2014年6月2日，梅奥诊所与Caris生命科学合作的一项新研究指出，免疫治疗可能是难治性三阴性乳腺癌治疗的一种可行性选择。该研究发布于在芝加哥举行的第50届美国临床肿瘤年会“Oral Abstract”专场。

该研究可能会改变我们对三阴性乳腺癌患者的治疗。该研究的主要研究者、梅奥诊所外科医生Barbara Pockaj说。有迹象表明，免疫治疗可能对这些患者有效。对于这些患者，我们没有太多的治疗选择，而这将真正扩展我们的治疗选择。

三阴性乳腺癌是一种侵袭性强的乳腺癌，可以逃避免疫系统的查杀。因为其缺少雌激素受体、孕激素受体和HER2基因的表达。这限制了其治疗的选择。该研究检测了涉及免疫逃避的生物标志物，包括PD-L1和其与其他生物通路的联合作为可能的治疗选择。拥有PD-L1基因的其他癌症的患者已经开始使用免疫治疗来增强机体的免疫系统，其中一些结果非常具有戏剧性。Pockaj医生说。

这是非常重要的，因为免疫治疗正成为癌症患者的一种有效的治疗。她说。我们已经看到黑色素瘤、肾细胞癌甚至肺癌的患者的免疫治疗取得了显著的成果。问题是，我们能否拓展这一类型的乳腺癌患者的治疗选择。

该研究应用了多种方法对511位三阴性乳腺癌患者进行了分析，包括整个基因组mRNA的表达、蛋白质的表达、基因拷贝数的变化和基因测序。该研究发现，25%-30%的患者拥有PD-L1基因，这意味着这些患者可以应用免疫治疗。有人认为，拥有BRCA1基因的患者所占的百分比更高，该基因可以产生肿瘤抑制蛋白。但是该结果需要进一步调查研究，他们阐明了分子表达谱如何用于发现三阴性乳腺癌和其他难治性癌症的治疗靶点。

我们现在想做一些研究来判断那些PD-L1过度表达的患者的DNA修复基因是否发生了改变。Pockaj医生说。如果既有PD-L1过度表达，又有DNA修复基因的改变，那就提示免疫治疗+化疗可能有效。

编译自：Immunotherapy May Be an Option in Challenging Breast Cancer, Mayo Clinic Study Finds.newswise,June 2,2014.

医脉通整理报道，转载请注明出处。

会议专题》》》2014年ASCO年会专题报道

阅读英文摘要

Expression of novel immunotherapeutic targets in triple-negative breast cancer.（Abstract No:1001）

Authors: Gargi Dan Basu, Anatole Ghazalpour,Barbara A. Pockaj, et al.

Session Type: Oral Abstract Session

Background: Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that lacks expression of ER, PR and HER2. Targeted treatment options for TNBC are limited, and novel potential molecular targets need to be evaluated. This study examined biomarkers involved in immune evasion including PD-L1 and its association with other biological pathways as potential treatment options for TNBC patients. 

Methods: We analyzed 511 TNBC samples using a multiplatform approach including whole genome mRNA expression (HumanHT-12 v4 BeadChip Illumina Inc., San Diego, CA), protein expression (immunohistochemistry), gene copy number changes (in situ hybridization) and gene sequencing. PD-L1 IHC was performed on 22 samples. 

Results: Within the TNBC patient cohort, there were subsets with elevated mRNA expression of immune markers including PD-L1, CTLA4, IDO1 and B7-H3. Cancer cell-specific over-expression of PD-L1 protein was present in 50% of TNBC tumors. Androgen receptor (AR) was over-expressed in 17% of the TNBC cohort and AR-negative TNBC patients were more likely to express PD-L1 (p =.05), CTLA-4 (p =.001), and IDO1 (p = 2.8e-05). Spearman correlation test showed a positive correlation of PD-L1 with CTLA-4 (0.52), IDO1 (0.48), PIK3CA (0.39), and PTEN (0.11). Differential expression analysis between high and low PD-L1 expressing tumors identified 144 genes. Pathway analysis of the 144 genes indicated significant enrichment of DNA repair genes. Consistent with these findings, PD-L1 expression was negatively associated with BRCA1 expression (p=0.001) and positively correlated with HUS1 and FANCA expression (p=8e-13). 

Conclusions: The expression of immune regulatory targets in the TNBC population suggests that immune- targeted therapies may be effective in subsets of TNBC. This is particularly true for patients with AR-negative TNBCs who may benefit from PD-L1 and CTLA-4 targeted therapies. The positive correlation of PIK3CA and PD-L1 may indicate that combination therapy targeting both pathways may be beneficial. In addition, the inverse correlation of BRCA1 with PD-L1 suggests a potential role for platinum-based therapy in combination with anti-PD-L1. Further prospective validation of these findings is ongoing.

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