Of the 652258 women with early breast cancer in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) database on 17 January 2023, patient-level data were available from 151 randomised trials that included 155746 women. Data strongly suggest that long-term estimates of the annual risk of distant recurrence in women with early-stage breast cancer are lower for patients diagnosed since 2000 than in earlier decades. Although most of the recurrences for oestrogen receptor (ER)-negative cancers occur during the first 5 years, for those with ER-positive disease the risk persists at a constant rate beyond 5 years.
Most of the improvement in trial outcomes is explained by a greater proportion of women with lower-risk disease entering trials and improved adjuvant treatment. The findings are published on 12 October 2024 in The Lancet.
Previous EBCTCG work identified that, among women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy, risks of distant recurrence and death persisted at a relatively constant rate for at least the subsequent 15 years. Recurrence risk was strongly related to tumour stage (lymph node status and tumour size). The pattern of long-term recurrence risk was confirmed in population-based data from the Danish Breast Cancer Group, which found that risks persisted for up to 32 years after diagnosis.
Assessment of long-term outcomes is necessarily based on women diagnosed and treated many years, or even decades ago. Overestimates in the risk of recurrence could have implications for current patients and clinicians when balancing risks of recurrence and breast cancer mortality with toxicities and treatment-associated morbidities. Overestimating recurrence risks could also affect clinical trial design. Using the EBCTCG database, the EBCTCG researchers investigated rates of distant breast cancer recurrence in ER-positive and ER-negative tumours and trends in outcomes over time.
In this pooled analysis of randomised controlled trial data, patients in the EBCTCG database of more than 650000 women in trials of treatment for early-stage breast cancer were screened for eligibility. Women were eligible if they were enrolled between 1990 and 2009 and newly diagnosed with ER-positive breast cancer and scheduled for at least 5 years of endocrine therapy, or ER-negative disease, and if they were younger than 75 years at diagnosis, had a tumour diameter of 50 mm or less, and fewer than ten positive axillary lymph nodes, and no evidence of distant metastases at entry. Trial of neoadjuvant therapy, or those in which adjuvant therapy was unclear, and women with ER-negative, progesterone receptor-positive disease, or those for whom outcome or baseline data were missing were excluded.
The primary outcome was time to first distant recurrence as defined by each trial, ignoring any locoregional recurrence or contralateral breast cancer. 10-year risks of distant recurrence by period of diagnosis were compared using Cox regression adjusted for patient and tumour characteristics, trial, and assigned treatment.
Rates of distant tumour recurrence improved similarly in women with ER-positive and ER-negative tumours; 80.5% of the improvement for ER-positive disease and 89.8% of the improvement for ER-negative disease was explained by changes in patient and tumour characteristics and improved treatments, but remained significant (p < 0.0001). More recently diagnosed patients were more likely to have node-negative disease.
10-year distant recurrence risks during 1990-1999 versus 2000-2009 were as follows: for node-negative disease, 10.1% versus 7.3% for ER-positive disease and 18.3% versus 11.9% for ER-negative disease; for disease with one to three positive nodes, 19.9% versus 14.7% for ER-positive disease and 31.9% versus 22.1% for ER-negative disease; and for disease with four to nine positive nodes, 39.6% versus 28.5% for ER-positive disease and 47.8% versus 36.5% for ER-negative disease. After adjustment for therapy, rates were reduced by 25% for ER-positive disease and 19% for ER-negative disease after 2000 versus the 1990s, with similar improvements observed in ER-positive disease beyond 5 years.
Data suggest that for women with ER-positive disease diagnosed after 2000 who have at least 5 years of endocrine therapy planned, the risk of distant recurrence persists but is about a tenth lower than equivalent women in the previous report. By contrast, for those with ER-negative disease, most recurrences occurred in the first 5 years after diagnosis.
The improvements in outcome in more recently diagnosed women have a variety of causes. The proportion of women with node-negative disease entering trials increased over time, accounting for a third to a half of the improvement in outcomes. This change coincided with the widespread application of mammographic screening and increased breast cancer awareness. Another possible explanation is more accurate tumour staging resulting from improvements in diagnostic accuracy. It is possible that changes in methods for evaluating lymph node involvement over time from dissection, sampling, and sentinel node biopsy might have altered estimates of prognosis among different categories of axillary nodal status.
