David Cohen, M.D.·Published 20 April 2012·8 min read
Key points
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 National Breast Cancer Coalition (NBCC) is a grassroots organization dedicated to ending breast cancer through action and advocacy.
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.
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.
Breast Cancer Statistics Aside from non-melanoma skin cancer, breast cancer is the most common cancer among women in the United States. It is also one of the leading causes of cancer death among women of all races and Hispanic origin populations.
In 2007 (the most recent year numbers are available) -
202,964 women were diagnosed with breast cancer. 40,598 women died from breast cancer.
*Incidence counts cover approximately 99% of the U.S. population. Death counts cover 100% of the U.S. population. Use caution in comparing incidence and death counts. †Source: U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2007 Incidence and Mortality Web-based Report.
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.
Breast Cancer in the United States: 2011
The National Breast Cancer Coalition (NBCC) is a grassroots organization dedicated to ending breast cancer through action and advocacy. NBCC members are committed to reaching this goal by 2020. Following are a few statistics that speak to the need to end this deadly disease:
Written and revised by
David Cohen, M.D.
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- The National Cancer Institute estimates that a woman in the United States has a 1 in 8 chance of developing invasive breast cancer during her lifetime. This risk was about 1 in 11 in 1975 (ACS, 2010).
- On January 1, 2008, in the United States there were approximately 2,632,005 women alive who had a history of breast cancer (SEER, 2011).
- Breast cancer is the second leading cause of cancer death for women in the U.S, after lung cancer. Approximately 39,970 women and 450 men in the U.S. will die from the disease in 2011 (ACS, 2011).
- Excluding skin cancer, breast cancer is the most commonly diagnosed cancer among women in the United States. It is estimated that 230,480 new cases of invasive breast cancer will be diagnosed among women in the U.S. in 2011. In addition to invasive cancers, 57,650 new cases of in situ breast cancer will be diagnosed; approximately 49,003 of which will be ductal carcinoma in situ (DCIS). Approximately 2,140 new cases of invasive breast cancer will be diagnosed among U.S men (ACS, 2011).
- The incidence of breast cancer declined from 1999 to 2003, with the greatest decline among white women. Incidence rates have remained relatively stable since 2003 (SEER, 2011).
- According to the SEER data from 2001-2007, approximately 90% of women diagnosed with invasive breast cancer were still living five years after getting the disease; among black women, approximately 77% were still living five years after getting the disease (SEER, 2011).
- Older women are much more likely to get breast cancer than younger women. From 2004-2008, the median age for a breast cancer diagnosis was 61 years of age. Approximately 0.0% were diagnosed under age 20; 1.9% between 20 and 34; 10.2% between 35 and 44; 22.6% between 45 and 54; 24.4% between 55 and 64; 19.7% between 65 and 74; 15.5% between 75 and 84; and 5.6% 85+ years of age. (SEER, 2011).
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.
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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.
- Mammography screening has led to a dramatic increase in the incidence of ductal carcinoma in situ (DCIS). The diagnosis was relatively rare before the early 1980's and the widespread use of mammography. Today, approximately one woman is diagnosed with DCIS for every four women diagnosed with invasive breast cancer (Allegra et al, 2010). - All women are at risk for breast cancer. Only 5-10% of those with breast cancer have inherited a mutation in the known breast cancer genes (BRCA1 and BRCA2) and 90-95% of breast cancer cases do not involve these inherited mutations. (ACS 2010; NCI 2006). - Factors that increase a woman's risk of breast cancer include older age, genetic factors, family history of breast or ovarian cancer, long menstrual history, null parity (having no children), older than 30 years of age at first full-term pregnancy, daily alcohol consumption, use of combined postmenopausal hormone replacement therapy (HRT), postmenopausal obesity and ionizing radiation. Factors that decrease a woman's risk of breast cancer include breast-feeding and physical activity (exercise) (ACS, 2010). - There is some new data to suggest that these risk factors have less influence among Hispanic women. According to results of the 4-Corners Breast Cancer Study, Hispanic women with breast cancer were more likely than white women with breast cancer to have characteristics associated with a lower risk of breast cancer, such as younger age at first birth, having more children, less hormone use, and less alcohol consumption (Hines et al, 2010). - Higher breast density has been shown to be associated with the risk of breast cancer. It was found that the rate of breast cancer was almost four times greater in those with extremely dense breast tissue as opposed to those with fatty breast tissue. It is important to remember that since mammography is less sensitive in detecting breast cancer for dense breasts, the effect of breast density may be somewhat underestimated (Barlow et al, 2006). - Studies on chemo preventive agents tamoxifen and raloxifene were not adequately designed to determine their impact on the prevention of breast cancer for healthy women, nor are the studies long enough to assess long term side effects and impact on mortality (Vogel et al, 2010).
"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.
### Written by Catharine Paddock PhD
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