Breast cancer is the second most common cancer worldwide, with 1.6 million new cases and over half a million deaths each year1. However, early detection and good treatments mean that survival rates have increased to about 80% in more developed regions. Animal studies led to the development of tamoxifen, one of the most successful treatments, and more recently Herceptin (trastuzumab) and aromatase inhibitors.
The risk of developing breast cancer increases with age, like most cancers. However, there are several factors that affect the likelihood of developing breast cancer.
The risk for developing breast cancer approximately doubles if a parent or sibling has been diagnosed with the disease, for example from a 1 in 10 chance to a 1 in 5 chance. This likelihood increases further if there have been several cases in the family or if it has been diagnosed at a young age.
A very strong family history can indicate a faulty gene as a major factor. The most common genes that patients are tested for are BRCA1 and BRCA2 - a fault in either of these genes can raise the risk of breast cancer to 45-90%2. Similarly, tests are available to check for faulty TP53 and PTEN genes. However tests have not developed for many more genes known to be linked to breast cancer, including CASP8, FGFR2, TNRCP, MAP3K1, rs4973768, LSP1, CHEK2, ATM, BRIP1 and PALB2.
Post-menopausal women with high levels of the sex hormones oestrogen and testosterone have a 2 to 3 times higher risk of developing breast cancer. Studies have also shown that hormone replacement therapy (HRT), taken by women to relieve symptoms of menopause, also increases the risk of breast cancer3. Oestrogen levels may also explain why women who have more children at an earlier age and breastfeed have a reduced risk of breast cancer.
Mice and rats have been crucial
Normal breast development is controlled by hormones, including oestrogens and progesterone. These hormones and their roles in fertility and development were discovered during the 1930s through fundamental research on animals. However, even before hormones were discovered, researchers noticed that removing ovaries from mice reduced their likelihood of developing breast cancer4. Further evidence for their role in the development of some cancers came in the 1950s, when researchers discovered that hormone changes can induce breast tumours in rats.
Tamoxifen emerged from a research programme aimed at the development of an anti-oestrogen oral contraceptive. However, tamoxifen actually boosted fertility and was actually marketed as an inducer of ovulation5. Tamoxifen has opposing effects in different species and in different tissues in the body, either increasing or decreasing the effects of oestrogen. Its oestrogen boosting activity in the ovaries make it unsuitable for a contraceptive, but its role in reducing oestrogen in breast tissue ultimately proved much more interesting as a treatment for breast cancer6.
Although the significance of this is clear today, in the late 1960s breast cancer was not a significant issue and tamoxifen did not initially generate much excitement5. It was first licensed for use in 1973, even though little was known about how effective it was and who the target population were. Studies using the dimethylbenzathracene (DMBA)-induced rat mammary carcinoma model allowed researchers to systematically study the anti-tumour effects of tamoxifen and determine how useful it would be to patients. Studies in breast cancer cell cultures showed that high concentrations of tamoxifen would kill the cancer7 and given medical concerns about the cancer developing resistance, initial clinical trials only ran for one year, which showed tamoxifen to be ineffective. However, tests in the rat model showed that one month treatment (equivalent to a year in humans) only delayed the onset of cancer8,9, while five months of small doses could prevent it completely10,11. Longer trials were then conducted in humans, which showed it to enhance survival rates and prevent nearly half of cancers12.
An analysis in 2000 showed that there was an unprecedented fall of about 30% in the death rate from breast cancer in the UK in the 1990s. This improvement is due in part to use of tamoxifen, which was then in widespread use in the UK - earlier than in the USA or other European countries.
Tamoxifen has also been used to develop alternatives to using animals in breast cancer research, by proving that human tumour cells grown in laboratory cell cultures will respond to the same drugs that work in patients. Without the animal work, it would have been difficult if not impossible to demonstrate that the cell culture results were relevant and reliable.
In early 2013, it was shown that tamoxifen reduces the chances of developing breast cancer by 38% in high-risk women13. Taking tamoxifen for 5 years provides this protective effect for another 5 years after treatment ends. This study was based on previous research on rats and mice14, which showed that tamoxifen provided long-lasting protection against breast cancer and many other cancers. When given tamoxifen from an early age for life it increases the rats' risk of liver cancer, but does not increase the risk when given at an older age, which is more applicable to most human patients.
