同源重组修复基因突变预测奥拉帕利联合贝伐珠单抗在一线卵巢癌 PAOLA-1/ENGOT-ov25 试验中的疗效。

PURPOSE

The PAOLA-1/ENGOT-ov25 trial of maintenance olaparib plus bevacizumab for newly diagnosed advanced high-grade ovarian cancer demonstrated a significant progression-free survival (PFS) benefit over placebo plus bevacizumab, particularly in patients with homologous recombination deficiency (HRD)-positive tumors. We explored whether mutations in non- or homologous recombination repair (non-BRCA HRRm) genes predicted benefit from olaparib plus bevacizumab in PAOLA-1.

METHODS

Eight hundred and six patients were randomly assigned (2:1). Tumors were analyzed using the Myriad MyChoice HRD Plus assay to assess non-BRCA HRRm and HRD status; HRD was based on a genomic instability score (GIS) of ≥ 42. In this exploratory analysis, PFS was assessed in patients harboring deleterious mutations using six non-BRCA HRR gene panels, three devised for this analysis and three previously published.

RESULTS

The non-BRCA HRRm prevalence ranged from 30 of 806 (3.7%) to 79 of 806 (9.8%) depending on the gene panel used, whereas 152 of 806 (18.9%) had non- or mutation HRD-positive tumors. The majority of tumors harboring non-BRCA HRRm had a low median GIS; however, a GIS of > 42 was observed for tumors with mutations in five HRR genes (, , , , and ). Rates of gene-specific biallelic loss were variable (0% to 100%) in non-BRCA HRRm tumors relative to -mutated (99%) or -mutated (86%) tumors. Across all gene panels tested, hazard ratios for PFS (95% CI) ranged from 0.92 (0.51 to 1.73) to 1.83 (0.76 to 5.43).

CONCLUSION

Acknowledging limitations of small subgroup sizes, non-BRCA HRRm gene panels were not predictive of PFS benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in PAOLA-1, irrespective of the gene panel tested. Current gene panels exploring HRRm should not be considered a substitute for HRD determined by BRCA mutation status and genomic instability testing in first-line high-grade ovarian cancer.

目的

PAOLA-1/ENGOT-ov25 试验表明，新诊断的晚期高级别卵巢癌患者接受奥拉帕利联合贝伐珠单抗维持治疗相比于安慰剂联合贝伐珠单抗具有显著的无进展生存期（PFS）获益，尤其是同源重组缺陷（HRD）阳性肿瘤患者。我们探索了 PAOLA-1 中，非同源重组修复（非 BRCA HRRm）基因突变是否可预测奥拉帕利联合贝伐珠单抗的获益。

方法

806 例患者按 2:1 随机分组。使用 Myriad MyChoice HRD Plus 检测评估非 BRCA HRRm 和 HRD 状态；HRD 基于基因组不稳定性评分（GIS）≥42。在这项探索性分析中，使用 6 个非 BRCA HRR 基因panel（3 个为本研究设计，3 个为既往发表的）评估携带有害突变患者的 PFS。

结果

非 BRCA HRRm 的发生率为 30/806（3.7%）至 79/806（9.8%），取决于使用的基因 panel；152/806（18.9%）患者的肿瘤为非 BRCA HRD 阳性。携带非 BRCA HRRm 的大多数肿瘤具有较低的中位 GIS；然而，在携带 HRR 基因（、、、、和）突变的肿瘤中，观察到 GIS＞42。非 BRCA HRRm 肿瘤中基因特异性双等位基因缺失率存在差异（0%至 100%），而 -突变（99%）或 -突变（86%）肿瘤的缺失率均较高。在所有检测的基因 panel 中，PFS 的风险比（95%CI）范围为 0.92（0.51 至 1.73）至 1.83（0.76 至 5.43）。

结论

考虑到亚组规模较小的局限性，在 PAOLA-1 中，无论使用哪种基因 panel，非 BRCA HRRm 基因 panel 均不能预测维持性奥拉帕利联合贝伐珠单抗与安慰剂联合贝伐珠单抗治疗的 PFS 获益。目前探索 HRRm 的基因 panel 不应替代一线高级别卵巢癌中基于 BRCA 突变状态和基因组不稳定性检测的 HRD。