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Journal of Clinical Oncology logoLink to Journal of Clinical Oncology
. 2009 Aug 31;27(30):4939–4947. doi: 10.1200/JCO.2008.21.5764

Impact of Pathological Characteristics on Local Relapse After Breast-Conserving Therapy: A Subgroup Analysis of the EORTC Boost Versus No Boost Trial

Heather A Jones 1, Ninja Antonini 1, Augustinus AM Hart 1, Johannes L Peterse 1,, Jean-Claude Horiot 1, Françoise Collin 1, Philip M Poortmans 1, S Bing Oei 1, Laurence Collette 1, Henk Struikmans 1, Walter F Van den Bogaert 1, Alain Fourquet 1, Jos J Jager 1, Dominic AX Schinagl 1, Carla C Wárlám-Rodenhuis 1, Harry Bartelink 1,
PMCID: PMC2799051  PMID: 19720914

Abstract

Purpose

To investigate the long-term impact of pathologic characteristics and an extra boost dose of 16 Gy on local relapse, for stage I and II invasive breast cancer patients treated with breast conserving therapy (BCT).

Patients and Methods

In the European Organisation for Research and Treatment of Cancer boost versus no boost trial, after whole breast irradiation, patients with microscopically complete excision of invasive tumor, were randomly assigned to receive or not an extra boost dose of 16 Gy. For a subset of 1,616 patients central pathology review was performed.

Results

The 10-year cumulative risk of local breast cancer relapse as a first event was not significantly influenced if the margin was scored negative, close or positive for invasive tumor or ductal carcinoma in situ according to central pathology review (log-rank P = .45 and P = .57, respectively). In multivariate analysis, high-grade invasive ductal carcinoma was associated with an increased risk of local relapse (P = .026; hazard ratio [HR], 1.67), as was age younger than 50 years (P < .0001; HR, 2.38). The boost dose of 16 Gy significantly reduced the local relapse rate (P = .0006; HR, 0.47). For patients younger than 50 years old and in patients with high grade invasive ductal carcinoma, the boost dose reduced the local relapse from 19.4% to 11.4% (P = .0046; HR, 0.51) and from 18.9% to 8.6% (P = .01; HR, 0.42), respectively.

Conclusion

Young age and high-grade invasive ductal cancer were the most important risk factors for local relapse, while margin status had no significant influence. A boost dose of 16 Gy significantly reduced the negative effects of both young age and high-grade invasive cancer.

INTRODUCTION

Breast conserving therapy (BCT) is now a standard therapeutic option for the treatment of many women with early-stage invasive breast cancer and is a preferred treatment to mastectomy because of the cosmetic benefit of breast preservation.15 Four percent to 15% of patients with early-stage breast carcinoma treated with BCT will have a local relapse within 10 years.110 We and Romestaing et al1113 demonstrated that a higher radiation dose to the tumor bed significantly reduced the local relapse rate. The Early Breast Cancer Trialists Collaborative Group meta-analysis demonstrated that preventing breast recurrences improves survival.14 Thus, minimizing the risk of local relapse in patients choosing BCT remains an important clinical objective.

There is increasing recognition of the complex role prognostic factors other than those included in the conventional staging system have in determining the risk of local relapse after BCT. Integrating and interpreting these relationships between prognostic factors such as margin status, age, histologic grade, size of primary tumor, number of positive nodes, HER2 status, peritumoral vascular invasion, and other such clinicopathological features will provide a useful platform for interpreting the risk of local recurrence and additionally provide guidance as to the role of adjuvant therapy and the intensity of such adjuvant therapy. Several publications indicate that the final margin status ranks among the pathologic risk factors most strongly associated with local relapse.923 This association has also been reported in three prospective randomized trials that compared BCT with mastectomy in early-stage breast cancer patients.2425 Several factors have been associated with a reduced risk for local relapse in patients with positive margins such as focally positive margins compared to more extensively involved margins.18,19,21 These patients have been considered candidates for BCT, particularly in the absence of an associated extensive intraductal component (EIC).26 A higher total dose of radiation to the tumor bed has been found to decrease the risk of local relapse associated with positive margins in some series,2733 but not in others.18,20,34 To address these complex issues, a subset analysis of patients with completely excised tumors entered in the first years of the European Organisation for Research and Treatment of Cancer (EORTC) trial 22881/10882 was performed. Pathologic factors including the margin status were assessed by central pathology review. The purpose of the study was to examine each of these pathologic features as prognostic factors on the subsequent risk of local relapse after BCT with or without a16-Gy boost.

PATIENTS AND METHODS

The EORTC 22881/10882 boost versus no boost trial accrued 5,569 patients from 1989 to 1996. The main objective of the trial was to assess the effect of the boost dose in early -stage breast cancer patients treated with BCT. All patients underwent lumpectomy and axillary dissection followed by whole breast irradiation (WBI; total dose of 50 Gy in 5 weeks with a dose per fraction of 2 Gy). After informed consent, patients with microscopically complete excision (negative margin for the invasive component) were randomly assigned to receive WBI with either no boost or a boost of 16 Gy on the tumor bed. Patients with microscopically incomplete excision (positive margins for the invasive component) received WBI of 50 Gy to the breast and were randomly assigned to receive an extra boost dose of 10 or 26 Gy to the tumor bed. Details of this trial have been published previously.1112,34 Data with a median follow-up time of 10 years were used for this analysis.