Furthermore, methods of analysis of tumour biomarker tests, including ER and HER2, have also evolved over the past four decades. Additionally, trial design and selection of participants have changed over time as more specific questions have been addressed. In the 1980s and 1990s, patients with poor prognosis entered trials of anthracycline and taxane chemotherapy or high-dose chemotherapy with haematopoietic stem cell transplant, regardless of tumour receptor profile. By contrast, more recently, clinical trials addressing endocrine therapy questions with aromatase inhibitors enrolled only patients with ER-positive disease, often with earlier stage disease. In the early 2000s several trials focused on trastuzumab and only recruited patients with HER2-positive breast cancers.
To address confounding, the researchers explored the influence of other possible reasons for improving prognosis in this dataset. In addition to changes in patient and tumour characteristics, between a third and a half of the improvement can be explained by changes in therapy. Breast cancer outcomes are improved with better adjuvant chemotherapy. For patients with ER-positive cancers, more effective adjuvant endocrine therapies, such as aromatase inhibitors, and, possibly, longer endocrine therapy duration, have been introduced into standard care. Adjuvant anti-HER2 therapies, such as trastuzumab, have greatly improved outcomes for patients with HER2-positive disease. Significant reductions in bone recurrence is a result from the use of bisphosphonates. More-recently introduced adjuvant treatments, such as immune checkpoint inhibitors, PARP inhibitors, and novel anti-HER2 treatments, have the potential to further reduce distant tumour recurrence rates.
The absolute benefit of continuing endocrine therapy will be lower than that calculated from previous analyses. If extended endocrine therapy beyond 5 years reduces the subsequent distant recurrence by approximately a quarter, clinicians should use these updated risk estimates rather than previous report to estimate the absolute potential benefit. This potential benefit must be considered alongside the known ongoing side-effects that affect quality-of-life and the potential risk of life-threatening toxicities, such as thrombosis or endometrial cancer with tamoxifen and osteoporosis and fracture with aromatase inhibitors (somewhat mitigated with the use of bisphosphonates).
Despite improvements in outcomes, women with ER-positive breast cancer and four to nine positive nodes still have a substantial risk of late recurrence after 5 years of adjuvant endocrine therapy of about 2.7% per year, or about 13% over the period of 5-10 years after diagnosis. A 25% reduction from extended endocrine therapy would equate to about a 3% absolute reduction over this period and more over a longer period of follow-up.
Rather than using overall outcomes from previous trials, it would be preferable to model event rates using expected numbers of participants by ER status and nodal status, and potentially by tumour size as well. Consequently, future trials might need to be larger than previously anticipated. Alternatively, clinical investigators might need to collect longer follow-up.
In an accompanied comment, Drs. Paolo Tarantino and Sara M Tolaney wrote that several considerations should be acknowledged to interpret these results in the context of modern clinical practice. Treatment advances only benefit patients who can access them. In this context, wide disparities remain worldwide in the implementation of screening practices and access to adequate cancer treatment. Only by maximising efforts to achieve equitable access to cancer care can transform the improvement in trial outcomes seen in the EBCTCG analysis into tangible benefits for real-world patients with cancer, building upon the efforts of the past 50 years to attempt to erase breast cancer as a cause of death in the decades to come.
The EBCTCG Secretariat is funded by Cancer Research UK, with additional support from core funding to the Clinical Trial Service Unit and to the Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK, and from Cancer Research UK, London, UK and the UK Medical Research Council, London, UK.
References
- Early Breast Cancer Trialists’ Collaborative Group. Reductions in recurrence in women with early breast cancer entering clinical trials between 1990 and 2009: a pooled analysis of 155746 women in 151 trials. The Lancet 2024;404(10461):1407–1418.
- Tarantino P, Tolaney SM. Progress in breast cancer management. The Lancet 2024;404(10461):1376-1378.