The result of this study may lead to a re-evaluation of the importance of breast density, which is far the most undervalued and underutilized risk factor for breast cancer. Commenting on the study, Cuzick said that ‘Apart from age and BRCA1 and BRCA2 mutations, increased breast density is the leading risk factor for breast cancer.’
Density is a factor
Because of the differences in tissue composition and differences in the radiographic attenuation properties of fat, stroma, and epithelium, mammographic appearance of the breast varies among women.
In a study published in the January 2004 edition of Radiology, the journal of the Radiological society of North America, Dr Jennifer A. Harvey, MD and Dr Viktor E. Bovbjerg, PhD of the Departments of Radiology and Health Evaluation Sciences, of the University of Virginia in Charlottesville say that a plausible explanation of the association of breast density with increased breast cancer risk is the development of premalignant lesions such as atypical ductal hyperplasia, levated growth factors, or increased estrogen production within the breast due to overactive aromatase. The amount of breast density may also be due in part to genetic heredity.
Harvey and Bovbjerg noted that, unlike other risk factors, breast density may be influenced. 'Because breast density is very hormonally responsive, it may be influenced by lifestyle factors such as alcohol intake and diet,' Harvey explained. 'Breast density may reflect increased risk due to other causes or it may be an independent risk factor,' she continued. While weight, body mass index, age, menopausal status, age at first birth, nulliparity, family history, hormone use, and previous breast biopsy may all influence breast density, it is consistently identified as an independent risk factor after adjustment for other variables associated with both density and breast cancer risk
A number of studies in varied settings and populations have shown that women with dense tissue in 75% or more of the breast have a risk of breast cancer four to six times as great as the risk among women with little or no dense tissue. Based on this and other observations, Dr Karla Kerlikowske, MD, of the University of California in San Francisco, suggested, in an editorial in the January 2007 edition of the New England Journal of Medicine, that breast density should be measured in clinical practice and used to maximize primary and secondary prevention of cancer.
A Biomarker
However, for mammographic density to be considered as a biomarker, it is necessary to demonstrate that the risk reduction induced by a preventive intervention can be predicted by change in density, and that patients experiencing the largest change are most likely to benefit from treatment. Cuzick said that if their findings are validated in follow-up studies, women at risk for developing breast cancer should have a baseline mammogram before starting use of tamoxifen, and then a follow-up scan a year or two later to monitor breast density.
‘If there is a reduction, the agent is having an effect; if density is the same, it may not be a beneficial drug for the individual woman,' Cuzick noted. ‘It is important to find a way to predict who will respond to tamoxifen, and changes in breast density may constitute an early indicator of benefit,' he continued. ‘This is important to know because other preventive options now exist or are being tested.’
IBIS-1 and tamoxifen
Cuzick also led the International Breast Intervention Study I (IBIS-I), an international trial in which postmenopausal women at high risk of breast cancer were given tamoxifen to see how effective this drug is in preventing them from developing the disease. This trial involved more than 7,000 participants.
‘In the IBIS-1 study, tamoxifen reduced the risk of breast cancer by about 40%,’ Cuzick explained. In this study, we focus on whether the change in breast density after 12-18 months of prophylactic treatment predicts the subsequent impact of tamoxifen on the development of breast cancer.
Results of this study found the agent reduces the risk of estrogen-positive (ER) breast cancer by 30 to 40% among women at high risk. During that study, researchers collected baseline mammograms, as well as mammograms at 18, 36, and 54 months to check for breast cancer development. Based on analysis of these mammograms, Cuzick and his colleagues later found a strong correlation between reduction of breast density in women who use tamoxifen and lowered breast cancer risk. But for the rest of the women - where tamoxifen did not reduce breast density – risk of the disease was not significantly reduced.
In this follow-up study, the investigators examined a subpopulation of the IBIS-I participants (120 women who developed breast cancer and 943 who didn’t), to see if their mammograms changed over time and if tamoxifen treatment reduced breast density. They also looked at changes in other variables, such as hormone status, body weight and familial factors. They found that only change in mammographic density predicted reduction of risk for ER-positive breast cancer.
