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.

Abstract and Introduction

Abstract

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.

Introduction

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.^[1] 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.^[2] Additionally, reduction in recurrence varied by age and tumor characteristics.^[2] 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.^[3]

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.^[5] 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.^[3]

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.

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Next Section

Table 1. Sample characteristics
Characteristic	Total (%) (N = 1778)	%	Radiotherapy (n = 1405)		No radiotherapy (n = 373)		P*
Characteristic	Total (%) (N = 1778)	%	No.	Col %	No.	Col %	P*
Mean age (SD), y	1778	59 (9)	1405	58 (9)	373	63 (9)	<.001
Age at random assignment/enrollment
<60 years	903	50.8	773	55.1	130	34.8	<.001
60–70 years	296	16.6	174	12.3	122	32.7
>70 years	579	32.6	458	32.6	121	32.5
Tumor grade
Low	439	24.7	341	24.3	98	26.3	<.001
Intermediate	765	43.0	610	43.4	155	41.6
High	157	8.8	121	8.6	36	9.6
Missing/Unknown	417	23.5	333	23.7	84	22.5
Pathological tumor size, cm
≤ 1	518	29.1	357	25.4	161	43.1	<.001
>1	1005	56.5	904	64.3	101	27.1
Unknown (but stage I or ≤2 cm per protocol)	255	14.4	144	10.3	111	29.8
Hormone status
ER+ and PR+	1361	76.5	1143	81.3	218	58.4	<.001
Other (ER+ or PR+ or one unknown and the other +)	417	23.5	262	18.7	155	41.6
HER2 status
Known negative	986	55.5	835	59.5	151	40.5	<.001
Unknown	792	44.5	570	40.5	222	59.5
Initial endocrine therapy
Tamoxifen	1145	64.4	815	58	330	88.5	<.001
AI †	434	24.4	403	28.7	31	8.3
AI and Tamoxifen	161	9.1	152	10.9	9	2.4
Ovarian suppression (+/- AI or Tam)	38	2.1	35	2.5	3	0.8
Study
NSABP B-21	216	12.2	103	7.4	113	30.3	<.001
CALGB 9343	135	7.6	68	4.8	67	17.9
Toronto/Vancouver Trial	177	10	87	6.2	90	24.1
GBSG V	88	4.9	46	3.3	42	11.3
TAILORx	809	45.5	748	53.2	61	16.4
NSABP B-14	208	11.7	208	14.8	−‡	−‡
NSABP B-20	145	8.1	145	10.3	−‡	−‡
Years of diagnosis
1980–1989	353	19.8	353	25.1	−‡	−‡	<.001
1990–2000	616	34.7	304	21.7	312	83.7
2001 or later	809	45.5	748	53.2	61	16.3
Overall median length of follow-up (range), y	1778	5(0.1–23)	1405	5(0.1–23)	373	8(0.2–18)	<.001
Radiotherapy randomized
Yes	616	34.7	304	21.6	312	83.7	<.001
No	1162	65.3	1101	78.4	61	16.3
Oncotype DX risk group
0–10	1120	63.0	959	68.3	161	43.1	<.001
11–18	658	37.0	446	31.7	212	56.9

*Two-sided P values are based on χ² or Student t tests. ER = estrogen receptor; PR = progesterone receptor; AI = aromatase inhibitor; NSABP = National Surgical Adjuvant Breast and Bowel Project; CALGB = Cancer And Leukemia Group B; TAILORx = Trial Assigning IndividuaLized Options for Treatment (Rx); GBSG V = German Breast Cancer Study Group V.
†Approximately 20% women younger than age 60 years and 30% women aged 60 years and older received aromatase inhibitors only.
‡Radiotherapy was given to women per treatment protocol. Assumed 100% compliance to protocol.