Pathology Review

From the first years of the accrual period (1989 to 1996), pathology slides from 1,616 patients (which represent 30% of the whole population) with clinical stage I or II breast cancer were centrally collected. The pathologic characteristics and the status of the surgical margins were determined by one pathologist (H.L.P.). Tumors were scored according to their proximity to the inked surgical margin. Thus, margins status was defined as followed: a positive surgical margin as tumor (invasive or ductal carcinoma in situ [DCIS]) seen immediately at the inked edge of the resection, a close margin as tumor (invasive or DCIS) seen at 2 mm or less from the inked resection edge, and a negative margin as greater than 2 mm of tumor free margin from the inked resection edge or no residual tumor on re-excision. The extent of invasive tumor positivity at the margin was not recorded. The extent of DCIS was estimated by counting the number of ducts involved with DCIS in the breast tissue adjacent to the primary tumor. The DCIS component was considered as minimal if three or fewer ducts were involved, as moderate if four to nine ducts were involved, and as extensive if 10 or more ducts were involved. DCIS tumors with focal areas of invasion were classified as invasive carcinomas with an EIC. For 1,494 patients, the margin status could be scored for involvement of invasive cancer. In 805 patients with invasive tumor and a DCIS component, the margin for DCIS could be scored. The histologic grade of all 1,616 invasive tumors was defined according to the Elston/Ellis modification of the Bloom-Richardson system35 and the histologic grade of the DCIS component was classified as low, intermediate, or high.36 Mitotic activity index was also scored and represented the number of mitoses in 10 consecutive high power fields of 0.045 mm2. Vascular invasion was considered to be present when distinct tumor emboli were seen in at least three endothelium-lined (blood or lymphatic) vessels in breast tissue surrounding the tumor.

Statistical Analysis

Differences in patient, treatment, and tumor characteristics (ie, menopausal status, size of biopsy specimen, nodal status, estrogen and progesterone receptor status, DCIS, systemic treatment [chemo- or hormone therapy], and histologic grade) between margin status categories were investigated with Kruskal-Wallis test for continuous and the χ2 test for categoric variables.

To investigate the association between margin status and local failure, univariate and multivariate survival analysis was performed with Cox proportional hazard models, which takes censoring into account. Time was calculated from the random assignment date. An event was defined as first recurrence in the ipsilateral breast. All other patients were censored at the time of another breast cancer event, death from any cause, or at last follow-up. Age was calculated from date of birth until date of random assignment. Patients were excluded from a given analysis, if the data for the required factor was missing. Local failure was defined as disease recurrence in the treated breast. Hazard ratio (HR) and 95% CI are presented. At the time of this analysis, 126 local failures were observed in this patient subset of completely excised tumors according to the local pathologist, 81 in the no boost, and 45 in the 16-Gy boost, respectively. Because of the exploratory nature and the limited statistical power, no formal correction for multiple comparisons was applied. Thus, P values less than .01 were considered statistically significant. All analyses were performed using SAS version 9.1 (SAS Inc, Bethesda, MD).

RESULTS

In the 1,616 patients randomly assigned after complete resection according to local pathology, the central pathology review revealed that the final resection margins for invasive tumors were negative in 1,137 patients (76%), close in 306 patients (20%), and positive in 51 patients (3.4%; Table 1). The final resection margins were negative for DCIS in 478 (59%), close in 216 patients (27%), and positive in 111 patients (14%; Table 2). Compared to patients with negative margins, the patients with close margins were younger and had different histologic tumor features, such as lobular cancer, slightly more DCIS component, and had a higher risk of regional nodal involvement. A minority of the patients received adjuvant hormone therapy (22.2%) or adjuvant chemotherapy (15.7%); however, patients with invasive tumor involving the margins or close to the margins were more likely to receive chemotherapy (P = .004). There were a few patients in any subgroup with EIC-positive tumor, which was associated with DCIS involved margins (Table 2). High-grade invasive tumors were more common in patients who were younger, had a larger tumor, those with positive lymph nodes, and in those who received systemic treatment (Table 3). A total of 126 recurrences was found in the breast as a first event. Two of these local failures were diagnosed concurrently with distant metastases. These local failures were also scored as primary event.

Table 1.

