Tamoxifen Lasting Benefits Sees Breast Cancer Deaths Down By Third

The benefits of using tamoxifen to prevent recurrence of breast cancer after surgery continue to accrue long after women stop taking the drug, a study led by Oxford University has found.

The findings suggest that for women with the most common type of breast cancer, full compliance with daily tamoxifen therapy for five years would reduce the long-term chances of dying by at least a third.

Oxford researchers used data from 20 trials comparing tamoxifen use for five years against no tamoxifen.

Credit: US National Cancer Institute

‘Breast cancer is a nasty disease because it can come back years later,’ says Dr Christina Davies of the Clinical Trial Service Unit at Oxford University, and one of the lead investigators. ‘This study now shows that tamoxifen produces really long-term protection.

‘For ER-positive disease, tamoxifen reduces 15-year breast cancer mortality by at least a third, whether or not chemotherapy has been given.’

Most breast cancers are oestrogen receptor (ER)-positive – in the US or UK, it’s about 4 out of 5 breast cancers that are ER-positive.

Since tamoxifen acts on the ER protein in breast cancer cells, it can have an effect only if those cells contain some ER protein. But a simple test on surgically removed breast cancers can determine whether the cancer is ER-positive or not.

Various treatments can be given after apparently successful breast cancer surgery to prevent any tiny residual fragments eventually causing the cancer to come back as an incurable disease.

Many randomised trials have been conducted to try to determine the best treatment options, and every 5 years for the past 25 years the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) has brought together all the evidence from all of these trials.

In the current study, funded by Cancer Research UK, the Medical Research Council and the British Heart Foundation, the researchers brought together individual patient data for over 20,000 women with early-stage breast cancer from 20 randomised trials. The trials compared treatment with tamoxifen for 5 years against no tamoxifen, with participants showing 80% compliance in taking the daily pill.

Most of the trials of tamoxifen began in the 1980s, meaning there is now lots of data available on the long-term effects of treatment after women stopped taking the drug. That long-term analysis, published in the Lancet medical journal, now reveals large additional benefits of tamoxifen in reducing breast cancer deaths, not only during the first decade but also during the second decade after treatment began.

The researchers found that in women with ER-positive disease, 5 years of daily tamoxifen safely reduced the long-term (15-year) risks of breast cancer recurrence and death. It was effective whether or not chemotherapy had been given.

Remarkably, the researchers found a highly significant reduction in breast cancer mortality, not only during the five years of treatment and the five years following, but also during years 10–14.

Even in weakly ER positive disease, tamoxifen substantially reduced the likelihood of the cancer recurring.

There is a newer class of drugs called aromatase inhibitors (AIs) that offer an alternative to tamoxifen for some patients, but AIs are effective only in post-menopausal women.

Dr Davies explains that tamoxifen was developed 50 years ago and is long out of patent, so is relatively cheap. But even if costs are ignored it remains a major first-line treatment option for women with ER-positive breast cancer, she says – especially for women pre-menopause.

Moreover, the rare life-threatening side-effects of tamoxifen (uterine cancer and blood clots) are mainly experienced by women over 55 years of age, so there is little risk from giving tamoxifen to younger women.

Worldwide, half of all new patients diagnosed with breast cancer are younger than 55 years – that’s 0.7 million women.

Contacts and sources:
The Lancet/Oxford University

Why Plant 'Clones' Aren’t Identical

A new study of plants that are reproduced by ‘cloning’ has shown why cloned plants are not identical.

Scientists have known for some time that ‘clonal’ (regenerant) organisms are not always identical: their observable characteristics and traits can vary, and this variation can be passed on to the next generation. This is despite the fact that they are derived from genetically identical founder cells.

Clones of the plant 'thalecress' were analysed. 

Photo: Alberto Salguero
Now, a team from Oxford University, UK, and King Abdullah University of Science and Technology, Saudi Arabia, believe they have found out why this is the case in plants: the genomes of regenerant plants carry relatively high frequencies of new DNA sequence mutations that were not present in the genome of the donor plant.

The team report their findings in this week’s Current Biology.

‘Anyone who has ever taken a cutting from a parent plant and then grown a new plant from this tiny piece is actually harnessing the ability such organisms have to regenerate themselves,’ said Professor Nicholas Harberd of Oxford University’s Department of Plant Sciences, lead author of the paper. ‘But sometimes regenerated plants are not identical, even if they come from the same parent. Our work reveals a cause of that visible variation.’

Using DNA sequencing techniques that can decode the complete genome of an organism in one go (so-called ‘whole genome sequencing’) the researchers analysed ‘clones’ of the small flowering plant ‘thalecress’ (Arabidopsis). They found that observable variations in regenerant plants are substantially due to high frequencies of mutations in the DNA sequence of these regenerants, mutations which are not contained in the genome of the parent plant.

‘Where these new mutations actually come from is still a mystery,’ said Professor Harberd. ‘They may arise during the regeneration process itself or during the cell divisions in the donor plant that gave rise to the root cells from which the regenerant plants are created. We are planning further research to find out which of these two processes is responsible for these mutations. What we can say is that Nature has safely been employing what you might call a ‘cloning’ process in plants for millions of years, and that there must be good evolutionary reasons why these mutations are introduced.’

