First results from the AURORA programme were presented at the ESMO Breast Cancer 2019, held 2 to 4 May in Berlin, Germany. This large pan-European molecular screening programme sponsored by the Breast International Group aims to portray the comprehensive longitudinal molecular disease evolution in metastatic breast cancer.
Philippe Aftimos, Clinical Trials Development Leader at Institut Jules Bordet in Brussels, Belgium is the co-principal investigator of this programme in which patients with metastatic breast cancer at first diagnosis or after receiving one line of therapy for metastatic disease are included.
Targeted gene sequencing (TGS) on DNA that was extracted from the primary tumour, from a metastatic biopsy, from whole blood, and on circulating tumour DNA (ctDNA) that was extracted from baseline plasma were performed real-time in a central lab. RNA sequencing and copy number variations (CNVs) analyses were performed in batches. All samples including fresh frozen biopsies and sequential plasma and serum samples are biobanked for future research.
The ongoing analysis is designed to include a total of 1000 patients and up to 100 patients with bone-only disease. Pathology, clinical baseline and follow-up data are collected, and pathology slides are scanned at high resolution. In patients with assessable data, a report with the TGS data was annotated by a molecular advisory board and provided to the treating physician.
AURORA study design. © Philippe Aftimos.
Molecular results
Dr Aftimos presented the results that were available for the first 381 patients that had been included by November 2017. The pathological subtype distribution included 228 hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, 71 triple-negative (TNBC) and 51 HER2-positive tumours; for 31 cases the information was not available. In total, 292 (77%) patients were treatment naïve in the metastatic setting including 76 patients (20%) with de novo metastatic disease.
The analysis focused on patients with paired samples (primary and metastases) and showed a global increase in the number of mutations in metastatic samples. TGS and CNV analyses data identified molecular alterations enriched in the metastatic samples such as ESR1, PTEN, KAT6A, MYC, MDM4 and AKT3. Copy number losses more prevalent in metastatic samples included RB1 and ARID1A.
RNA sequencing showed some subtype switching between the primary tumour and subsequent metastasis as well as a lower expression of immune signatures in the metastatic samples.
TGS of ctDNA extracted from the baseline plasma samples proved to be complementary in certain cases by identifying potentially actionable molecular alterations that would have been missed otherwise.
While applying the new ESMO Scale for Clinical Actionability of molecular Targets (ESCAT), the investigators found that as much as 52% (42% when excluding HER2 amplification) of included metastatic breast cancer patients had at least one Tier I or Tier II alteration.
ESCAT application in the AURORA programme. © Philippe Aftimos.
Conclusions
The integrated molecular analyses (DNA-TGS, RNAseq, CNV analyses) from the AURORA programme highlight molecular alterations enriched in metastatic breast cancer and correlated with disease progression and therapeutic resistance. The prevalence of Tier I and Tier II molecular alterations per ESCAT provides a promise for routine molecular profiling in metastatic breast cancer. The biobank and curated clinical database within AURORA will empower future research for metastatic breast cancer, which remains an incurable disease and the second cause of cancer mortality for women worldwide.
While evidence supports molecular evolution of the disease during its life cycle, there remain few molecular profiling studies that provide comprehensive longitudinal molecular and clinical data.
Disclosure
Funding for this study was provided by the Breast Cancer Research Foundation (BCRF) as the main funder, Fondation Cancer (Luxembourg), National Lottery (Belgium), Fondation NIF, Family Webb and individual donors.
References
152O - Aftimos PG, Antunes De Melo e Oliveira AM, Hilbers F, et al. First report of AURORA, the Breast International Group (BIG) molecular screening initiative for metastatic breast cancer (MBC) patients (pts). ESMO Breast Cancer 2019, 2-4 May, Berlin, Germany.
Mateo J, Chakravarty D, Dienstmann R, et al. A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Annals of Oncology 2018; 29(9):1895–1902.