Population Characteristics by Margins for Invasive Cancer According to Central Pathology Review

Parameter Margin for Invasive Tumor
P
Positive
Close
Free
No. % No. % No. %
No. of patients 51 306 1,137
Complete WBI, 50 Gy
    No boost 27 53 160 52 549 48 .4003
    Boost 16 Gy 24 47 146 48 588 52
Volume of excision biopsy specimen, cm3
    Median 104.8 108.0 120.0 .04056
    Range 7.9-540.0 4.5-1,800.0 1.3-1,680.0
Largest diameter, mm
    Median 15.0 17.0 15.0 .00163
    Range 5.0-35.0 4.0-50.0 2.0-50.0
Age at random assignment, years
    Median 54 51.5 55 .01788
    Range 29-69 27-71 28-76
    Younger than 50 19 37 132 43 375 33 .0088
    50-60 17 33 106 35 411 36
    Older than 60 15 29 68 22 351 31
N+ according to local pathology 12 24 79 26 242 21 .2167
Postmenopausal 33 65 164 54 718 63 .0084
Receptor status
    Estrogen+ 22 71 145 67 621 73 .1628
    Progesterone+ 25 83 128 67 472 62 .0330
Systemic treatment 21 41 120 39 379 33 .0992
Mitotic activity index
    < 10 40 80 203 67 831 74 .0967
    10-19 4 8 51 17 142 13
    ≥ 20 6 12 51 17 156 14
Histology
    Ductal 28 56 207 68 839 74 .0006
    Lobular 9 18 20 7 55 5
    Mixed pattern 11 22 58 19 162 14
    Other 2 4 20 7 74 7
Differentation of the invasive tumor
    Low 28 60 143 48 561 51 .2737
    Intermediate 9 19 73 24 292 26
    High 10 21 83 28 250 23
Extensive intraductal component 8 16 39 13 111 10 .1552
Differentiation of DCIS
    Low 10 20 64 21 173 15 .0788
    Intermediate 7 14 78 25 277 24
    High 7 14 42 14 145 13
    No DCIS 27 53 122 40 540 47
Vascular invasion
    None 37 74 220 72 866 77 .2843
    Present 10 20 50 16 152 14
    Doubtful 3 6 35 11 107 10

NOTE. Patients were randomly assigned according to local pathology.

Abbreviations: WBI, whole breast irradiation; DCIS, ductal carcinoma in situ.

Table 2.

Population Characteristics by Margins for DCIS According to Central Pathology Review

Parameter Margin at DCIS
P
Positive
Close
Negative
No. % No. % No. %
No. of patients 111 216 478
Volume of excision biopsy specimen, cm3
    Median 110.0 120.0 120.0 .81720
    Range 4.5-567.0 5.6-1,800.0 1.3-1,584.0
Largest diameter, mm
    Median 15.0 15.0 15.0 .13729
    Range 4.0-40.0 4.0-40.0 4.0-40.0
Age at random assignment, years
    Median 51 52 54 .00997
    Range 28-70 27-69 28-76
    Younger than 50 52 47 84 39 154 32 .0122
    50-60 42 38 78 36 186 39
    Older than 60 17 15 54 25 138 29
N+ according to local pathology 30 27 55 26 116 25 .8314
Postmenopausal 57 51 125 58 292 61 .1611
Receptor status
    Estrogen+ 54 68 103 64 277 77 .0029
    Progesterone+ 44 61 92 63 219 68 .3858
Systemic treatment 46 41 88 41 162 34 .1218
Mitotic activity index
    < 10 75 68 133 62 377 79 < .0001
    10-19 16 14 50 23 60 13
     ≥ 20 20 18 32 15 39 8
Histology
    Ductal 88 79 177 82 391 82 .8108
    Mixed pattern 23 21 39 18 87 18
Differentation of the invasive tumor
    Low 50 46 85 41 247 53 < .0001
    Intermediate 21 19 66 32 136 29
    High 38 35 58 28 80 17
Extensive intraductal component 59 53 46 21 44 9 < .0001
Differentiation of DCIS
    Low 52 47 73 34 122 26 < .0001
    Intermediate 27 24 91 42 244 51
    High 32 29 52 24 110 23
Vascular invasion
    None 80 72 142 66 353 74 .125
    Present 23 21 45 21 75 16
    Doubtful 8 7 29 13 48 10

Abbreviation: DCIS, ductal carcinoma in situ.

Table 3.

Population Characteristics for Histologic Grade According to Central Pathology Review

Parameter Histologic Grade of Invasive Carcinoma
P
Low
Intermediate
High
No. % No. % No. %
No. of patients 782 395 362
Volume of excision biopsy specimen, cm3
    Median 105.0 122.5 140.0 < .00001
    Range 4.5-1,584.0 1.3-1,616.0 9.0-1,800.0
Largest diameter, mm
    Median 15.0 15.0 20.0 < .00001
    Range 2.0-40.0 2.0-45.0 5.0-50.0
Age at random assignment, years
    Median 55.0 54.0 50.0 < .00001
    Range 27.0-76.0 28.0-75.0 28.0-73.0
    Younger than 50 231 30 130 33 179 49 < .0001
    50-60 289 37 155 39 107 30
    Older than 60 262 34 110 28 76 21
N+ according to local pathology 153 20 101 26 92 25 .0275
Postmenopausal 509 65 241 61 187 52 .0001
Receptor status
    Estrogen+ 462 84 228 75 119 42 < .0001
    Progesterone+ 386 79 189 67 81 33 < .0001
Systemic treatment 243 31 158 40 145 40 .0012
Mitotic activity index
    < 10 778 99 273 69 56 15 < .0001
    10-19 3 0.4 119 30 88 24
    ≥ 20 1 0.1 3 0.8 218 60
Histology
    Invasive ductal carcinoma 422 54 376 95 323 89 < .0001
    Invasive lobular carcinoma 90 12 1 0.3
    Mixed invasive pattern 211 27 16 4 3 0.8
    Other 59 8 2 0.5 36 10
Extensive intraductal component 58 7 47 12 53 15 .0004
Differentiation of DCIS
    Low 13 2 63 16 161 44 ≤ .0001
    Intermediate 207 26 143 36 12 3
    High 168 21 18 5 3 0.8
    No DCIS 394 50 171 43 186 51
Vascular invasion
    None 665 86 231 59 255 71 < .0001
    Present 63 8 89 23 69 19
    Doubtful 49 6 74 19 33 9

Abbreviation: DCIS, ductal carcinoma in situ.

