Metastatic triple-negative breast cancer patient with TP53 tumor mutation experienced 11 months progression-free survival on bortezomib monotherapy without adverse events after ending standard treatments with grade 3 adverse events.
Metastatic triple-negative breast cancer patient with TP53 tumor mutation experienced 11 months progression-free survival on bortezomib monotherapy without adverse events after ending standard treatments with grade 3 adverse events.
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DOI：
10.1101/mcs.a001677
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发表时间：
2017-07
影响因子：
1.8
通讯作者：
Forster M
中科院分区：
文献类型：
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作者：
Meißner T;Mark A;Williams C;Berdel WE;Wiebe S;Kerkhoff A;Wardelmann E;Gaiser T;Müller-Tidow C;Rosenstiel P;Arnold N;Leyland-Jones B;Franke A;Stanulla M;Forster M
三阴性乳腺癌患者没有遗传性BRCA1，BRCA2或TP53风险变异。在标准治疗耗尽后，她接受了实验性治疗和肿瘤，血液和转移的全外显子组测序。给予耐受性良好的实验性硼替佐米单药治疗11个月的无进展期。进展后，改变治疗方法，评估外显子组数据，用晚期转移的RNA和外显子组测序进行扩增。在最后阶段，给予单独的艾日布林和与蒽环类药物的组合。在遭受3级不良事件的同时，皮肤转移进展。她在初步诊断后存活了51个月。蒽环类和顺铂的毒性可能分别是由于相关的生殖系变体CBR3 C4 Y和V224 M以及GSTP1 I105 V。在肿瘤组织中检测到38个预测或报告为致病性的体细胞突变。所有的肿瘤样本都含有杂合的TP53 Y220C变异体，已知该变异体使p53不稳定并下调p53介导的细胞凋亡。硼替佐米的成功可能是由先前报道的半胱天冬酶介导的细胞凋亡的上调，这是p53非依赖性的解释。血液、原发性肿瘤和两个转移瘤的系统发育分析推断出具有12个表达的肿瘤突变的祖先肿瘤细胞，所有三种肿瘤可能都是从该肿瘤细胞进化而来的。虽然我们的第一次紧急分析只能包括40个基因，但尸检分析揭示了侵略性，并提出了包括16个可操作目标的实验疗法，部分通过免疫组织化学验证。外显子组和转录组分析产生了全面的治疗相关信息，应在首次诊断时考虑患者。
A triple-negative breast cancer patient had no hereditary BRCA1, BRCA2, or TP53 risk variants. After exhaustion of standard treatments, she underwent experimental treatments and whole-exome sequencing of tumor, blood, and a metastasis. Well-tolerated experimental bortezomib monotherapy was administered for a progression-free period of 11 mo. After progression, treatments were changed and the exome data were evaluated, expanded with RNA and exome sequencing of a late-stage metastasis. In the final stage, eribulin alone and in combination with anthracyclines were administered. While suffering from grade 3 adverse events, skin metastases progressed. She lived 51 mo after initial diagnosis. Toxicity from anthracyclines and cisplatin may have been due to associated germline variants CBR3 C4Y and V224M and GSTP1 I105V, respectively. Somatic mutations predicted or reported as pathogenic were detected in 38 genes in tumor tissues. All tumor samples harbored the heterozygous TP53 Y220C variant, known to destabilize p53 and down-regulate p53-mediated apoptosis. The success of bortezomib may be explained by the previously reported up-regulation of caspase-mediated apoptosis, which is p53-independent. Phylogenetic analysis of blood, primary tumor, and two metastases inferred an ancestral tumor cell with 12 expressed tumor mutations from which all three tumors may have evolved. Although our first urgent analysis could only include 40 genes, postmortem analysis uncovered the aggressiveness and suggested experimental therapies including 16 actionable targets, partly validated by immunohistochemistry. Exome and transcriptome analyses yielded comprehensive therapy-relevant information and should be considered for patients at first diagnosis.