Mayo Clinic, Phoenix, AZ.
Foundation Medicine, Inc, Boston, MA.
JCO Precis Oncol. 2023 Sep;7:e2300091. doi: 10.1200/PO.23.00091.
Poly ADP-ribose polymerase inhibitors (PARPi) are approved for patients with human epidermal growth factor receptor 2-negative metastatic breast cancer (mBC) and germline pathogenic/likely pathogenic variant (hereafter mutation) in the / genes (g); however, clinical benefit has also been demonstrated in mBC with somatic / mutations (s) or germline mutations (g). This study aims to describe the genomic landscape of homologous recombination repair (HRR) gene alterations in mBC and assess PARPi treatment outcomes for patients with g compared with other HRR genes and by status of a novel homologous recombination deficiency signature (HRDsig).
A real-world (RW) clinico-genomic database (CGDB) of comprehensive genomic profiling (CGP) linked to deidentified, electronic health record-derived clinical data was used. CGP was analyzed for HRR genes and HRDsig. The CGDB enabled cohort characterization and outcomes analyses of 177 patients exposed to PARPi. RW progression-free survival (rwPFS) and RW overall survival (rwOS) were compared.
Of 28,920 patients with mBC, g was detected in 3.4%, whereas the population with any alteration or g increased to 9.5%. HRDsig+ represented 21% of patients with mBC. and g had higher levels of biallelic loss and HRDsig+ than other HRR alterations. Outcomes on PARPi were assessed for 177 patients, and g and s/ cohorts were similar: g versus s/g rwPFS was 6.3 versus 5.4 months (hazard ratio [HR], 1.37 [0.77-2.43]); rwOS was 16.2 versus 21.2 months (HR, 1.45 [0.74-2.86]). Additionally, patients with HRDsig+ versus HRDsig- had longer rwPFS (6.3 2.8 months; HR, 0.62 [0.42-0.92]) and numerically longer rwOS (17.8 13.0 months; HR, 0.72 [0.46-1.14]).
Patients with s and g derive similar benefit from PARPi as those with g alterations. In combination, HRDsig+, s, and g represent an additional 19% of mBC that can potentially benefit from PARPi. Randomized trials exploring a more inclusive biomarker such as HRDsig are warranted.
聚腺苷二磷酸核糖聚合酶抑制剂（PARPi）已获批用于人表皮生长因子受体 2 阴性转移性乳腺癌（mBC）患者，以及种系致病性/可能致病性变异（以下简称突变）在 BRCA1/2 基因（g）中；然而，mBC 中也已证实存在体细胞 BRCA1/2 突变（s）或种系 BRCA1/2 突变（g）具有临床获益。本研究旨在描述 mBC 中同源重组修复（HRR）基因改变的基因组图谱，并评估 g 与其他 HRR 基因相比以及与新型同源重组缺陷标志物（HRDsig）状态的 PARPi 治疗结果。
使用了一个真实世界（RW）临床基因组数据库（CGDB），该数据库与去识别的、源自电子健康记录的临床数据相关联。对 HRR 基因和 HRDsig 进行了 CGP 分析。CGDB 能够对 177 名接受 PARPi 治疗的患者进行队列特征描述和结局分析。比较了 RW 无进展生存期（rwPFS）和 RW 总生存期（rwOS）。
在 28920 名 mBC 患者中，g 的检出率为 3.4%，而任何 改变或 g 的人群增加到 9.5%。HRDsig+ 占 mBC 患者的 21%。 和 g 比其他 HRR 改变具有更高水平的双等位基因缺失和 HRDsig+。对 177 名患者进行了 PARPi 治疗的结局评估，g 和 s/g 队列相似：g 与 s/g 的 rwPFS 分别为 6.3 个月与 5.4 个月（风险比 [HR]，1.37 [0.77-2.43]）；rwOS 分别为 16.2 个月与 21.2 个月（HR，1.45 [0.74-2.86]）。此外，HRDsig+ 患者与 HRDsig-患者的 rwPFS 更长（6.3 个月与 2.8 个月；HR，0.62 [0.42-0.92]），rwOS 也更长（17.8 个月与 13.0 个月；HR，0.72 [0.46-1.14]）。
s 和 g 的患者从 PARPi 中获益与 g 改变的患者相似。联合起来，HRDsig+、s 和 g 代表了另外 19%的 mBC，这些患者可能从 PARPi 中受益。需要进行探索更具包容性生物标志物（如 HRDsig）的随机试验。
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