Univariate and Multivariate Analysis of Prognostic Factors for Local Relapse

In the univariate analysis (Table 4), high tumor grade of invasive tumor and young age (younger than 50 years) were predictive for an increased risk of local relapse, whereas adjuvant hormone or chemotherapy and an additional boost on the tumor bed were associated with a decreased risk of local relapse. In the multivariate analysis, the boost dose significantly reduced the local relapse rate (P = .0006; HR, 0.47). The presence of high grade invasive ductal carcinoma was associated with an increased risk of local relapse (P = .026; HR, 1.67), as was age younger 50 years (P < .0001; HR, 2.38). Margin involvement or differentiation grade of DCIS had no significant impact on the risk of local relapse (Table 5).

Table 4.

Univariate Analysis for Local Relapse in Patients With 0 or 16 Gy Boost

Contrast by Factor P Hazard Ratio 95% CI
Age > 50, yes v no < .0001 0.40 0.28 to 0.57
N+ according to local pathology, N+ v N− .2585 0.77 0.48 to 1.22
Systemic treatment (chemotherapy or tamoxifen), yes v no .0088 0.57 0.38 to 0.87
Volume of excision biopsy specimen, cm3 .1068 1.00 1.00 to 1.00
Treatment, no boost v boost 16 Gy .0008 1.86 1.29 to 2.68
Vascular invasion, yes v no .9715 0.99 0.65 to 1.50
Extensive intraductal component, yes v no .8975 1.04 0.57 to 1.90
Histology
    Lobular v ductal .4451 0.72 0.32 to 1.66
    Mixed pattern v ductal .3184 0.72 0.37 to 1.38
    Other v ductal .6439 0.88 0.50 to 1.54
Histologic grade
    Intermediate v high .0320 0.60 0.37 to 0.96
    Low v high .0003 0.46 0.31 to 0.70
Ductal component involved, yes v no .5254 1.17 0.72 to 1.89
Lobular component involved, yes v no .2482 0.73 0.43 to 1.24
Mitotic activity index, < 10 v > 10 .0267 0.66 0.45 to 0.95
Margin involved of DCIS, not involved v involved .3710 0.82 0.53 to 1.27
Margin involved of DCIS/invasive tumor, not involved v involved .6779 0.92 0.64 to 1.34
Margin involved of invasive tumor, not involved v involved .4127 1.20 0.78 to 1.84
Margin of DCIS
    No DCIS v positive .4862 0.78 0.38 to 1.58
    Close v positive .9276 0.97 0.46 to 2.03
    Negative v positive .8362 0.93 0.48 to 1.81
Grade of DCIS
    No DCIS v high grade .9640 1.02 0.51 to 2.03
    Low v high .1826 1.57 0.81 to 3.06
    Moderate v high .7437 1.12 0.58 to 2.16
Margin of invasive tumor
    Negative v close .6589 1.11 0.71 to 1.73
    Incomplete v close .3191 0.48 0.11 to 2.03
Estrogen positive, yes v no .0330 0.63 0.41 to 0.96
Progesterone positive, yes v no .4286 0.84 0.54 to 1.30

Abbreviation: DCIS, ductal carcinoma in situ.

Table 5.

Multivariable Analysis of Time to Local Relapse for All Patients

Parameter P Hazard for Local Failure
Estimate 95% CI
Randomized treatment 50 Gy WBI, 0 Gy v 16 Gy .0006 0.47 0.31 to 0.73
Age, > 50 v ≤ 50 years < .0001 0.42 0.28 to 0.65
Systemic treatment, yes v no .088 0.66 0.41 to 1.06
Differentiation grade of the invasive tumor, high v low/intermediate .026 1.67 1.06 to 2.62
Differentiation grade of DCIS
    High v low/intermediate .96 1.02 0.54 to 1.93
    No DCIS v high .39 0.80 0.48 to 1.33
Margin of invasive tumor, not involved v involved .33 0.78 0.49 to 1.27

Abbreviations: WBI, whole breast irradiation; DCIS, ductal carcinoma in situ.

Final Margin Status, Age, and Grade of the Tumor

The cumulative local relapse rate as first event at 10 years was not significantly influenced by the margin status (negative, close, or positive) for invasive tumor or DCIS (Fig 1). The cumulative incidence of local relapse at 10 years was higher for patients younger than 50 years old (14.8%; 95% CI, 11.6 to 18.3) compared with patients who were 50 years or older (6.2%; 95% CI, 4.5 to 8.0; P < .001). The cumulative incidence of local relapse at 10 years was 7.3% (95% CI, 5.2 to 9.5), 8.4% (95% CI, 5.3 to 12.0), and 13.7% (95% CI, 9.7 to 17.9) for low-, intermediate-, and high-grade invasive ductal cancer, respectively (P = .0003).

