晚期三阴性乳腺癌的基因靶向化疗
编者按：最早发现的两个乳腺癌易感基因（BRCA）被命名为BRCA1和BRCA2，通常用于预测乳腺癌的发生风险。生殖细胞的BRCA突变通过妨碍同源重组引起基因组不稳定，可使人体容易发生乳腺癌，被之称为种系BRCA突变乳腺癌。对于已经发生乳腺癌的患者，同源重组还可修复由铂类药物和多腺苷二磷酸核糖聚合酶（PARP）抑制剂引起的DNA损伤，故BRCA突变的三阴性乳腺癌被认为可能对铂类特别敏感。此外，BRCAness亚组乳腺癌，包括BRCA1甲基化、BRCA1信使核糖核酸（mRNA）低表达、同源重组缺陷突变特征、基底样表现型也被认为可能对铂类敏感。
2018年5月，英国《自然》旗下《自然医学》正式发表英国伦敦癌症研究院、皇家马斯登医院、伦敦国王学院、盖伊和圣托马斯医院、韦林德癌症中心、苏格兰西部癌症中心、伦敦帝国学院、诺丁汉大学医院、梅德斯通和滕布里奇韦尔斯医院、威斯顿帕克医院、弗朗西斯克里克研究院、伦敦大学学院医院、国家卫生研究院生物医学研究中心、曼彻斯特大学健康科学中心、曼彻斯特克里斯蒂医院、美国麦利亚德基因、北卡罗来纳大学、旧金山加利福尼亚大学的随机对照3期临床研究报告，通过分析种系BRCA突变乳腺癌和BRCAness亚组生物标志与治疗的相互影响，评定了卡铂和多西他赛对未经选择晚期三阴性乳腺癌患者的有效性。
该随机对照3期研究（TNT）共入组未经选择的晚期转移性三阴性乳腺癌患者376例，其中，种系BRCA突变乳腺癌患者43例（BRCA1突变31例、BRCA2突变12例）。将按1∶1随机分配接受卡铂（188例）或多西他赛（188例），主要研究终点为客观缓解率。
结果发现，卡铂与多西他赛相比，客观缓解率相似（59例比64例，31.4%比34.0%，绝对差：-2.6%，95%置信区间：-12.1～6.9，P=0.66），药物相关严重不良事件较少（102例比174例）。
相比之下，对于种系BRCA突变乳腺癌患者，卡铂25例与多西他赛18例相比，客观缓解率高一倍（17例比6例，68%比33%，绝对差：34.7%，95%置信区间：6.3～63.1，P=0.03；生物标志与治疗相互影响分析，P=0.01）。BRCA1甲基化、BRCA1 mRNA低表达、同源重组缺陷评分高的三阴性乳腺癌患者，并未见此获益。非基底与基底样亚型相比，多西他赛的缓解率显著较高。
因此，根据BRCA是否突变，可以预测晚期转移性三阴性乳腺癌患者能否获益，但是无法通过BRCA1甲基化、BRCA1 mRNA表达、同源重组缺陷分析选择铂类化疗。此外，基底样乳腺癌基因表达分析也可能影响治疗选择。原发性与转移性乳腺癌的DNA修复通路功能缺陷可能发生变化，这可以解释为什么该研究BRCA1表观遗传失调并未使乳腺癌对铂类更敏感。目前尚无证据检测BRCA1甲基化乳腺癌，但是需要考虑进一步评定基因表达谱以定义亚型，因为铂类似乎仅有依据用于基底样三阴性乳腺癌。该研究产生的数据足以改变实践，目前已将卡铂作为对BRCA突变乳腺癌非常有效的药物。有必要在早期三阴性乳腺癌新辅助治疗研究中，对卡铂的晚期三阴性乳腺癌研究数据检验。
对此，哈佛大学医学院达纳法伯癌症研究所发表同期评论：预测乳腺癌治疗效果。2018年5月24日，英国《柳叶刀》肿瘤学分册在线发表新闻报道：卡铂对BRCA突变乳腺癌的效果。
Nat Med. 2018 May;24(5):628-637.
Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial.
Tutt A, Tovey H, Cheang MCU, Kernaghan S, Kilburn L, Gazinska P, Owen J, Abraham J, Barrett S, Barrett-Lee P, Brown R, Chan S, Dowsett M, Flanagan JM, Fox L, Grigoriadis A, Gutin A, Harper-Wynne C, Hatton MQ, Hoadley KA, Parikh J, Parker P, Perou CM, Roylance R, Shah V, Shaw A, Smith IE, Timms KM, Wardley AM, Wilson G, Gillett C, Lanchbury JS, Ashworth A, Rahman N, Harries M, Ellis P, Pinder SE, Bliss JM.
