Clinicopathologic and Genomic Landscape of Breast Carcinoma Brain Metastases
Clinicopathologic and Genomic Landscape of Breast Carcinoma Brain Metastases
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DOI：
10.1002/onco.13855
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发表时间：
2021-06-23
期刊：
影响因子：
5.8
通讯作者：
Ramkissoon, Shakti H.
中科院分区：
文献类型：
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作者：
Huang, Richard S. P.;Haberberger, James;Ramkissoon, Shakti H.
在有转移性疾病的乳腺癌患者中，15%-30%最终会发生脑转移。我们研究了一大批乳腺癌脑转移（BCBMs）患者的基因组图谱，并将其与原发性乳腺癌（BCs）患者进行了比较。材料和方法我们回顾性分析了733例经综合基因组图谱（CGP）检测的BCBMs，并将其与10772例原发性乳腺癌（非配对）标本进行了比较。对于16例三阴性乳腺癌（TNBC）脑转移样本，同时进行程序性死亡-配体1 （PD-L1）免疫组织化学（IHC）。结果共分析733例连续脑卒中患者。与原发性bc相比，BCBMs中TP53（72.0%, 528/733）、ERBB2（25.6%, 181 /733）、RAD21（14.1%, 103/733）、NF1（9.0%, 66/733）、BRCA1（7.8%, 57/733）和ESR1（6.3%,46/733）的基因组改变丰富（所有比较p < 0.05）。免疫检查点抑制剂生物标志物，如高肿瘤突变负担（TMB-high; 16.2%, 119/733）；微卫星高不稳定性（1.9%,14/733）；CD274扩增（3.6%,27/733）；载脂蛋白B mRNA编辑酶、催化多肽样突变特征（5.9%,43/733）在BCBM队列中显著高于原发性BC队列（所有比较p < 0.05）。当同时使用CGP和PD-L1免疫组化时，37.5%（6/16）的TNBC脑转移患者符合基于PD-L1免疫组化的atezolizumab， 18.8%（3/16）的TNBC脑转移患者符合基于TMB-high状态的pembrolizumab。结论：我们发现BCBM患者中临床相关基因组改变的发生率很高，这表明除了原发肿瘤的CGP外，CGP的组织获取（手术）和/或脑脊液治疗可能在临床上是有必要的。本研究发现乳腺癌脑转移（BCBM）患者中临床相关基因组改变的发生率很高，这表明除了原发肿瘤的CGP外，组织采集（手术）和/或脑脊液综合基因组分析（CGP）可能在临床上是有必要的。此外，该研究还发现，CGP在BCBM患者中检测到的fda批准的免疫治疗生物标志物的阳性率更高，这为新的标签治疗开辟了可能性。最后，本研究指出肿瘤突变负担与PD-L1免疫组化（IHC）之间的有限相关性，这表明用PD-L1免疫组化和CGP检测三阴性BCBM患者免疫检查点抑制剂资格的重要性。
Background Among patients with breast carcinoma who have metastatic disease, 15%-30% will eventually develop brain metastases. We examined the genomic landscape of a large cohort of patients with breast carcinoma brain metastases (BCBMs) and compared it with a cohort of patients with primary breast carcinomas (BCs). Material and Methods We retrospectively analyzed 733 BCBMs tested with comprehensive genomic profiling (CGP) and compared them with 10,772 primary breast carcinomas (not-paired) specimens. For a subset of 16 triple-negative breast carcinoma (TNBC)-brain metastasis samples, programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) was performed concurrently. Results A total of 733 consecutive BCBMs were analyzed. Compared with primary BCs, BCBMs were enriched for genomic alterations in TP53 (72.0%, 528/733), ERBB2 (25.6%, 188/733), RAD21 (14.1%, 103/733), NF1 (9.0%, 66/733), BRCA1 (7.8%, 57/733), and ESR1 (6.3%,46/733) (p < .05 for all comparisons). Immune checkpoint inhibitor biomarkers such as high tumor mutational burden (TMB-high; 16.2%, 119/733); high microsatellite instability (1.9%, 14/733); CD274 amplification (3.6%, 27/733); and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like mutational signature (5.9%, 43/733) were significantly higher in the BCBM cohort compared with the primary BC cohort (p < .05 for all comparisons). When using both CGP and PD-L1 IHC, 37.5% (6/16) of patients with TNBC brain metastasis were eligible for atezolizumab based on PD-L1 IHC, and 18.8% (3/16) were eligible for pembrolizumab based on TMB-high status. Conclusion We found a high prevalence of clinically relevant genomic alterations in patients with BCBM, suggesting that tissue acquisition (surgery) and/or cerebrospinal fluid for CGP in addition to CGP of the primary tumor may be clinically warranted. Implications for Practice This study found a high prevalence of clinically relevant genomic alterations in patients with breast carcinoma brain metastasis (BCBM), suggesting that tissue acquisition (surgery) and/or cerebrospinal fluid for comprehensive genomic profiling (CGP) in addition to CGP of the primary tumor may be clinically warranted. In addition, this study identified higher positive rates for FDA-approved immunotherapy biomarkers detected by CGP in patients with BCBM, opening a possibility of new on-label treatments. Last, this study noted limited correlation between tumor mutational burden and PD-L1 immunohistochemistry (IHC), which shows the importance of testing patients with triple-negative BCBM for immune checkpoint inhibitor eligibility with both PD-L1 IHC and CGP.