Fig 1.

Fig 1.

Cumulative incidence of local failure as first event according to the margins for (A) invasive tumor and for (B) ductal carcinoma in situ.

Influence of the 16-Gy Boost Dose and the Final Margin Status

In patients with no invasive tumor at the margin and in those with no DCIS at the margin, the additional boost of 16 Gy significantly reduced the local relapse rate (P = .0004; HR, 0.47; P = .0003; HR, 0.30), while for patients with close or positive margins the effect of the boost was not significant (P = .65, P = .25, respectively for invasive cancer and DCIS).

Influence of the 16-Gy Boost in High-Risk Patients

The multivariate analysis indicated that both young patients and high-grade invasive cancer were independently associated with an increased risk of local relapse. For patients younger than 50 years, the boost dose reduced the 10-year cumulative local relapse rate from 19.4% to 11.4% (P = .0046; HR, 0.51; Fig 2). For patients with high-grade invasive ductal carcinoma, the boost dose reduced the cumulative 10-year local relapse rate from 18.9% to 8.6% (P = .01; HR, 0.42; Fig 3).

Fig 2.

Fig 2.

Cumulative incidence of local failure by boost group and age. (A) Patients younger than 51 years (P = .0046). (B) Patients older than 50 years (P = .051).

Fig 3.

Fig 3.

Cumulative incidence of local failure by boost group and grading of invasive ductal carcinoma. (A) High grade of invasive carcinoma (P = .01). (B) Low/intermediate grade of invasive carcinoma (P = .05).

Additional Analysis of the Entire Central Pathology Review Cohort

Of note, 108 patients who had an incomplete tumor resection, and therefore were included in the 10 Gy versus 26 Gy boost section of the boost no boost trial, were also part of the central pathology review, but were not included in the analysis presented. A secondary analysis including the entire cohort of 1,724 (1,616 completely resected patients and 108 incomplete resected patients, according to the local pathologist) did not change the major findings (Appendix Tables A1 to A4 and Appendix Figs A1 to A3, online only).

DISCUSSION

This study with central pathology review, suggested that patients younger than 50 years and/or with high-grade breast cancer should be considered at high risk for local relapse. An additional boost dose of 16 Gy however significantly reduced the risk for local relapse in those high-risk patients as well as in other patients with negative margins. Close or positive tumor margin status had no significant effect on local relapse this, however, may in part be explained by the fact that a limited number of patients with involved margins with invasive tumor entered this randomized clinical trial.

Optimizing local control after BCT remains an important clinical issue, especially as the Early Breast Cancer Trialists Collaborative Group showed that reducing local relapse rate reduces breast cancer mortality.14 We have previously reported that an additional boost of 16 Gy to the primary tumor bed significantly decreases the 10-year cumulative local relapse rate from 10.2% to 6.2% (P < .001) in the whole patient population of the EORTC 22881/10882 boost no boost trial.12 In this study, one breast cancer pathologist (H.L.P.) reviewed one third of surgical specimens. This included patients who underwent a complete resection and 50 Gy of WBI, followed by no boost versus an additional boost of 16 Gy to the tumor bed, as well as those who underwent incomplete tumor resection and 50 Gy of WBI followed by an additional dose boost of 10 Gy versus 26 Gy to the tumor bed, the latter data are presented in the Appendix (online only). This centralized pathology review provided a unique opportunity to evaluate the relationship between margin status, tumor type, histologic grade, and other prognostic factors, and to identify a subgroup of patients at high risk for local relapse. In addition to the study of clinical and histopathologic prognostic factors, the value of the boost dose to the tumor bed in the high risk group for local relapse could be assessed.

In our study, the additional boost to the primary tumor bed significantly increased local control in patients with negative margins, which is consistent with our previous publication.12 However, a dose-effect on local control could not be confirmed in the case of positive margins whatever the tumor type (DCIS and/or invasive tumors) found at the resection margin. The extent of margin involvement has been described as a prognostic factor of local relapse risk.19,20 However, this was not determined in this study. Several authors have reported that the additional radiation boost can indeed reduce local relapse rates in margin of positive patients.9,3741 An adjusted radiotherapeutic approach, in which the boost dose is tailored to the margin status, might be expected to optimize local control. Smitt et al18 showed a dose-response effect for doses greater than 66 Gy. Of note, Wazer et al20 noted a lower recurrence rate for higher doses of radiation in case of margin involvement. Pezner et al,42 Vicini et al,43 and Perez et al37 also found that, if close attention is paid to the pathologic assessment of the margins, increasing doses of irradiation for patients with close or positive margins reduced the local relapse rate to those with negative margins. These long-term results indicate that the prognostic significance of the surgical margins status might be negated by margin directed tumor bed dose escalation.13,20,40,44 Based on these previously published results, the EORTC boost trial 22881/10882 evaluated in a separate stratum of the trial those patients who underwent incomplete tumor resection (positive margins) followed by 50 Gy of WBI who were randomly assigned to a boost dose of 10 versus 26 Gy. Although the P value was not significant (probably due to a small sample size), the cohort of patients that received a higher boost dose to the tumor bed seemed to have a lower rate of local relapse than those receiving the lower boost dose of radiation.34

