A total of 10,709 women were enrolled onto the five studies: 9,118 were randomly assigned, and 1,591 were registered. Among the 9,118 randomly assigned patients, 3,799 (42.8%) underwent lumpectomy, had follow-up information, and were eligible for this analysis. This group, which had a median time on study of 16.1 years, constituted our population at risk for LRF.
Patient characteristics of the cohort treated by lumpectomy in these trials are listed in Appendix Table A1 (online only). The rates of lumpectomy were lower in earlier trials than in later trials. Overall at entry, 49.3% of the women were aged 49 years or younger, and 27.7% were aged 60 years or older. More than half of the patients in the ER-negative cohort were younger than 50 years at entry. In contrast, there were proportionately older patients in the ER-positive cohort.
The majority of tumors (67%) measured clinically were 2 cm or less. The distribution of patients by race varied considerably among the trials, and black patients were in lower proportions in ER-positive lumpectomy trials (2.7% in B-14 and 5.5% in B-20) and in higher proportions in ER-negative trials (6.4% to 14.9%).
As of March 2006, 342 (9.0%) of the 3,799 patients developed IBTR, and 77 (2.0%) developed oLRR (). Of the 342 who developed IBTR, 127 (37.1%) occurred within 5 years, and 233 (68.1%) occurred within 10 years, of the initial surgery. Of the 77 oLRRs, 56 (72.7%) occurred within 5 years, and 71 (92.2%) occurred within 10 years, of the initial surgery. The pooled 12-year cumulative incidences were 7.6% for IBTR and 2.0% for oLRR.
Rates of IBTR and oLRR After Lumpectomy
Cumulative Incidence of LRF by Patient Characteristics
Cumulative incidences of LRF by patient characteristics are summarized in Appendix Figures A1 and A2 (online only), respectively. Younger women had a significantly higher cumulative incidence of IBTR than did older women (P < .0001; Fig A1A). The 12-year incidences of IBTR for women aged 49 years or younger, 50 to 59 years, and 60 years or older were 9.6%, 5.8%, and 5.6%, respectively (Fig A2A).
Race had marginal significance associated with IBTR univariately (P = .04; Fig A1B) but was not significant when adjusted for age, tumor size, and BMI. In contrast, race was highly significantly associated with oLRR (P = .001; Fig A2B). For both outcomes, black women fared more poorly than did white women. BMI was not significantly associated with IBTR or oLRR.
Clinical tumor size was not significantly associated with IBTR (P = .26) but was significantly associated with oLRR (P = .006; Figs A1C and A2C), whereas pathologic tumor size was a significant predictor of IBTR (P = .003) but not of oLRR (P = .07; Figs A1D and A2D). As expected, patients with larger tumors fared more poorly than did those with smaller tumors.
ER status was not significantly associated with either the incidence of IBTR (P = .81; Fig A1E) or oLRR (P = .95; Fig A2E). However, ER-negative patients appeared to have an increased incidence of early IBTR and oLRR events, which leveled off over time, whereas ER-positive patients had a fairly constant incidence of both IBTR and oLRR. PR status was not significantly associated with either the incidence of IBTR or oLRR (P = .83 and P = .19, respectively; analyses not shown).
Adjuvant therapy had great influence on the incidence of IBTR (P < .0001; Fig A1F) but not on oLRR (P = 0.21; Fig A2F). For patients who were assigned to the arms with no adjuvant therapy, the pooled 12-year incidence of IBTR was 12.3%. In contrast, those assigned to tamoxifen alone, chemotherapy alone, and tamoxifen plus chemotherapy had 12-year incidences of 6.7%, 6.4%, and 6.8%, respectively (pooled value, 6.6%).
DDFI and OS After LRF
As shown in , 5-year DDFI and OS after IBTR were 66.9% and 76.6%, respectively. Patients who experienced oLRR had worse outcomes (ie, 27.8% 5-year DDFI after oLRR, and 34.9% 5-year OS after oLRR). Overall, the risk of developing distant disease and mortality were consistently greater after oLRR than after IBTR, irrespective of the original treatment.
Fig 1. Outcomes after ipsilateral breast tumor recurrence (IBTR) and other locoregional recurrence (oLRR) by estrogen receptor (ER) status. (A) Distant-disease–free interval (DDFI) and (B) overall survival (OS) for the first 5 years after IBTR by ER (more ...)
A model of OS that used IBTR and other significant factors is listed in . There was significant interaction between ER status and IBTR (P = .002), and IBTR had greater impact on mortality in ER-negative than in ER-positive patients. The adjusted hazard ratio (HR) for mortality after development of IBTR was 4.49 (95% CI, 3.29 to 6.13) in ER-negative patients and 2.32 (95% CI, 1.72 to 3.14) in ER-positive patients. Other significant multivariate predictors of mortality included age at entry, race, BMI, and clinical and pathologic tumor sizes. Older women and those with larger tumors (> 2.0 cm) had significantly higher mortality than did younger women and those with smaller tumors. BMI was also highly significantly associated with mortality (P = .0089). Black women experienced an elevated mortality even after analyses were adjusted for BMI and other factors.
Multivariate Cox Model of Mortality Using IBTR and Other Factors
The effect of oLRR on mortality () was magnified compared with that of IBTR, but a similar interaction with ER status was observed (P < .0001); oLRR had a greater impact on mortality in ER-negative patients than in ER-positive patients. The adjusted HR for mortality after development of oLRR was 19.84 (95% CI, 13.33 to 29.74) in ER-negative patients versus 6.43 (95% CI, 4.29 to 9.64) in ER-positive patients. All the other clinical factors mentioned for IBTR were significantly associated with mortality in patients who experienced oLRR with similar HRs. For the occurrence of distant disease after LRF, somewhat higher risks were observed with similar patterns, but the differential effects by ER status were nonsignificant.
Multivariate Cox Model of Mortality Using oLRR and Other Factors
Timing of LRF As Predictor of OS and DDFI
By using different time cutoffs, we observed substantial and significant decreases in death at 5 years for patients who experienced late LRF versus early LRF (). OS and DDFI after oLRR were much worse than after IBTR at every time interval. The 5-year OS after LRF for those whose oLRR occurred within 2 years of their original diagnosis of cancer was only 19.5%.
Comparison of OS and DDFI After IBTR and oLRR for Early Versus Late Event Occurrences in Lumpectomy Patients From NSABP Protocols