三阴性乳腺癌术前艾立布林化疗效果

　　蒽环类＋紫杉类是乳腺癌首选化疗方案之一，可是对三阴性乳腺癌效果欠佳，尤其对染色体DNA同源重组缺陷或乳腺癌易感基因BRCA种系突变患者，效果不如铂类。软海绵素类细胞微管动力抑制剂艾立布林（海乐卫）与紫杉类的作用机制相似，还可改变肿瘤微环境，对周围神经的毒性也较低，已被批准用于晚期乳腺癌。不过，艾立布林对早期三阴性乳腺癌的化疗效果尚不明确。

　　2021年3月25日，施普林格自然旗下《乳腺癌研究与治疗》在线发表日本国立大阪医院、筑波大学、神奈川癌症中心、广岛大学、北海道癌症中心、埼玉癌症中心、广岛市立广岛市民医院、东京都立驹込医院、京都大学、神户市立医疗中心综合医院、埼玉医科大学国际医疗中心、东京虎之门医院、癌症研究会有明医院的日本乳腺癌研究协作组JBCRG-22研究报告，根据染色体DNA同源重组缺陷或乳腺癌易感基因BRCA种系突变状态，探讨了艾立布林用于早期三阴性乳腺癌术前新辅助化疗的临床效果。

UMIN000023162 (JBCRG-22): A multicenter randomized phase II clinical trial with neo -adjuvant chemotherapy containing eribulin mesylate for triple negative primary breast cancer patients (Neo-Entrance study)

　　该多中心随机对照二期临床研究于2017年2月～2019年1月从日本全国入组早期三阴性乳腺癌术前患者99例，按1∶1∶1∶1的比例随机分入4组：

  • A组（年龄<65岁且同源重组缺陷评分≥42，或任何年龄伴有种系BRCA突变）

  • A1组23例：紫杉醇＋卡铂4个周期→蒽环类4个周期

  • A2组22例：海乐卫＋卡铂4个周期→蒽环类4个周期

  • B组（年龄<65岁且同源重组缺陷评分<42，或年龄≥65岁不伴种系BRCA突变）

  • B1组27例：海乐卫＋环磷酰胺6个周期（前4个周期无效者接受蒽环类）

  • B2组27例：海乐卫＋卡培他滨6个周期（前4个周期无效者接受蒽环类）

　　主要研究终点为集中确认的病理完全缓解率（ypT0-is，ypN0）。次要关键终点为安全性。

　　结果，病理完全缓解率：

  • A1组：65%（90%置信区间：46%～81%）

  • A2组：45%（90%置信区间：27%～65%）

  • B1组：19%（90%置信区间：8%～35%）

  • B2组：19%（90%置信区间：8%～35%）

　　次要终点未见显著差异，除了周围神经病变发生率：

  • A1组：74%

  • A2组：32%

  • B1组：22%

  • B2组：26%

　　因此，该小样本研究结果表明，对于年龄<65岁且同源重组缺陷评分较高或任何年龄伴有种系BRCA突变的早期三阴性乳腺癌术前患者，每周紫杉醇或艾立布林＋卡铂→蒽环类的病理完全缓解率分别超过60%和40%，同源重组缺陷评分可能有助于对患者进行分层；同源重组缺陷阴性肿瘤患者的病理完全缓解率似乎较低。艾立布林化疗方案的周围神经毒性较少。

Breast Cancer Res Treat. 2021 Mar 25. Online ahead of print.

Eribulin-based neoadjuvant chemotherapy for triple-negative breast cancer patients stratified by homologous recombination deficiency status: a multicenter randomized phase II clinical trial.

Masuda N, Bando H, Yamanaka T, Kadoya T, Takahashi M, Nagai SE, Ohtani S, Aruga T, Suzuki E, Kikawa Y, Yasojima H, Kasai H, Ishiguro H, Kawabata H, Morita S, Haga H, Kataoka TR, Uozumi R, Ohno S, Toi M.

NHO Osaka National Hospital, Chuou-ku, Osaka, Japan; University of Tsukuba, Ibaraki, Japan; Kanagawa Cancer Center, Kanagawa, Japan; Hiroshima University, Hiroshima, Japan; NHO Hokkaido Cancer Center, Hokkaido, Japan; Saitama Cancer Center, Saitama, Japan; Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan; Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan; Kyoto University, Kyoto, Japan; Kobe City Medical Center General Hospital, Hyogo, Japan; Kyoto University Hospital, Kyoto, Japan; Saitama Medical University International Medical Center, Saitama, Japan; Toranomon Hospital, Tokyo, Japan; Kyoto University Graduate School of Medicine, Kyoto, Japan; The Cancer Institute Hospital of JFCR, Tokyo, Japan.

PURPOSE: To investigate clinical usefulness of eribulin-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients.

METHODS: Patients in group A (aged < 65 years with homologous recombination deficiency, HRD, score ≥ 42, or those at any age with germline BRCA mutation, gBRCAm) were randomized to 4 cycles of paclitaxel plus carboplatin (group A1) or eribulin plus carboplatin (group A2), followed by 4 cycles of anthracycline. Patients in group B (aged < 65 years with HRD score < 42, or aged ≥ 65 years without gBRCAm) were randomized to 6 cycles of eribulin plus cyclophosphamide (group B1) or eribulin plus capecitabine (group B2); non-responders to the first 4 cycles of the eribulin-based therapy received anthracycline. Primary endpoint was pCR rate (ypT0-is, ypN0; centrally confirmed). Main secondary endpoint was safety.

RESULTS: The full analysis set comprised 99 patients. The pCR rate was 65% (90% CI, 46%-81%) and 45% (27%-65%) in groups A1 and A2, respectively, and 19% (8%-35%) in both groups B1 and B2. No major difference was seen in secondary endpoints, but peripheral neuropathy incidence was 74% in group A1, whereas it was 32%, 22%, and 26% in groups A2, B1, and B2, respectively.

CONCLUSIONS: In patients aged < 65 years with high HRD score or gBRCAm, weekly paclitaxel plus carboplatin and eribulin plus carboplatin followed by anthracycline resulted in a pCR rate of > 60% and > 40%, respectively, suggesting potential usefulness of patient stratification using HRD; pCR tended to be low in patients with HRD-negative tumors. Neurotoxicity was less frequent with the eribulin-based regimen.

TRIAL REGISTRATION: UMIN000023162 (JBCRG-22)

KEYWORDS: BRCA mutation status; Eribulin; Homologous recombination deficiency score; Neoadjuvant chemotherapy; Pathological complete response; Triple-negative breast cancer

PMID: 33763789

DOI: 10.1007/s10549-021-06184-w

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