AURORA

BIG 14-01

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Aiming to understand the molecular aberrations in metastatic breast cancer
(public name: Metastatic Breast Cancer GPS)

AURORA is an international, academic research programme that uses molecular screening technology to decode the genetic characteristics of a tumour and identify the genetic changes (i.e., molecular aberrations) that drive disease evolution over time, in patients with recurrent or locally relapsed metastatic breast cancer.

According to recent estimations, about 30% of patients with breast cancer will eventually develop metastases in other parts of the body[1]. This advanced form of the disease is responsible for the great majority of breast cancer deaths. Metastatic breast cancer is more difficult to treat and currently remains essentially incurable, and whilst some individuals live much longer than others with the disease, we do not understand why.

The current treatment options are usually based on the clinical-pathological characteristics of the primary tumour (where the cancer began) rather than on the characteristics of the tumour once it has spread.

Decoding the genes of cancer

AURORA aims to better understand how and why a breast cancer tumour spreads.

Thanks to the highly advanced technologies available today, such as next-generation sequencing analysis, researchers are able to characterise tumours on the genetic level in great detail. 

Several studies have already shown that there are genetic changes that are different in the primary tumour and in the metastases. In addition, different resistance mechanisms to treatments may emerge over time.

By analysing the molecular/genetic profiles of tumours, AURORA is laying the groundwork for answering key questions in metastatic breast cancer, such as:

– How do tumour cells spread to other organs?

– Is this due to the genetic profile of the primary tumour or to genetic changes that occur over time?

– How do mechanisms of treatment resistance develop?

This is why the AURORA study consists in the collection, for each patient, of primary and metastatic tumour samples, as well as serial blood samples, and the long-term follow-up (up to 10 years) of patients to monitor the disease evolution over time.

AURORA could open new treatment strategies leading to prolonged disease control and better quality of life for people affected by metastatic breast cancer.

The huge amount of collected information will also enable new hypotheses to be generated for future research.

[1] Ross C, Szczepanek K, Lee M et al. The genomic landscape of metastasis in treatment-naïve breast cancer models. PLoS Genet 16(5): e1008743. May 28, 2020 https://doi.org/10.1371/journal.pgen.1008743

The initial results for the first 381 patients included in the study were presented at the ESMO Breast Cancer Congress in 2019 and published in Cancer Discovery in June 2021.

AURORA researchers have identified genetic changes that are more common in metastatic samples than in samples from the primary tumours.

The analyses of RNA sequencing data from paired primary and metastatic samples from the same patients showed that, in 36% of the cases, the subtype of breast cancer changes between the primary and the metastatic disease, usually towards a more aggressive form.

The analyses also indicated that metastases expressed fewer immune-related genes and had a different immune cell composition, which may create a microenvironment more favourable to the development of metastases.

The analysis of how long patients survived with the disease showed that those with hormone receptor-positive (HR+) HER2-negative breast cancer who also had high tumour mutational burden (TMB), meaning whose primary tumour had a large number of somatic mutations (genetic changes that are not inherited), had both shorter overall survival and shorter time to relapse, indicating that TMB is a factor of poor prognosis.

Finally, researchers also found that more than 50% of patients had genetic changes that could be matched with existing targeted therapies. These patients could be considered for clinical trials testing these new targeted drugs.

Clinical data and biological samples (blood and tumour tissue) are collected from all patients and analysed based on a panel of 411 cancer-related genes.

A unique aspect of AURORA is that these genetic tests are done on samples available from the primary tumour, as well as on samples taken after the cancer has metastasised.

The results of the tests done for each patient are analysed by the AURORA Molecular Advisory Board, which delivers a report to the treating physician.

If a genetic change is found, a clinical trial testing a new drug that targets that change may be proposed to the patient (if the physician finds it appropriate). If no drug or clinical trial is available, or if no genetic change is found, the physician chooses the best available standard treatment for the patient.

Whole exome sequencing analysis is performed on tumour materials from patients whose disease responded either exceptionally well or poorly to standard treatment. Exome analysis looks at a subset of genetic information and aims to identify the mechanisms that drive these exceptional cases. 

All patients participating in AURORA are followed-up every 6 months and for up to 10 years.

A specific platform has been developed to support the huge collection of data from the patients enrolled in AURORA.

as well as blood to be available for genetic testing.

Recruitment of the first 1,000 patients concluded in August 2020. As of February 2022, over 1,150 patients had been included in the programme.

An extension of the study starting in 2022 will focus on specific subtypes of metastatic breast cancer, namely invasive lobular cancer, triple negative breast cancer, and late relapses, those occurring 10 or more years after a primary diagnosis.

About 260 patients will be recruited in this extension phase of the study.

The programme was set up and launched by the Breast International Group, which is also the legal sponsor.

It is coordinated by BIG Headquarters, in collaboration with the Institut Jules Bordet’s Clinical Trials Support Unit (IJB-CTSU) and Frontier Science Scotland (FSS).

Recruitment of patients in the first phase of the programme ran from 2014 to 2021.

An extension of the study starting in early 2022 will focus on specific subtypes of metastatic breast cancer, namely invasive lobular cancer, triple negative breast cancer, and late relapses, those occurring 10 or more years after a primary diagnosis. BIG considers these as areas of high unmet need, for which AURORA could provide high scientific and clinical impact.

The initial results of AURORA, which report on the first 381 patients included in the study, were presented at the ESMO Breast Cancer Congress in 2019 and were published in Cancer Discovery in June 2021.

Over 60 hospitals located in 12 different countries across Europe are participating in the programme, which involves 10 BIG member groups and 1 independent site.

Aftimos P, Oliveira M, Irrthum A et al. Genomic and Transcriptomic Analyses of Breast Cancer Primaries and Matched Metastases in AURORA, the Breast International Group (BIG) Molecular Screening Initiative. Cancer Discovery. DOI: 10.1158/2159-8290.CD-20-1647 Published November 2021

AURORA is made possible in part by generous grants from the Breast Cancer Research Foundation® (BCRF) as the main funder, Fondation Cancer (Luxembourg), Pfizer grant for non-drug research, Fondation contre le Cancer (Belgium), National Lottery (Belgium), NIF Foundation, Rhone Trust, Barrie and Dena Webb, Candriam, Fondation Futur 21, Sogerim, Think Pink Belgium (SMART Fund), Cognizant Foundation, Eurofins Foundation and many individual donors. AURORA has also been supported by the Fund Friends of BIG, managed by the King Baudouin Foundation.

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