Effects of Radiotherapy in Early-Stage, Low-Recurrence Risk, Hormone-Sensitive Breast Cancer

Jinani Jayasekera; Clyde B. Schechter; Joseph A. Sparano, Reshma Jagsi; Julia White; Judith-Anne W. Chapman; Timothy Whelan; Stewart J. Anderson; Anthony W. Fyles; Willi Sauerbrei; Richard C. Zellars; Yisheng Li; Juhee Song; Xuelin Huang; Thomas B. Julian; George Luta; Donald A. Berry; Eric J. Feuer; Jeanne Mandelblatt; for the CISNET-BOLD Collaborative Group

Disclosures

J Natl Cancer Inst. 2018;110(12):1370-1379. 

In This Article

Discussion

This study extends prior research to examine the effects of omitting radiotherapy in breast cancer patients aged 40–74 years who are at low risk of recurrence based on information about molecular subtypes and tumor gene expression profiles. Although the absolute differences in RFI rates were small, results indicated that omitting radiotherapy would increase the risk of recurrence, even in a group defined as low risk by gene expression profile. This result is largely due to a statistically significant increase in locoregional recurrence events with omission of radiotherapy, with no statistically significant effect on distant recurrences or death. However, there may be patient subgroups within the low-risk population where it may be reasonable to consider omitting radiotherapy, such as those with the lowest Oncotype scores or low tumor grade. Finally, there was no statistically significant effect of radiotherapy on distant recurrence, breast cancer–specific mortality, or all-cause mortality, suggesting that this is an appropriate population for the investigation of radiotherapy omission among women willing to tolerate a modest increased risk of locoregional recurrence.

The recent EBCTCG meta-analyses of 10 801 patients from 17 trials demonstrated that omission of radiotherapy increased the five-year risk of any breast cancer recurrence in node-negative women from 10.6% to 22.5% (absolute difference = 11.9%).[2] In contrast, by only focusing on hormone-sensitive breast cancers with favorable prognosis further defined by estimated Oncotype scores, we found that omission of radiotherapy increased the 5-year risk of any recurrence by a more modest absolute difference of 4.4%. Further, our analysis showed that the vast majority of recurrences prevented by radiotherapy are clinically salvageable locoregional events rather than distant metastases.[5,13] The effect of radiotherapy on the absolute differences of RFI and locoregional RFI increased with increasing follow-up. Locoregional recurrences are known to occur later in follow-up especially among ER-positive tumors. Therefore, the benefits of radiotherapy on reducing the risk of locoregional recurrence may increase with even longer-term follow-up than included in this analysis. Radiation-induced harms will also be more likely to be observed with longer follow-up.

The pooled analysis included seven clinical trials relevant for evaluating the risk of omitting radiotherapy in low-risk breast cancer. In contrast to previous studies, the majority of women included in the current analysis were younger (<60 years) and diagnosed after year 2000, allowing us to evaluate the likely effects of omitting radiotherapy in younger women with low Oncotype scores. Although studies were selected for using modern radiotherapy regimens and most of the women included in this study were diagnosed after the year 2000, medical care and breast cancer treatment have changed over the past 20 years, potentially limiting the generalizability of the study findings to current populations.

The results of the subgroup analyses for RFI with omission of radiotherapy were consistent with past studies showing that certain subgroups have sufficiently low recurrence risks to potentially opt out of radiation.[2] Although the rate of events observed was low and the original studies were not powered to detect subgroup effects, the trends in absolute differences in the pooled data suggest that there may be lower risk categories within subgroups defined by age, Oncotype, tumor size, hormonal status, and/or grade where the increase in recurrence is sufficiently small (and primarily locoregional) without radiotherapy. In these cases, decisions about use of radiotherapy might be preference-based. These results suggest that future trials should consider including sufficiently large samples in subgroups to detect relevant differences in primary endpoints and to collect data on patient preferences for study outcomes.

The results of this pooled data analysis were robust, but several caveats should be considered in evaluating the findings. First, when data were combined, radiotherapy was either no longer randomly assigned or may not have been randomly assigned in the original trial. The selection of patients to radiotherapy and/or imbalance of any unmeasured covariates by radiotherapy group could have biased results. However, results of the propensity-weighted analyses were similar to unweighted analyses and findings from the pooled sample were similar to prior published studies[7,14,24] and the Oxford Overview[2] for comparable populations, so the results are not likely to be spurious. Second, we could not assess the effect of radiotherapy among postmenopausal women receiving aromatase inhibitors. Future research might consider whether aromatase inhibitors lower the risk of recurrence sufficiently more than tamoxifen such that omission of radiotherapy might not lead to an elevated risk of recurrence events. Here, 64% of women younger than 60 years received tamoxifen; and there were too few patients aged 40–49 years to estimate radiotherapy effects separately for premenopausal patients. The younger women were predominantly from the TAILORx trial and systematically different to other patients in this age group from older trials. Next, we could not differentiate clinically from pathologically determined node status among women enrolled in certain trials. However, given that the majority of women included in the trials required or included pathologically determined node-negative status (52%), we do not expect our findings to differ by clinical vs pathological node status. Finally, we did not impute missing HER2 information for this analysis, assuming that HER2 was missing at random and independent of time-to-events. The magnitude and direction of potential biases introduced by missing HER2 data are unknown.

Another consideration is that Oncotype results were imputed because they were not available in the original trials (except for TAILORx).[8] We employed a population-based donor dataset,[22] and a deterministic regression–based multiple imputation approach,[20] to estimate missing Oncotype scores. Although the distribution of observable patient characteristics between the population-based donor dataset and the pooled clinical trial dataset were comparable, women eligible for clinical trials could differ from population-based data in terms of eligibility, compliance, and other unobservable characteristics. As a result, even though our imputation was robust, it may have not removed all bias due to missing data. Additionally, women receiving Oncotype testing in the population-based registry mostly included women with low- and intermediate-risk cancers.[21,22] However, women enrolled in these trials were selected to participate in the trials without knowledge of Oncotype; therefore they may have had higher or lower scores than the source population from which they were drawn. Hence it is not possible to infer the impact of the Oncotype score imputation on misclassification and bias.

Finally, even in this large pooled sample there were few events, limiting power to detect statistically significant differences in radiotherapy effects in subgroups. However, the trends in absolute differences in RFI rates were consistent with clinical expectations. The trials included did not explicitly consider any excess deaths due to radiotherapy-induced lung cancer or cardiovascular disease, so we could not directly assess the impact of radiation-induced harms.[4] However, these would have likely been captured in the analysis as other-cause deaths, and radiotherapy did not decrease overall survival. Although these effects are uncommon, especially among nonsmokers,[4] it will be important to specifically capture these events in future trials to more completely understand the balance of benefits and harms of radiotherapy in low-risk patients.

Overall, the results of this pooled analysis suggest that omission of radiotherapy after breast conservation in hormone-sensitive, low-risk patients could lead to higher relative differences, but small absolute differences in RFI rates. Clinical decision making is usually based on absolute differences. Moreover, omission of radiotherapy does not appear to increase distant recurrences or early death in this low-risk population. Future trial design with modern clinical management should consider focusing on subgroups within the population presently considered low risk for recurrence to determine if there are those who can safely omit radiotherapy after breast conservation.

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