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

Orsolya Sipos, Holly Tovey, Jelmar Quist, Syed Haider, Salpie Nowinski, Patrycja Gazinska, Sarah Kernaghan, Christy Toms, Sarah Maguire, Nick Orr, Sabine Linn, Julie Owen, Cheryl Gillet, Sarah Pinder, Judith Bliss, Andrew Tutt, Maggie Cheang, Anita Grigoriadis

Research output: Contribution to journalArticle

Abstract

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.
Original languageEnglish
JournalAnnals of Oncology
Early online date20 Oct 2020
DOIs
Publication statusEarly online date - 20 Oct 2020

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