As reported by other authors the identification of risk factors for local relapse among patients after a microscopically complete tumorectomy is of particular interest and importance.21,38 In this study, histologic grade for invasive tumor, as well as age were independent risk factors for the local relapse risk. This is consistent with other studies reporting that patients with high-grade tumors have a worse local control.45,46 A remarkable finding in our study was the ability of the boost to effectively reduce the risk of local relapse in patients with high grade invasive tumors and to a lesser extent in terms of absolute reduction in low or intermediate grade tumors (Fig 3).

The effect of young age on the risk of local relapse for patients treated with BCT has been recognized in many studies using various age cut points.15,4648 This analysis and previously published result of the central pathology review demonstrated that high grade invasive tumors were more common in the young patients.45 There is also now a suggestion that young breast cancer patients have a different biologic entity.49 The 10-year results of our EORTC 22881/10882 trial demonstrated that the additional dose of 16 Gy had to the largest absolute benefit on local control in young patients.12,48

We fully acknowledge that this analysis is a subset analysis and is beset by all the caveats associated with a subset analysis. Despite biases, we believe that these results have important implications for clinical practice, and may guide in the decision which patients will benefit from a boost dose of 16 Gy. The absolute gain will notably be highest in patients with high-risk factors for local relapse (ie, younger age and high tumor grade). Even for patients older than 60 years having high grade invasive tumor the boost dose does reduce the 10-year cumulative local relapse rate from 10.8% to 4% at (Appendix Table A5, online only). However, the benefit of the boost dose in reducing local relapse has to be weighted against the adverse effects. Our previous study has shown that fibrosis, the major adverse effect of the boost dose, was independent of age. To tailor locoregional treatment, Collette et al50 recently developed a nomogram to assess the risk of fibrosis development for a single patient based on a number of patient-, tumor-, and treatment-related factors.

In summary, the EORTC 22881/10882 trial has demonstrated the benefit of a 16 Gy boost dose of radiation in all patients, irrespective of age.12 The present subset analysis suggests that young age and high-grade invasive ductal cancer were the most important risk factors for local relapse, while margin status had no significant influence. An additional dose of 16 Gy to the tumor bed significantly reduced the negative effects of both young age and high grade invasive tumor.

Acknowledgment

We acknowledge and thank the following for their active participation: R.P. Müller, Cologne, Germany; J. Kurtz, Geneva, Switzerland; D.A.L. Morgan, Nottingham, Great Britain; J.B. Dubois, Montpellier, France; E. Salamon, Namur, Belgium; R.O. Mirimanoff, Lausanne, Switzerland; J.W.H. Leer, Nijmegen, the Netherlands; M. Bolla, Grenoble, France; A. Kuten, Haifa, Israel; A. Renaud, La Louviere, Belgium; U. Schulz, Krefeld, Germany; P.C.M. Koper, Rotterdam, the Netherlands; D. Van den Weyngaert, Antwerp, Belgium; G.A. Storme, Brussels, Belgium; G.H.M. Calitchi, Creteil, France; W. Budach, Berlin, Germany; S. Roth, Dusseldorf, Germany; M. Poulsen, Brisbane, Australia; M.A. Dominguez, Pamplona, Spain; E. Monpetit, Vannes, France; F. Kovner, Tel Aviv, Israel; A. Biete Sola, Barcelona, Spain; Calvo, Madrid, Spain; I. Barillot, Tours, France; J. Borger, Maastricht, the Netherlands.

Appendix

Table A1.

Population Characteristics by Margins for Invasive Cancer According to Central Pathology Review for All Patients

Parameter Margin for Invasive Tumor
P
Positive
Close
Negative
No. % No. % No. %
No. of patients 102 332 1,162
Complete WBI 50 Gy
    No boost 27 4 160 22 549 75
    Boost 16 Gy 24 3 146 19 588 78
Incomplete WBI 50 Gy and 10 Gy
    No extra boost 27 56 9 19 12 25
    Extra boost (16 Gy) 24 44 17 31 13 24
Volume of excision biopsy specimen, cm3
    Median 90 105 120 .0038
    Range 7.9-540 4.5-1,800 1.3-1,680
Largest diameter, mm
    Median 15.0 17.0 15.0 .00131
    Range 5.0-45.0 4.0-50.0 2.0-50.0
Age at random assignment, years
    Median 54 51 55 .0068
    Range 29-70 27-71 28-76
    Younger than 50 36 35 145 44 384 33 .0029
    50-60 35 34 115 35 419 36
    Older than 60 31 30 72 22 359 31
N+ according to local pathology 36 35 91 28 250 22 .0014
Postmenopausal 66 65 175 53 736 63 .0017
Receptor status
    Estrogen+ 51 76 160 66 637 73 .080
    Progesterone+ 44 72 140 66 485 62 .21
Systemic treatment 53 52 138 42 392 34 .0001
Mitotic activity index
    < 10 79 78 215 65 847 73 .023
    10-19 11 11 58 18 147 13
    ≥ 20 11 11 58 18 160 14
Histology
    Ductal 61 60 224 68 861 75 < .0001
    Lobular 19 19 22 7 57 5
    Mixed pattern 18 18 63 19 163 14
    Other 3 3 22 7 74 6
Differentation of the invasive tumor
    Low 52 54 150 46 573 51 .29
    Intermediate 22 23 83 26 296 26
    High 22 23 92 28 258 23
Extensive intraductal component 13 13 47 14 121 10 .15
Differentiation of DCIS
    Low 19 19 77 23 190 16 .036
    Intermediate 19 19 85 26 299 26
    High 12 12 46 14 155 13
    No DCIS 52 51 124 37 518 45
Vascular invasion
    None 77 76 236 71 884 77 .096
    Present 19 19 58 18 158 14
    Doubtful 5 5 37 11 108 9