Table 2. Hazard ratios for recurrence-free interval and overall and breast cancer–specific survival for omission vs receipt of radiotherapy
Study endpoints	No.	No. of events/Total No. of women		HR (95% CI)	P*
Study endpoints	No.	No RT	RT	HR (95% CI)	P*
RFI
Unweighted (no RT vs RT)†	1778	53/373	91/1405	2.59 (1.38 to 4.89)	.003
Propensity weighted (no RT vs RT)‡	1778			2.75 (1.67 to 4.54)	<.001
Competing risk model (no RT vs RT)†	1778			2.63 (1.40 to 4.92)	.003
Locoregional RFI§
Unweighted (no RT vs RT)†	1741	38/366	30/1375	3.91 (1.81 to 8.45)	.001
Propensity weighted (no RT vs RT)‡	1741			3.92 (1.87 to 8.20)	<.001
Competing risk model (no RT vs RT)†	1741			3.97 (1.85 to 8.50)	<.001
Distant RFI∥
Unweighted (no RT vs RT)†	1710	7/335	30/1375	0.90 (0.26 to 3.10)	.90
Propensity weighted (no RT vs RT)‡	1710			0.84 (0.30 to 2.34)	.81
Competing risk model (no RT vs RT)†	1710			0.82 (0.24 to 2.75)	.75
Mortality outcomes
All-cause mortality†	1778	44/373	104/1405	0.88 (0.53 to 1.44)	.61
Breast cancer–specific mortality†	1778	6/373	19/1405	1.14 (0.30 to 4.43)	.85

*Two-sided P values are based on Student t test. RFI = recurrence-free interval; CI = confidence interval; RT = radiotherapy.
†Adjusted for patient age, tumor grade (low, moderate, high, or unknown), ER/PR status (ER+ and PR+ or other), HER2 (negative or unknown), initial hormonal treatment (tamoxifen, aromatase inhibitors or other), tumor size, trial, and Oncotype DX recurrence score.
‡Inverse probability of treatment weighted (IPTW) analysis.
§Excluding distant recurrence events.
∥Excluding locoregional recurrence events.

Table 3. Hazard ratios and five-year recurrence-free interval rates for omission vs receipt of radiotherapy for patient subgroups
Characteristics	N	No. of events/Total No. of women		HR (95% CI)	5-year RFI rates, %
Characteristics	N	No RT	RT	HR (95% CI)	No RT	RT	Absolute differences, % (95% CI)
Overall*	1778	53/373	91/1405	2.59 (1.38 to 4.89)	93.5	97.9	4.4 (0.7 to 8.1)
Hormone status†
ER+ and PR+	1361	25/218	39/1143	2.47(0.92 to 6.68)	94.5	98.0	3.5 (−1.3 to 8.3)
Other	417	20/155	22/262	2.55 (1.15 to 5.66)	92.0	97.7	5.7 (0.4 to 11.8)
Oncotype DX recurrence score‡
0–10	1120	10/161	16/959	2.39 (0.87 to 6.58)	94.7	98.6	3.9 (−1.2 to 8.9)
11–18	658	19/212	25/446	2.62 (1.10 to 6.28)	92.0	97.3	5.3 (0.3 to 11.0)
Age Group, at random assignment/enrollment§
<60 y	903	17/130	42/773	2.45 (1.00 to 7.82)	90.0	95.4	5.4 (2.9 to 13.7)
60–70 y	296	13/122	12/174	2.37 (0.89 to 10.35)	93.4	98.4	5.0 (1.0 to 9.0)
>70 y	579	14/121	6/458	1.99 (0.29 to 13.47)	95.1	98.1	3.0 (−0.9 to 6.9)
Grade ∥
Low	439	6/98	9/341	2.33 (0.59 to 9.20)	99.0	99.8	0.8 (−1.4 to 2.9)
Intermediate/High	922	20/191	23/731	2.16 (0.90 to 5.18)	91.6	96.1	4.5 (−1.9 to 10.9)
Tumor size¶
≤ 1 cm	635	24/209	19/426	2.37 (1.07 to 5.26)	92.8	96.4	3.6 (−1.6 to 8.7)
> 1 cm	1143	20/164	42/979	2.74 (1.42 to 5.32)	92.0	96.8	4.8 (−2.6 to 12.2)

