Abstract and Introduction
Background: Radiotherapy after breast conservation has become the standard of care. Prior meta-analyses on effects of radiotherapy predated availability of gene expression profiling (GEP) to assess recurrence risk and/or did not include all relevant outcomes. This analysis used GEP information with pooled individual-level data to evaluate the impact of omitting radiotherapy on recurrence and mortality.
Methods: We considered trials that evaluated or administered radiotherapy after lumpectomy in women with low-risk breast cancer. Women included had undergone lumpectomy and were treated with hormonal therapy for stage I, ER+ and/or PR+, HER2− breast cancer with Oncotype scores no greater than 18. Recurrence-free interval (RFI), type of RFI (locoregional or distant), and breast cancer–specific and overall survival were compared between no radiotherapy and radiotherapy using adjusted Cox models. All statistical tests were two-sided.
Results: The final sample included 1778 women from seven trials. Omission of radiotherapy was associated with an overall adjusted hazard ratio of 2.59 (95% confidence interval [CI] = 1.38 to 4.89, P = .003) for RFI. There was a statistically significant increase in any first locoregional recurrence (P = .001), but not distant recurrence events (P = .90), or breast cancer–specific (P = .85) or overall survival (P = .61). Five-year RFI rate was high (93.5% for no radiotherapy vs 97.9% for radiotherapy; absolute reduction = 4.4%, 95% CI = 0.7% to 8.1%, P = .03). The effects of radiotherapy varied across subgroups, with lower RFI rates for those with Oncotype scores of less than 11 (vs 11–18), older (vs younger), and ER+/PR+ status (vs other).
Conclusions: Omission of radiotherapy in hormone-sensitive patients with low recurrence risk may lead to a modest increase in locoregional recurrence event rates, but does not appear to increase the rate of distant recurrence or death.
Over the last two decades, breast cancer survival has steadily improved, in part due to early detection, use of new treatment agents, and more intensive regimens. With increasing knowledge of molecular heterogeneity, there is a growing recognition that certain subgroups of breast cancer patients may have comparable benefits and lower burden with less, rather than more, treatment.[2–4]
A 2011 meta-analysis of 17 randomized clinical trials conducted by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) found that although radiotherapy after breast-conserving surgery reduced overall recurrence rates in node-negative patients, it only provided a modest survival benefit, and that benefit appeared confined to subsets of patients who experienced a 10% or greater reduction in local recurrence with radiotherapy. Additionally, reduction in recurrence varied by age and tumor characteristics. For instance, one of the trials that enrolled women aged 70 years and older concluded that radiotherapy might be safely omitted in older patients with hormone-sensitive breast cancer who are willing to accept a slightly higher risk of local recurrence.
However, understanding factors associated with recurrence risk has dramatically evolved since the 2011 EBCTCG analyses. Molecular tumor markers and gene-expression profiling (GEP), especially for hormone-sensitive breast cancer, are now the standard of care for chemotherapy decision making. Further, GEP is increasingly demonstrated as prognostic for locoregional recurrence, supporting its potential to identify patients at the lowest risk of recurrence where radiotherapy might be reasonably omitted. A recent retrospective study of tumor genomic profiling of specimens from two older trials demonstrated a statistically significant association between locoregional recurrence rates and recurrence-risk scores. Unfortunately, that study did not examine the effects of radiotherapy and other outcomes important in treatment decision making, such as distant recurrence and mortality. It has become increasingly difficult to conduct new randomized trials to compare broad outcomes related to radiotherapy in all clinically relevant subgroups, given the large sample sizes required with low event rates, increasingly effective hormonal therapy regimens, and the long follow-up required to capture any late distant events.
To help fill current gaps in clinical practice, this study determined the effect of radiotherapy on locoregional and distant recurrence and breast cancer–specific and all-cause mortality conditional on genomic risk assessments in a pooled analysis of breast cancer patients from seven clinical trials.[3,6–11] Our results are intended to inform clinical debates about care for groups that might consider omission of radiotherapy and to highlight considerations for the efficient design of future clinical trials.
J Natl Cancer Inst. 2018;110(12):1370-1379. © 2018 Oxford University Press