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Ebctcg early breast cancer trialists collaborative group

 LOG IN TO EBCTCG COLLABORATORS' SPACE

In high-income countries, most breast cancers are diagnosed early (stages I, II or IIIA) when all detected cancer cells are in the breast or nearby lymph nodes can be removed surgically. Although most women diagnosed with early breast cancer now survive, in some women undetected deposits of cancer cells remain after surgery in, or near, the breast, or in other parts of the body. These cells can start to proliferate, sometimes many years later, resulting in a recurrence of the original breast cancer.  To try to kill or suppress any cancer cells remaining after surgery ‘adjuvant’ treatments such as radiotherapy, different types of chemotherapy and hormonal therapy may be given in addition to surgery.

Radiotherapy and chemotherapy are ‘cytotoxic’ treatments that act directly on cancer cells but can also damage healthy cells. Early clinical trials established that the benefits outweigh the harms for most patients so the focus of many recent trials has switched to identifying more effective and/or less toxic radio- and chemotherapy regimens.

There are other potential ways to treat or prevent breast cancer in addition to cytotoxic treatments, in particular using hormonal therapy. 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, e.g by removing a woman’s ovaries or stopping them from producing oestrogen with an aromatase inhibitor (AI), which blocks the pathway through which oestrogen is produced, or by blocking the oestrogen receptor, e.g, with selective oestrogen receptor modulators such as tamoxifen.

A substantial minority of breast cancers can be treated effectively by blocking other receptors (eg, with trastuzumab, which blocks the Her2-neu receptor). As we learn more 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.

Since the 1950s  hundreds of randomised trials of various aspects of early breast cancer treatment have assessed the long-term benefits and side-effects of different treatment options. Hundreds of thousands of women have been involved in these trials and many trials are still being undertaken. To understand this huge body of evidence, since 1985, the EBCTCG has been bringing together all the evidence on the major questions for central analysis with the emphasis on evidence from 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. Trialists are periodically invited to send data on each woman who participated in their study to the EBCTCG Secretariat in the Clinical Trial Service Unit (CTSU), based in the Nuffield Department of Population Health at the University of Oxford.

Several hundred research groups have shared individual patient data on more than 600,000 women in 500 randomised trials for the EBCTCG 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. These treatments include various types of surgery, radiotherapy, chemotherapy, endocrine therapy, biological therapies, and other agents such as bisphosphonates. Reviews on the trials of mammographic screening are also being undertaken.

As well as providing definitive estimates of the overall, average effects of the treatments, the large EBCTCG datasets allow the most reliable exploration of any differences in the effects of the treatments in particular subgroups of women, or between treatments within the same class for example, different types of chemotherapy, or different types of endocrine therapy.  The prognostic importance of baseline characteristics can also 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 by August 2019 had been cited more than 25,000 times. The group’s findings are widely used in consensus statements, clinical guidelines, decision aids, and treatment decisions around the world. They have influenced the care of millions of women over the last four decades, making a major contribution to the large falls in worldwide breast cancer mortality seen over this period. The EBCTCG results help define the treatment questions to be tested in future trials and, by developing and demonstrating appropriate methods for individual studies and systematic reviews, the EBCTCG also influences research strategies in areas of health care other than breast cancer.

 

The EBCTCG is funded by the long-term support of the CTSU by Cancer Research UK and the UK Medical Research Council and receives no funding from any commercial organisations.

 

Our team

Current and Planned Projects

The international Steering Committee of the EBCTCG meets annually to discuss current and emerging results from EBCTCG meta-analyses and to prioritise future meta-analyses. Emerging results include:

  • comparing different types and methods of administration of chemotherapy
  • comparison of 10 vs 5 years of endocrine therapy (tamoxifen or AI)
  • ovarian suppression in the presence and absence of chemotherapy
  • trials of trastuzumab and other biological agents (eg bevacizumab)
  • assessing the benefits and risks of different radiotherapy techniques
  • establishing appropriate primary and adjuvant therapy for older women
  • reviews of tumour characteristics (e.g, rate of proliferation, immune response, gene expression) and of body-mass index to risk of breast cancer recurrence. 

Previous findings 

The 2019 report on 37,000 women in 26 trials of  chemotherapy dose intensification showed that increasing dose intensity (eg by 2-weekly rather than 3-weekly administration) reduced the risk of breast cancer recurrence and death.

The 2018 report on 4500 women in 10 trials of neoadjuvant chemotherapy (given before surgery) versus adjuvant chemotherapy (given after surgery) showed that there was no significant different between neoadjuvant and adjuvant chemotherapy for distant recurrence, breast cancer mortality or death from any cause. Neoadjuvant chemotherapy allowed more women to have breast-conserving therapy than adjuvant chemotherapy. However, the risk of cancer recurring in the breast or adjacent lymph glands (local recurrence) was somewhat higher in the neoadjuvant than the adjuvant chemotherapy group. This increased risk of local recurrence was greater in trials which omitted surgery in the event of a good response to neoadjuvant chemotherapy.

A 2017 report on the 20-year risks of breast cancer recurrence after stopping endocrine therapy after 5 years showed that when endocrine therapy ended, the risk of the cancer reappearing and spreading throughout the body continued at a similar rate over at least the next 15 years. The risk depended mainly on the original cancer’s size, and the number of lymph nodes that were cancerous. But, even for those patients with the best outlook (small tumours with no spread to the lymph nodes), there was a 10% chance of cancer spread 20 years after the initial diagnosis, sufficient for further endocrine therapy to be at least considered

The 2017 report on the risks of breast cancer radiotherapy included more than 40,000 women in 75 randomised trials and showed that that late side-effects of modern radiation therapy for breast cancer depend largely on a woman’s smoking status. For non-smokers, the absolute risks of lung cancer and heart disease from modern radiation therapy were <1%. But for long-term continuing smokers they were close to 5%, which may outweigh the benefit. Stopping smoking at the time of radiotherapy may avoid much of this risk.

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 significantly extends survival. However, bisphosphonate treatment appears effective only for post-menopausal women and had little effect in premenopausal women.

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 starting treatment.

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 starting 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 2011-12 Lancet reports updated evidence from 2005, 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 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 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 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.

Related research themes