大部分肌层浸润型膀胱癌（MIBC）患者在接受辅助性顺铂为基础的化疗（NAC）时往往会出现耐药性而无法根治，或再接受根治性膀胱切除术进行治疗。NAC后肿瘤细胞基因的改变或许可以帮助我们了解基因性的耐药机制并且帮助我们寻找到新的治疗策略。该研究发表于ASCO的2016年会，摘要号为4518。

研究人员从31名MIBC患者中获取到NAC治疗前后的肿瘤细胞样本并进行配对，随后进行全外显子测序（whole exome sequencing）。应用线性回归分析对样本之间纯度等方面的差异进行调整。应用串行肿瘤活检的系统进化分析法识别治疗之后出现的遗传物质的改变或缺失。

研究人员在NAC治疗后的肿瘤样本中发现了大范围的变异（5-81%，中位=31%）以及新型肿瘤抗原（4-77%，中位=32%），这些改变在NAC治疗前的肿瘤样本中未观测到。在对样本纯度差异进行调整之后，未见NAC疗法后样本在突变或新型肿瘤抗原负荷的显著有统计学意义的改变。但是，改变明显与NAC治疗前突变与肿瘤抗原水平有关（R²=0.44，p<0.0001；R²=0.40，p=0.0002）：基线水平更高的肿瘤样本降低的更明显。10名患者（32%）的潜在可改变基因发生了改变，包括PIK3CA和MTOR基因；同时在NAC前后的肿瘤样本中未发现单一基因的非同义突变。

这些结果暗示NAC减少现存的突变和肿瘤抗原的负荷并同时揭示新型变异和肿瘤抗原。该结果的产生可能与终止不适合的基因复制并经DNA损伤诱导产生新型突变有关。

会议专题》》》2016年ASCO年会专题报道

摘要原文：

Background: The majority of patients with muscle-invasive bladder cancer (MIBC) treated with neoadjuvant cisplatin-based chemotherapy (NAC) have residual disease at time of cystectomy. Changes in the tumor genomic landscape after NAC may inform genetic resistance patterns and treatment strategies. 

Methods: Matched pre- and post-NAC tumor samples were obtained from 31 patients with MIBC who had gross residual disease (≥ pT2) at cystectomy, followed by whole exome sequencing of these “trios” (pre- and post-NAC tumor with matched germline samples). Linear regression was used to adjust for differences in sample purity and predict changes in mutation and neoantigen burden from pre- to post-NAC. Phylogenetic analysis of serial tumor biopsies was performed to identify alterations gained or lost after treatment. 

Results: A wide proportion of mutations (5-81%, median = 31%) and neoantigens (4-77%, median = 32%) in the post-NAC tumor were not seen in the matched pre-NAC tumor. After adjusting for differences in sample purity, there was no statistically significant overall change in the mutational or neoantigen burden post-NAC (mean = -0.67 mut/Mb [p = 0.06] and -0.88 neoantigens/Mb [p = 0.10] respectively), but the change was strongly associated with pre-NAC mutation and neoantigen levels (R2= 0.44, p < 0.0001; R2= 0.40, p = 0.0002 respectively): tumors with higher baseline levels experienced greater decreases. While no single gene was significantly enriched for nonsynonymous mutations exclusively in pre- or post-NAC samples, 32% (10/31) of patients had either a gain or loss of alterations in potentially actionable genes, including PIK3CA and MTOR. Four post-NAC tumors harbored focal E2F3 amplification, including one acquired after NAC. 

Conclusions: These results suggest that NAC decreases pre-existing mutation and neoantigen burden while simultaneously revealing new mutations and neoantigens. This may occur by elimination of less fit subclones and induction of new mutations from DNA damage.