Tumor BRCA1 Reversion Mutation Arising during Neoadjuvant Platinum-Based Chemotherapy in Triple-Negative Breast Cancer Is Associated with Therapy Resistance.
Tumor BRCA1 Reversion Mutation Arising during Neoadjuvant Platinum-Based Chemotherapy in Triple-Negative Breast Cancer Is Associated with Therapy Resistance.
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DOI：
10.1158/1078-0432.ccr-16-2174
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发表时间：
2017-07-01
期刊：
影响因子：
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通讯作者：
Telli ML
中科院分区：
文献类型：
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作者：
Afghahi A;Timms KM;Vinayak S;Jensen KC;Kurian AW;Carlson RW;Chang PJ;Schackmann E;Hartman AR;Ford JM;Telli ML
在生殖系BRCA 1或BRCA 2（BRCA 1/2）突变携带者中，通过继发突变恢复肿瘤BRCA 1/2功能被认为是对铂和PARP抑制剂耐药的机制，主要发生在卵巢癌中。我们在新诊断的BRCA 1/2突变乳腺癌患者中评估了这种耐药机制，这些患者对新辅助铂类药物治疗反应较差。PrECOG 0105是一项在I-IIIA期三阴性或BRCA 1/2突变相关乳腺癌患者中进行的吉西他滨、卡铂和iniparib的II期新辅助治疗研究（n=80）。所有患者均接受了全面的BRCA 1/2基因分型。对于新辅助治疗后具有中度或广泛残留疾病的突变携带者，在残留的手术乳腺肿瘤组织中重新测序BRCA 1/2状态。19例患者有有害的生殖系BRCA 1/2突变，4例在手术时有中度残留疾病。对3名患者进行了残留组织的BRCA 1/2测序。这些患者分别具有BRCA 1 1479 delAG、3374 insGA和W1712 X突变，在治疗前肿瘤中这些基因座处具有杂合性丢失。在第一个病例中，在残留疾病中检测到新的BRCA 1突变。这导致14个氨基酸的缺失和BRCA 1阅读框的恢复。四个月后局部复发活检显示相同的回复突变，患者随后死于转移性乳腺癌。我们报告了一例新诊断的三阴性乳腺癌患者的BRCA 1回复突变，该患者接受了超过18周的铂类新辅助治疗。这与治疗反应差、早期复发和死亡有关。
In germline BRCA1 or BRCA2 (BRCA1/2) mutation carriers, restoration of tumor BRCA1/2 function by a secondary mutation is recognized as a mechanism of resistance to platinum and PARP inhibitors, primarily in ovarian cancer. We evaluated this mechanism of resistance in newly diagnosed BRCA1/2-mutant breast cancer patients with poor response to neoadjuvant platinum-based therapy. PrECOG 0105 was a phase II neoadjuvant study of gemcitabine, carboplatin and iniparib in patients with stage I-IIIA triple-negative or BRCA1/2 mutation-associated breast cancer (n=80). All patients underwent comprehensive BRCA1/2 genotyping. For mutation carriers with moderate or extensive residual disease after neoadjuvant therapy, BRCA1/2 status was re-sequenced in the residual surgical breast tumor tissue. Nineteen patients had a deleterious germline BRCA1/2 mutation and 4 had moderate residual disease at surgery. BRCA1/2 sequencing of residual tissue was performed on three patients. These patients had BRCA1 1479delAG, 3374insGA and W1712X mutations, respectively, with loss of heterozygosity at these loci in the pre-treatment tumors. In the first case, a new BRCA1 mutation was detected in the residual disease. This resulted in a 14 amino acid deletion and restoration of the BRCA1 reading frame. A local relapse biopsy four months later revealed the identical reversion mutation, and the patient subsequently died of metastatic breast cancer. We report a BRCA1 reversion mutation in a newly diagnosed triple-negative breast cancer patient that developed over 18 weeks of platinum-based neoadjuvant therapy. This was associated with poor therapy response, early relapse and death.