*Cox models adjusted for patient age, tumor grade (low, moderate, high, or unknown), ER/PR status (ER+ and PR+ or other), HER2 (negative or unknown), initial hormonal treatment (tamoxifen, aromatase inhibitors or other), tumor size, trial, and Oncotype DX recurrence score. RFI rates 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. RFI = recurrence-free interval; CI = confidence interval; HR = hazard ratio; RT = radiotherapy.
†Cox models adjusted for patient age, tumor grade (low, moderate, high, or unknown), tumor size, trial type, and Oncotype DX recurrence score.
‡Cox models adjusted for patient age, tumor grade (low, moderate, high, or unknown), ER/PR status (ER+ and PR+ or other), tumor size, trial type, and Oncotype DX® recurrence score.
§Cox models adjusted for patient age, tumor grade (low/moderate, high, or unknown), ER/PR status (ER+ and PR+ or other), tumor size, trial type and Oncotype DX® recurrence score.
∥Cox models adjusted for patient age, ER/PR status (ER+ and PR+ or other), tumor size, trial type, and Oncotype DX® recurrence score.
¶Cox models adjusted for patient age, ER/PR status (ER+ and PR+ or other), and Oncotype DX recurrence score.

Table 4. Sensitivity analyses
Study endpoints	N	No. of events/Total No. of women		HR* (95% CI)	P†
Study endpoints	N	No RT	RT	HR* (95% CI)	P†
Excluding NSABP B-14, B-20, and TAILORx (radiotherapy not randomized)
RFI	616	43/312	17/304	2.70 (1.36 to 5.36)	.005
Locoregional RFI	603	37/306	10/297	4.11 (1.78 to 9.47)	.001
Distant RFI	570	6/275	7/295	0.95 (0.26 to 3.48)	.94
Excluding TAILORx only
RFI	969	44/312	54/657	2.66 (1.36 to 5.23)	.005
Locoregional RFI	935	37/305	27/630	3.97 (1.72 to 9.10)	.001
Distant RFI	906	6/275	28/631	0.99 (0.27 to 3.64)	.98
Including ages 40 to 75 years and older
RFI	2080	54/524	76/1556	2.01 (1.18 to 3.45)	.01
Locoregional RFI	1994	35/501	23/1493	3.81 (1.88 to 7.72)	<.001
Distant RFI	1974	10/472	41/1502	0.65 (0.26 to 1.60)	.40
5-year study duration
RFI	1778	22/373	37/1405	2.55 (1.06 to 6.18)	.04
Locoregional RFI	1742	19/367	19/1375	3.69 (1.36 to 10.03)	.01
Distant RFI	1710
9-year study duration
RFI	1778	22/373	37/1405	2.64 (1.35 to 5.15)	.005
Locoregional RFI	1742	41/367	55/1375	4.25 (1.58 to 9.81)	.001
Distant RFI	1710	6/335	28/1375	0.90 (0.25 to 3.19)	.87

*Cox models 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, study type, and Oncotype DX recurrence score. RFI = recurrence-free interval; CI = confidence interval; HR = hazard ratio; NSABP = National Surgical Adjuvant Breast and Bowel Project; TAILORx = Trial Assigning IndividuaLized Options for Treatment (Rx).
†Two-sided P values are based on Student t test.

