(B)(extract): Static PET-CT images in coronal plane pre- and post-metformin are from an individual with an
increase in KFDG-2cpt following metformin;note increased uptake in axillary lymph nodes (circled).
An international collaborative team of medical oncologists, radiologists, cell biologists and bioinformaticians led from Oxford by Simon Lord and Adrian Harris, have identified different metabolic response to metformin in breast tumours that link to change in a transcriptomic proliferation signature.
Published last week in Cell Metabolism, the team integrated tumour metabolomic and transcriptomic signatures with dynamic FDG PET imaging to profile the bioactivity of metformin in primary breast cancer.
Simon Lord stated: “This study shows how the integrated study of dynamic response to a short window of treatment can inform our understanding of drug bioactivity including mechanism of action and resistance. Further work will look to identify how mutations in mitochondria may define the metabolic response of tumours.”
The group demonstrated that metformin reduces the levels of several mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumours.
The paper “Integrated pharmacodynamic analysis identifies two metabolic adaption pathways to metformin in breast cancer” defines two distinct metabolic signatures after metformin treatment, linked to mitochondrial metabolism. These differential metabolic signatures apparent in tumour biopsy samples, did not link to changes in systemic metabolic blood markers including insulin and glucose, suggesting metformin has a predominant direct effect on tumour cells. Analysis of the dynamic FDG-PET-CT data showed that this novel imaging technique may have potential to identify early response to treatment that is not apparent using standard static clinical FDG-PET-CT.
Key point summary of the study:
- There is great interest in repurposing metformin, a diabetes drug, as a cancer treatment
- Two distinct metabolic responses to metformin seen in primary breast cancer
- Increased 18-FDG flux, a surrogate marker of glucose uptake, observed in primary breast tumours following metformin treatment
- Multiple pathways associated with mitochondrial metabolism activated at the transcriptomic level
- Further evidence that metformin’s predominant effects in breast cancer are driven by direct interaction with tumour mitochondria rather than its effects on ‘host’ glucose/insulin metabolism
The study has been funded by Cancer Research UK, the Engineering and Physical Sciences Research Council, the Medical Research Council, and the Breast Cancer Research Foundation.
The published paper can be found at:
Content adapted from the original paper by Simon Lord et al.
A team of Cancer Centre researchers lead by Associate Professor Ross Chapman have discovered a novel DNA repair protein complex called ‘Shieldin’.
Published in Nature, the paper describes the identification of ‘Shieldin’, which was shown to be essential for generating genetic diversity in antibodies produced during immune responses.
When activated following an infection or immunisation, B cells activate the expression of enzymes that induce multiple breaks in the genes encoding the different antibody fragments. Highly specialised DNA repair proteins are essential for the generation of the deletions and mutations required to generate new antibody genes, which enables the production of antibodies with different or improved specificities towards an antigen. Researchers found Shieldin binds to specific DNA structures present at the ends of DNA breaks formed during these processes, and was essential for their repair.
Shieldin was found to link the adaptive immune system to a mutagenic DNA repair process associated with the progression of hereditary breast and ovarian cancers caused by BRCA1 mutations.
Commenting on the link between DNA, the immune system and cancer, Associate Professor Ross Chapman, lead author of the study and group leader at the Wellcome Centre for Human Genetics remarked “For some time, my lab has been puzzled over why a DNA repair pathway that normally only functions in the immune system, is also the primary pathway responsible for cancers driven by BRCA1 gene mutations. In finding Shieldin, we have taken a major step in answering this question. DNA breaks generated during antibody class-switch recombination are known to have single stranded DNA tails at their ends. The fact that Shieldin binds these structures and promotes their repair, also suggests that the recognition and repair of similar DNA structures by Shieldin when the BRCA1 protein is no longer functional, may be what leads to the mutations that cause cancer.”
The group’s findings also provide new insights into how cancer cells can become resistant to anti-cancer drugs: “PARP inhibitors are proving to be an extremely powerful drugs to treat cancers driven by BRCA mutations, however a lot of these cancers are known to then go on to develop resistance. Our work shows mutations that effect any of the four Shieldin proteins will render these cancers completely resistant to PARP inhibitors. By working out exactly how Shieldin works, we hope to identify secondary vulnerabilities in these resistant cancers, which can be exploited in anti-cancer therapies to counteract the threat of this resistance.”