Aromatase inhibitors block production of the oestrogen, ‘starving’ breast cancer cells of growth stimuli. Professor Angela Brodie of the University of Maryland School of Medicine developed the aromatase inhibitors15 and tested them in mice, comparing them with tamoxifen, then the gold-standard treatment for ‘oestrogen-receptor-positive’ cancers.
This research showed how animal models can predict patient response not just to a particular medicine, but to different combinations of therapy – a critical factor in cancer treatment. For example, animal studies with combinations of tamoxifen and aromatase inhibitors did not show any improvement over established treatments.
Aromatase inhibitor therapy alone was shown to be the most effective16, and after clinical trials aromatase inhibitors were approved for use in patients with oestrogen-fuelled breast cancer. Later studies with patients showed that sequential treatment with tamoxifen and then the aromatase inhibitor exemestane improved survival rates for this type of breast cancer, and could save a further 1,300 lives a year in the UK alone17.
In December 2013, the IBIS II trial of 4000 post-menopausal women showed that taking the aromatase inhibitor anastrozole (Arimidex) for 5 years reduces the risk by 50% for high-risk women18. Not only did this provide better protection than tamoxifen, but it also had fewer side-effects. This has led to calls for changes in the guidance for doctors when considering preventative treatment for post-menopausal women. Because it blocks production of oestrogen, anastrozole is only suitable to give to women after menopause, while tamoxifen is suitable both pre- and post-menopause.
Aromatase inhibitors are linked with reduced bone density, potentially making it unsuitable for women with severe osteoporosis. Bone-strengthening drugs called bisphosphonates can be used prevent bone density problems in women at risk.
Herceptin can halve the chance of breast cancer returning following treatment
Herceptin (trastuzumab) was the first humanised monoclonal antibody used to successfully treat cancer. Its development was another landmark in breast cancer research. It is described as humanised because it is an antibody that was originally produced in a mouse, but has altered to make it more similar to human antibodies and so less likely to trigger an immune reaction against it. By going through this process the antibody can be considered to be 95% human and 5% mouse, where the mouse region is the important part for functioning.
Herceptin was produced as an antibody to target the HER2 protein, which helps breast cancer cells to grow. By blocking HER2 from working, Herceptin can help to destroy cancers that produce a lot of HER2 and need it to survive. Over-expression of HER2 occurs in 20% to 30% of breast tumours.
The discovery of HER2 was published in 1982 after researchers studied neurological tumours in rats19. In 1985, the first monoclonal antibodies to target against HER2 in mice showed they could reduce tumour growth and prolong survival20.
Herceptin was developed in 1991 and is produced using Chinese hamster ovary cells. Trials in animals and humans revealed the benefits of the treatment and which women should receive it. For example, Herceptin is not routinely recommended for pregnant or nursing women after studies showed that monkeys pass it through to the foetus and secrete it in milk21. Following these tests, Herceptin was first approved in 1998.
Herceptin was originally given after initial treatment of metastatic breast cancer to help to prevent the cancer from returning, but is now also applied to early-stage breast cancer. In 2005, researchers reported a 50% fall in the rate of breast cancer recurrence after one year of treatment22. This degree of benefit in early breast cancer was the largest reported since the introduction of tamoxifen.
For more information, see this audio slideshow on Herceptin or download the Powerpoint file from here.
5. Jordan, VC (2003) Tamoxifen: a most unlikely pioneering medicine Nature Reviews Drug Discovery 2, 205-213 doi:10.1038/nrd1031
7. Lippman ME and Bolan G (1975) Oestrogen-responsive human breast cancer in long term tissue culture Nature 256, 592–593 (1975) doi:10.1038/256592a0
8. Jordan VC and Allen KE (1980) Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model Eur. J. Cancer 16, 239–251
13. Cuzick J et al (2013) Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data The Lancet 381(9880):1827-1834 doi:10.1016/S0140-6736(13)60140-3
16. Schuetz K (2004) See Translating Basic Research into Patient Care: An Interview with Dr. Angela Brodie http://www.umgcc.org/news/brodie_home.htm (accessed 16 February 2007)
18. Cuzick J et al (2013) Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial The Lancet doi:10.1016/S0140-6736(13)62292-8
20. Drebin JA, Link VC, Stern DF, Weinberg RA, Greene MI (1986) Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen. Proc. Nat. Acad. Sci. USA 83: 9129-9133