新辅助 Nab-紫杉醇+卡铂与 Nab-紫杉醇+吉西他滨治疗三阴性乳腺癌的比较：随机 WSG-ADAPT-TN 试验结果。

Comparison of Neoadjuvant Nab-Paclitaxel+Carboplatin vs Nab-Paclitaxel+Gemcitabine in Triple-Negative Breast Cancer: Randomized WSG-ADAPT-TN Trial Results.

机构信息

Moenchengladabach, West German Study Group.

Moenchengladbach, Breast Center Niederrhein, Evangelical Hospital Johanniter Bethesda.

出版信息

J Natl Cancer Inst. 2018 Jun 1;110(6):628-637. doi: 10.1093/jnci/djx258.

DOI:10.1093/jnci/djx258

PMID:29228315

Abstract

BACKGROUND

Pathological complete response (pCR) is associated with improved prognosis in triple-negative breast cancer (TNBC). The optimal chemotherapy regimen is unclear. Weekly nab-paclitaxel vs conventional paclitaxel or addition of carboplatin to anthracycline-taxane results in higher pCR rates with uncertain survival impact. We evaluated carboplatin vs gemcitabine with a nab-paclitaxel backbone as a short 12-week A-free regimen with a focus on early response.

METHODS

Patients with TNBC (estrogen receptor/progesterone receptor < 1%, human epidermal growth factor receptor 2-negative, cT1c-cT4c, cN0/+) were randomly assigned to A: nab-paclitaxel 125 mg/m2/gemcitabine 1000 mg/m2 d1,8 three times weekly (q3w); vs B: nab-paclitaxel 125 mg/m2/carboplatin AUC2 day 1,8 q3w. The trial was powered for a pCR (ypT0/is ypN0) comparison by therapy arm and early response (defined as Ki-67 decrease >30% or < 500 invasive tumor cells in the three-week serial biopsy). All statistical tests were two-sided.

RESULTS

A total of 336 patients were enrolled (48 centers, arms A/B: n = 182/154). The median age was 50 years. At baseline (A vs B), 62.6% and 62.9% had cT2-4c tumors; 86.8% and 90.9% completed therapy per protocol, respectively. pCR favored arm B (28.7%, 95% CI = 0.22 to 0.36, vs 45.9%, 95% CI = 0.38 to 0.54; 95% CI(dBA) = 6.2% to 27.9%, P = .002) and was lower in nonresponders than in early responders (19.5% vs 44.4%, P < .001) or in patients with unclassifiable early response (50.0%). The nab-paclitaxel/gemcitabine was associated with more frequent dose reductions (20.6% vs 11.9%, P = .04), treatment-related serious adverse events (11.1% vs 5.3%, P = .07), grade 3-4 infections (7.2% vs 2.6%, P = .07), and grade 3-4 ALAT elevations (11.7 vs 3.3%, P = .01).

CONCLUSIONS

This first large randomized trial suggests high efficacy and excellent tolerability of a neoadjuvant nab-paclitaxel/carboplatin regimen, superior to nab-paclitaxel/gemcitabine in TNBC. De-escalation of further chemotherapy in patients with early pCR after a short anthracycline-free regimen is a promising field of future research. Early necrotic morphological changes and/or proliferation decrease after the first therapy cycle seem to be associated with subsequent pCR.

摘要

背景

病理完全缓解（pCR）与三阴性乳腺癌（TNBC）的预后改善相关。最佳化疗方案尚不清楚。每周紫杉醇纳米白蛋白与常规紫杉醇或加用卡铂与蒽环类药物-紫杉烷相比，pCR 率更高，但生存影响不确定。我们评估了紫杉醇纳米白蛋白联合卡铂作为一种新的 12 周无 A 方案，重点关注早期反应。

方法

入组患者为 TNBC（雌激素受体/孕激素受体<1%，人表皮生长因子受体 2 阴性，cT1c-cT4c，cN0/+），随机分为 A 组：紫杉醇纳米白蛋白 125mg/m2+吉西他滨 1000mg/m2，d1、8 ，q3w；B 组：紫杉醇纳米白蛋白 125mg/m2+卡铂 AUC2，d1、8，q3w。该试验按照治疗臂和早期反应（定义为 Ki-67 下降>30%或在三周连续活检中<500 个侵袭性肿瘤细胞）对 pCR（ypT0/is ypN0）进行了统计学检验。所有统计检验均为双侧检验。

结果

共纳入 336 例患者（48 个中心，A/B 臂：n=182/154）。中位年龄为 50 岁。基线时（A 与 B 相比），62.6%和 62.9%的患者为 cT2-4c 肿瘤；分别有 86.8%和 90.9%的患者按方案完成了治疗。B 臂的 pCR 更优（28.7%，95%CI=0.22-0.36，vs 45.9%，95%CI=0.38-0.54；95%CI（dBA）=6.2%至 27.9%，P=0.002），且在无反应者中低于早期反应者（19.5% vs 44.4%，P<0.001）或早期反应不可分类者（50.0%）。紫杉醇纳米白蛋白/吉西他滨更常出现剂量减少（20.6% vs 11.9%，P=0.04）、与治疗相关的严重不良事件（11.1% vs 5.3%，P=0.07）、3-4 级感染（7.2% vs 2.6%，P=0.07）和 3-4 级丙氨酸氨基转移酶升高（11.7% vs 3.3%，P=0.01）。

结论

这是第一项大型随机试验，提示新辅助紫杉醇纳米白蛋白/卡铂方案具有较高的疗效和良好的耐受性，优于紫杉醇纳米白蛋白/吉西他滨在 TNBC 中的应用。在接受短程无蒽环类药物方案治疗后早期 pCR 的患者中进一步化疗降级是未来研究的一个有前景的领域。在第一个治疗周期后出现早期坏死性形态学改变和/或增殖减少，可能与后续 pCR 相关。