersensitivity, HR 4.783 (1.008-22.689). Moreover, we found that hypersensitive patients who underwent carboplatin desensitization had a 48-month longer OS than patients without hypersensitivity to carboplatin not undergoing carboplatin desensitization (p = 0.0094). A subgroup analysis indicated that gBRCA1/2-proficient hypersensitive patients undergoing carboplatin desensitization had a 43-month longer OS than gBRCA1/2-proficient patients without HSRs (p = 0.034).
We confirmed that gBRCA1/2 deficiency and advanced stage are independent risk factors for development of carboplatin hypersensitivity in ovarian cancer patients. Our study also shows improved OS in hypersensitive patients receiving CD compared to non-hypersensitive patients, independent of gBRCA1/2.
化疗引起的过敏反应（HSR）是癌症治疗中的一个持续存在的问题。诱导耐受和最大化化疗疗效的策略包括脱敏方案。然而，这些方案在长期治疗中的确切影响尚不清楚。我们旨在比较接受卡铂脱敏治疗的过敏患者与无过敏反应患者的总生存期（OS）。我们还试图确定 HSR 的新危险因素，并再次证实种系 BRCA1/2（gBRCA1/2）DNA 修复酶是过敏的危险因素。
对 2005 年 8 月至 2016 年 11 月接受超过 6 次卡铂输注的卵巢癌患者进行回顾性研究，检测 gBRCA1/2 突变。使用双侧 Fisher 确切检验、Student t 检验和 Gehan-Breslow-Wilcoxon 检验进行统计分析。完成单变量和多变量分析以确定生存的独立预测因素。统计显著性设定为双侧 p 值为 0.05。
91 名接受 gBRCA1/2 检测的患者符合纳入标准。40 名患者（44%）为 gBRCA1/2 缺乏，51 名患者（56%）为 gBRCA1/2 功能正常。gBRCA1/2 缺乏的患者发生卡铂过敏的可能性更高，HR 6.433（95%CI：1.868-22.149）。在发生 HSR 之前，没有接受卡铂过敏的患者给予 PARP 抑制剂。复发性晚期（III-IV 期）卵巢癌患者发生卡铂过敏的可能性更高，HR 4.783（1.008-22.689）。此外，我们发现接受卡铂脱敏治疗的过敏患者的 OS 比未接受卡铂脱敏治疗的无卡铂过敏患者长 48 个月（p=0.0094）。亚组分析表明，gBRCA1/2 功能正常的过敏患者接受卡铂脱敏治疗的 OS 比 gBRCA1/2 功能正常且无 HSR 的患者长 43 个月（p=0.034）。
我们证实 gBRCA1/2 缺乏和晚期是卵巢癌患者发生卡铂过敏的独立危险因素。我们的研究还表明，接受 CD 的过敏患者的 OS 得到改善，与 gBRCA1/2 无关。