Sarah Blagden Associate Professor of Experimental Cancer Medicine & Consultant Medical Oncologist, and Director of Early Phase Cancer Trials Unit & Oxford ECMC lead, emphasises the importance of the new findings: “In this paper, Ross Chapman and his team have unpicked the main method of DNA damage repair in patients with BRCA1 mutations called non-homologous end joining (NHEJ). By comparing NHEJ in different cellular processes they have shown that, in cells lacking BRCA1, NHEJ is reliant on the four-protein complex Shieldin. Not only do they indicate Shieldin is responsible for the cancers that develop in patients with BRCA1 mutations, but also that Shieldin drives resistance to PARP inhibitors. Chapman’s findings are important in our understanding of why it is that patients with BRCA1 mutations that are taking PARP inhibitors like olaparib, rucaparib or niraparib eventually become resistant to them. By providing these new insights into BRCA1 biology, they open future avenues for tackling PARP resistance and improving outcomes for BRCA1-cancer patients in the future.”
This project was funded by Medical Research Council (MRC) Grant (MR/ M009971/1) and Cancer Research UK Career Development Fellowship (C52690/A19270) awarded to J.R.C.
Oxford University scientist developing new treatments to tackle breast cancer that has spread to the brain
Professor Nicola Sibson of the Department of Oncology has been awarded a grant worth almost £200,000 by research charity Breast Cancer Now to fund cutting-edge research to uncover novel treatment combinations to control breast cancer that has spread to the brain.
The news comes on Secondary Breast Cancer Awareness Day (Friday 13th October 2017), as leading charity Breast Cancer Now announces more than £700,000 of funding across the UK for research specifically targeting secondary (or metastatic) breast cancer – where the disease has spread to another part of the body.
When breast cancer spreads, known as secondary or metastatic breast cancer, it becomes incurable. While metastatic breast cancer can sometimes be controlled using different combinations of treatments, it cannot be cured, and almost all of the 11,500 women that die as a result of breast cancer each year in the UK will have seen their cancer spread. Nearly 600 women in Oxfordshire are diagnosed with breast cancer every year, and over 100 women in the region die from the disease each year.1
The brain is protected by its own security system, a structure called the blood-brain barrier (BBB). The BBB acts as a filter, preventing harmful substances from reaching the brain. However the virtually impenetrable nature of the BBB makes delivery of drugs to the brain extremely difficult, meaning there are few effective treatments for breast tumours that have spread to the brain (brain metastases).
Up to a third of patients with secondary breast cancer have seen their cancer spread to the brain. This can cause varying problems with brain function depending on which areas the breast cancer cells have spread to, and can often severely affect a patient’s quality of life, with debilitating symptoms such as changes in mood or behaviour, seizures, headaches, vomiting and uncoordinated movement.
Professor Sibson, Professor of Imaging Neuroscience at the CRUK/MRC Oxford Institute for Radiation Oncology has previously found that one element of the immune system, the inflammatory response, is important in the spread of breast cancer to the brain. Her team has previously found that certain inflammatory molecules are present at higher levels in brain metastases, and may be key drivers of tumour growth.
With funding from Breast Cancer Now, Professor Sibson and her team will undertake a three-year project to pinpoint which combinations of anti-inflammatory drugs, which are able to cross the BBB, reduce the growth of breast tumours in the brain most effectively, and whether these could also be given alongside radiotherapy with greater effect.
Professor Sibson said “We urgently need to find ways to treat brain metastases more effectively and improve survival rates. With this funding from Breast Cancer Now our aim is to increase treatment options for patients suffering metastatic spread to the brain. We hope that by targeting the innate immune system we can halt or reduce tumour growth, and enhance the effectiveness of radiotherapy.”
The scientists will first implant breast tumours into the brains of mice, before testing a range of anti-inflammatory drugs and examining the effect on tumour growth. The team will then combine the most effective anti-inflammatories with radiotherapy in mice to identify which combinations best control tumour growth in the brain. The researchers hope to identify new ways to predict which patients are most likely to benefit from anti-inflammatory drugs and radiotherapy. In addition, the team will explore how another component of the inflammatory response, adhesion molecules, are involved in tumour growth, and whether targeting these directly could also be an effective treatment strategy.
Dr Richard Berks, Senior Research Communications Officer at Breast Cancer Now said “Professor Sibson’s research could pave the way for new treatment combinations that could halt tumour growth in men and women whose breast cancers have sadly spread to the brain. Anti-inflammatory drugs are already used to treat arthritis – and if these new combinations are found to be effective, these drugs could be made available for treating patients with brain metastases much more quickly.
“It is essential that we find new ways to treat secondary breast cancer in the brain – to improve quality of life and chances of survival for those living with this debilitating disease.
“Our ambition is that by 2050, everyone who develops breast cancer will live. But if we are to achieve this, we desperately need to raise funds for research to find ways to stop the disease spreading. Professor Sibson’s project could help bring us one step closer to our 2050 vision and we’d like to thank our supporters across Oxford who continue to help make our world-class research possible.”
