奥拉帕利单药作为未经选择的三阴性乳腺癌的一线治疗。
Olaparib monotherapy as primary treatment in unselected triple negative breast cancer.
机构信息
Department of Oncology, Haukeland University Hospital, Bergen, Norway; K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.
Department of Oncology, Haukeland University Hospital, Bergen, Norway; K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.
出版信息
Ann Oncol. 2021 Feb;32(2):240-249. doi: 10.1016/j.annonc.2020.11.009. Epub 2020 Nov 24.
BACKGROUND
The antitumor efficacy of PARP inhibitors (PARPi) for breast cancer patients harboring germline BRCA1/2 (gBRCA1/2) mutations is well established. While PARPi monotherapy was ineffective in patients with metastatic triple negative breast cancer (TNBC) wild type for BRCA1/2, we hypothesized that PARPi may be effective in primary TNBCs without previous chemotherapy exposure.
PATIENTS AND METHODS
In the phase II PETREMAC trial, patients with primary TNBC >2 cm received olaparib for up to 10 weeks before chemotherapy. Tumor biopsies collected before and after olaparib underwent targeted DNA sequencing (360 genes) and BRCA1 methylation analyses. In addition, BRCAness (multiplex ligation-dependent probe amplification), PAM50 gene expression, RAD51 foci, tumor-infiltrating lymphocytes (TILs) and PD-L1 analyses were performed on pretreatment samples.
RESULTS
The median pretreatment tumor diameter was 60 mm (range 25-112 mm). Eighteen out of 32 patients obtained an objective response (OR) to olaparib (56.3%). Somatic or germline mutations affecting homologous recombination (HR) were observed in 10/18 responders [OR 55.6%, 95% confidence interval (CI) 33.7-75.4] contrasting 1/14 non-responders (OR 7.1%; CI 1.3-31.5, P = 0.008). Among tumors without HR mutations, 6/8 responders versus 3/13 non-responders revealed BRCA1 hypermethylation (P = 0.03). Thus, 16/18 responders (88.9%, CI 67.2-96.9), in contrast to 4/14 non-responders (28.6%, CI 11.7-54.7, P = 0.0008), carried HR mutations and/or BRCA1 methylation. Excluding one gPALB2 and four gBRCA1/2 mutation carriers, 12/14 responders (85.7%, CI 60.1-96.0) versus 3/13 non-responders (23.1%, CI 8.2-50.3, P = 0.002) carried somatic HR mutations and/or BRCA1 methylation. In contrast to BRCAness signature or basal-like subtype, low RAD51 scores, high TIL or high PD-L1 expression all correlated to olaparib response.
CONCLUSION
Olaparib yielded a high clinical response rate in treatment-naïve TNBCs revealing HR deficiency, beyond germline HR mutations.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT02624973.
背景
PARP 抑制剂（PARPi）在携带种系 BRCA1/2（gBRCA1/2）突变的乳腺癌患者中的抗肿瘤疗效已得到充分证实。虽然 PARPi 单药治疗对转移性三阴性乳腺癌（TNBC）野生型 BRCA1/2 患者无效，但我们假设 PARPi 可能对未经化疗的原发性 TNBC 有效。
方法
在 II 期 PETREMAC 试验中，接受化疗前肿瘤直径>2cm 的原发性 TNBC 患者接受奥拉帕利治疗 10 周。在奥拉帕利治疗前后采集肿瘤活检标本，进行靶向 DNA 测序（360 个基因）和 BRCA1 甲基化分析。此外，在预处理样本上进行 BRCAness（多重连接依赖性探针扩增）、PAM50 基因表达、RAD51 焦点、肿瘤浸润淋巴细胞（TIL）和 PD-L1 分析。
结果
中位预处理肿瘤直径为 60mm（范围 25-112mm）。32 例患者中有 18 例（56.3%）对奥拉帕利有客观缓解（OR）。18 例应答者中有 10 例（OR 55.6%，95%置信区间[CI]33.7-75.4）出现影响同源重组（HR）的体细胞或种系突变，而 14 例无应答者中仅有 1 例（OR 7.1%；CI 1.3-31.5，P=0.008）。在无 HR 突变的肿瘤中，6/8 例应答者与 3/13 例无应答者显示 BRCA1 高甲基化（P=0.03）。因此，18 例应答者中有 16 例（88.9%，CI 67.2-96.9），而无应答者中有 4 例（28.6%，CI 11.7-54.7，P=0.0008），携带 HR 突变和/或 BRCA1 甲基化。排除 1 例 gPALB2 和 4 例 gBRCA1/2 突变携带者后，14 例应答者中有 12 例（85.7%，CI 60.1-96.0），而无应答者中仅有 3 例（23.1%，CI 8.2-50.3，P=0.002）携带体细胞 HR 突变和/或 BRCA1 甲基化。与 BRCAness 特征或基底样亚型相比，RAD51 评分低、TIL 高或 PD-L1 高表达均与奥拉帕利反应相关。
结论
奥拉帕利在未经化疗的原发性 TNBC 患者中产生了高临床缓解率，揭示了 HR 缺陷，而不仅仅是种系 HR 突变。
试验注册
ClinicalTrials.gov 标识符：NCT02624973。
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