Supplemental Table 1. Summary of Trials Included in the Analyses
Study	Years of randomization	Country	N	Age	Trial eligibility	Comparators	Study End Points	Trial Design	Median Length of Follow-up (range) (years)	RT randomized
CALGB 9343(12, 13)	July 1994 and February 1999	US	636	≥70 years	Women with clinical stage I, ER-positive breast cancer (97%). Initial eligibility criteria included breast cancers up to 4 cm regardless of estrogen receptor status, but this was reduced in August 1996 to ≤2 cm (T1) with ER-positive or indeterminate receptor status. Patients were required to have clinically negative axillae.	Tamoxifen RT + tamoxifen	Time to loco-regional recurrence, frequency of mastectomy for recurrence, breast cancer– specific survival, time to distant metastasis, and overall survival.	RCT	10.3 (0.1 to 16)	Yes
NSABP B-21(14)	June 1, 1989-April 6, 1994, and April 1, 1996, - December 31, 1998	US	1,009	32–82 years (Approximately 80% of the women were aged ≥50 years.)	Women had primary invasive pathological breast tumor size of <1 cm (if the pathologic size of a tumor was not available, both the clinical and mammographic sizes of the tumor had to be less than 1 cm). All tumors had to have been removed by lumpectomy and axillary dissection, margins of the resected specimen had to be tumor-free on pathologic examination, and axillary lymph nodes had to be negative on histologic examination.	Tamoxifen RT + placebo RT + tamoxifen	Rate of ipsilateral breast tumor recurrence and both systemic recurrence (local, regional and distant) and contralateral breast cancer.	RCT	12.7 (0 to 18)	Yes
Toronto/Van couver Hospital (15)	December 1992 and June 2000	Canada	769	≥50 years	Women who had undergone breast-conserving surgery (BCS) for an invasive	Tamoxifen RT + tamoxifen	Time from randomization to the first treatment failure in ipsilateral breast, in the axillary nodes, or at a distant site) or death (with no recurrence).	RCT	9.7 (0 to 18)	Yes
GBSG V (16)	1991 and 1998	Germany	347	45–75 years	Women with primary breast cancer, stage pT 1pN0M0, histological tumor grades I or II according, absence of lymphovascular invasion tumor-free margins (at least 2 mm) after BCS, no extensive intraductal component (EIC), positive estrogen and/or progesterone receptor status.	BCS without any further treatment, BCS + RT, BCS + TAM and BCS + RT + TAM.	Event-free survival defined as the time from primary diagnosis to the first event of local or regional recurrence without simultaneous distant failure or distant recurrence, contralateral or second cancer and death without previous recurrence. Distant disease-free survival defined as the time from primary diagnosis to distant recurrence, contralateral or second cancer and/or death without previous distant recurrence.	2X2-factorial design with four treatment arms.	9.1 (0.3 to 16)	Yes
TAILORx (17)	April 7, 2006, and October 6, 2010	US	1,629	18–75 years	Women with axillary node– negative invasive breast cancer that was estrogenreceptor– positive or progesteronereceptor– positive (or both) and that did not overexpress HER2 and a recurrence score of 0 to 10 (indicating low risk).	Patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10.	Rate of survival free from first event of recurrence of ipsilateral breast tumor, local/regional/distant recurrence, second primary cancer or death without evidence of recurrence.	prospectively conducted clinical trial	5 (0 to 5)	No: among those who underwent lumpectomy 92% received radiation therapy.
NSABP B-14(18)	January 4, 1982, and December 15, 1987	US	2,892	≤70 years	Women with operable primary breast cancer and axillary nodes negative for cancer at histologic examination were eligible for this study if their tumors were estrogen-receptor positive (≥10 fmol) and they fulfilled specific criteria common to all NSABP clinical trials evaluating systemic therapy.(19, 20)	Tamoxifen only Placebo	Disease-free survival included first local recurrences of disease, regional and distant metastases, recurrence of tumor in the ipsilateral breast after lumpectomy, occurrence of tumor in the contralateral breast, occurrence of a second primary tumor, and death due to causes other than cancer.	RCT	18.5 (0 to 25)	No: per protocol RT required after BCS We assumed 100% compliance with protocol.
NSABP B-20(19)	October 17, 1988, and March 5, 1993	US	2,363	21–75 years	Women who had primary operable, histologically node-negative, ER-positive breast cancer and who had a life expectancy of at least 10 years were eligible for this study.	Tamoxifen ONLY MF+ Tamoxifen CMF+ Tamoxifen	Disease-free survival was defined as time on the study without recurrence of breast cancer at local, regional, or distant sites; occurrence of a second primary cancer; or occurrence of death prior to those events.	RCT	14 (0 to 17)	No: per protocol RT required after BCS We assumed 100% compliance with protocol.

Supplemental Table 2. Comparison of patient characteristics
Characteristics	Pooled Clinical Trial Data (%) N=4,249	SEER-GHI (%) N= 27,033
Grade¹
Good	29.4	30.8
Intermediate	50.4	51.9
Poor	12.9	14.6
Unknown/Missing	7.4	2.7
Tumor size (cm)	Mean 1.2 (SD 0.5)	1.3 (0.4)
Hormone status
ER+ and PR+	72.7	89.3
Other	27.3	10.7
Age (years)
<60	48.4	40.0
60–70	29.0	38.0
70+	22.6	21.0
Radiation
Yes	78.8	85.0
No	21.2	15.0

¹ Trials providing grade information

Supplemental Table 4. Distribution of Oncotype DX® scores in the Validation Sample
	Clinicopathologically estimated Oncotype DX® scores in SEER-GHI in Validation Sample	Observed Oncotype DX® scores in SEER-GHI in Validation Sample
N	13,464	13,464
Mean	17.3	17.4
Median	16.0	17.0
Standard Deviation	7.9	8.3
Histogram

