Breast cancer brain metastases show increased levels of genomic aberration-based homologous recombination deficiency scores relative to their corresponding primary tumors.
Breast cancer brain metastases show increased levels of genomic aberration-based homologous recombination deficiency scores relative to their corresponding primary tumors.
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DOI：
10.1093/annonc/mdy216
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发表时间：
2018-09-01
期刊：
影响因子：
--
通讯作者：
Szallasi Z
中科院分区：
文献类型：
--
作者：
Diossy M;Reiniger L;Sztupinszki Z;Krzystanek M;Timms KM;Neff C;Solimeno C;Pruss D;Eklund AC;Tóth E;Kiss O;Rusz O;Cserni G;Zombori T;Székely B;Kulka J;Tímár J;Csabai I;Szallasi Z
根据其作用机制，PARP抑制剂疗法预计将主要使具有同源重组缺陷（HRD）的肿瘤病例受益。因此，鉴定 HRD 增加的肿瘤类型对于此类治疗药物的最佳使用非常重要。可以使用下一代测序数据中的各种突变特征来估计 HRD 水平，我们使用这种方法来确定乳腺癌脑转移相对于相应的原发肿瘤是否显示出 HRD 评分水平的改变。我们使用之前发布的 21 个匹配的原发性乳腺癌/脑转移对的下一代测序数据集来得出与 HRD 密切相关的各种突变特征/HRD 评分。我们还对 17 名具有匹配的原发/脑转移对的乳腺癌患者的独立队列进行了 myChoice HRD 分析。在之前发布的全外显子组测序数据集中，所有表明 HRD 的突变特征均显示，相对于其匹配的原发肿瘤，脑转移灶显着增加。在独立验证队列中，myChoice HRD 检测显示 87.5% 的脑转移瘤相对于原发肿瘤的水平有所增加，根据 myChoice 标准，56% 的脑转移瘤呈 HRD 阳性。乳腺癌脑转移往往具有较高 HRD 测量值的一致观察结果可能会增加脑转移可能对 PARP 抑制剂治疗更敏感的可能性。这一观察结果值得进一步研究，以评估这种增加是否也常见于其他转移部位，以及临床试验是否应该调整其应用 HRD 措施的策略，以优先考虑患者接受 PARP 抑制剂治疗。
Based on its mechanism of action, PARP inhibitor therapy is expected to benefit mainly tumor cases with homologous recombination deficiency (HRD). Therefore, identification of tumor types with increased HRD is important for the optimal use of this class of therapeutic agents. HRD levels can be estimated using various mutational signatures from next generation sequencing data and we used this approach to determine whether breast cancer brain metastases show altered levels of HRD scores relative to their corresponding primary tumor. We used a previously published next generation sequencing dataset of 21 matched primary breast cancer/brain metastasis pairs to derive the various mutational signatures/HRD scores strongly associated with HRD. We also carried out the myChoice HRD analysis on an independent cohort of 17 breast cancer patients with matched primary/brain metastasis pairs. All of the mutational signatures indicative of HRD showed a significant increase in the brain metastases relative to their matched primary tumor in the previously published whole exome sequencing dataset. In the independent validation cohort, the myChoice HRD assay showed an increased level in 87.5% of the brain metastases relative to the primary tumor, with 56% of brain metastases being HRD positive according to the myChoice criteria. The consistent observation that brain metastases of breast cancer tend to have higher HRD measures may raise the possibility that brain metastases may be more sensitive to PARP inhibitor treatment. This observation warrants further investigation to assess whether this increase is common to other metastatic sites as well, and whether clinical trials should adjust their strategy in the application of HRD measures for the prioritization of patients for PARP inhibitor therapy.
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影响因子：
28.2
作者：
Birkbak NJ;Wang ZC;Kim JY;Eklund AC;Li Q;Tian R;Bowman-Colin C;Li Y;Greene-Colozzi A;Iglehart JD;Tung N;Ryan PD;Garber JE;Silver DP;Szallasi Z;Richardson AL
通讯作者：
Richardson AL
DOI：
10.1093/annonc/mdu479
发表时间：
2015-01
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Favero F;Joshi T;Marquard AM;Birkbak NJ;Krzystanek M;Li Q;Szallasi Z;Eklund AC
通讯作者：
Eklund AC
影响因子：
2.8
作者：
Quigley, Matthew R.;Fukui, Olivia;Karlovits, Steven
通讯作者：
Karlovits, Steven
影响因子：
82.9
作者：
Davies H;Glodzik D;Morganella S;Yates LR;Staaf J;Zou X;Ramakrishna M;Martin S;Boyault S;Sieuwerts AM;Simpson PT;King TA;Raine K;Eyfjord JE;Kong G;Borg Å;Birney E;Stunnenberg HG;van de Vijver MJ;Børresen-Dale AL;Martens JW;Span PN;Lakhani SR;Vincent-Salomon A;Sotiriou C;Tutt A;Thompson AM;Van Laere S;Richardson AL;Viari A;Campbell PJ;Stratton MR;Nik-Zainal S
通讯作者：
Nik-Zainal S
影响因子：
14.9
作者：
Costello M;Pugh TJ;Fennell TJ;Stewart C;Lichtenstein L;Meldrim JC;Fostel JL;Friedrich DC;Perrin D;Dionne D;Kim S;Gabriel SB;Lander ES;Fisher S;Getz G
通讯作者：
Getz G