NOTE. Randomized according to local pathology.

Abbreviations: WBI, whole breast irradiation; DCIS, ductal carcinoma in situ.

Table A2.

Population Characteristics by Margins for DCIS According to Central Pathology Review for All Patients

Parameter Margin for DCIS
P
Positive
Close
Negative
No. % No. % No. %
No. of patients 139 229 498
Volume of excisional biopsy specimen, cm3
    Median 102.3 120 118.5 .48
    Range 4.5-614.1 5.6-1,800 1.3-1,584
Largest diameter, mm
    Median 15.0 15.0 15.0 .21
    Range 4.0-40.0 4.0-40.0 4.0-40.0
Age at random assignment, years
    Median 51 52 54 .014
    Range 28-70 27-69 28-76
    Younger than 50 62 45 92 40 163 33
    50-60 54 39 81 35 192 39
    Older than 60 23 17 56 24 143 29
N+ according to local pathology 40 29 63 28 126 26 .67
Postmenopausal 74 53 130 57 303 61 .22
Receptor status
    Estrogen+ 66 67 113 65 292 78 .0029
    Progesterone+ 54 61 101 64 233 69 .32
Systemic treatment 63 45 96 42 176 35 .051
Mitotic activity index
    < 10 94 68 139 61 391 79 < .0001
    10-19 21 15 56 25 64 13
    ≥ 20 24 17 33 14 41 8
Histology
    Ductal 110 79 188 82 408 82 .73
    Mixed pattern 29 21 41 18 90 18
Extensive intraductal component 71 51 50 22 50 10 < .0001
Differentiation of the invasive tumor
    Low 64 47 87 39 253 53 < .0001
    Intermediate 27 20 76 34 141 29
    High 46 34 59 27 87 18
Differentiation of DCIS
    Low 63 45 80 35 130 26 < .0001
    Intermediate 37 27 96 42 254 51
    High 39 28 53 23 112 23
Vascular invasion
    None 100 72 150 66 364 73 .20
    Doubtful 11 8 30 13 49 10
    Present 28 20 49 21 83 17

Abbreviation: DCIS, ductal carcinoma in situ.

Table A3.

Univariable Analysis of Ipsilateral Breast Cancer Recurrence for All Patients Stratified by Randomized Treatment

Parameter P Hazard for Local Failure
Estimate 95% CI
Complete: WBI 50 Gy, 0 Gy v 16 Gy boost .0008 0.54 0.37 to 0.77
Incomplete: WBI 50 Gy and 10 Gy, 0 Gy v 16 Gy extra boost .62 0.74 0.23 to 2.42
Both complete and incomplete, 0 and 10 Gy v 16 and 26 Gy .0008 0.55 0.39 to 0.780
Age, > 50 v ≤ 50 years < .0001 0.40 0.28 to 0.56
Nodal status, N+ v N− .52 0.87 0.57 to 1.32
Systemic treatment (chemotherapy or tamoxifen), yes v no .012 0.61 0.41 to 0.89
Volume of excisional biopsy specimen, cm3 .13 0.990 0.998 to 1.00
Estrogen receptor, + v .083 0.70 0.46 to 1.05
Progesterone receptor, + v .52 0.87 0.57 to 1.33
Angioinvasive growth, yes v no .86 1.04 0.69 to 1.55
Extensive intraductal component, yes v no .39 1.24 0.77 to 2.00
Histology invasive tumor
    Lobular v ductal .65 0.85 0.41 to 1.75
    Mixed v ductal .32 0.78 0.47 to 1.28
    Other v ductal .66 0.85 0.41 to 1.75
Ductal component, yes v no .33 1.23 0.81 to 1.90
Lobular component, yes v no .33 0.81 0.52 to 1.24
Differentiation grade of the invasive tumor
    Intermediate v high .027 0.60 0.38 to 0.94
    Low v high .0004 0.49 0.33 to 0.72
Differentiation grade of DCIS
    Intermediate v high .057 1.75 0.98 to 3.12
    Low v high .55 1.19 0.67 to 2.11
    No DCIS v high .70 0.89 0.50 to 1.60
Mitotic activity index, < 10 v ≥ 10 .069 1.401 0.97 to 2.01
Invasive tumor at the margin
    Close v positive .99 1.00 0.44 to 2.28
    Negative v positive .69 1.17 0.53 to 2.54
    Not involved v involved .45 1.17 0.78 to 1.74
DCIS at the margin
    No DCIS v positive .15 0.54 0.24 to 1.48
    Negative v positive .22 0.50 0.17 to 1.51
    Close v positive .23 0.43 0.11 to 1.73
    Not involved v involved .52 0.87 0.57 to 1.34
DCIS and/or invasive at the margin, involved v not involved .63 0.92 0.64 to 1.30

NOTE. Randomized according to local pathology.

