What do we know today about the formation and development of breast cancer metastases? Steffi Österreich and Adrian Lee from the University of Pittsburgh and Andreas Schneeweiss from Heidelberg University Hospital addressed this issue at the 11th Charité-Mayo Conference. Among other things, Austria and Lee evaluated results from the Aurora project, Schneeweiss presented the Catch Programme.
Cancer develops over time and in response to therapy. Against this background, Professors Steffi Österreich and Adrian Lee are investigating the molecular basis of breast cancer development in their laboratory with the aim of uncovering the reasons for therapy resistance in metastatic breast cancer. Their findings should help to improve precision medicine and thus also the outcomes for breast cancer patients. To do this, they have analysed studies on the development of metastatic breast cancer:
At Utrecht University, Willemijne Schrijver and her colleagues used a meta-analysis of 39 studies to examine receptor conversions for the oestrogen receptor-alpha (ERα), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) status in the course of disease progression in metastatic breast cancer and found that they occur frequently. Until now, the tissue characteristics of the primary tumor determined whether hormone- and/or HER2-targeted therapy was used. However, the analysis shows that changes in ERα, PR and HER2 also occur in distant metastases, which should also play a role in the decision for therapy. In order to investigate the influence of receptor conversion on treatment efficacy and survival, the study authors recommend prospective studies and a re-determination of the receptor status in metastases.
Lee and Austria themselves collaborated in the study "Intrinsic subtype switching and acquired ERBB2/HER2 amplifications and mutations in breast cancer brain metastases" at the University of Pittsburgh. Here, the subtype differences between primary tumors and matched breast cancer metastases were investigated in 20 tissue samples of primary breast cancer tumors. There were expression changes in 17 cases. Overall, expression changes of brain metastases were detected in 127 genes within BrCa signatures, PAM50 assignments and ERBB2/HER2 DNA gains. ERBB2/HER2 gains were the most common (7). These results show: Breast cancer metastases frequently acquire alterations in clinically effective genes, with metastasis-acquired ERBB2/HER2 alterations in approximately 20% of ERBB2/HER2-negative cases. These observations help to provide a comprehensive profile of metastases for the clinical care of patients.
The Aurora programme examines the RNA and DNA of metastatic breast cancer to determine treatment options. The programme also aims to determine how the molecular biology of the tumor affects prognosis. The European Aurora Programme will analyse biopsy samples from 1,000 patients with metastatic breast cancer from 12 countries at different times of the disease and treatment, and monitor the patients' condition for ten years. This clinical study should make it possible to draw more precise conclusions about the development of tumors.
The American Aurora Program also analyses molecular changes in breast cancer over time. A sub-study of the programme, which has already been completed, analysed tissue samples from deceased patients with metastatic breast cancer and compared the data with data from existing tumor banks. The researchers wanted to know how tumors change and why metastases grow in the brain, liver, lungs and bones. The tissue samples were analysed for DNA, RNA and methylation abnormalities. In a second study, tissue biopsies from several hundred women with metastatic disease were compared to identify disease drivers.
To date, 90 retrospective cases have been collected and 55 validated for analysis. After molecular profiling, the data were stored on the Cancer Genetics Web. Preliminary analysis shows that metastases from one patient are similar to each other, while they are different from metastases from other patients. The metastases show proliferation, fewer differentiation signatures and fewer immune cell infiltrates. The metastases continue to develop and some show more mutations. DNA methylation was present in the primary tumor and stably maintained in the majority of metastatic lesions.
Cancers are caused by a variety of genetic changes and vary from patient to patient. However, they determine how the disease progresses and which therapies can be used. The CATCH study (Comprehensive Assessment of Clinical Features and Biomarkers To Identify Patients with Advanced or Metastatic Breast Cancer for Marker Driven Trials in Humans) is a clinical trial at Heidelberg University Hospital in which patients with advanced metastatic breast cancer can participate. After tissue analysis of the metastases, a genetic profile is created which makes a tailor-made therapy possible. In this way, active substances can also be used that are only approved for the treatment of other diseases or therapy methods that are still being tested.
Prof. Andreas Schneeweiss from the Section of Gynaecological Oncology is leading the project together with his colleague Prof. Peter Lichter and presented the first data at the Mayo Conference. So far, 128 patients have been treated as part of the ongoing study. With 64 patients, half of them could be treated. Usable data are already available from 53 patients. Of these, 21 achieved a stable course of the disease or responded to the recommended form of therapy. In the further course of the study, genomic analysis procedures for breast cancer will be further researched and anchored in clinical routine. The study leaders also see the application in other forms of cancer as a possible option.