Assessment of structural chromosomal instability phenotypes as biomarkers of carboplatin response in triple negative breast cancer: the TNT trial

TY - JOUR

T1 - Assessment of structural chromosomal instability phenotypes as biomarkers of carboplatin response in triple negative breast cancer

T2 - the TNT trial

AU - Sipos, Orsolya

AU - Tovey, Holly

AU - Quist, Jelmar

AU - Hyder, Syed

AU - Nowinski, Salpie

AU - Gazinska, Patricja

AU - Kernaghan, Sarah

AU - Toms, C

AU - Maguire, Sarah

AU - Orr, Nick

AU - Linn, Sabine

AU - Owen, Julie

AU - Gillett, Cheryl

AU - Pinder, Sarah

AU - Bliss, Judith

AU - Tutt, Andrew

AU - Cheang, Maggie C.U.

AU - Grigoriadis, Anita

N1 - Funding Information: AT , HT , MCUC , SK , PG , AG , SEP and JMB report that their institutional departments have received grants from Breast Cancer Now and/or Cancer Research UK and other support for costs or consumables in this research from Myriad Genetics Inc. and NanoString Technologies Inc. during the conduct of the TNT trial. Furthermore, the salary of HT has been part supported by educational grants from Merck Sharp & Dohme Ltd and Pfizer Inc. MCUC has a patent: US Patent No. 9,631,239 with royalties paid. SCL received institutional research support funding from Agendia, Amgen, AstraZeneca, Eurocept, Genentech, Roche, Sanofi and Tesaro. SCL is an advisory board member for Cergentis, IBM, Novartis, Pfizer, Roche and Sanofi. JMB also reports grants and non-financial support from AstraZeneca, Novartis, Janssen-Cilag, Merck Sharpe & Dohme, Pfizer, Roche, and Clovis Oncology outside the submitted work. All remaining authors have declared no conflicts of interest. Funding Information: The authors thank all subjects and the families of those who took part in the trial and all involved staff at the participating centres. The authors acknowledge past and present colleagues on the TNT Trial Management Group, the Independent Data Monitoring Committee and Trial Steering Committee who oversaw the trial, the Response Evaluation Committee who conducted the independent radiology review and Cancer Research UK and Breast Cancer Now (and their legacy charity Breakthrough Breast Cancer) as well as the National Institute for Health Research Cancer Research Networks in England and their equivalent NHS research and development (R&D)-funded networks in Scotland, Wales and Northern Ireland for ‘in-kind’ support. The authors would like to thank Nazneen Rahman at the Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK for conducting the targeted sequencing of the germline variants in cancer predisposition genes. This study represents independent research supported by the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Funding Information: This work was supported by Cancer Research UK and Breast Cancer Now (and their legacy charity Breakthrough Breast Cancer ) [grant number CRUK/07/012 , KCL-BCN-Q3 ]. Funding was provided from Myriad Genetics, Inc, to cover costs of nucleic extraction from tumour blocks appropriate for Next Generation Sequencing, and Prosigna reagent kits were provided by NanoString Technologies, Inc. Funding Information: The authors thank all subjects and the families of those who took part in the trial and all involved staff at the participating centres. The authors acknowledge past and present colleagues on the TNT Trial Management Group, the Independent Data Monitoring Committee and Trial Steering Committee who oversaw the trial, the Response Evaluation Committee who conducted the independent radiology review and Cancer Research UK and Breast Cancer Now (and their legacy charity Breakthrough Breast Cancer) as well as the National Institute for Health Research Cancer Research Networks in England and their equivalent NHS research and development (R&D)-funded networks in Scotland, Wales and Northern Ireland for ?in-kind? support. The authors would like to thank Nazneen Rahman at the Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK for conducting the targeted sequencing of the germline variants in cancer predisposition genes. This study represents independent research supported by the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This work was supported by Cancer Research UK and Breast Cancer Now (and their legacy charity Breakthrough Breast Cancer) [grant number CRUK/07/012, KCL-BCN-Q3]. Funding was provided from Myriad Genetics, Inc, to cover costs of nucleic extraction from tumour blocks appropriate for Next Generation Sequencing, and Prosigna reagent kits were provided by NanoString Technologies, Inc. AT, HT, MCUC, SK, PG, AG, SEP and JMB report that their institutional departments have received grants from Breast Cancer Now and/or Cancer Research UK and other support for costs or consumables in this research from Myriad Genetics Inc. and NanoString Technologies Inc. during the conduct of the TNT trial. Furthermore, the salary of HT has been part supported by educational grants from Merck Sharp & Dohme Ltd and Pfizer Inc. MCUC has a patent: US Patent No. 9,631,239 with royalties paid. SCL received institutional research support funding from Agendia, Amgen, AstraZeneca, Eurocept, Genentech, Roche, Sanofi and Tesaro. SCL is an advisory board member for Cergentis, IBM, Novartis, Pfizer, Roche and Sanofi. JMB also reports grants and non-financial support from AstraZeneca, Novartis, Janssen-Cilag, Merck Sharpe & Dohme, Pfizer, Roche, and Clovis Oncology outside the submitted work. All remaining authors have declared no conflicts of interest. Publisher Copyright: © 2020 The Authors Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2021/1/1

Y1 - 2021/1/1

N2 - 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 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). 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), P HLAMP,quiet = 0.085; PFS 6.1 months (C) versus 4.1 months (D), P interaction/HLAMP = 0.047]. In the carboplatin arm, patients with tumours showing intermediate telomeric NtAI and AiCNA had higher ORR [54% (C) versus 20% (D), P NtAI,intermediate = 0.03; 62% (C) versus 33% (D), P AiCNA,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; P interaction/AiCNA = 0.027, P adj.interaction/AiCNA = 0.125 and P interaction/PGA = 0.053, P adj.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.

AB - 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 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). 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), P HLAMP,quiet = 0.085; PFS 6.1 months (C) versus 4.1 months (D), P interaction/HLAMP = 0.047]. In the carboplatin arm, patients with tumours showing intermediate telomeric NtAI and AiCNA had higher ORR [54% (C) versus 20% (D), P NtAI,intermediate = 0.03; 62% (C) versus 33% (D), P AiCNA,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; P interaction/AiCNA = 0.027, P adj.interaction/AiCNA = 0.125 and P interaction/PGA = 0.053, P adj.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.

UR - http://www.scopus.com/inward/record.url?scp=85096404341&partnerID=8YFLogxK

U2 - 10.1016/j.annonc.2020.10.475

DO - 10.1016/j.annonc.2020.10.475

M3 - Article

SN - 0923-7534

VL - 32

SP - 58

EP - 65

JO - Annals of Oncology

JF - Annals of Oncology

IS - 1

ER -