Should All Patients With Early Breast Cancer Receive ART?

Adjuvant radiotherapy reduces the risk for short-term recurrence in patients with early breast cancer, but it may have no impact on long-term recurrence or overall survival, based on a 30-year follow-up of the Scottish Breast Conservation Trial.
These findings suggest that patients with biology predicting late relapse may receive little benefit from adjuvant radiotherapy, lead author Linda J. Williams, PhD, of The University of Edinburgh, Edinburgh, Scotland, and colleagues, reported.
“During the past 30 years, several randomized controlled trials have investigated the role of postoperative radiotherapy after breast-conserving surgery for early breast cancer,” the investigators wrote in The Lancet Oncology. “These trials showed that radiotherapy reduces the risk of local recurrence but were underpowered individually to detect a difference in overall survival.”
How Did the Present Study Increase Our Understanding of the Benefits of Adjuvant Radiotherapy in Early Breast Cancer?
The present analysis included data from a trial that began in 1985, when 589 patients with early breast cancer (tumors ≤ 4 cm [T1 or T2 and N0 or N1]) were randomized to receive either high-dose or no radiotherapy, with final cohorts including 291 patients and 294 patients, respectively. The radiotherapy was given 50 Gy in 20-25 fractions, either locally or locoregionally.
Estrogen receptor (ER)–positive patients (≥ 20 fmol/mg protein) received 5 years of daily oral tamoxifen. ER-poor patients (< 20 fmol/mg protein) received a chemotherapy combination of cyclophosphamide, methotrexate, and fluorouracil on a 21-day cycle for eight cycles.
Considering all data across a median follow-up of 17.5 years, adjuvant radiotherapy appeared to offer benefit, as it was associated with significantly lower ipsilateral breast tumor recurrence (16% vs 36%; hazard ratio [HR], 0.39; P < .0001).
But that tells only part of the story.
The positive impact of radiotherapy persisted for one decade (HR, 0.24; P < .0001), but risk beyond this point was no different between groups (HR, 0.98; P = .95).
“[The] benefit of radiotherapy was time dependent,” the investigators noted.
What’s more, median overall survival was no different between those who received radiotherapy and those who did not (18.7 vs 19.2 years; HR, 1.08; log-rank P = .43), and “reassuringly,” omitting radiotherapy did not increase the rate of distant metastasis.
How Might These Findings Influence Treatment Planning for Patients With Early Breast Cancer?
“The results can help clinicians to advise patients better about their choice to have radiotherapy or not if they better understand what benefits it does and does not bring,” the investigators wrote. “These results might provide clues perhaps to the biology of radiotherapy benefit, given that it does not prevent late recurrences, suggesting that patients whose biology predicts a late relapse only might not gain a benefit from radiotherapy.”
Gary M. Freedman, MD, chief of Women’s Health Service, Radiation Oncology, at Penn Medicine, Philadelphia, offered a different perspective.
“The study lumps together a local recurrence of breast cancer — that is relapse of the cancer years after treatment with lumpectomy and radiation — with the development of an entirely new breast cancer in the same breast,” Freedman said in a written comment. “When something comes back between years 0-5 and 0-8, we usually think of it as a true local recurrence arbitrarily, but beyond that they are new cancers.”
He went on to emphasize the clinical importance of reducing local recurrence within the first decade, noting that “this leads to much less morbidity and better quality of life for the patients.”
Freedman also shared his perspective on the survival data.
“Radiation did reduce breast cancer mortality very significantly — death from breast cancers went down from 46% to 37%,” he wrote (P = .054). “This is on the same level as chemo or hormone therapy. The study was not powered to detect significant differences in survival by radiation, but that has been shown with other meta-analyses.”
Are Findings From a Trial Started 30 Years Ago Still Relevant Today?
“Clearly the treatment of early breast cancer has advanced since the 1980s when the Scottish Conservation trial was launched,” study co-author Ian Kunkler, FRCR, of The University of Edinburgh, said in a written comment. “There is more breast screening, attention to clearing surgical margins of residual disease, more effective and longer periods of adjuvant hormonal therapy, reduced radiotherapy toxicity from more precise delivery. However, most anticancer treatments lose their effectiveness over time.”
He suggested that more trials are needed to confirm the present findings and reiterated that the lack of long-term recurrence benefit is most relevant for patients with disease features that predict late relapse, who “seem to gain little from adjuvant radiotherapy given as part of primary treatment.”
Kunkler noted that the observed benefit in the first decade supports the continued use of radiotherapy alongside anticancer drug treatment.
When asked the same question, Freedman emphasized the differences in treatment today vs the 1980s.
“The results of modern multidisciplinary cancer care are much, much better than these 30-year results,” Freedman said. “The risk for local recurrence in the breast after radiation is now about 2%-3% at 10 years in most studies.”
He also noted that modern radiotherapy techniques have “significantly lowered dose and risks to heart and lung” compared with techniques used 30 years ago.
“A take-home point for the study is after breast conservation, whether or not you have radiation, you have to continue long-term screening mammograms for new breast cancers that may occur even decades later,” Freedman concluded.
How Might These Findings Impact Future Research Design and Funding?
“The findings should encourage trial funders to consider funding long-term follow beyond 10 years to assess benefits and risks of anticancer therapies,” Kunkler said. “The importance of long-term follow-up cannot be understated.”
This study was funded by Breast Cancer Institute (part of Edinburgh and Lothians Health Foundation), PFS Genomics (now part of Exact Sciences), The University of Edinburgh, and NHS Lothian. The investigators reported no conflicts of interest.
 
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