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

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 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 ¼ 0.085; PFS 6.1 months (C) versus 4.1 months (D), P interaction/HLAMP ¼ 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 ¼ 0.03; 62% (C) versus 33% (D), P AiCNA,intermediate ¼ 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 ¼ 0.027, P adj.interaction/AiCNA ¼ 0.125 and P interaction/PGA ¼ 0.053, P adj.interaction/PGA ¼ 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.

Deep learning predicts chromosomal instability from histopathology images

“…We obtained H&E slides and genomic profiles from patients with breast cancer in TCGA. Here we quantify CIN using the fraction genome altered (FGA, see transparent methods ), which is one of the most commonly used quantitative measurements of CIN ( Sipos, et al., 2021 ; Burrell, et al., 2013 ). FGA quantifies the burden of aneuploidies detectable in bulk genomic profiles.…”

Pancancer Analyses Reveal Genomics and Clinical Characteristics of the SETDB1 in Human Tumors

“…Tumor tissues have many chromosomal variants. Chromosome 1q gains occurred in various human cancers, such as LUAD, LIHC, OV, BRCA, and multiple myeloma [ 32 , 34 , 35 ]. Chromosome 1q21.3 abnormalities are related to breast cancer recurrence, and they can promote cell proliferation and DNA damage response in metastatic melanoma [ 35 , 36 ].…”

“…Chromosome 1q gains occurred in various human cancers, such as LUAD, LIHC, OV, BRCA, and multiple myeloma [ 32 , 34 , 35 ]. Chromosome 1q21.3 abnormalities are related to breast cancer recurrence, and they can promote cell proliferation and DNA damage response in metastatic melanoma [ 35 , 36 ]. SETDB1 is located in the 1q21.3 region that encodes a histone methyltransferase which regulates transcriptional repression, histone methylation, and gene silencing [ 37 , 38 ].…”

Association of 17q22 Amplicon Via Cell-Free DNA With Platinum Chemotherapy Response in Metastatic Triple-Negative Breast Cancer

“…Although specificity is a favorable characteristic in a predictive biomarker, future studies should consider combination of 17q22 amplification with other minimally invasive biomarkers of platinum response. Recently, Sipos et al 68 published biomarker analyses of the TNT study demonstrating that intermediate chromosomal instability measurements were most associated with platinum benefit. However, the association of individual amplicons such as 17q22 was not evaluated in that study and will be important to validate the findings from the current report in prospective studies, such as TNT.…”

“…Confirmation of our findings in a validation cohort of patients with mTNBC is needed. We investigated potential validation cohorts such as the TNT trial and TBCRC009, 19 , 20 , 68 two completed clinical trials of platinum chemotherapy for mTNBC; copy number is not available for either but we anticipate may be in the future. Although we suspect based on previous work from our group that SCNAs are an early event in the natural history of a cancer and remain stable over time, it would be valuable in future work to show with serial ctDNA samples from each individual that 17q21-22 amplifications do not change with platinum chemotherapy or other treatments.…”