A new study led by Dr John Marshall, Reader in the Centre for Tumour Biology, has been published online in the Journal of the National Cancer Institute. The paper will be available in print next month.
This work by first author Dr Kate Moore and colleagues not only reveals that high levels of integrin αvβ6 in breast tumours identifies patients at high risk of developing secondary tumours (and poor survival).
Importantly, they have also shown that targeting αvβ6 with blocking antibody therapy could be effective against some of the most aggressive types of breast cancer - tumours were even eliminated in their combination therapy model.
We don't yet know all of breast cancer's secrets
These findings come as Breast Cancer Campaign launches a new educational campaign – "#spreadtheword to stop the spread", which highlights that it is not a done deal, with 12,000 women still dying from the disease every year.
Around 1 in 5 breast cancers – 10,000 cases a year in the UK – are HER2-positive, a particularly aggressive type of breast cancer where increased levels of the HER2 protein gives cancer cells the ability to grow and spread. The researchers found that up to 4,000 of these 10,000 cases may be high-risk tumours.
Currently, the first line of treatment for patients with HER2-positive breast cancer is the targeted therapy Herceptin, also known as trastuzumab. Herceptin blocks growth signals from HER2 to stop the cancer cells growing and spreading. However, it has been estimated that up to 7 in 10 patients either do not respond to Herceptin, or develop resistance to it - leaving up to 7,000 women in the UK every year with limited treatment options.
Our lead researcher, Dr Kate Moore, explained:
“The αvβ6-targeting antibody called 264RAD had been shown to reduce tumour size and spread in our previous studies, but hadn’t been tested in combination with other drugs.
We found that simultaneously targeting αvβ6 and HER2 in mice with tumours grown from human breast cancer cells greatly improved the effectiveness of Herceptin (trastuzumab) – even eliminating tumours that did not respond to Herceptin alone, which could have the potential to improve treatments for patients with these highly aggressive cancers.”
αvβ6, which belongs to the family of proteins called integrins, is usually not detectable on healthy cells. Previous work shows that αvβ6 is found in cancer cells and promotes cell migration, invasion and survival, but until now its relevance and role in breast cancer growth and spread was unknown.
What we've learned
The team analysed breast cancer samples from over 2000 patients from Nottingham and London and found that while normal breast tissue contained no trace of αvβ6, high levels of αvβ6 were found in 40 per cent of tumours from HER2-positive patients, and this was associated with poor survival. Even when results were adjusted for other tumour features, HER2-positive patients with high αvβ6 were twice as likely to die within five years of diagnosis compared to those with low levels.
To investigate this αvβ6/HER2 link, they studied HER2-positive breast cancer cell lines, including one which was Herceptin-resistant. Using the experimental antibody 264RAD (provided by Oncology iMED, AstraZeneca) to block αvβ6, the team was able to confirm that the ability of the cancer cells to invade was dependent on the presence of αvβ6.
Breast cancer cells not treated with avB6 blocking antibody (control, left) have grown extensively and invaded the gel, but this spreading is blocked in the cancer cells treated with αvβ6 blocking antibody (right). Image by Dr Kate Moore.
In further experiments, treating mice that had Herceptin-resistant tumours for six-weeks with a combination of 264RAD and Herceptin completely eradicated tumours, whereas the tumours in mice treated with only 264RAD or Herceptin continued to grow.
In mice with tumours that were sensitive to Herceptin, just two weeks of combination treatment caused a 94.8 per cent decrease in the final tumour size, compared with the untreated control group. In comparison, the reduction caused with Herceptin alone was only 77.8 per cent, suggesting that targeting αvβ6 could improve the effectiveness of Herceptin even against tumours which appear to be responding to the drug.
Dr John Marshall said,
“The results of this pre-clinical study suggest that targeting the αvβ6 molecule may enhance the effectiveness of Herceptin – and that a combination treatment could be effective for patients where Herceptin alone has not worked,”
“High αvβ6 levels could be tested for in routine biopsies to identify which women are at a high risk of metastasis, ensuring these women can receive personalised treatment, improving their chances of survival.”
Baroness Delyth Morgan, Chief Executive at Breast Cancer Campaign, said:
“Despite great advances in the past 20 years, five-year breast cancer survival in the UK is worse than the European average. Our Spread the word campaign highlights that breast cancer is not a done deal and that much more must be done to improve survival rates.
“There is a desperate need for drugs which work in new ways to give the thousands of women diagnosed with HER2-positive breast cancer the best possible chances of surviving the disease. This study could pave the way for new treatments and bring us closer to our goal of preventing half of the deaths from breast cancer by 2025, through improved and personalised treatments.”
With further support from a Breast Cancer Campaign grant, Dr Marshall and Dr Moore are now investigating the most effective time to treat tumours with 264RAD – this could show whether targeting αvβ6 in combination with Herceptin could stop the spread of HER2-positive breast cancer, and have the potential to prevent a significant number of the 12,000 deaths from breast cancer in the UK each year.
Kate working in Tissue Culture in the Centre for Tumour Biology
Ideally we would also set up and run of clinical trials to test the combination over the course of several years after these preliminary studies are completed; standard practice before any new treatment can be taken to patients more widely.
As well as this news being promising for breast cancer patients, since αvβ6 is expressed by many other tumour types, similar effective combination therapies could be developed for other cancers. Considering normal tissues also do not express this integrin, we should see minimal side-effects from these treatments - again something clinical trials can confirm.
The work was funded by grants from Breast Cancer Campaign and the Medical Research Council (MRC).
Therapeutic Targeting of Integrin αvβ6 in Breast Cancer
Moore, K.M , Gareth J. Thomas, Stephen W. Duffy, Jane Warwick, Rhian Gabe, Patrick Chou, Ian O. Ellis, Andrew R. Green, Syed Haider, Kellie Brouilette, Antonio Saha, Sabari Vallath, Rebecca Bowen, Claude Chelala, Diana Eccles, William J. Tapper, Alastair M. Thompson, Phillip Quinlan, Lee Jordan, Cheryl Gillett, Adam Brentnall, Shelia Violette, Paul H. Weinreb, Jane Kendrew, Simon T. Barry, Ian R. Hart, J. Louise Jones, John F. Marshall (2014) JCNI. Published online June 30 2014, DOI: 10.1093/jnici/dju169
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With thanks to the Breast Cancer Campaign's Press Office for their press release work, which helped this research to reach a potential audience of more than 15 million people last week alone.