Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study.
Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study.
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DOI：
10.1016/s1470-2045(16)30631-3
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Loi S
中科院分区：
文献类型：
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作者：
Luen SJ;Salgado R;Fox S;Savas P;Eng-Wong J;Clark E;Kiermaier A;Swain SM;Baselga J;Michiels S;Loi S
原发性her2阳性乳腺癌中大量肿瘤浸润淋巴细胞（til）与预后改善和治疗反应相关。我们的目的是研究宿主抗肿瘤免疫在晚期her2阳性乳腺癌患者中所起的预后作用，包括在曲妥珠单抗和多西他赛之外接受帕妥珠单抗或安慰剂治疗的患者中TILs的基线量。CLEOPATRA是一项随机3期研究，比较了在曲妥珠单抗和多西他赛的一线治疗中，帕妥珠单抗或安慰剂对局部复发、不可切除或转移性her2阳性乳腺癌患者的疗效。我们评估了前瞻性收集的肿瘤样本中基质til的数量，并研究了它们与无进展生存期、总生存期、临床病理特征和帕妥珠单抗治疗的关系。我们用多变量Cox回归模型拟合基质TILs作为连续变量（每增加10%），估计了风险比（HR）和95% ci。克利奥帕特拉试验已在ClinicalTrials.gov注册，编号NCT00567190。808名参与者中678例（84%）的肿瘤样本可用于til评估，包括519例（77%）档案样本，155例（23%）新获得的样本（随机化前45天或更短时间收集），以及4例未知档案状态的样本。无进展生存期中位随访为50个月（IQR 41-54），总生存期中位随访为51个月（IQR 46-57）。519例无进展生存事件发生，358例患者死亡。TIL中位值为10% （IQR 5-30）。新获得的肿瘤样本的TIL值明显低于档案样本（10.00% [95% CI 5.00 - 20.00] vs 15.00% [5.00 - 35.00]; p= 0.00036）。我们发现TIL值与无进展生存期之间无显著关联（调整后危险度0.95,95% CI 0.90 - 1.00, p= 0.063）。然而，对于总生存率，基质TILs每增加10%与总生存率延长显著相关（调整后危险度0.89,95% CI 0.83 - 0.96, p= 0.0014）。对于无进展生存期（p相互作用= 0.23）或总生存期（p相互作用= 0.21），间质TIL值对帕妥珠单抗的治疗效果均无显著差异。在接受多西他赛、曲妥珠单抗、帕妥珠单抗或安慰剂治疗的晚期her2阳性乳腺癌患者中，较高的TIL值与改善的总生存期显著相关，这表明抗肿瘤免疫的作用延伸到晚期。未来对这种癌症亚型的临床研究应考虑til作为分层因素，并研究增强免疫的治疗是否可能进一步提高生存率。
High quantities of tumour-infiltrating lymphocytes (TILs) in primary HER2-positive breast cancer are associated with improved prognosis and response to therapy. We aimed to investigate the prognostic role of host antitumour immunity as represented by baseline quantities of TILs in patients with advanced HER2-positive breast cancer treated with either pertuzumab or placebo in addition to trastuzumab and docetaxel. CLEOPATRA was a randomised phase 3 study comparing the addition of either pertuzumab or placebo to first-line therapy with trastuzumab and docetaxel for patients with locally recurrent, unresectable, or metastatic HER2-positive breast cancer. We assessed the quantity of stromal TILs in prospectively collected tumour samples and investigated their association with progression-free survival, overall survival, clinicopathological characteristics, and pertuzumab treatment. We estimated hazard ratios (HR) and 95% CIs with multivariate Cox regression models fitting stromal TILs as a continuous variable (per 10% increment). The CLEOPATRA trial is registered with ClinicalTrials.gov, number NCT00567190. Tumour samples from 678 (84%) of 808 participants were evaluable for TILs, including 519 (77%) archival samples, 155 (23%) freshly obtained samples (collected 45 days or fewer before randomisation), and four samples of unknown archival status. Median follow-up was 50 months (IQR 41–54) for progression-free survival and 51 months (IQR 46–57) for overall survival. 519 progression-free survival events occurred and 358 patients died. The median TIL value was 10% (IQR 5–30). Freshly obtained tumour samples had significantly lower TIL values than did archival samples (10·00% [95% CI 5·00–20·00] vs 15·00% [5·00–35·00]; p=0·00036). We detected no significant association between TIL values and progression-free survival (adjusted HR 0·95, 95% CI 0·90–1·00, p=0·063). However, for overall survival, each 10% increase in stromal TILs was significantly associated with longer overall survival (adjusted HR 0·89, 95% CI 0·83–0·96, p=0·0014). The treatment effect of pertuzumab did not differ significantly by stromal TIL value for either progression-free survival (pinteraction=0·23) or overall survival (pinteraction=0·21). In patients with advanced HER2-positive breast cancer treated with docetaxel, trastuzumab, and pertuzumab or placebo, higher TIL values are significantly associated with improved overall survival, suggesting that the effect of antitumour immunity extends to the advanced setting. Future clinical studies in this cancer subtype should consider TILs as a stratification factor and investigate whether therapies that can augment immunity could potentially further improve survival.