Fiona Leslie, 49 from Aylesbury, is living with incurable metastatic breast cancer. Having first been diagnosed with breast cancer in 2013, Fiona underwent a mastectomy, radiotherapy and chemotherapy, before learning that her breast cancer had unfortunately spread to her lungs and her spine.
In April 2015, Fiona began receiving revolutionary drug Kadcyla, which kept her disease at bay for over two years, and enabled her to live a relatively normal life in the meantime. However in June 2017, scans showed that Fiona’s breast cancer had spread to her brain.
1. Local incidence and mortality survival statistics were provided on request by Public Health England, April 2017.
Drugs used to treat the bone condition osteoporosis could prevent 1000 breast cancer deaths a year, according to a large analysis of previous clinical trials.
The study published in The Lancet, showed that the drugs – called bisphosphonates – reduced the risk of breast cancer coming back, as well as significantly reducing the risk of death, in women diagnosed after their menopause with early-stage breast cancer.
Breast cancers most commonly spread to the bone, and treatment with bisphosphonates alters the bone tissue. This potentially makes the bone a more challenging environment for rogue cancer cells to survive in, reducing the risk of the cancer coming back.
To test this, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) set up by researchers at the Nuffield Department of Population Health,University of Oxford, alongside collaborators from Oxford University Hospitals NHS Trust and many other institutes, combined data from 18,766 women from 26 clinical trials, comparing women who took bisphosphonates for between two and five years, with those who had no bisphosphonates.
Postmenopausal women on bisphosphonates saw a 28 per cent reduction in the chances of their cancer coming back. Bisphosphonates also reduced the risk of dying from the disease during the first 10 years after diagnosis by 18 per cent.
Professor Robert Coleman, who led the study, said that the results show that giving postmenopausal women bisphosphonates after surgery could “prevent around a quarter of bone recurrences and one in six of all breast cancer deaths in the first decade of treatment”.
Cancer Research UK’s chief clinician, Professor Peter Johnson, said that while findings had the potential to save many lives, further in-depth research will be needed.
“This large analysis suggests that, if post-menopausal women with early breast cancer were given bisphosphonates after surgery, it could stop cancer spreading to their bones and save around 1,000 lives a year,” he said.
“Many women already get bisphosphonates to protect against bone disease, but before doctors give this drug to all post-menopausal women at high-risk of breast cancer, more thorough clinical trials are needed,” he added.
A second study by the EBCTCG, also published in The Lancet, looked at the effectiveness of different hormone therapies for breast cancer.
It’s results provide further support for recommendations by NICE that hormone therapies called aromatase inhibitors should be offered to women with early-stage oestrogen receptor (ER)-positive breast cancer, over an older hormone therapy called tamoxifen.
Researchers found that women with ER-positive breast cancer taking aromatase inhibitors for five years had a 40 per cent lower risk of dying within 10 years of starting treatment, compared to those who didn’t take hormone therapy.
This compared to a 30 per cent lower risk following five years of treatment with tamoxifen.
Aromatase inhibitors work by preventing the body from producing oestrogen, and are taken by postmenopausal women with ER-positive breast cancer. They have previously been shown to be more effective than tamoxifen in reducing the chances of cancer coming back, but the new study is the first to show a greater reduction in death rates.
The study looked at data from 31,920 women across nine international clinical trials, with each study including women who had been treated with aromatase inhibitors or tamoxifen at various times during the study.
Lead author Professor Mitch Dowsett, from The Royal Marsden and The Institute of Cancer Research, London, said the global research effort confirmed that aromatase treatment provided “significantly greater protection than that offered by tamoxifen”.
But he cautioned that aromatase therapy was not without its side-effects.
“Aromatase inhibitor treatment is not free of side-effects, and it’s important to ensure that women with significant side-effects are supported to try to continue to take treatment and fully benefit from it,” he said.
The power of such long-term analyses was welcomed by Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, who said they were crucial for bringing the best treatments to patients.
“It tends to be the discovery of new treatments that grabs the headlines, but it is just as important to maximise the benefit patients get from existing treatments, through major, practice-changing studies like this,” he said.
Both studies were funded by Cancer Research UK and the Medical Research Council.
- Early Breast Cancer Trialists’ Collaborative Group: Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet (2015) DOI:10.1016/ S0140-6736(15)60908-4
- Early Breast Cancer Trialists’ Collaborative Group: Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet (2015) DOI:10.1016/S0140-6736(15)61074-1
Men with naturally high levels of the female hormone oestrogen may have a greater risk of developing breast cancer, according to research by an international collaboration including Cancer Research UK published in the Journal of Clinical Oncology.
