Society of Surgical Oncology–American Society for Radiation Oncology–American Society of Clinical Oncology Consensus Guideline on Margins for Breast-Conserving Surgery with Whole-Breast Irradiation in Ductal Carcinoma In Situ

To address the question of optimal negative margin width, the MP considered data on the distribution of DCIS in the breast. Studies of mastectomy specimens using whole-organ sectioning and radiologic–pathologic correlation have demonstrated that although most cases of DCIS are unicentric, the involvement of the segment may be multifocal, with so-called gaps of uninvolved tissue between foci of DCIS.20 Given this, a negative margin does not guarantee the absence of residual DCIS in the breast.

There are also technical limitations to margin assessment that affect the relationship between margin width and IBTR. For example, margins are artifactually narrower ex vivo, when specimens become flattened from lack of surrounding supportive tissue, a phenomenon exaggerated by compression for specimen radiography. Additionally, surface ink can track into deeper portions of the specimen, posing significant challenges in determining true margin location. Finally, tumor-to-ink distance on any single slide may not be representative of the entire specimen; an adequate margin on one section may become positive if additional or deeper sections are examined. Two common methods for margin evaluation include sectioning perpendicular to ink (to determine tumor-to-ink width) or en-face examination of shaved margins (where any residual tumor in the shaved specimen is considered a positive margin). Although an advantage of the shaved method is greater surface-area examination, a known disadvantage is the higher frequency of margins categorized as positive that are, in comparison, negative by the perpendicular method, which may in turn result in unnecessary re-excision or even mastectomy.21 Specimen sampling is also highly variable, and even total sequential embedding results in only a small proportion (< 1%) of the specimen margins being examined.22 Together, these studies highlight the substantial variability in margin assessment irrespective of the technique used.

Despite variability in margin assessment, great emphasis has been placed on achieving specific negative margin widths. In the frequentist meta-analysis by Marinovich et al,16 comparison of specific margin width thresholds (2, 3 or 5, and 10 mm) relative to negative margins defined as wider than 0 or 1 mm included 7,883 patients with a median follow-up of 6.5 years. The ORs for 2 mm (0.51; 95% CI, 0.31 to 0.85; P = .01), 3 or 5 mm (0.42; 95% CI, 0.18 to 0.97; P = .04), and 10 mm (0.60; 95% CI, 0.33 to 1.08; P = .09) showed comparable reductions in the odds of IBTR compared with wider than 0 or 1 mm, and pairwise comparisons found no significant differences in the odds of IBTR between the 2-, 3- or 5-, and 10-mm margin thresholds (all P > .40). In this model, the predicted 10-year IBTR probability for 2-mm negative margins was 10.1% (95% CI, 6.3% to 16.0%) compared with 8.5% for 3- or 5-mm (95% CI, 3.6% to 18.9%) and 11.7% (95% CI, 6.7% to 19.4%) for 10-mm margins. In the Bayesian network meta-analysis (Table 4),16 the ORs of incrementally wider negative margins relative to the positive margin category were 0.45 (95% CrI, 0.32 to 0.61) for wider than 0 or 1 mm, 0.32 (95% CrI, 0.21 to 0.48) for 2 mm, 0.30 (95% CrI, 0.12 to 0.76) for 3 mm, and 0.32 (95% CrI, 0.19 to 0.49) for 10 mm. Adjustments for clinically relevant covariates, including sensitivity analysis limited to studies using radiation therapy (RT), did not alter these mean OR estimates (Table 4). In this analysis, the relative OR of IBTR between the 10- and 2-mm threshold groups compared with positive margins was 0.99 (95% CrI, 0.61 to 1.64), indicating no statistically meaningful difference.

The choice of the 2-mm threshold rather than wider than 0 (no ink on tumor) or 1 mm was based on evidence of a statistically significant decrease in IBTR for 2 mm compared with 0 or 1 mm in the frequentist analysis (OR, 0.51; 95% CI, 0.31 to 0.85; P = .01), coupled with weak evidence in the Bayesian model of a reduction in IBTR with the 2-mm distance compared with smaller distances (relative OR, 0.72; 95% CrI, 0.47 to 1.08). However, although the MP felt that there was evidence that the 2-mm margin optimized local control, clinical judgment must be used in determining whether patients with smaller negative margin widths (> 0 or 1 mm) require re-excision. Factors felt to be important to consider include assessment of IBTR risk (residual calcifications on postexcision mammography, extent of DCIS in proximity to margin, and which margin is close [i.e. anterior excised to skin or posterior excised to pectoral fascia v margins associated with residual breast tissue]), cosmetic impact of re-excision, and overall life expectancy. The conclusion that re-excision could be selectively employed with margins smaller than 2 mm was influenced by the high long-term rates of local control reported in the NSABP DCIS trials,7 which required a margin of no ink on tumor, as well as the study by Van Zee et al,23 which, after adjusting for multiple covariates, found no difference in risk between margins of 2 mm or narrower and more widely clear margins in patients receiving WBRT.