Confirmation required
For the 46 percent of women in the tamoxifen-treatment group whose breast density was reduced by 10 percent or more, the risk of breast cancer was reduced by 52 percent relative to the control group (women who did not develop breast cancer). Conversely, the 54 percent of women whose density was not reduced by 10 percent only had a non-significant, 8 percent reduction in breast cancer risk. The findings suggest that the impact of tamoxifen on risk reduction is predictable by changes it induces on breast density after 12 to 18 months of treatment, Cuzick said.
Although these findings need confirmation in an independent study, based on this data, Cuzick and his team concluded that changes in breast density may constitute an early indicator of treatment efficacy, which would be useful for the evaluation of new chemoprevention therapies. They also believe that by measuring density changes between baseline and initial follow up mammograms in high-risk patients receiving tamoxifen, it may be possible to determine which women are actually benefiting from the intervention (and should therefore continue treatment), and those who might benefit more from alternative risk reducing strategies.
A step towards personalized medicine
Researchers at the Cancer Research UK Cambridge Research Institute recently discovered the mechanism by which tamoxifen operates in breast cancer patients and how some women build up resistance to the drug.
Dr Lesley Walker, PhD., Cancer Research UK's director of cancer information, said: ‘Tamoxifen has been a huge success story helping to prevent breast cancer recurring for many women. Understanding why it occasionally stops working is really important because it allows us to identify new targets for drug development and who will need such treatments.’
Commenting on the importance of this study, she added: ‘We are moving into an era of personalised medicine and now, Professor's Cuzick's work has increased our knowledge of which high risk women will benefit from tamoxifen as a preventative drug, and which women won't benefit. This is a key advance as we try to ensure women get the most suitable treatment.’
For more information, read:
- Cuzick J, Warwick J, Pinney L, Warren R, et al. Change in breast density as a biomarker of breast cancer risk reduction; results from IBIS-1. (General Session 6) Abstract 61 San Antonio Breast Cancer Symposium. Contact the author.
For additional information:
- Understanding Cancer Series: Estrogen Receptors/SERMs (National Cancer Institute)
- Nolvadex® full prescribing information
Also read PubMed abstracts:
- Cuzick J, Forbes JF, Sestak I, Cawthorn S, et al. Long-term results of tamoxifen prophylaxis for breast cancer--96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst. 2007 Feb 21;99(4):272-82.
- Poweles TJ, Ashley S, Tidy A, et al. Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst. 2007 Feb 21;99(4):283-90 Contact the author.
- Boyd NF, Guo H, Martin LJ, Sun L, et al. Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007 Jan 18;356(3):227-36. Contact the author. Full text article (PDF).
- Kerlikowske K. The mammogram that cried Wolfe. N Engl J Med. 2007 Jan 18;356(3):297-300.
- Vachon CM, van Gils CH, Sellers TA, Ghosh K et al. Mammographic density, breast cancer risk and risk prediction Breast Cancer. Res. 2007;9(6):217. Contact the author.
- McCormack VA, dos Santos Silva I. Breast density and parenchymal patterns as markers of breast cancer risk: a metaanalysis. Cancer Epidemiol Biomarkers Prev 2006;15:1159-69 Contact the author.
- Boyd NF, Rommens JM, Vogt K, et al. Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol 2005;6:798-808.
- Harvey JA, Bovbjerg VE. Quantitative assessment of mammographic breast density: relationship with breast cancer risk. Radiology 2004;230:29-41 Contact the author. Full text article.
- Ursin G, Ma H, Wu AH, et al. Mammographic density and breast cancer in three ethnic groups. Cancer Epidemiol Biomarkers. Prev 2003;12:332-8.
- Byrne C, Schairer C, Brinton LA, et al. Effects of mammographic density and benign breast disease on breast cancer risk (United States). Cancer Causes Control 2001;12:103-10.
- Duncan JA, Reeves JR, Cooke TG. BRCA1 and BRCA2 proteins: roles in health and disease. Mol Pathol. 1998 Oct;51(5):237-47.
- Boyd NF, Byng JW, Jong RA, et al. Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study. J Natl Cancer Inst 1995; 87:670-5.
- Byrne C, Schairer C, Wolfe J, et al. Mammographic features and breast cancer risk: effects with time, age, and menopause status. J Natl Cancer Inst 1995;87:1622-9.
- Wolfe JN, Saftlas AF, Salane M. Mammographic parenchymal patterns and quantitative evaluation of mammographic densities: a case-control study. AJR Am J Roentgenol 1987;148:1087-92.
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