Abstract：
BACKGROUND: Mutations in the BRCA1/2 (BRCA) genes are associated with response to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). In addition, there are different homologous recombination deficiency (HRD) biomarkers available in clinical practice [e.g., genome-wide loss-of-heterozygosity (gLOH) and myChoice® score] that identify patients who can benefit from PARPi. Inconsistencies in biomarkers used in PARPi clinical trials make it challenging to identify clinically relevant predictive biomarkers. This study aims to compare clinically available HRD biomarkers in terms of benefits from PARPi.
METHODS: We performed database search for phase II or III randomized clinical trials comparing PARPi versus chemotherapy, and meta-analysis using generic inverse variance and a Random Effects model. Patients were classified according to their HRD status: (I) BRCAm (patients with BRCA mutation of germline or somatic origin); (II) non-BRCA HRD [patients BRCA wild-type (wt) with another HRD biomarker-gLOH or myChoice®]; and (III) homologous recombination proficiency (HRP) (BRCAwt and without HRD biomarkers). From those that were BRCAwt, we compared myChoice®+ with gLOH-high.
RESULTS: Five studies (3,225 patients) analyzing PARPi in first line setting were included. Patients with BRCAmut had progression-free survival (PFS) with hazard ratio (HR) 0.33 [95% confidence interval (CI): 0.30-0.43]; patients with non-BRCA HRD had a PFS HR 0.49 (95% CI: 0.37-0.65), and patients with HRP had a PFS HR 0.78 (95% CI: 0.58-1.03). Eight studies (5,529 patients) with PARPi including first line and recurrence settings were included. BRCAmut had PFS HR 0.37 (95% CI: 0.30-0.48), BRCAwt & HRD 0.45 (95% CI: 0.37-0.55) and HRP 0.70 (95% CI: 0.57-0.85). Patients with BRCAwt & myChoice® ≥42 had PFS HR 0.43 (95% CI: 0.34-0.56), similar to patients with BRCAwt & gLOH-high with PFS HR 0.42 (95% CI: 0.28-0.62).
CONCLUSIONS: Patients with HRD derived significantly more benefit from PARPi when compared to patients with HRP. The benefit of PARPi in patients with HRP tumors was limited. Careful cost-effectiveness analysis, and alternative therapies or clinical trial enrollment should strongly be considered for patients with HRP tumors. Among patients with BRCAwt, a similar benefit was found in patients with gLOH-high and those myChoice®+. The clinical development of further HRD biomarkers (e.g., Sig3) may help identify more patients who benefit from PARPi.
METHODS: We performed database search for phase II or III randomized clinical trials comparing PARPi versus chemotherapy, and meta-analysis using generic inverse variance and a Random Effects model. Patients were classified according to their HRD status: (I) BRCAm (patients with BRCA mutation of germline or somatic origin); (II) non-BRCA HRD [patients BRCA wild-type (wt) with another HRD biomarker-gLOH or myChoice®]; and (III) homologous recombination proficiency (HRP) (BRCAwt and without HRD biomarkers). From those that were BRCAwt, we compared myChoice®+ with gLOH-high.
RESULTS: Five studies (3,225 patients) analyzing PARPi in first line setting were included. Patients with BRCAmut had progression-free survival (PFS) with hazard ratio (HR) 0.33 [95% confidence interval (CI): 0.30-0.43]; patients with non-BRCA HRD had a PFS HR 0.49 (95% CI: 0.37-0.65), and patients with HRP had a PFS HR 0.78 (95% CI: 0.58-1.03). Eight studies (5,529 patients) with PARPi including first line and recurrence settings were included. BRCAmut had PFS HR 0.37 (95% CI: 0.30-0.48), BRCAwt & HRD 0.45 (95% CI: 0.37-0.55) and HRP 0.70 (95% CI: 0.57-0.85). Patients with BRCAwt & myChoice® ≥42 had PFS HR 0.43 (95% CI: 0.34-0.56), similar to patients with BRCAwt & gLOH-high with PFS HR 0.42 (95% CI: 0.28-0.62).
CONCLUSIONS: Patients with HRD derived significantly more benefit from PARPi when compared to patients with HRP. The benefit of PARPi in patients with HRP tumors was limited. Careful cost-effectiveness analysis, and alternative therapies or clinical trial enrollment should strongly be considered for patients with HRP tumors. Among patients with BRCAwt, a similar benefit was found in patients with gLOH-high and those myChoice®+. The clinical development of further HRD biomarkers (e.g., Sig3) may help identify more patients who benefit from PARPi.
