In high-income countries, most breast cancers are diagnosed at an “early” stage (ie I, II or IIIA), when all detected deposits of the disease are in the breast or nearby lymph nodes and can be removed surgically. Although most women with early breast cancer now survive, some have undetected deposits of cancer cells remaining after surgery in, or near, the breast, or at distant sites. These can start to proliferate, sometimes many years later, resulting in a recurrence of the original breast cancer. Hence, in addition to surgery for early breast cancer some “adjuvant” treatments may also be given - most commonly radiotherapy, various different types of chemotherapy and hormonal therapy – to try to kill any cancer cells remaining after surgery.
Radiotherapy and chemotherapy are ‘cytotoxic’ treatments that act directly on cancer cells though, unfortunately, can also damage healthy cells. Early clinical trials have established that the benefits outweigh the risks for most patients so the focus of many recent trials is to identify more efficacious and/or less toxic radio- and chemotherapy regimens. There are many other potential ways that breast cancer can be treated, or prevented, in addition to cytotoxic treatments. Most breast cancers express the oestrogen receptor (ER) and are driven by the female hormone oestrogen. These “ER-positive” cancers can be treated effectively by greatly reducing natural oestrogen levels, eg with an aromatase inhibitor (AI), which blocks the pathway through which oestrogen is produced, or by blocking the ER, eg, with selective oestrogen receptor modulators, the most well-known and most thoroughly researched of which is tamoxifen. A substantial minority of breast cancers can be treated effectively by blocking other receptors (eg, with trastuzumab, which blocks the Her2-neu receptor) and, as more is learnt about the complex biology of breast cancer, other such “biological” therapies that “attack” the breast cancer stimulation pathway, are being developed and tested in clinical trials.
To assess the long-term benefits and side-effects of this wide range of treatment options, over the past half-century there have been several hundred randomised trials of various aspects of the treatment of early breast cancer, involving in total several hundred thousand women (and millions of woman-years of follow-up). Moreover, many more such trials are still being undertaken. To understand this huge body of evidence, every few years since 1985, the EBCTCG has brought together all the evidence on the major questions for central analysis, and it continues to do so, with the emphasis being on large-scale randomisation and long-term follow-up.
The EBCTCG involves almost all trialists worldwide who have done relevant randomised trials of the treatment of women with breast cancer, inviting them periodically to send data on each individual woman randomised in each relevant study to the EBCTCG Secretariat in the University of Oxford’s Clinical Trial Service Unit (CTSU), now based in the Nuffield Department of Population Health (NDPH). Several hundred research groups have shared individual patient data on more than 450,000 women in 400 randomised trials for meta-analyses that have produced definitive estimates of the effects of various treatments on time to recurrence, breast cancer death, second cancers and death from other causes. The treatments include various types of surgery, radiotherapy, chemotherapy, endocrine therapy, other agents such as bisphosphonates, and reviews are in preparation on the trials of trastuzumab and of mammographic screening. The large, centrally collected EBCTCG datasets allow a more reliable exploration of any differences in the effects of the treatments in particular subgroups of women, or between treatments within the same class (eg, different types of chemotherapy, or different types of endocrine therapy). In addition, the prognostic importance of baseline risk factors can be investigated, for example, the impact of various tumour characteristics and body-mass index on risk of recurrence.
The EBCTCG reports are published in major medical journals and have, thus far, been cited more than 17,000 times. The EBCTCG findings are widely used in consensus statements, clinical guidelines, decision aids, and treatment decisions world-wide. They have influenced the care of millions of women over the last 30-40 years, making a major contribution to the large falls in worldwide breast cancer mortality seen over recent decades. The EBCTCG results help define the treatment questions to be tested in future trials and, by developing and demonstrating the appropriate methods for individual studies and systematic reviews, EBCTCG has also influenced research strategies not just in breast cancer but in other areas of health care too.
Recent findings (2005-15):
- The 2005 EBCTCG Lancet report on systemic therapies showed the substantial effects on 15-year survival of the chemotherapy regimens (eg, about 6 months of anthracycline-based chemotherapy) and endocrine regimens (eg, 5 years of tamoxifen) that were being tested in the 1980s.
- The 2011-12 Lancet reports updated this evidence, bringing together data from 100,000 women in 123 randomised trials of chemotherapy, showing that chemotherapy can reduce breast cancer mortality not only in ER-negative but also in ER-positive disease, and showing benefits of taxane-based over standard anthracycline chemotherapy .
- The 2005 EBCTCG report on surgery and radiotherapy showed that regimens that substantially reduce 5-year local recurrence rates have little effect on 5-year breast cancer mortality, but moderately reduce 15-year breast cancer mortality.
- The 2011 EBCTCG report on radiotherapy after breast-conserving surgery showed that radiotherapy halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth...
- The 2014 Lancet report showed that after mastectomy and axillary clearance radiotherapy reduced breast cancer recurrence and mortality not only in women whose breast cancer had spread to many lymph nodes but also in those with spread to only 1-3 axillary lymph nodes.
- The 2012 EBCTCG report on 20 000 women in 20 randomised trials of about 5 years of tamoxifen versus no tamoxifen, showed a highly significant reduction of about a third in breast cancer mortality not only during years 0-4 and 5-9 after beginning treatment but also during years 10-14. Tamoxifen is effective whether or not chemotherapy has been given and, importantly, even in weakly ER positive disease.
- The 2015 report on 30 000 postmenopausal women in 9 randomised trials comparing aromatase inhibitors (AIs) with tamoxifen, showed that 5 years of treatment with an AI produces even better survival than five years of tamoxifen. Compared to tamoxifen, taking AIs for five years further reduced the likelihood of the cancer recurring by 30%, and the risk of dying from breast cancer by around 15%. Thus taking an AI for 5 years, compared to no endocrine treatment, would reduce the risk of dying from breast cancer by around 40% in the decade after beginning treatment.
- The 2015 report on 20 000 women in 26 randomised trials of bisphosphonates, showed that 2–5 years of treatment with these drugs, which are usually used to treat osteoporosis, reduces the risk of breast cancer recurring in the bones, and also significantly extends survival. However, bisphosphonate treatment appears effective only for post-menopausal women with little effect in premenopausal women.
Current and planned projects (2015-18)
The international Steering Committee of the EBCTCG meets annually to discuss current and emerging results from EBCTCG meta-analyses and to prioritize future meta-analyses. In 2015, these included trials of trastuzumab, assessment of radiotherapy side-effects, comparison of 10 vs 5 years of tamoxifen, assessment of preoperative (neo-adjuvant) systemic therapy, establishing appropriate adjuvant therapy for older women, consideration of different types and methods of administration of chemotherapy and reviews of the prognostic relevance, in otherwise similar women, of tumour characteristics (eg, grade, diameter, nodal spread, receptor status) and of body-mass index (strongly adversely associated with breast cancer prognosis only in pre-menopausal patients with ER-positive cancers).
The EBCTCG is funded only by the long-term support of the CTSU by the UK Medical Research Council and Cancer Research UK.
Further information: http://www.ctsu.ox.ac.uk/ebctcg/