ABSTRACT: Adequate surgical margins in breast-conserving surgery are an important predictor of local recurrence (LR) rates. The definition of tumor-free margins in National Surgical Adjuvant Breast and Bowel Project (NSABP) trials requires that tumor cells do not touch ink, but subsequent retrospective single-institution studies have suggested that wider margins confer greater protection against LR. Particularly wide margins have been proposed for ductal carcinoma in situ. However, wider margin requirements lead to higher re-excision rates, with attendant economic, psychological, and cosmetic costs, and perhaps increased mastectomy rates. Juxtaposed against these concerns about optimal margin width, a meta-analysis of clinical trials has demonstrated the survival value of minimizing LR. We are therefore at a juncture where a reduction of LR may be achieved by tumor resection with wide margins, but data regarding optimal margin width are conflicting and the risk/benefit balance of tumorectomy with wide margins has not been demonstrated. A randomized trial of re-excision for close margins inserted into trials of systemic therapy could be considered but seems unlikely. Alternatively, detailed longitudinal data need to balance the value and the cost of wide margins. Until better data are available, the desirable margin width will vary depending on individual circumstances, including age, histology, and patient preference.
The safety and efficacy of breast-conserving therapy (BCT) for women with early-stage breast cancer are well established.[1,2] BCT entails wide excision of the tumor and appropriate nodal evaluation, followed by radiation therapy to the breast. There is broad agreement that successful breast conservation requires complete tumor excision, commonly described as a "tumor-free" or "negative" margin of resection, but the definition of a negative margin is controversial. Opinions range from the original National Surgical Adjuvant Breast and Bowel Project (NSABP) definition of "no ink on tumor," to a recommended width of 10 mm or more. A widely held position based on single-institution retrospective data is that a mandatory minimum distance between ink and tumor is necessary for good local control, but the margin width is debated. A commonly accepted definition of adequate margins requires a 2-mm distance between ink and tumor.
Randomized Trials, Resection Margins, and Recurrence in Invasive Breast Cancer
The original definition of a negative margin proposed by the NSABP was the absence of tumor cells at the ink, and subsequent NSABP studies follow this simple rule. The landmark NSABP study of breast conservation involved 1851 patients; the positive margin rate was 6.8%, and with a 20-year follow-up the in-breast tumor recurrence rate was 14.2%. Importantly, there was no attempt to distinguish new primary tumors from true recurrences, and given the 20-year follow-up interval, there was undoubtedly a substantial proportion of new primaries among the 14.2% of women who experienced ipsilateral breast tumor recurrence (IBTR). According to recent studies that have tried to distinguish between these events, the new primary cancer rate at 10 years may account for up to half of all observed IBTRs.[2,3] If one estimates the true recurrence rate in the NSABP B-06 trial based on this estimate, then true local recurrences occurred in about 7% of women. Other randomized trials of breast conservation are summarized in Table 1; all used either "grossly free margins" or "microscopically free margins" with no minimal width required, and none distinguished new primaries from true recurrences except for the Danish trial, which reported an overall IBTR rate of less than 6%. In these large studies with long follow-up periods, IBTR rates range from 6% to 19.7%, but margins were not microscopically defined for most of these trials, so the impact of margin width on IBTR rates is difficult to assess.
Nonrandomized Data on Resection Margins and Recurrence in Invasive Breast Cancer
More recently, NSABP investigators have published two separate analyses of local recurrence, distant disease, and breast cancer mortality, using pooled data from adjuvant therapy trials subsequent to B-06. One report dealt with patients with node-negative breast cancer and included a total of 3,799 women who participated in five NSABP protocols and underwent BCT with or without adjuvant systemic therapy. Patients treated with adjuvant systemic therapy had a 12-year cumulative incidence of IBTR of 6.6%, with a 1.8% "other local recurrence" rate (oLRR, or regional nodal recurrence). Younger women had a significantly higher cumulative incidence of IBTR than did older women. In a similar pooled analysis of trials enrolling women with node-positive disease, the 10-year incidences of IBTR and oLRR were 8.7% and 6.0%, respectively. The time period over which these women were treated extends into the 1990s; and although NSABP protocols required only that tumor should not touch the margin ink, it is not known how individual NSABP surgeons applied this protocol definition, nor whether or not re-excisions were being performed at these institutions for margins less than 1 or 2 mm. Throughout the 1990s, several single-institution retrospective analyses designed to identify risk factors for local recurrence of breast cancer have examined the impact of wider resection margins on local control. In particular, much attention has been paid to the definition of a negative margin, with several studies showing that a minimum margin width of 1 or 2 mm or more was associated with reduced risk of local recurrence.[5-7] These studies described a lower recurrence rate than the B-06 study, albeit with substantially shorter follow-up durations. Subsequent single-institution studies have demonstrated a strong temporal effect on IBTR rates, with a significant decline in later time-periods[8,9]; although these declines are undoubtedly related to better radiological and pathological evaluation, and to boost radiotherapy and uniform use of systemic therapy, it is not possible to say what the contribution is of wider excisions and re-excisions. More recent, larger studies that examined margin status and recurrence rate are summarized in Table 2. Interestingly, the findings remain controversial, with two publications from 2011 showing that margins less than 2 mm do and do not (respectively) affect local control.[10,11] These recent data are consistent with an earlier review of margin width and IBTR risk by Singletary et al, who found no direct relationship between the width of the negative margin and the IBTR rate. Thus in the setting of contemporary breast cancer care, obtaining wider negative margins may not in reality confer any added benefit, but may carry a significant potential for harm (psychological, cosmetic, financial).
Randomized Trial Data on Resection Margins and Recurrence in DCIS
Wapnir et al have recently reported on pooled data from patients participating in NSABP B-17 (testing excision alone vs excision with radiotherapy) and B-24 (testing excision with radiotherapy, with or without tamoxifen(Drug information on tamoxifen)).Importantly, margin-positive patients were allowed to participate in B-24, and the free margin definition in both studies was "no ink on tumor." The 15-year outcomes were pooled and published recently, showing that IBTR rates in women treated with excision and radiation have climbed since the original reports; they are now 19.8% (B-17) and 16.6% (B-24) with radiation therapy alone, and a reduction to 13.2% is seen with the addition of tamoxifen in B-24. The ductal carcinoma in situ (DCIS) trial by the European Organisation for Research and Treatment of Cancer (EORTC), using a similar margin definition, showed similar results, with a 10-year local recurrence rate of 15% in the radiated group. Thus long-term IBTR rates in prospective studies of DCIS tend to be somewhat higher in DCIS patients than in patients with invasive breast cancer when a similar margin threshold (no ink on tumor) is applied. Table 3 highlights IBTR rates relative to margin width in women treated with radiotherapy for DCIS.
Nonrandomized Data on Resection Margins and Recurrence in DCIS
A meta-analysis of data from DCIS trials and observational studies that included patients treated with radiotherapy has provided information on incremental margin width and local control. Positive margins are clearly associated with an increased risk of IBTR, but it appears that for DCIS (in contrast to invasive cancer) there is a significant trend towards greater benefit with margins of 2 mm or more that seems to plateau at a margin distance of 2 mm. Only a small number of patients have margins of 5 mm or more, however. These data contrast with reports by Silverstein and colleagues, who suggest that margins exceeding 10 mm are optimal for excision of DCIS. Since the interval between 1 mm and 10 mm in their study is not broken out into smaller intervals, one cannot determine whether the 2-mm threshold is also significant in their experience. Other observational studies also suggest that for DCIS, a close margin may increase the hazard of local recurrence, and therefore it may be reasonable to define the optimal free margin for DCIS as a width of 2 mm.