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

Results

Trials and Patient Characteristics

Of the trials[3,6–11,13–15] considered for the analysis, we excluded women if chemotherapy was included in the trial arm (n = 1),[15] information on ER/PR status was not provided (n = 1),[14] and/or the study could not provide individual-level data (n = 1).[13] Four of the included trials randomized radiotherapy: Cancer and Leukemia Group-B [CALGB]-9343,[3] National Surgical Adjuvant Breast and Bowel Project [NSABP] B-21,[9] Toronto/Vancouver trial,[6] and the German Breast Cancer Study Group [GBSG-V]).[7] One trial allowed radiotherapy to be assigned based on clinical decisions (Trial Assigning Individualized Options for Treatment [TAILORx]),[8] and two (NSABP B-14/B-20)[10,11] gave radiotherapy after breast conservation to all patients as part of the treatment protocol.

The Oncotype imputation model and validation results are provided in Supplementary Table 2, Supplementary Table 3, Supplementary Table 4 and Supplementary Table 5 and Supplementary Figures 1–2 (available online). The imputation model showed good fit, and the distributions of the estimated and actual Oncotype scores were similar at the cohort level.

Supplemental Figure 1.

Goodness of fit statistics for the Generalized Linear Model Used to Estimate Oncotype DX® Scores
Skewness=-0.07, Kurtosis=6.0, Shapiro-Wilk test= two-sided p-value<0.001 (z-test)

Supplemental Figure 2.

Scatter Plot of Actual vs. Predicted Oncotype DX® scores in the NSABP-GHI Data (node negative and ER+ and/or PR+ breast cancer)

The final sample included 1778 women from seven trials. The mean age of women in the sample was 59 years (median = 59, range = 40–74 years), with 50.8% younger than 60 years (Table 1); 64.4% received tamoxifen. Women who did not receive radiotherapy were older or had smaller tumor sizes than those who received radiotherapy. The mean Oncotype DX score among eligible women was 10 (median = 10, SD = 4, range = 0–18). The five-year RFI rates across the trials included in the analysis were low and comparable (range = 92.3–98.9%) (Supplementary Table 6, available online).

Primary Endpoint-RFI

Omission of radiotherapy was associated with approximately a 2.5-fold increase of any occurrence of locoregional, distant recurrence or breast cancer death (adjusted RFI HR = 2.59, 95% CI = 1.38 to 4.89; P = .003) (Table 2). The adjusted five-year RFI rate with radiotherapy was 97.9% compared with 93.5% without radiotherapy (absolute difference = 4.4%, 95% CI = 0.7% to 8.1%; P = .03) (Figure 2A). The adjusted 10-year RFI rate with radiotherapy was 95.3% and 86.1% without radiotherapy (absolute difference = 9.2%, 95% CI = 1.8% to 16.6%, P = .02).

Figure 2.

Recurrence-free interval (RFI) and overall survival (OS) by receipt of radiotherapy (RT). Recurrence-free interval (A) and overall survival (B) were determined using a Cox model adjusted for patient age, tumor grade (low, moderate, high, or unknown), ER/PR status (ER+ and PR+ or other), HER2 (negative or unknown), type of initial hormonal treatment (tamoxifen, aromatase inhibitors, or other), tumor size, trial, and Oncotype DX recurrence score. Evaluated at mean age, tumor size, Oncotype DX recurrence score, and tamoxifen hormonal treatment, low grade, ER+/PR+ status, and in studies where radiotherapy was randomized. P values for rate differences are based on a two-tailed Z test.

Omission of radiotherapy statistically significantly increased the risk of locoregional recurrence events (adjusted HR = 3.91, 95% CI = 1.81 to 8.45, P = .001), but not the risk of distant recurrence (P = .90) (Table 2). The adjusted five-year locoregional RFI rate with radiotherapy was 98.6% compared with 93.7% without radiotherapy (absolute difference = 4.9%, 95% CI = 2.5% to 7.2%, P < .001), whereas the 10-year adjusted rate with radiotherapy was 96.6% and 85.5% without radiotherapy (absolute difference = 11.1%, 95% CI = 6.8% to 15.4%, P < .001). The results were unchanged in propensity score weighted and competing risk analyses (Table 2).

Overall and Breast Cancer–specific Survival

Radiotherapy was not statistically significantly associated with overall (P = .61) or breast cancer–specific survival (P = .85) (Table 2). The adjusted five- and 10-year overall survival rates were 96.8% and 88.2% with radiotherapy compared with 97.3% and 90.1% without radiotherapy, respectively (absolute difference at five years = −0.5%, 95% CI = −4.8% to 3.8%, P = .39, 10 years = −1.9%, 95% CI = −16.5% to 12.7%, P = .39) (Figure 2B). The adjusted five-year breast cancer–specific survival rate with radiotherapy was 99.2% and 99.1% without radiotherapy (absolute difference = 0.1%, 95% CI = −1.3% to 1.5%, P = .40).

Subgroup Analyses

The adjusted RFI hazard ratios and five-year rates by radiotherapy tended to vary by patient characteristics (Table 3). The differences in RFI rates for omission of radiotherapy followed a similar pattern, with smaller absolute differences in RFI rates in the lower risk subgroups compared to the higher risk subgroups.

Sensitivity Analyses

Exclusion of the three trials where radiotherapy was not randomized (B-14/B-20/TAILORx trials), exclusion of the TAILORx trial only, use of different study follow-up, or differences in ages included in the sample did not substantially change the results (Table 4).

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