Supplemental Table 5. Comparison of actual vs. predicted Oncotype DX® scores by Oncotype DX® 0–18 and 19+ categories (NSABP-GHI data for stage I, node negative and ER+ and/or PR+ breast cancer)
Predicted Oncotype DX® scores (N, row %)	Actual Oncotype DX® scores (N, row %)
Predicted Oncotype DX® scores (N, row %)	0–18	19+	Total
0–18	535 (71.1%)	217 (28.9%)	752 (100%)
19+	153 (30.2%)	353 (69.8%)	506 (100%)
Total	688 (54.7%)	570 (45.3%)	1,258 (100%)
Kappa Statistic	71%

Supplemental Table 6. Characteristics of Patients by Study (N=1,778)
Characteristics	Trial
	B-21 (N= 217)	CALGB 9343 (N=135)	GBSG V (N=88)	Toronto/Vancouver Trial (N= 177)	TAILORx (N= 809)	B-14 (N= 208)	B-20 (N= 145)	TOTAL (N=1778)
	Col. %	Col. %	Col. %	Col. %	Col. %	Col. %	Col. %	Col. %
Age at randomization
40–49 years	15.0	0	9.8	0	19.4	26.5	39.0	17.4
50–59 years	34.2	0	37.3	28.1	38.8	34.8	35.0	33.4
60–69 years	34.7	0	35.2	40.7	36.0	36.9	23.1	32.6
70–74 years	16.1	100	17.8	31.2	5.8	1.8	2.9	16.6
Age at randomization (years) (mean and SD)	60 (8.5)	72 (1.2)	61 (8)	64 (7)	57 (8)	56 (8)	53 (8)	59 (9)
Tumor Grade
Low	40.2	NA²	43.0	14.8	31.9	NA	20.7	24.7
Intermediate	37.5	NA	53.5	55.3	58.7	NA	43.9	43.0
High	10.6	NA	3.5	25.1	6.8	NA	21.7	8.8
Missing/Unknown	11.7	100	0	4.9	2.6	100	13.7	23.5
Pathological tumor size
≤ 1 cm	97.6	0	0	38.5	17.4	28.5	26.5	29.1
>1-2 cm	0	0	0	61.5	82.6	60.1	71.0	56.5
Unknown (but </= 2 cm per study protocol)	2.44	100	100	0	0	11.4	2.6	14.4
Tumor size (pathological, clinical or mammographic)
≤ 1 cm	100	57.5	25.8	38.5	17.4	33.3	26.9	35.7
>1cm	0	42.5	74.2	61.5	82.6	66.7	73.1	64.3
Endocrine therapy
Tamoxifen	100	100	100	100	21.8	100	100	64.4
Aromatase Inhibitor (AI)	0	0	0	0	53.65	0	0	24.4
AI/Tamoxifen	0	0	0	0	19.9	0	0	9.1
Ovarian Function Suppression (with or without AI/Tam)	0	0	0	0	4.7	0	0	2.1
Radiation randomized
Yes	100	100	100	100	0	0	0	34.7
No	0	0	0	0	100	100	100	65.3
Any first event³	9.5	10.3	9.7	9.9	1.0	11.3	9.0	5.1
5-year RFI rates	94.8	94.1	92.3	93.3	98.9	92.9	96.2	94.6
Time to any first event (median and SD) (in years)	10(2)	10(3)	9(3)	10(3)	5(1)	10(2)	10(2)	5(3)
Length of follow-up (median and SD) (in years)	11 (3)	11 (3)	9 (3)	10 (4)	5 (1)	19 (6)	14 (3)	5 (5)
Type of first event
Local-regional Recurrence	7.7	8.1	8.2	6.8	0.6	3.7	5.9	3.8
Distant recurrence	1.7	2.2	1.6	3.2	0.4	7.6	2.7	2.1
Breast cancer death	0.0	0.0	0.0	0.0	0.0	0.0	0.4	0.0
Censored (alive at the end of study or death due to other causes)	90.5	89.7	90.3	90.1	99.0	88.7	91.0	94.1
`Predicted Risk group
0–10	31.2	34.1	32.7	31.4	100.0	32.1	32.2	63.0
11–18	68.8	65.9	67.3	68.6	0.0	67.9	67.8	37.0

