Olaparib monotherapy as primary treatment in unselected triple negative breast cancer

被引：142

作者：

Eikesdal, H. P. ^{[1
,2
]}

Yndestad, S. ^{[1
,2
]}

Elzawahry, A. ^{[1
,2
]}

Llop-Guevara, A. ^{[3
]}

Gilje, B. ^{[4
]}

Blix, E. S. ^{[5
,6
]}

Espelid, H. ^{[7
]}

Lundgren, S. ^{[8
,9
]}

Geisler, J. ^{[10
,11
]}

Vagstad, G. ^{[12
]}

Venizelos, A. ^{[1
,2
]}

Minsaas, L. ^{[1
,2
]}

Leirvaag, B. ^{[1
,2
]}

Gudlaugsson, E. G. ^{[13
]}

Vintermyr, O. K. ^{[14
,15
]}

Aase, H. S. ^{[16
]}

Aas, T. ^{[17
]}

Balmana, J. ^{[3
]}

Serra, V ^{[3
]}

Janssen, E. A. M. ^{[13
]}

Knappskog, S. ^{[1
,2
]}

Lonning, P. E. ^{[1
,2
]}

机构：

[1] Haukeland Hosp, Dept Oncol, Jonas Lies Vei 65, N-5021 Bergen, Norway

[2] Univ Bergen, KG Jebsen Ctr Genome Directed Canc Therapy, Dept Clin Sci, Bergen, Norway

[3] Vall dHebron Inst Oncol, Barcelona, Spain

[4] Stavanger Univ Hosp, Dept Hematol & Oncol, Stavanger, Norway

[5] UiT Arctic Univ Norway, Inst Med Biol, Immunol Res Grp, Tromso, Norway

[6] Univ Hosp North Norway, Dept Oncol, Tromso, Norway

[7] Haugesund Hosp, Dept Surg, Haugesund, Norway

[8] Trondheim Reg & Univ Hosp, Canc Clin, St Olavs Hosp, Trondheim, Norway

[9] Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway

[10] Akershus Univ Hosp, Dept Oncol, Lorenskog, Norway

[11] Univ Oslo, Inst Clin Med, Oslo, Norway

[12] Forde Hosp, Dept Oncol, Forde, Norway

[13] Stavanger Univ Hosp, Dept Pathol, Stavanger, Norway

[14] Haukeland Hosp, Dept Pathol, Bergen, Norway

[15] Univ Bergen, Dept Clin Med, Gade Lab Pathol, Bergen, Norway

[16] Haukeland Hosp, Dept Radiol, Bergen, Norway

[17] Haukeland Hosp, Dept Surg, Bergen, Norway

来源：

ANNALS OF ONCOLOGY | 2021年 / 32卷 / 02期

基金：

欧盟地平线“2020”;

关键词：

triple negative breast cancer; PARP inhibitor; olaparib; homologous recombination deficiency; prediction; neoadjuvant therapy; GERMLINE MUTATIONS; PARP INHIBITOR; OPEN-LABEL; CHEMOTHERAPY; CARBOPLATIN; DNA; RESISTANCE; VELIPARIB; MULTICENTER; REVERSION;

D O I：

10.1016/j.annonc.2020.11.009

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 PDL1 expression all correlated to olaparib response. Conclusion: Olaparib yielded a high clinical response rate in treatment-naive TNBCs revealing HR deficiency, beyond germline HR mutations.

引用

页码：240 / 249

页数：10

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