The Institute of Cancer Research, London, UK; King's College London, Guy's Hospital, London, UK; King's College London, London, UK; Velindre Cancer Centre, Cardiff, UK; Beatson West of Scotland Cancer Centre, Glasgow, UK; Imperial College London, London, UK; Nottingham University Hospitals NHS Trust, Nottingham, UK; Royal Marsden Hospital, London, UK; Myriad Genetics, Inc., Salt Lake City, UT, USA; Maidstone and Tunbridge Wells NHS Trust, Kent, UK; Weston Park Hospital, Sheffield, UK; University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Guy's and St Thomas' Hospitals NHS Foundation Trust, London, UK; Francis Crick Institute, London, UK; University College London Hospitals NHS Foundation Trust and NIHR University College London Hospitals Biomedical Research Centre, London, UK; Guy's and St Thomas' NHS Foundation Trust, London, UK; The Royal Marsden NHS Foundation Trust, London, UK; Manchester Academic Health Science Centre, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK; University of California, San Francisco, San Francisco, USA; Guy's and St Thomas Foundation Trust, London, UK.
Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative 'BRCAness' subgroups-tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes-may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker-treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P=0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P=0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection.
PMID: 29713086
DOI: 10.1038/s41591-018-0009-7
Nat Med. 2018 May;24(5):535-537.
Predicting breast cancer therapeutic response.
Garrido-Castro AC, Winer EP.
Dana-Farber Cancer Institute, Boston, MA, USA.
In triple-negative breast cancer, therapeutic response to carboplatin and docetaxel is similar. However, carboplatin therapy is superior to docetaxel in patients with germline BRCA1 or BRCA2 mutations, but 'BRCAness' does not predict sensitivity to carboplatin.
PMID: 29736021
DOI: 10.1038/s41591-018-0033-7
Lancet Oncol. 2018 May 24. [Epub ahead of print]
Responses to carboplatin in BRCA1/2-mutated breast cancer.
Talha Khan Burki.
Women with metastatic, triple-negative breast cancer who have BRCA1 or BRCA2 mutations are more likely to respond to carboplatin as docetaxel, according to a new study.
In the phase 3 trial, Andrew Tutt (Institute of Cancer Research, London, UK) and colleagues randomly assigned 376 women with advanced triple-negative breast cancer to receive either carboplatin (area under the curve 6; n=188) or docetaxel (100 mg; n=188). 43 women had germline-mutated BRCA1 or BRCA2 breast cancer (31 BRCA1 and 12 BRCA2). The primary endpoint was objective response. A prespecified interaction analysis between carboplatin and loss-of-function of BRCA1 and BRCA2 was planned.
An objective response was achieved in 59 (31%) of 188 patients in the carboplatin group and 64 (34%) of 188 patients in the docetaxel group (absolute difference -2.6% [95% CI -12.1 to 6.9]; p=0.66). In patients with BRCA1 or BRCA2 mutations, 17 (68%) of 25 patients in the carboplatin group and six (33%) of 18 patients in the docetaxel group achieved an objective response (absolute difference 34.7% 6.3-63.1; p=0.03, with a significant test for treatment; pinteraction=0.01). Carboplatin was not more effective in patients who had BRCA1 methylation. Carboplatin was associated with 102 serious adverse events in the carboplatin group, compared with 174 in the docetaxel group.
Tutt points out that triple-negative breast cancer ought to be considered a collection of diseases. "We should be testing many patients with triple-negative breast cancer for germline BRCA mutations, that is clear from this study", he said. He noted that the loss-of-function status of DNA repair pathways can change between primary and metastatic disease, which could explain why epigenetic dysregulation of BRCA1 did not sensitise the tumours to platinum in this study. He added, "There is currently no evidence to test tumours for BRCA1 methylation, but we need to consider further assessment of gene expression profiling to define subtypes, since the use of platinum only seems to have a basis in basal-like triple-negative breast cancer."
David Cameron (University of Edinburgh, UK) welcomed the findings. "The data this trial has generated have already changed practice; it has put carboplatin up there as an extremely effectively drug in BRCA1/2-mutated breast cancer", he commented. Cameron added that data from studies testing carboplatin in the neoadjuvant setting support this conclusion.
DOI: 10.1016/S1470-2045(18)30407-8
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