The EBCTCG DCIS meta-analysis showed that the 10-year IBTR rate for patients treated with excision alone was higher than that with excision and WBRT, both for those with negative (26.0% v 12.0%; P < .001) and positive margins (48.3% v 24.2%; P < .001).1 The same proportional benefit for WBRT was seen in women treated with local excision and those having large sector resections. In the Radiation Therapy Oncology Group (RTOG) 9804 trial, where patients with small, mammographically detected low- to intermediate-grade DCIS and margins of 3 mm or wider were randomly assigned to excision alone or excision plus WBRT, 7-year IBTR rates were 6.7% and 0.9% (P < .001), respectively.4 The prospective, multi-institutional Eastern Cooperative Oncology Group (ECOG) E5194 study of patients with low-risk DCIS treated with excision alone (negative margin width ≥ 3 mm) reported 12-year rates of IBTR of 14.4% for non–high-grade DCIS 2.5 cm or smaller in size and 24.6% for high-grade DCIS 1 cm or smaller in size. However, IBTR rates did not differ significantly for margins narrower than 5, 5 to 9, or 10 mm or wider (P = .85).24 A prospective single-arm study of patients with mammographically detected DCIS 2.5 cm or smaller in size reported a 10-year IBTR rate of 15.6%,25 despite requiring margins of 1 cm or wider.4 In contrast, Van Zee et al23 found in 1,266 patients treated with excision alone that the 10-year IBTR rate was 16% for margins wider than 10 mm and increased to 23% for margins between 2.1 and 10 mm, 27% for margins greater than 0 to 2 mm, and 41% for positive margins. After adjustment for multiple factors, margin width was a more highly significant predictor of IBTR (P < .001). The MP felt that overall, the heterogeneity of the evidence among these studies did not allow for a definitive recommendation for margin widths greater than 2 mm in patients foregoing RT.

Tamoxifen reduces the incidence of both IBTR and contralateral breast cancer, but the absolute benefit is relatively small.7,26 In the NSABP B-24 trial, patients treated with lumpectomy and WBRT were randomly assigned to tamoxifen or placebo; 25% of the population had positive or unknown margins. The 15-year IBTR rate for the placebo group was 17.4% in those with positive margins compared with 7.4% for clear margins. Adjuvant tamoxifen lowered IBTR rates among those with positive margins to levels similar to those in the negative-margin cohort (placebo, 17.4%; tamoxifen, 11.5%); conversely, there was little impact of tamoxifen in the negative-margin cohort (IBTR: placebo, 7.4%; tamoxifen, 7.5%).7 Hence, the MP felt that although tamoxifen decreased IBTR in patients with positive margins, there was no evidence to suggest an association between negative margin width and benefit of endocrine therapy.

Young patient age has consistently been associated with IBTR, and tumor factors such as histologic pattern, comedo necrosis, and nuclear grade and size of DCIS also modify the risk of IBTR.18,27,28 More recently, unfavorable gene profile scores have also been associated with IBTR.29,30 However, there are no data addressing whether margin widths should be influenced by these factors, and this represents an appropriate area for further study.

A vast majority of patients treated in the five prospective randomized DCIS trials of excision with or without WBRT underwent conventionally fractionated WBRT without a boost. Only one of the trials allowed the option of hypofractionated WBRT in addition to standard WBRT,4 and 10% or fewer of the patients in three of the trials received a boost.6‐8 None of the randomized trials varied RT technique according to margin status, and neither intensity-modulated RT nor APBI were used. There is no direct evidence from randomized trials to support the use of a boost to the primary tumor site for patients with DCIS, although in patients with invasive breast carcinoma, the long-term value of a boost in reducing IBTR has been demonstrated.31

Two ASTRO consensus guidelines have addressed technical issues in the setting of BCT. Although largely focusing on invasive breast carcinoma, the ASTRO statement on hypofractionated WBRT concluded there was insufficient evidence to recommend for or against hypofractionated WBRT in the setting of DCIS.32 In the ASTRO statement on APBI, DCIS was placed in the cautionary group based on the lack of evidence from randomized trials; however, it was noted that patients with DCIS have been included in some retrospective cohort studies.33

Therefore, there is no evidence that margin width, in isolation, should determine radiation delivery technique, fractionation of WBRT, or use or dose of a boost. The MP considered the evidence base insufficient to address optimal margin width in APBI.

There are two diagnoses for which there is overlap between our DCIS margin guideline and the SSO-ASTRO invasive cancer margin guideline:34 DCIS-M and invasive carcinoma associated with DCIS (extensive intraductal component or lesser amounts of scattered DCIS). In DCIS-M, defined by the American Joint Committee on Cancer as the extension of cancer cells beyond the basement membrane with no focus more than 0.1 cm in greatest dimension,35 small retrospective studies have suggested that rates of IBTR are similar to those seen with pure DCIS.36,37 In the absence of specific data to address margin width in DCIS-M, the MP, based on expert opinion, felt that DCIS-M should be considered DCIS when determining the optimal margin width, given that the majority of the lesion is composed of DCIS and that systemic therapy utilization for DCIS-M more closely reflects the treatment pattern for DCIS than for invasive carcinoma.

In contrast, when considering margin width for an invasive cancer with a DCIS component, regardless of extent, the MP felt that the invasive cancer guideline34 was applicable, primarily because the natural history and treatment of these lesions are more similar to those of invasive cancer than DCIS, even when the close margin contains DCIS. In particular, a vast majority of patients with invasive cancer receive systemic therapy, which remains less common for pure DCIS. The invasive cancer guideline34 does note that an extensive intraductal component is a marker for a potential heavy burden of residual DCIS and that postexcision mammography, presence of multiple close margins, and young patient age can be used to select patients who will benefit from re-excision. These statements echo the discussion of the MP regarding the use of re-excision in pure DCIS with margins narrower than 2 mm discussed previously, and thus, we believe the guidelines are compatible.