This is the first time a link between oestrogen levels in the blood and male breast cancer has been identified, despite its connection to breast, womb and ovarian cancers in women.
Men with the highest levels of oestrogen were two and a half times more likely to develop breast cancer than men with the lowest levels of the hormone. Low levels were classified as less than 52.23 picomols of oestrogen per litre of blood (pmol/L), and high levels were more than 86.76pmol/L.
Male breast cancer is very rare with one man in every 100,000 diagnosed with breast cancer each year in the UK. Around 350 male cases are diagnosed each year in the UK compared with nearly 50,000 cases of breast cancer in women.
The research at the National Cancer Institute in the United States was part of an international collaboration between Cancer Research UK, the National Cancer Institute and many other vital funders.
The aim was to study a large international pool of men with breast cancer. The research compared oestrogen levels in 101 men who went on to develop breast cancer with 217 healthy men.
Mark Cross, 46, a police officer from Cambridgeshire, was diagnosed with breast cancer in 2009. He had a mastectomy and then follow-up treatment of chemotherapy and radiotherapy. His treatment ended in September 2010. He said: “The police sometimes get a bit of a reputation for being macho but I had great support from everyone within the Metropolitan police service. Not many people know that men get breast cancer too and it was a complete surprise to be diagnosed. My advice to all men is if you develop a lump on your chest – or anywhere else on your body – get it checked by your doctor as soon as possible. I hope my experience will raise awareness for other men.”
Study author Professor Tim Key, Cancer Research UK’s hormone and nutrition expert at the University of Oxford, said: “We’ve shown for the first time that just like some forms of the cancer in women, oestrogen has a big role to play in male breast cancer. So now the challenge is to find out exactly what this hormone is doing to trigger this rare form of the disease in men, and why some men have higher levels of oestrogen in their blood. Our discovery is a crucial step forward in understanding the factors behind male breast cancer.”
The symptoms, diagnosis and treatment of male breast cancer are very similar to breast cancer in women. The main risk of developing the disease in men is age and almost eight in 10 cases are diagnosed in those aged 60 and older.
Dr Julie Sharp, head of health information at Cancer Research UK, said: “Breast cancer in men isn’t discussed very often, so a diagnosis can be a big shock for the small group of men who develop the disease.
“Some of the oestrogen variation in men will simply be natural, but for others there may be a link to being overweight. Fat cells in the body are thought to drive up the body’s level of this hormone in men and women, so this is another good reason to try and keep a healthy weight.
“This early research is crucial in understanding why these men get breast cancer – so that one day we can treat it more effectively.”
A team, led by Oxford University scientists, took techniques normally used to analyse trace metal isotopes for studying climate change and planetary formation and applied them to how the human body processes metals.
In a world-first the researchers were able to show that changes in the isotopic composition of zinc, which can be detected in a person’s breast tissue, could make it possible to identify a ‘biomarker’ (a measurable indicator) of early breast cancer.
A report of the research by the Oxford University-led team, which included researchers from Imperial College London and the Natural History Museum, London, is published in the Royal Society of Chemistry journal Metallomics.
The pilot study analysed zinc in the blood and blood serum of ten subjects (five breast cancer patients and five healthy controls) alongside a range of breast tissue samples from breast cancer patients. By using techniques that are over 100 times more sensitive to changes in the isotopic composition of metals than anything currently used by clinicians, the researchers were able to show that they could detect key differences in zinc caused when cancer subtly alters the way that cells process the metal. Similar changes in copper in one of the breast cancer patients is additional evidence that it may be possible to identify a biomarker for early breast cancer that could form the basis of a simple, non-invasive, diagnostic blood test.
‘It has been known for over a decade that breast cancer tissues contain high concentrations of zinc but the exact molecular mechanisms that might cause this have remained a mystery,’ said Dr Fiona Larner of Oxford University’s Department of Earth Sciences & CRUK Oxford Centre Member, who led the research. ‘Our work shows that techniques commonly used in earth sciences can help us to understand not only how zinc is used by tumour cells but also how breast cancer can lead to changes in zinc in an individual’s blood – holding out the promise of an easily-detectable biomarker of early breast cancer.’
The researchers say that this new understanding of cancer cell behaviour – in particular the role sulfur-containing proteins play in how tumours process zinc – could also help in the development of new cancer treatments.
‘The hope is that this research is the beginning of a whole new approach,’ said Dr Larner. ‘Understanding how different cancers alter different trace metals within the body could enable us to develop both new diagnostic tools and new treatments that could lead to a ‘two-pronged’ attack on many cancers. Further research is already underway to see what changes in other metals may be caused by other cancers.’
A report of the research, entitled ‘Zinc isotopic compositions of breast cancer tissue’, is published in the journal Metallomics.