TBCRC 001: Randomized Phase II Study of Cetuximab in Combination With Carboplatin in Stage IV Triple-Negative Breast Cancer
TBCRC 001: Randomized Phase II Study of Cetuximab in Combination With Carboplatin in Stage IV Triple-Negative Breast Cancer
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DOI：
10.1200/jco.2010.34.5579
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发表时间：
2012-07-20
影响因子：
45.3
通讯作者：
Winer, Eric P.
中科院分区：
文献类型：
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作者：
Carey, Lisa A.;Rugo, Hope S.;Winer, Eric P.
表皮生长因子受体（epidermal growth factor receptor，EGFR）是一种靶向受体，在基底细胞样乳腺癌（basal-like breast cancer，基底细胞样乳腺癌）中频繁过表达，其中包括大多数三阴性乳腺癌（triple-negative breast cancer，TNBC），是唯一没有建立靶向治疗的亚型。转移性TNBC患者接受抗EGFR抗体西妥昔单抗（400 mg/m2负荷量，然后每周静脉注射250 mg/m2 [IV]）单独给药，进展后加用卡铂（曲线下面积为2，每周IV一次）或从一开始就作为伴随治疗。缓解率（RR）是主要终点;其他终点包括疾病进展时间（TTP）、总生存期（OS）和毒性。嵌入式相关研究包括档案组织的分子亚型。新鲜的肿瘤组织治疗前和治疗后7至14天被用于微阵列分析，探索EGFR通路的活性和inhibit 102例TNBC，RR分别为6%（31）西妥昔单抗和16%（25）西妥昔单抗加卡铂后进展。从西妥昔单抗联合卡铂开始治疗的患者的RR为17%（12/71）; 31%的患者有反应或延长了疾病稳定期。西妥昔单抗联合卡铂方案耐受性良好，但TTP和OS均较短，分别为2.1个月（95% CI，1.8 - 5.5个月）和10.4个月（95% CI，7.7 - 13.1个月）。在73例存档组织进行分析的患者中，74%具有基底样分子亚型。16例患者的肿瘤活检治疗前和1周后，EGFR途径的基因组模式显示激活13和抑制治疗five.ConclusionDespite强大的临床前数据，西妥昔单抗加卡铂在转移性TNBC产生的反应在不到20%的患者。EGFR通路分析显示，大多数TNBC涉及活化。然而，西妥昔单抗仅在少数情况下阻断EGFR通路的表达，这表明大多数通路活化具有替代机制。
PurposeEpidermal growth factor receptor (EGFR) is a targetable receptor frequently overexpressed in basal-like breast cancer, which comprises most triple-negative breast cancers (TNBCs), the only subtype without established targeted therapy.Patients and MethodsIn this randomized phase II trial, patients with metastatic TNBC received anti-EGFR antibody cetuximab (400 mg/m(2) load then 250 mg/m(2) per week intravenously [IV]) alone, with carboplatin (area under the curve of 2, once per week IV) added after progression or as concomitant therapy from the beginning. Response rate (RR) was the primary end point; others included time to progression (TTP), overall survival (OS), and toxicity. Embedded correlative studies included molecular subtyping on archival tissue. Fresh tumor tissue before and after 7 to 14 days of therapy was used for microarray analyses exploring EGFR pathway activity and inhibition.ResultsIn 102 patients with TNBC, RRs were 6% (two of 31) to cetuximab and 16% (four of 25) to cetuximab plus carboplatin after progression. RR to those treated from the beginning with cetuximab plus carboplatin was 17% (12 of 71); 31% of patients responded or had prolonged disease stabilization. The cetuximab plus carboplatin regimen was well tolerated, but both TTP and OS were short at 2.1 months (95% CI, 1.8 to 5.5 months) and 10.4 months (95% CI, 7.7 to 13.1 months), respectively. Of 73 patients with archival tissue for analysis, 74% had basal-like molecular subtype. Sixteen patients had tumor biopsies before and 1 week after therapy; genomic patterns of the EGFR pathway showed activation in 13 and inhibition by therapy in five.ConclusionDespite strong preclinical data, combination cetuximab plus carboplatin in metastatic TNBC produced responses in fewer than 20% of patients. EGFR pathway analysis showed that most TNBCs involved activation. However, cetuximab blocked expression of the EGFR pathway in only a minority, suggesting that most had alternate mechanisms for pathway activation.