The new results suggest that variation in clones of plants may have different underlying causes from that of variation in clones of animals – where it is believed that the effect of environmental factors on how animal genes are expressed is more important and no similar high frequencies of mutations have been observed.

Professor Harberd said: ‘Whilst our results highlight that cloned plants and animals are very different they may give us insights into how both bacterial and cancer cells replicate themselves, and how mutations arise during these processes which, ultimately, have an impact on human health.’

A report of the research, ‘Regenerant Arabidopsis Lineages Display a Distinct Genome-Wide Spectrum of Mutations Conferring Variant Phenotypes’, is published this week online in Current Biology.

The project is a collaboration between scientists at Oxford University’s Department of Plant Sciences, Oxford University’s Wellcome Trust Centre for Human Genetics, and King Abdullah University of Science and Technology (KAUST), Saudi Arabia. The research was supported by KAUST and the UK’s Biotechnology and Biological Sciences Research Council.

Contacts and sources:
Oxford University

Lost Gospels Found? Ancient Lives Project Seeks Public Help Translating Ancient Papyri

Members of the public are being asked to help decode papyri, in order to find fragments of lost gospels, works of literature, and letters about everyday life in ancient Egypt, in a new project launched by Oxford University.

Oxyrhynchus Papyrus 5072 (3rd century AD), Uncanonical Gospel. Credit: Photo courtesy of the Egypt Exploration Society and Imaging Papyri Project, Oxford. 

  

Credit: Oxford. All rights reserved.

Ancient Lives (ancientlives.org), which launches today, is putting hundreds of thousands of images of fragments of papyri written in Greek online. Researchers say that ‘armchair archaeologists’ visiting the website can help with cataloguing the collection, and could make amazing finds, such as the recent discovery of fragments of a previously unknown ‘lost’ gospel which describes Jesus Christ casting out demons.

Nobody knows who wrote this lost gospel: it is part of a treasure trove of papyri recovered in the early 20th century from the Egyptian city of Oxyrhynchus, the ‘City of the Sharp-Nosed Fish’. The texts were written in Greek during a period when Egypt was under the control of a Greek (and later Roman) settler class. Many of the papyri had not been read for over a thousand years.

Because of the huge number of images involved researchers need volunteers to look through and catalogue them or transcribe the text using a simple web interface, which displays both known and unknown texts.

‘It’s with the digital advancements of our own age, that we're able to open up this window into the past, and see a common human experience in that intimate, traditional medium, handwriting,’ said lead developer and designer, William MacFarlane of Oxford University’s Department of Physics.

Experts have been studying the collection for over a hundred years. It is because of Oxyrhynchus that we now have lost masterpieces that went missing during the medieval period: the lost poetry of Sappho, the lost comedies of Menander and the lost plays of Sophocles. There are personal documents too – we learn from a letter that Aurelius the sausage-maker has taken out a loan of 9000 silver denarii, perhaps to expand his business, whilst in another letter of 127 AD a grandmother, called Sarapias, asks that her daughter is brought home so that she can be present at the birth of her grandchild.

‘Discovering new texts is always exciting,’ explains team papyrologist Dr James Brusuelas, ‘but the fact that you’re reading a piece of literature or a private letter that hasn’t been read in over a thousand years, that’s what I like about papyrology.’ Paul Ellis, an imaging specialist who assisted with the digitization of the papyrus texts, said: ‘Online images are a window into ancient lives.’

The project is a collaboration between Oxford University papyrologists, the Egypt Exploration Society, and a team in Oxford University’s Department of Physics who specialise in building ‘citizen science’ projects that allow anyone to make an authentic contribution to research.

‘Until now only experts could explore this incredible collection,’ said project leader Dr Chris Lintott of Oxford University’s Department of Physics, ‘but with so much of the collection unstudied there’s plenty for everyone. We’re excited to see what visitors to ancientlives.org can unearth.’

‘Papyrologists are well known for friendship among those interested in ancient texts,’ said Project Director Dr Dirk Obbink, Oxford University Lecturer in Papyrology and Greek Literature at the University of Oxford. ‘This effort is pervaded by a spirit of collaboration. We aim to transcribe as much as possible of the original papyri, and then identify and reconstruct the text. No single pair of eyes can see and read everything. From scientists and professors to school students and ancient enthusiasts, everyone has something to contribute – and gain.’

Ancientlives.org is part of the www.zooniverse.org network of public participation projects, which includes Old Weather, which aims to rescue weather records contained in World War I ship’s logs. More than 500,000 logbook pages have been transcribed so far. The original Zooniverse project was Galaxy Zoo, and a total of more than 400,000 people have registered to take part.

The project was supported by a grant from the Arts and Humanities Research Council and the John Fell Fund, and is indebted to the Oxford University Department of Classics and the Egypt Exploration Society, London who oversee the Oxyrhynchus Collection in the Sackler Library, Oxford as part of a wide range of scholarly and outreach activities.

Contacts and sources:

Oxford University