Study reveals magnitude of variation in gene expression measurements within breast cancers
An important new study has revealed the clearest picture yet of precisely how much measurement variation influences gene expression profiles of breast cancer.
The results show, for the first time, which gene expression measurements may benefit from pooling of biopsies from a single tumour, researchers said at the 5th IMPAKT Breast Cancer Conference in Brussels, Belgium.
These findings represent an important step toward allowing doctors to more precisely tailor an individual’s treatment to a detailed analysis of their tumour’s gene expression.
Over recent years, scientists have identified many genes, and groups of genes, that can provide crucial information about how an individual patient’s cancer will respond to treatment with different drugs.
But a number of hurdles need to be cleared before tests to measure the expression of these genes can be used in clinical situations.
One important challenge is the fact that many different cell types can be present within a single tumour (known as intratumoural heterogeneity), each with different patterns of gene expression and potentially different sensitivity to drugs.
- White women are slightly more likely to develop breast cancer than African-American women. However, in women under 45, breast cancer is more common in African-American women than white women. Overall, African-American women are more llkely to die of breast cancer. Asian, Hispanic, and Native-American women have a lower risk of developing and dying from breast cancer.
- In 2011, there were more than 2.6 million breast cancer survivors in the US.
- A woman’s risk of breast cancer approximately doubles if she has a first-degree relative (mother, sister, daughter) who has been diagnosed with breast cancer. About 15% of women who get breast cancer have a family member diagnosed with it.
- About 5-10% of breast cancers can be linked to gene mutations (abnormal changes) inherited from one’s mother or father. Mutations of the BRCA1 and BRCA2 genes are the most common. Women with these mutations have up to an 80% risk of developing breast cancer during their lifetime, and they are more likely to be diagnosed at a younger age (before menopause). An increased ovarian cancer risk is also associated with these genetic mutations.
- In men, about 1 in 10 breast cancers are believed to be due to BRCA2 mutations, and even fewer cases to BRCA1 mutations.
- About 85% of breast cancers occur in women who have no family history of breast cancer. These occur due to genetic mutations that happen as a result of the aging process and life in general, rather than inherited mutations.
- The most significant risk factors for breast cancer are gender (being a woman) and age (growing older).
- As of Jan. 1, 2009, there were about 2,747,459 women alive in the United States with a history of breast cancer. This includes women being treated and women who are disease-free.
“Performing these tests with a single biopsy may or may not accurately represent that cancer, depending on intratumoural heterogeneity,” explains lead author Dr Rosanna Lau from the University of Texas MD Anderson Cancer Center, US.
A further complication is that some of the variation between test results can arise from technical variations in the testing process, and not by real differences between samples (analytical variance).
To differentiate between these sources of variation in breast cancer, Dr Lau and colleagues performed DNA microarray analysis on three biopsies each from 51 breast cancers.
Breast cancer statistics are presented here.
In 2010, 49,564 women and 397 men in the UK were diagnosed with invasive breast cancer.
In 2010 there were 11,556 female and 77 male deaths from invasive breast cancer in the UK.
In 2005-2009, 85.1% of adult female breast cancer patients in England survived their cancer for five years or more.
In 2010, 5,765 women and 26 men in the UK were diagnosed with in situ breast carcinoma.
“Our results indicate that analytical variance, resulting from technical aspects of the assay, can be dramatically reduced by standard data processing methods such as normalizing and scaling,” Dr Lau says. “Pre-analytical sources of variance, such as tissue preservation method and ischemia mostly did not affect gene measurements.”
The dominant source of variance between biopsies from the same tumour was due to intratumoural heterogeneity, Dr Lau’s group found. However, the extent of that variation depended on the particular gene or groups of genes being studied.
“Some genes, such as ESR1 and HER2, are very consistently expressed across the tissue, thus gene expression measurements display little variation between biopsies. However, other genes such as MKI67, which is known to be highly variable, is expressed less consistently, and therefore can produce vastly different results depending on the area of the tumour that is sampled,” Dr Lau says.
- About 1 in 8 U.S. women (just under 12%) will develop invasive breast cancer over the course of her lifetime.
- In 2011, an estimated 230,480 new cases of invasive breast cancer were expected to be diagnosed in women in the U.S., along with 57,650 new cases of non-invasive (in situ) breast cancer.
- About 2,140 new cases of invasive breast cancer were expected to be diagnosed in men in 2011. A man’s lifetime risk of breast cancer is about 1 in 1,000.
- From 1999 to 2005, breast cancer incidence rates in the U.S. decreased by about 2% per year. The decrease was seen only in women aged 50 and older. One theory is that this decrease was partially due to the reduced use of hormone replacement therapy (HRT) by women after the results of a large study called the Women’s Health Initiative were published in 2002. These results suggested a connection between HRT and increased breast cancer risk.
- About 39,520 women in the U.S. were expected to die in 2011 from breast cancer, though death rates have been decreasing since 1990 — especially in women under 50. These decreases are thought to be the result of treatment advances, earlier detection through screening, and increased awareness.
- For women in the U.S., breast cancer death rates are higher than those for any other cancer, besides lung cancer.
- Besides skin cancer, breast cancer is the most commonly diagnosed cancer among American women. Just under 30% of cancers in women are breast cancers.
For the first time, Dr Lau’s group also showed how combining samples of two or three biopsies from a single breast tumour could effectively overcome this variation for selected genes.
“Differences between tumours are much greater than variability within a tumour or a test. Our current study shows that we can get a comprehensive picture of the genes being expressed in the tumour by sampling multiple areas of the tumour and pooling the samples together. This increases the precision of the assay and allows us to make more reliable predictions related to the disease. The trade-off is that intratumoural heterogeneity is also averaged to a single, more consistent measurement.”
This study is an excellent example of how researchers are rising to the challenges of tumour heterogeneity, comments Prof Charles Swanton, Chair in Personalised Cancer Medicine at the UCL Cancer Institute in London and from the Cancer Research UK London Research Institute, member of the ESMO Translational Research Working Group, who was not involved in the study.
“Developing accurate biomarkers that are not subject to real tumour sampling bias is of critical importance. This intricate study will likely be a gold standard by which other studies in this area are measured. Such in-depth analyses will ultimately be essential in the biomarker qualification process,” he said.
“The study also emphasises the need to limit the potential for tissue processing or assay technologies to lead to spurious measurements through well-defined standardised operating procedures,” Prof Swanton said.
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