Abbreviations: WBI, whole breast irradiation; DCIS, ductal carcinoma in situ.

Table A4.

Multivariable Analysis of Time to Local Relapse for All Patients

Parameter P Hazard for Local Failure
Estimate 95% CI
Randomized treatment 50 Gy WBI
    0 Gy v 16 Gy .0007 0.48 0.31 to 0.73
    50 Gy WBI and 10 Gy, 0 Gy v 16 Gy .26 0.50 0.13 to 1.87
    16 and 26 Gy v 0 and 10 Gy .0005 0.49 0.32 to 0.73
Age > 50 v ≤ 50 years < .0001 0.40 0.26 to 0.60
Systemic treatment, yes v no .042 0.63 0.40 to 0.98
Differentiation grade of the invasive tumor, high v low/intermediate .024 1.65 1.07 to 2.55
Differentiation grade of DCIS
    High v low/intermediate .98 1.01 0.540 to 1.86
    No DCIS v high .45 0.83 0.51 to 1.34
Margin of invasive tumor, not involved v involved .36 0.82 0.52 to 1.29

Abbreviations: WBI, whole breast irradiation; DCIS, ductal carcinoma in situ.

Table A5.

Relation Between the Effect of the Boost on the 10-Year Ipsilateral Breast Cancer Recurrence Rate in High-Grade Invasive Ductal Cancer According to Age, With Cutoff Level of 60 Years for All Patients

Local Relapse at 10 Years High Grade, No Boost
High Grade, 16 Gy Boost
Overall
No. % 95% CI No. % 95% CI No. % 95% CI
Age < 60 years 156 21.1 14.1 to 28.7 138 9.9 4.6 to 16.2 294 15.9 11.3 to 20.8
Age ≥ 60 years 33 10.8 0.0 to 26.1 65 4.0 0.0 to 10.6 98 6.3 0.8 to 13.1
Overall 189 19.5 13.2 to 26.1 203 8.0 4.0 to 12.7

Fig A1.

Fig A1.

Cumulative incidence of local relapse as first event according to the margins for (A) invasive tumor and (B) ductal carcinoma in situ for all patients.

Fig A2.

Fig A2.

(A-D) Cumulative incidence of local failure according to the margin status for invasive tumor and ductal carcinoma in situ (DCIS), split according to boost group for all patients. (B, D) Involved margins combines close and positive margins. (A) Margin not involved with invasive carcinoma (P = .0004). (B) Close or involved margin with invasive carcinoma (P = .55). (C) Margin not involved with DCIS (P = .0001). (D) Close or involved margin with DCIS (P = .21).

Fig A3.

Fig A3.

(A, B) Cumulative incidence of local failure by boost group and grade of invasive ductal carcinoma. (A) High grade of invasive carcinoma (P = .0030). (B) Low/intermediate grade of invasive carcinoma (P = .055).

Footnotes

European Organisation for Research and Treatment of Cancer was supported by Grants No. 5R10-CA11488-11 through 5U10-CA11488-38 from the National Cancer Institute (Bethesda, MD) for conducting trial 22881/10882.

The contents of this article are solely the responsibility of the authors and do not necessarily reflect the official views of the National Cancer Institute.

Written on behalf of the European Organisation for Research and Treatment of Cancer Radiation Oncology and Breast Cancer Groups.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

See accompanying editorial on page 4929

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Harry Bartelink

Provision of study materials or patients: Johannes L. Peterse, Jean-Claude Horiot, Françoise Collin, Philip M. Poortmans, S. Bing Oei, Alain Fourquet, Jos J. Jager, Dominic A.X. Schinagl, Carla C. Wárlám-Rodenhuis, Harry Bartelink

Collection and assembly of data: Laurence Collette, Harry Bartelink

Data analysis and interpretation: Heather A. Jones, Ninja Antonini, Augustinus A.M. Hart, Laurence Collette, Harry Bartelink

Manuscript writing: Heather A. Jones, Harry Bartelink

Final approval of manuscript: Heather A. Jones, Ninja Antonini, Augustinus A.M. Hart, Johannes L. Peterse, Jean-Claude Horiot, Françoise Collin, Philip M. Poortmans, S. Bing Oei, Laurence Collette, Henk Struikmans, Walter F. Van den Bogaert, Alain Fourquet, Jos J. Jager, Dominic A.X. Schinagl, Carla C. Wárlám-Rodenhuis, Harry Bartelink

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