Profiling gene messages could guide chemotherapy for triple negative breast cancer
Image: Breast cancer cells. Anne Weston, Francis Crick Institute.
A new study sheds light on the genetic messages encoded by genes within ‘triple negative’ breast cancers – and poses important questions on how they could be better treated in future.
The study, by researchers at The Institute of Cancer Research, London, and published today in Clinical Cancer Research, shows that certain characteristics within patients’ primary tumours can predict how they will respond to different treatments after their tumours have spread around the body.
For example, women whose primary tumours have a higher presence of immune cell genes, and genes linked to their activity, are more likely to respond to a specific type of chemotherapy called docetaxel than another called carboplatin.
And patients whose cancer has spread but who have not yet received chemotherapy, and whose primary tumours have markers of faults in genes linked to DNA repair pathways, tend to respond better to carboplatin.
Accelerate the development of personalised treatments
The presence of these characteristics, or ‘biomarkers’, can be tested for in the clinic and could be used to accelerate the development of more personalised treatments for triple negative breast cancers.
They also found that while some markers in primary tumours can still predict responses by the time cancer has spread around the body, other markers have changed significantly by this point. They therefore recommend a careful approach to using primary tumour biomarkers to predict responses in advanced cancers.
Around 15 per cent of all breast cancers are triple negative. These cancers are not driven by any of the three molecules that can be blocked by targeted hormone receptor drugs – the HER2 protein and two hormone receptors for oestrogen and progesterone – and so current treatment options are limited.
These cancers also tend to be more aggressive and disproportionately affect younger women and Black women.
Scientists from the ICR aimed to better understand the underlying biology behind responses to different chemotherapies amongst women with triple negative breast cancer that had turned ‘metastatic’, or spread.
In the new study researchers looked at biopsies taken when patients had had their initial surgery from 186 women who took part in a trial for subsequent recurrent breast cancer called TNT. The study was funded by the ICR, which is a research institute and a charity, Breast Cancer Now, Cancer Research UK and the USA NCI.
The TNT trial, which was managed by the Cancer Research UK funded Clinical Trials and Statistics Unit (ICR-CTSU) at the ICR, has already shown in previously published work that carboplatin is more effective than docetaxel for women whose primary tumours have mutations in the BRCA1 or BRCA2 genes.
In the new study, the researchers were aiming to better understand whether other genetic markers in these patients’ primary tumours could be used to determine their best treatment option.
Patients with high levels of markers related to immune pathways in their primary tumours were more likely to see their tumours shrink, or remain stable, when taking docetaxel for advanced breast cancer than patients without the markers. Immune features were not linked to carboplatin response.
In samples from patients who had not yet received chemotherapy, those with elevated markers related to faults in the pathways cancer cells use to repair their DNA tended to respond better to carboplatin. But these markers had no impact on response to docetaxel.
Biomarkers could be investigated in clinical trials
The findings suggest it might be possible to predict who will benefit from carboplatin and docetaxel using a range of different biomarkers and suggest further investigation of these biomarkers in clinical trials is warranted.
The researchers also explored whether immune signatures were conserved between primary tumour samples and secondary tumour samples taken after the cancer had become metastatic.
Although immune features remained relatively stable, RNA-based features related to DNA damage repair pathways changed significantly.
The authors therefore recommend against doctors routinely using biopsies taken from primary tumour samples to carry out gene-expression (RNA)-based biomarker tests for guiding the treatment for secondary cancers.
They suggest it would be better to use biopsies taken from secondary tumours as the cancers can evolve between first diagnosis and recurrence after initial therapy.
Dr Maggie Cheang, Group Leader of the ICR-CTSU Integrative Genomics Analysis in Trials group at The Institute of Cancer Research, London, who led the research, said:
“This is one of the first few studies to demonstrate how we embed discovery science within our clinical trial by generating high-quality, multi-dimensional biological data from routine clinical samples taken in clinical trials. We applied cutting edge whole genome RNA sequencing on tissue samples preserved in paraffin wax in a technique that we optimised through collaboration with colleagues at University of North Carolina at Chapel Hill. By combining all these data together, we are able to paint a comprehensive picture of patients’ individual tumour biology.”
Maximise knowledge from clinical trial data and samples
Holly Tovey, PhD Student within Dr Cheang’s group at The Institute of Cancer Research, London said:
“This study is a great example of how we can make the most of the data and samples collected routinely within our clinical trials to maximise the knowledge gained from each study.
“While each individual marker provides useful predictive information, there is more to the story. Advanced statistical methods have enabled us to integrate many different markers across several layers of biology and gain a more comprehensive picture of the biology of primary tumours, and how they relate to treatment responses in the advanced disease.”
Professor Andrew Tutt, Director of the Breast Cancer Now Toby Robins Research Centre at the ICR and Chief Investigator of the TNT trial, said:
“Triple negative breast cancers lack hormone receptors or the HER2 protein target and therefore are not treated with many of our targeted therapies for breast cancer – so chemotherapy remains the main treatment option. Women with this type of cancer are in real need of better, more personalised options.
