Abstract
BackgroundIn 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.Patients and methodsCopy 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).ResultsPatients 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), PHLAMP,quiet = 0.085; PFS 6.1 months (C) versus 4.1 months (D), Pinteraction/HLAMP = 0.047]. In the carboplatin arm, patients with tumours showing intermediate telomeric NtAI and AiCNA had higher ORR [54% (C) versus 20% (D), PNtAI,intermediate = 0.03; 62% (C) versus 33% (D), PAiCNA,intermediate = 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; Pinteraction/AiCNA = 0.027, Padj.interaction/AiCNA = 0.125 and Pinteraction/PGA = 0.053, Padj.interaction/PGA = 0.176], whilst no difference was observed in the docetaxel arm.ConclusionsPatients 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.
Highlights
We quantified the percentage of genome altered (PGA) measure,[21] a general proxy for the total amount of Copy number aberrations (CNAs) across the whole genome; number of telomeric allelic imbalances (NtAI),[6] that was shown to be indicative of DNA damage response (DDR) deficiency and platinum sensitivity in triple negative breast cancer (TNBC) patients; and the array comparative genomic hybridisation (aCGH)-based BRCA1like classifier (BRCA1-like),[5] that was shown to predict benefit from high-dose platinum-based chemotherapy
We identified intermediate levels of allelic imbalanced CNAs, as measured by AiCNA, that focuses on genomic segments larger than 8 Megabase pair,[9] and telomeric NtAI6 as being differentially associated with improved objective response rate (ORR) in the carboplatin arm
We noticed that in the TBCRC009 trial,[15] in which metastatic TNBC patients were treated with platinum monotherapy, the highest levels of tumour response were observed in cases with medium levels of the ‘genomic scar’ assays developed by Myriad that measure large loss of heterozygosity (LOH) events (HRD-LOH)[7] and large-scale state transition events (HRD-LST),[8] both of which have been associated with HR deficiency
Summary
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. Patients with tumours showing intermediate telomeric NtAI and AiCNA had higher ORR [54% (C) versus 20% (D), PNtAI,intermediate 1⁄4 0.03; 62% (C) versus 33% (D), PAiCNA,intermediate 1⁄4 0.076]. Conclusions: 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.
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