Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK.
Ann Oncol. 2021 Jan;32(1):58-65. doi: 10.1016/j.annonc.2020.10.475. Epub 2020 Oct 21.
In the TNT trial of triple negative breast cancer (NCT00532727), germline BRCA1/2 mutations were present in 28% of carboplatin responders. We assessed quantitative measures of structural chromosomal instability (CIN) to identify a wider patient subgroup within TNT with preferential benefit from carboplatin over docetaxel.
Copy number aberrations (CNAs) were established from 135 formalin-fixed paraffin-embedded primary carcinomas using Illumina OmniExpress SNP-arrays. Seven published [allelic imbalanced CNA (AiCNA); allelic balanced CNA (AbCNA); copy number neutral loss of heterozygosity (CnLOH); number of telomeric allelic imbalances (NtAI); BRCA1-like status; percentage of genome altered (PGA); homologous recombination deficiency (HRD) scores] and two novel [Shannon diversity index (SI); high-level amplifications (HLAMP)] CIN-measurements were derived. HLAMP was defined based on the presence of at least one of the top 5% amplified cytobands located on 1q, 8q and 10p. Continuous CIN-measurements were divided into tertiles. All nine CIN-measurements were used to analyse objective response rate (ORR) and progression-free survival (PFS).
Patients with tumours without HLAMP had a numerically higher ORR and significantly longer PFS in the carboplatin (C) than in the docetaxel (D) arm [56% (C) versus 29% (D), P = 0.085; PFS 6.1 months (C) versus 4.1 months (D), P = 0.047]. In the carboplatin arm, patients with tumours showing intermediate telomeric NtAI and AiCNA had higher ORR [54% (C) versus 20% (D), P = 0.03; 62% (C) versus 33% (D), P = 0.076]. Patients with high AiCNA and PGA had shorter PFS in the carboplatin arm [3.4 months (high) versus 5.7 months (low/intermediate); and 3.8 months (high) versus 5.6 months (low/intermediate), respectively; P = 0.027, P = 0.125 and P = 0.053, P = 0.176], whilst no difference was observed in the docetaxel arm.
Patients with tumours lacking HLAMP and demonstrating intermediate CIN-measurements formed a subgroup benefitting from carboplatin relative to docetaxel treatment within the TNT trial. This suggests a complex and paradoxical relationship between the extent of genomic instability in primary tumours and treatment response in the metastatic setting.
在三阴性乳腺癌（TNT）试验中（NCT00532727），卡铂应答者中有 28%存在种系 BRCA1/2 突变。我们评估了结构染色体不稳定性（CIN）的定量指标，以确定 TNT 中更广泛的患者亚组，这些患者从卡铂治疗中获益优于多西他赛。
使用 Illumina OmniExpress SNP 芯片从 135 例福尔马林固定石蜡包埋的原发性癌中建立拷贝数异常（CNAs）。从七个已发表的[等位基因失衡 CNA（AiCNA）；等位基因平衡 CNA（AbCNA）；拷贝数中性杂合性丢失（CnLOH）；端粒等位基因失衡数量（NtAI）；BRCA1 样状态；基因组改变百分比（PGA）；同源重组缺陷（HRD）评分]和两个新的[Shannon 多样性指数（SI）；高水平扩增（HLAMP）]CIN 测量中得出了七个已发表的[等位基因失衡 CNA（AiCNA）；等位基因平衡 CNA（AbCNA）；拷贝数中性杂合性丢失（CnLOH）；端粒等位基因失衡数量（NtAI）；BRCA1 样状态；基因组改变百分比（PGA）；同源重组缺陷（HRD）评分]和两个新的[Shannon 多样性指数（SI）；高水平扩增（HLAMP）]CIN 测量中得出了。HLAMP 是基于存在至少一个位于 1q、8q 和 10p 上的前 5%扩增的带定义的。连续的 CIN 测量被分为三分位数。使用所有 9 种 CIN 测量来分析客观缓解率（ORR）和无进展生存期（PFS）。
在卡铂组中，无 HLAMP 的肿瘤患者的 ORR 更高，无进展生存期显著延长[56%（C）与 29%（D），P=0.085；PFS 6.1 个月（C）与 4.1 个月（D），P=0.047]。在卡铂组中，中端粒 NtAI 和 AiCNA 中等的肿瘤患者的 ORR 更高[54%（C）与 20%（D），P=0.03；62%（C）与 33%（D），P=0.076]。在卡铂组中，高 AiCNA 和 PGA 的患者的无进展生存期较短[3.4 个月（高）与 5.7 个月（低/中）；3.8 个月（高）与 5.6 个月（低/中），P=0.027，P=0.125 和 P=0.053，P=0.176]，而在多西他赛组中没有观察到差异。
在 TNT 试验中，与多西他赛治疗相比，缺乏 HLAMP 且表现出中等 CIN 测量的肿瘤患者形成了从卡铂治疗中获益的亚组。这表明原发性肿瘤中基因组不稳定性的程度与转移性环境中的治疗反应之间存在复杂和矛盾的关系。
