在 WSG-ADAPT TN 试验中，三阴性早期乳腺癌中基质肿瘤浸润淋巴细胞（sTILs）对新辅助化疗反应的影响。
Impact of stromal tumor-infiltrating lymphocytes (sTILs) on response to neoadjuvant chemotherapy in triple-negative early breast cancer in the WSG-ADAPT TN trial.
机构信息
Department of Gynecology and Obstetrics, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany.
Institute of Pathology, Medical School Hannover, Hannover, Germany.
出版信息
Breast Cancer Res. 2022 Sep 2;24(1):58. doi: 10.1186/s13058-022-01552-w.
BACKGROUND
Higher density of stromal tumor-infiltrating lymphocytes (sTILs) at baseline has been associated with increased rates of pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC). While evidence supports favorable association of pCR with survival in TNBC, an independent impact of sTILs (after adjustment for pCR) on survival is not yet established. Moreover, the impact of sTIL dynamics during NACT on pCR and survival in TNBC is unknown.
METHODS
The randomized WSG-ADAPT TN phase II trial compared efficacy of 12-week nab-paclitaxel with gemcitabine versus carboplatin. This preplanned translational analysis assessed impacts of sTIL measurements at baseline (sTIL-0) and after 3 weeks of chemotherapy (sTIL-3) on pCR and invasive disease-free survival (iDFS). Predictive performance of sTIL-0 and sTIL-3 for pCR was quantified by ROC analysis and logistic regression; Kaplan-Meier estimation and Cox regression (with mediation analysis) were used to determine their impact on iDFS.
RESULTS
For prediction of pCR, the AUC statistics for sTIL-0 and sTIL-3 were 0.60 and 0.63, respectively, in all patients; AUC for sTIL-3 was higher in NP/G. The positive predictive value (PPV) of "lymphocyte-predominant" status (sTIL-0 ≥ 60%) at baseline was 59.3%, though only 13.0% of patients had this status. To predict non-pCR, the cut point sTIL-0 ≤ 10% yielded PPV = 69.5% while addressing 33.8% of patients. Higher sTIL levels (particularly at 3 weeks) were independently and favorably associated with better iDFS, even after adjusting for pCR. For example, the adjusted hazard ratio for 3-week sTILs ≥ 60% (vs. < 60%) was 0.48 [0.23-0.99]. Low cellularity in 3-week biopsies was the strongest individual predictor for pCR (in both therapy arms), but not for iDFS.
CONCLUSION
The independent impact of sTILs on iDFS suggests that favorable immune response can influence key tumor biological processes for long-term survival. The results suggest that the reliability of pCR following neoadjuvant therapy as a surrogate for survival could vary among subgroups in TNBC defined by immune response or other factors. Dynamic measurements of sTILs under NACT could support immune response-guided patient selection for individualized therapy approaches for both very low levels (more effective therapies) and very high levels (de-escalation concepts).
TRIAL REGISTRATION
Clinical trials No: NCT01815242, retrospectively registered January 25, 2013.
背景
在三阴性乳腺癌（TNBC）患者中，基线时基质肿瘤浸润淋巴细胞（sTILs）密度较高与新辅助化疗（NACT）后病理完全缓解（pCR）率增加相关。虽然有证据表明 pCR 与 TNBC 的生存呈有利关联，但 sTILs（在调整 pCR 后）对生存的独立影响尚未确定。此外，NACT 期间 sTIL 动态变化对 TNBC 的 pCR 和生存的影响尚不清楚。
方法
随机 WSG-ADAPT TN 期 II 期试验比较了 12 周 nab-紫杉醇联合吉西他滨与卡铂的疗效。这项预先计划的转化分析评估了基线时 sTIL 测量（sTIL-0）和化疗 3 周后（sTIL-3）对 pCR 和浸润性无病生存（iDFS）的影响。通过 ROC 分析和逻辑回归定量评估 sTIL-0 和 sTIL-3 对 pCR 的预测性能；使用 Kaplan-Meier 估计和 Cox 回归（具有中介分析）来确定它们对 iDFS 的影响。
结果
在所有患者中，sTIL-0 和 sTIL-3 的 AUC 统计数据分别为 0.60 和 0.63；NP/G 中 sTIL-3 的 AUC 更高。基线时“淋巴细胞占优势”状态（sTIL-0≥60%）的阳性预测值（PPV）为 59.3%，尽管只有 13.0%的患者存在这种状态。为了预测非 pCR，sTIL-0≤10%的截断值产生了 69.5%的 PPV，同时涵盖了 33.8%的患者。较高的 sTIL 水平（尤其是在 3 周时）与更好的 iDFS 独立且有利相关，即使在调整了 pCR 后也是如此。例如，与 sTIL-3<60%相比，3 周 sTILs≥60%的调整后风险比为 0.48[0.23-0.99]。3 周活检中的低细胞性是 pCR（在两种治疗臂中）的最强个体预测因子，但不是 iDFS。
结论
sTILs 对 iDFS 的独立影响表明，有利的免疫反应可以影响长期生存的关键肿瘤生物学过程。结果表明，新辅助治疗后 pCR 作为生存替代指标的可靠性可能因 TNBC 中免疫反应或其他因素定义的亚组而异。NACT 下 sTIL 的动态测量可以支持免疫反应指导患者选择，以用于非常低水平（更有效的治疗）和非常高水平（降级概念）的个体化治疗方法。
临床试验注册号
NCT01815242，于 2013 年 1 月 25 日进行了回顾性注册。
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