为三阴性乳腺癌提供靶向治疗机会

　　乳腺癌易感基因BRCA1和BRCA2是重要的抑癌基因，一旦发生致病突变，容易引起三阴性乳腺癌等恶性肿瘤。多腺苷二磷酸核糖聚合酶（PARP）抑制剂可改善BRCA突变乳腺癌患者的预后，但是既往研究显示，桑格测序或二代测序仅能发现BRCA点突变、小片段插入或缺失，而BRCA大片段改变常被遗漏，这需要进一步多重链接依赖探针扩增技术（MLPA）重复分析。因此，在临床实践中应对BRCA检测结果进行MLPA复验，以避免BRCA大片段缺失患者错过最佳治疗手段和时机。

　　2022年2月14日，美国休斯顿大学药物研究所主编的《当代抗癌药物靶点》在线发表中国医学科学院肿瘤医院王雪、胡南林、司怡然、岳健、郑方超、康一坤、袁芃等学者的病例报告，分享了一例携带BRCA基因大片段缺失的乳腺癌患者多次复发诊治经过和文献回顾。

　　患者女性，37岁，2011年7月出现右乳房肿块，诊断为三阴性乳腺癌（雌激素受体、孕激素受体和HER2免疫组化均为阴性）。患者接受了手术及术后化放疗，之后定期复查。2014年7月，患者又出现左乳房肿块，病理仍然提示为三阴性乳腺癌，再次接收了手术治疗及术后化放疗。

　　2017年7月，患者胸部CT提示右肺中叶新发孤立性病灶，手术切除后病理显示乳腺癌肺转移（三阴性）。

2017年7月，胸部CT显示肺转移瘤

　　术后1月，患者因头痛，语言障碍和活动障碍，行脑磁共振检查，发现左额叶转移瘤。2017年8月，行左侧额叶肿物切除术，病理为乳腺癌脑转移（三阴性），术后患者进行了额叶术后瘤床区放疗。

2017年8月，脑磁共振显示额叶转移瘤

　　患者多次出现肿瘤复发，故行二代测序，但是结果未发现致病突变，后续进一步行MLPA重复分析，结果显示：种系BRCA1基因2号外显子大片段缺失，为致病突变，同时伴体系BRCA2和STARD13重排和RAD51拷贝数缺失。BRCA2和STARD13变异导致BRCA2蛋白羧基端缺失，可能也具有致病性。DNA同源重组缺陷评分67分。

　　自2017年9月起，患者开始口服PARP抑制剂奥拉帕利（300毫克，每天2次），定期复查，至今疾病控制稳定。

2022年3月，脑磁共振显示额叶转移瘤治疗后改变

治疗过程

　　因此，该肺转移及脑转移的三阴性乳腺癌患者，最初的基因检测并未显示BRCA基因突变，但是经过MLPA进一步分析，发现患者携带BRCA大片段缺失和重排，且为致病性，接受奥拉帕利单药治疗后实现了长期无病生存，至今超过54个月。这是目前首例BRCA1合并BRCA2和STARD13大片段基因改变并对PARP抑制剂显著获益的病例，故临床医师需全面评估患者BRCA状态（包括大片段改变）以指导PARP抑制剂靶向治疗。

Curr Cancer Drug Targets. 2022 Feb 14. Online ahead of print.

Durable Disease-Free Survival in a Patient with Metastatic Triple-Negative Breast Cancer Treated With Olaparib Monotherapy.

Wang X, Hu N, Cui L, Si Y, Yue J, Zheng F, Kang Y, Yuan P.

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 3D Medicines Inc, Shanghai, China.

BACKGROUND: Metastatic triple-negative breast cancer (mTNBC) has a poor prognosis and few effective targeted therapy options. Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has been granted accelerated approval by FDA for patients with deleterious BRCA-mutated human epidermal growth factor receptor 2 (HER2)-negative advanced/metastatic breast cancer. However, there is few evidence demonstrating that patients with particular forms of germline and/or somatic BRCA1/2, such as large fragment variation, can benefit from PARP inhibitors.

CASE PRESENTATION: In 2011, a 40-year-old woman was diagnosed with TNBC having pT2N0M0 in the right breast, and a new irregular lesser tubercle in the left breast appeared after approximately 3 years, which was also diagnosed as TNBC. In 2017, the computed tomography (CT) showed TNBC metastases to lung and brain. A next-generation sequencing (NGS) was performed with lung metastasis sample and results showed a homologous recombination deficiency (HRD) score of 67, a germline large deletion of exon 2 in BRCA1, a novel somatic BRCA2-STARD13 rearrangement and copy number loss of RAD51. Since September 2017, the patient was treated with olaparib. Till the report date of this case, the patient underwent regular follow-up without disease recurrence.

CONCLUSION: To our knowledge, this is the first case describing a patient with lung- and brain-metastatic TNBC with combined germline and somatic large rearrangement and a high HRD score who achieved a long-term benefit from olaparib monotherapy. The use of NGS is promising in the treatment of TNBC in clinical practice.

KEYWORDS: BRCA1/2 rearrangement; HRD positive; PARP inhibitor; long-term disease-free survival.; metastatic triple-negative breast cancer; olaparib

PMID: 35156571

DOI: 10.2174/1568009622666220214092207