Assessment of structural chromosomal instability phenotypes as biomarkers of carboplatin response in Triple Negative Breast Cancer: the TNT trial

Background: 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 and methods: Copy number aberrations (CNAs) were established from 135 FFPE 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 index, SI; high-level amplifications, HLAMP) CIN-measurements were derived. HLAMP was defined based on the presence of at least 1 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).

Results: 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), PHLAMP,quiet=0.085; PFS 6.1 months(C) vs 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.

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.

Keywords: allelic imbalance; carboplatin; genomic instability; metastatic triple negative breast cancer.