“Our analysis takes a deep dive into tumour biology and how different tumour characteristics can predict which treatment patients’ tumours will respond to. Our findings paint a complex picture – with many, dynamic factors driving how tumours respond to treatment. I hope this work will contribute to a future where patients with triple negative breast cancer have more effective and personalised treatment options which extend their lives.”
Antibody immunotherapy could provide “long-awaited” new option for ‘triple negative’ breast cancer – after discovery of folate receptor as key target
19 May 2021
Researchers find that aggressive ‘triple negative’ breast cancers express high levels of folate receptor FRα – and could be targeted with immunotherapy and other antibody approaches
Targeted antibody therapies – including a new antibody immunotherapy – could offer “long-awaited” advances for patients with aggressive ‘triple negative’ breast cancer, following the discovery of a new target protein helping to drive the disease’s growth.
In a new study, scientists at the Breast Cancer Now Research Unit at King’s College London found that a significant proportion of highly aggressive triple negative tumours, including those that are resistant to chemotherapy, produce high levels of a protein called folate receptor alpha (FRα).
Importantly, the researchers found that antibody immunotherapies targeting FRα significantly reduced growth of triple negative tumours in mice, priming the immune system to recognise to attack cancer cells.
Triple negative breast cancer – which makes up around 15% of all breast cancers – is so-named for its lack of three key receptors that can be targeted with treatments in other forms of the disease. Treatment options for triple negative patients are therefore usually limited to surgery, as well as chemotherapy and radiotherapy, which can weaken patients’ immune systems.
In recent years, cancers such as melanoma and lymphoma have seen significant breakthroughs in immunotherapy, which involves reprogramming the immune system – the body’s major defence mechanism – to recognise and kill cancer cells. However, to date, immunotherapies that can benefit breast cancer patients have not seen the same success.
With triple negative breast cancers often being more aggressive as well as harder-to-treat than other types of the disease, survival outcomes are often poor for the 7,500 women diagnosed each year in the UK.
In the new study, a team of researchers led by Dr Sophia Karagiannis at King’s College London, first confirmed that FRα – a protein often produced at high levels in ovarian, lung, breast and other types of cancer – plays a crucial role in supporting growth and survival of triple negative breast tumours. The team proposed that FRα could be a suitable target for different antibody treatment approaches.
The team showed that antibodies were able to recognise the FRα receptor in both triple negative breast cancer cells and in patient tumours that had been transplanted into mice. These antibodies acted as an immunotherapy, activating immune cells and boosting their ability to target and destroy triple negative breast cancer cells expressing FRα.
When FRα-targeting antibodies were linked to cancer growth-inhibiting drugs, they successfully sought out FRα, directly delivering cancer growth-inhibiting drugs to triple negative breast cancer cells, which resulted in smaller, slower-growing tumours.
The team now hope to further develop these novel antibody approaches, with the aim of refining these new lines of attack, and advancing them into clinical trials for triple negative breast cancer patients.
The study is published in Clinical Cancer Research and was funded by leading research charity Breast Cancer Now.
Dr Sophia Karagiannis, Head of Cancer Antibody Discovery and Immunotherapy at King’s College London, said:
“Having identified antibodies against this novel target that are able to restrict the growth of triple negative breast cancer cells in the laboratory, we are now concentrating on bringing forth a new generation of more effective antibody therapy approaches. Our ultimate aim is to translate the most promising of these to clinical testing in patients.”
Professor Andrew Tutt, Director of the Breast Cancer Now Unit at King’s College London, said:
“Through our combined strengths in breast cancer biology, cancer immunology, antibody engineering, and translation of targeted therapies at the Breast Cancer Now Unit at King’s, we are able to venture beyond existing conventional treatments, identify new targets on cancer cells and develop new agents for therapy never before examined in breast cancer. But it’s important to remember that this research is at an early stage and further work is needed in the laboratory before we know if these could develop into treatments for patients.”
Dr Simon Vincent, Director of Research at Breast Cancer Now, which funded the study, said:
“This is a really important discovery. We hope this new line of attack could now lead to a long-awaited targeted therapy for patients with aggressive ‘triple negative’ breast cancer – for whom treatments are currently very limited.
“With triple negative breast cancer still severely lacking in targeted treatments, it remains one of the greatest areas of unmet need in breast cancer. The King’s College London Unit is a world-leading centre dedicated to finding new and kinder therapies for this hard-to-treat type of breast cancer – and crucial steps like this are extremely promising.
“Priming the immune system to attack tumours is an exciting approach that is now beginning to show promise in breast cancer, and we now hope to see new antibody immunotherapies enter trials for triple negative patients soon.
“The more aggressive breast cancers are, the more likely they are to spread around the body, where they become incurable. It’s vital that we find new ways to stop breast cancer spreading if we are to achieve our ambition that by 2050, everyone who develops breast cancer will live – and live well.”
The study was largely funded by Breast Cancer Now – with additional support from Cancer Research UK, the Medical Research Council, the Academy of Medical Sciences, the CR UK/NIHR in England/Department of Health for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre, the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ and King’s College London. Patient tissue samples were provided by King’s Heath Partners Cancer Biobank in London.