摘要：
背景：BRCA1/2（BRCA）基因的突变与对聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）的反应有关。此外,临床实践中有不同的同源重组缺陷(HRD)生物标志物[例如，全基因组杂合性缺失(gLOH)和myChoice®评分]，确定可以从PARPi中受益的患者。PARPi临床试验中使用的生物标志物的不一致使得鉴定临床相关的预测性生物标志物具有挑战性。本研究旨在从PARPi的益处方面比较临床上可用的HRD生物标志物。
方法：我们进行了数据库搜索，以比较PARPi与化疗的II期或III期随机临床试验，以及使用通用逆方差和随机效应模型的荟萃分析。根据其HRD状态对患者进行分类：（I）BRCAm（具有种系或体细胞起源的BRCA突变的患者）；（II）非BRCAHRD[具有另一种HRD生物标志物gLOH或myChoice®的患者BRCA野生型（wt）]；（III）同源重组能力（HRP）（BRCAwt且无HRD生物标志物）。从BRCAwt那里，我们将myChoice®+与gLOH-high进行了比较。
结果：纳入了5项研究（3,225例患者）在一线环境中分析了PARPi。BRCAmut患者的无进展生存期（PFS）的风险比（HR）为0.33[95％置信区间（CI）：0.30-0.43]；非BRCAHRD患者的PFSHR为0.49（95％CI：0.37-0.65），HRP患者的PFSHR为0.78（95％CI：0.58-1.03）。纳入了8项PARPi研究（5,529例患者），包括一线和复发设置。BRCAmut的PFSHR为0.37（95%CI：0.30-0.48），BRCAwt&HRD0.45（95%CI：0.37-0.55）和HRP0.70（95%CI：0.57-0.85）。BRCAwt和myChoice®≥42的患者的PFSHR为0.43（95％CI：0.34-0.56），与BRCAwt和gLOH高的患者相似，PFSHR为0.42（95％CI：0.28-0.62）。
结论：与HRP患者相比，HRD患者从PARPi获益更多。PARPi对HRP肿瘤患者的益处有限。仔细的成本效益分析，对于HRP肿瘤患者,应强烈考虑替代疗法或纳入临床试验.在BRCAwt患者中，gLOH-high和myChoice®+患者也有类似的获益.进一步的HRD生物标志物的临床开发(例如，Sig3）可能有助于识别更多受益于PARPi的患者。
方法：我们进行了数据库搜索，以比较PARPi与化疗的II期或III期随机临床试验，以及使用通用逆方差和随机效应模型的荟萃分析。根据其HRD状态对患者进行分类：（I）BRCAm（具有种系或体细胞起源的BRCA突变的患者）；（II）非BRCAHRD[具有另一种HRD生物标志物gLOH或myChoice®的患者BRCA野生型（wt）]；（III）同源重组能力（HRP）（BRCAwt且无HRD生物标志物）。从BRCAwt那里，我们将myChoice®+与gLOH-high进行了比较。
结果：纳入了5项研究（3,225例患者）在一线环境中分析了PARPi。BRCAmut患者的无进展生存期（PFS）的风险比（HR）为0.33[95％置信区间（CI）：0.30-0.43]；非BRCAHRD患者的PFSHR为0.49（95％CI：0.37-0.65），HRP患者的PFSHR为0.78（95％CI：0.58-1.03）。纳入了8项PARPi研究（5,529例患者），包括一线和复发设置。BRCAmut的PFSHR为0.37（95%CI：0.30-0.48），BRCAwt&HRD0.45（95%CI：0.37-0.55）和HRP0.70（95%CI：0.57-0.85）。BRCAwt和myChoice®≥42的患者的PFSHR为0.43（95％CI：0.34-0.56），与BRCAwt和gLOH高的患者相似，PFSHR为0.42（95％CI：0.28-0.62）。
结论：与HRP患者相比，HRD患者从PARPi获益更多。PARPi对HRP肿瘤患者的益处有限。仔细的成本效益分析，对于HRP肿瘤患者,应强烈考虑替代疗法或纳入临床试验.在BRCAwt患者中，gLOH-high和myChoice®+患者也有类似的获益.进一步的HRD生物标志物的临床开发(例如，Sig3）可能有助于识别更多受益于PARPi的患者。
