埃及艳后再度登场：肿瘤浸润淋巴细胞与晚期乳腺癌总生存有相关性
编者按：克娄巴特拉（又译克利欧佩特拉）七世，世称埃及艳后，古埃及托勒密王朝末代女王。在大多数的描绘中，她是超级漂亮的美人，充满知性、美貌和性感，并且成功征服当时西方世界最有权势的男人。她被认为是为了保护国家免受罗马并吞，而色诱盖乌斯·尤利乌斯·恺撒大帝及他的继承者马克·安东尼。被基因泰克和罗氏用于命名帕妥珠单抗＋曲妥珠单抗＋多西他赛对比安慰剂＋曲妥珠单抗＋多西他赛用于初治HER2阳性转移性乳腺癌的Ⅲ期随机双盲临床研究（A phase III, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of pertuzumab + trastuzumab + docetaxel vs. placebo + trastuzumab + docetaxel in previously untreated HER2-positive metastatic breast cancer）。
2016年12月6日，英国《柳叶刀肿瘤学分册》在线发表墨尔本大学彼得·麦卡勒姆癌症中心、比利时安特卫普医院、布鲁塞尔自由大学朱尔·博尔代研究所、基因泰克、罗氏、乔治城大学隆巴迪综合癌症中心、纽约纪念斯隆凯特林癌症中心、巴黎-萨克雷大学旗下巴黎第十一大学的研究报告，对CLEOPATRA研究进行了回顾分析，重点分析了肿瘤浸润淋巴细胞与晚期HER2阳性乳腺癌患者生存的关系。
CLEOPATRA（NCT00567190）是一项随机Ⅲ期临床研究，对于局部复发、无法切除或转移性HER2阳性乳腺癌，在一线曲妥珠单抗＋多西他赛基础上，联合帕妥珠单抗能否改善患者生存。其中，曲妥珠单抗＋多西他赛＋帕妥珠单抗402例，曲妥珠单抗＋多西他赛＋安慰剂406例。中位随访50个月（四分位范围：41～54），曲妥珠单抗＋多西他赛＋帕妥珠单抗与曲妥珠单抗＋多西他赛＋安慰剂相比，中位无进展生存增加6.1个月（18.5比12.4），中位总生存增加15.7个月（56.5比40.8）。
本二次分析对治疗前采集的肿瘤组织间质标本肿瘤浸润淋巴细胞进行定量，并探讨了肿瘤浸润淋巴细胞与无进展生存、总生存、临床病理特征与帕妥珠单抗之间的关系。
患者入组时肿瘤组织标本即被采集用于后续研究，678例（84%）患者可行肿瘤浸润淋巴细胞分析，包括519例陈旧标本和155例新鲜采集标本（随机分组前≤45天），其余4例状态未知。可行肿瘤浸润淋巴细胞分析患者的中位年龄为54岁；高加索裔占58%，亚洲裔占34%，非洲裔占4%；雌激素受体阳性占48%，PIK3CA基因突变占22%；新辅助治疗占41%，新辅助曲妥珠单抗治疗占11%；79%的患者在检查时存在内脏转移；无进展生存事件519例，死亡358例。
结果发现，肿瘤浸润淋巴细胞中位值为10%（四分位范围：5～30），新鲜标本低于陈旧标本（10比15%，P=0.00036），雌激素受体阳性低于阴性（10%比15%），亚裔高于高加索裔和非洲裔（15%比10%比5%）。
肿瘤浸润淋巴细胞值与无进展生存无显著相关性（校正风险比：0.95，95%置信区间：0.90～1.00，P=0.063）；肿瘤浸润淋巴细胞值每增加10%，总生存显著延长11%（校正风险比：0.89，95%置信区间：0.83～0.96，P=0.0014）。
无论是新鲜标本还是陈旧标本，肿瘤浸润淋巴细胞对患者生存的影响独立存在，与治疗方案、雌激素受体状态、PIK3CA基因型等因素均无关。
肿瘤浸润淋巴细胞对帕妥珠单抗的治疗效果无显著影响，无进展生存（交互P=0.23）和总生存（交互P=0.21）无显著差异。同样，PIK3CA突变/野生以及未经治/经治亚组，结果依然如此。
根据肿瘤浸润淋巴细胞中位值≤10%和＞10%进行亚组分析，曲妥珠单抗＋多西他赛＋安慰剂、曲妥珠单抗＋多西他赛＋帕妥珠单抗的5年预计总生存率分别为26%比39%、42%比56%。
因此，当曲妥珠单抗＋多西他赛＋帕妥珠单抗治疗晚期HER2阳性乳腺癌时，肿瘤浸润淋巴细胞高与总生存改善有相关性，提示抗肿瘤免疫可扩展到晚期肿瘤。此类乳腺癌亚型的进一步临床研究应该考虑将肿瘤浸润淋巴细胞作为分层因素，并调查免疫增强疗法可否进一步改善生存的可能性。
对此，澳大利亚科廷大学医学院西澳乳腺癌研究中心的学者发表同期述评《转移性乳腺癌的肿瘤浸润淋巴细胞：没有惊喜，但有更多问题》。
Lancet Oncol. 2016 Dec 6. [Epub ahead of print]
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.
Luen SJ, Salgado R, Fox S, Savas P, Eng-Wong J, Clark E, Kiermaier A, Swain SM, Baselga J, Michiels S, Loi S.
Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia; GZA-Hospitals, Antwerp, Belgium; Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Genentech, South San Francisco, CA, USA; Roche Products, Welwyn, UK; Roche, Basel, Switzerland; Lombardi Comprehensive Cancer Centre, Georgetown University, Washington, DC, USA; Memorial Sloan Kettering Cancer Center, New York, NY, USA; Université-Paris Sud, Université Paris-Saclay, Villejuif, France.
Background: 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.
Methods: 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.
Findings: 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).
Interpretation: 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.
Funding: F Hoffmann-La Roche-Genentech and the Breast Cancer Research Foundation.
PMID: 27964843
DOI: 10.1016/S1470-2045(16)30631-3
Lancet Oncol. 2016 Dec 6. [Epub ahead of print]
TILs in metastatic breast cancer - no surprises, but more questions.
Chan A.
Breast Cancer Research Centre-WA and School of Medicine, Curtin University, Nedlands, WA 6009, Australia.
PMID: 27964844
DOI: 10.1016/S1470-2045(16)30637-4