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Breast Cancer Is 10 Diseases Says Landmark Study

Breast cancer is at least 10 different diseases, each with its own genetic signature and pattern of weak spots, according to a new landmark study that promises to revolutionize diagnosis and prognosis, and pave the way for individualized, tailored treatment.

The study group, METABRIC (Molecular Taxonomy of Breast Cancer International Consortium), reports its findings in the 18 April online issue of Nature

The Cancer Research UK-funded study is the largest global gene study of breast cancer tissue ever conducted, involving a large team of researchers, primarily in the UK and Canada.

Led by Professor Carlos Caldas from Cancer Research UK's Cambridge Research Institute and Professor Sam Aparicio from the British Columbia Cancer Centre in Canada, the team uncovered crucial new information about breast cancer.

The researchers analyzed the DNA and RNA of breast tumor samples from nearly 2,000 women who had been diagnosed between five and 10 years ago, and for whom information about the tumor characteristics had been meticulously recorded.

They compared this with the women's survival, and other information, like their age at diagnosis.

Because the study was able to look at many tumors with rich data on each, it identified new patterns and "clusters" in the data not spotted before.

In the study, the team classified breast cancer into at least 10 different subtypes: each characterized by common genetic features that link to survival.

This suggests we need to rethink what we call breast cancer and start looking at it as at least 10 different diseases, each with its own molecular fingerprint and pattern of weak spots.

Dr Harpal Kumar, chief executive of Cancer Research UK, told the press the study will completely change the way we look at breast cancer. 

Caldas, who is also Professor of Cancer Medicine at Cambridge's Department of Oncology, said "breast cancer" should be regarded as an umbrella term for a range of diseases.

The findings could change the way drugs are tailored to treat individual women with breast cancer.

The team also discovered several previously unknown genes that drive breast cancer. Each of these is a potential target for new drugs, and should boost worldwide efforts to discover and develop new treatments.

The study also reveals the relationship between these breast cancer genes and known signalling pathways, the networks that control cell growth and division. This invaluable knowledge will help identify how variants of these genes cause cancer by interfering with cell processes.

Over decades, the METABRIC project has produced a "goldmine" of data, says Caldas.

The process is not unlike that of cartography. At first, intrepid explorers discover new continents, defined by outlines and some rough impressions of terrains and landscapes.

Then gradually, as mapping techniques improve, the data becomes more detailed and more precise.

The METABRIC team now has a detailed "map" of thousands of individual tumors that have been analyzed and re-analyzed in many different ways and linked to detailed information about the fate of the women they came from.

Not only has the team performed all kinds of analysis on the DNA of the tumors (for instance the map is now annotated with copy number changes and single letter variations or SNPs, for each tumor), it has also conducted a detailed analysis of their RNA so they can tell which genes were active in each sample. Altogether they did this for more than 30,000 types of RNA, each corresponding to the activity of a single gene.

"We've drilled down into the fundamental detail of the biological causes of breast cancer," said Caldas, "we've moved from knowing what a breast tumour looks like under a microscope to pinpointing its molecular anatomy".

"Our results will pave the way for doctors in the future to diagnose the type of breast cancer a woman has, the types of drugs that will work, and those that won't, in a much more precise way than is currently possible," he added.

Aparicio said:

"The new molecular map of breast cancer points us to new drug targets for treating breast cancer and also defines the groups of patients who would benefit most."

Caldas said these results will not affect women diagnosed with breast cancer today, but he envisages future breast cancer patients will receive treatments tailored specifically to the genetic fingerprints of their tumors.

From this huge leap forward, the next step is to find out how the tumors in each of subgroup behave. How fast do they grow and spread? 

Caldas said we also need to do more studies, both in the lab and in patients, to confirm the most effective treatments for each of the 10 types of breast cancer.

"The size of this study is unprecedented and provides insights into the disease such as the role of immune response, which will stimulate other avenues of research," added Aparicio.

Kumar said the study marks the result of decades of research by Cancer Research UK to find the causes and drivers of breast cancer and enables a further step-change for patients with breast cancer.

"We're entirely funded by the generosity of the public and this incredible support has put us at the heart of progress that's underpinned the dramatic increase in the number of women surviving from breast cancer in the UK," he added.

Caldas had this to say to the patients behind the study:

"I want to stress, this study wouldn't have been possible without the breast cancer patients who donated their samples and agreed to take part in the study. None of this would have happened without them, and I'm so grateful for their participation."

For an excellent account of how we have increased our understanding of breast cancer, plus a table showing the 10 disease subtypes, see Henry Scowcroft's post in the Cancer Research UK Science Update blog.

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