²Information not provided in the trial
³First occurrence of local (invasive), regional or distant recurrence or death due to breast cancer

Authors and Disclosures

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 and Jeanne Mandelblatt, for the CISNET-BOLD Collaborative Group

Department of Oncology, Georgetown University Medical Center and Cancer Prevention and Control Program, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC (JJ, JM); Departments of Family and Social Medicine and Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (CS); Department of Radiation Oncology, University of Michigan, Ann Arbor, MI (RJ); The James Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH (JW); Canadian Cancer Trials Group, Queen's University, Kingston, ON, Canada (JAWC-Retired); Research Department of Oncology, Division of Radiation Oncology, McMaster University, Hamilton, ON, Canada (TW); Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY (JAS); NRG Oncology, and the Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA (SJA); Radiation Medicine Program, Princess Margaret Cancer Centre, Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada (AWF); Institute for Medical Biometry and Statistics, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany (WS); Department of Radiation Oncology, Indiana University, Bloomington, IN (RCZ); Department of Biostatistics, Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX (YL, JS, XH, DB); NRG Oncology, and The Division of Breast Surgical Oncology, Allegheny General Hospital, Allegheny Health Network, Pittsburgh, PA (TBJ); Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD (EJF); Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC (GL).

Correspondence to
Jinani Jayasekera, PhD, Department of Oncology, Georgetown-Lombardi Comprehensive Cancer Center, 3300 Whitehaven St, NW, Ste 4100, Washington, DC 20007 (e-mail: jcj74@georgetown.edu).

Jinani Jayasekera, Yisheng Li, Clyde Schechter, Reshma Jagsi, Juhee Song, George Luta, Judith-Anne Chapman, Eric Feuer, Richard Zellars, Thomas Julian, Timothy Whelan, Xuelin Huang, Stewart Anderson, Anthony Fyles, Willi Sauerbrei, and Jeanne Mandelblatt have nothing to disclose.
Julia White received honoraria from Qfix. Joseph Sparano owns stock in Metastat, has served in an advisory role for Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack, and has received research funding from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. Donald Berry is co-owner of Berry Consultants, LLC, a company that designs adaptive Bayesian clinical trials for pharmaceutical and medical device companies, NIH cooperative groups, international consortia, and patient advocacy groups.
Jinani Jayasekera was responsible for conception, design, data analyses, interpretation of results, manuscript preparation, and approval of the final manuscript.
Clyde Schechter was responsible for conception, design, data analyses, interpretation of results, manuscript preparation, and approval of the final manuscript.
Reshma Jagsi was responsible for conception, interpretation of results, and approval of the final manuscript.
Joseph A. Sparano was responsible for conception, interpretation of results, and approval of the final manuscript.
Juhee Song was responsible for data analyses and approval of the final manuscript.
Yisheng Li was responsible for data analyses and approval of the final manuscript.
Julia White was responsible for conception, interpretation of results, and approval of the final manuscript.
George Luta was responsible for data analyses, interpretation of results, and approval of the final manuscript.
Judith-Anne Chapman was responsible for interpretation of results and approval of the final manuscript.
Eric J. Feuer was responsible for conception, provision of data, interpretation of results, and approval of the final manuscript.
Richard C. Zellars was responsible for interpretation of results and approval of the final manuscript.
Thomas B. Julian was responsible for conception, interpretation of results and approval of the final manuscript.
Timothy Whelan was responsible for interpretation of results and approval of the final manuscript.
Xuelin Huang was responsible for data analyses, interpretation of results, and approval of the final manuscript.
Stewart J. Anderson was responsible for provision of data, interpretation of results, and approval of the final manuscript.
Anthony W. Fyles was responsible for provision of data, interpretation of results, and approval of the final manuscript.
Willi Sauerbrei was responsible for provision of data, interpretation of results, and approval of the final manuscript.
Donald Berry was responsible for conception, design, data analyses, interpretation of results, manuscript preparation, and approval of the final manuscript.
Jeanne Mandelblatt was responsible for conception, design, data analyses, interpretation of results, manuscript preparation, and approval of the final manuscript.