Reevaluating Lumpectomy Margin Thresholds in HR-Positive DCIS: Insights from the NRG Oncology/NSABP B-35 Trial

Highlight

• The NRG Oncology/NSABP B-35 trial prospectively analyzed the association between lumpectomy margin width and ipsilateral breast tumor recurrence (IBTR) in postmenopausal women with hormone receptor-positive ductal carcinoma in situ (DCIS).
• Small absolute differences in 10-year IBTR rates were observed between margin widths below 1 mm or 2 mm versus wider margins among patients receiving whole-breast irradiation and endocrine therapy.
• Margin width was not a statistically significant predictor of IBTR after adjustment for clinical and tumor factors, challenging the necessity of reexcision for margins less than 1 mm or 2 mm in properly treated patients.

Study Background

Ductal carcinoma in situ (DCIS) represents a non-invasive form of breast cancer confined to the ductal system, with an increasing diagnosis frequency due to widespread mammographic screening. Optimal local control of DCIS following breast-conserving surgery remains a clinical challenge. Ensuring clear surgical margins post-lumpectomy is a cornerstone to reduce the risk of ipsilateral breast tumor recurrence (IBTR). However, the definition of an adequate margin width lacks consensus, with guidelines variably recommending margins of at least 2 mm or even wider. Overly aggressive resections potentially increase morbidity and compromise cosmetic outcomes without clear evidence of substantial benefit, particularly in the context of adjuvant whole breast irradiation (WBI) and endocrine therapy among hormone receptor (HR)-positive DCIS.

This study, utilizing data from the NRG Oncology/NSABP B-35 randomized clinical trial, offers a rigorous analysis of margin width impact on IBTR specifically in postmenopausal women treated with lumpectomy followed by WBI and either tamoxifen or anastrozole. This allows for a refined understanding of whether narrow margins (<1 mm or <2 mm) influence recurrence risk when comprehensive adjuvant treatment is delivered.

Study Design

The NSABP B-35 was a phase 3, double-blind, randomized clinical trial enrolling 3104 postmenopausal women diagnosed with hormone receptor-positive DCIS with confirmed tumor-free margins following lumpectomy. Participants were randomized to receive 5 years of adjuvant endocrine therapy with either tamoxifen or anastrozole. All patients underwent whole-breast irradiation (WBI) according to standard protocols.

Margin widths were prospectively recorded shortly after randomization using centralized pathology documentation. Margins were categorized as positive if ink was on the tumor, close if less than 1 mm, and negative if 1 mm or wider. The ancillary analysis further subdivided negative margins at 1 mm and 2 mm thresholds to evaluate clinical outcomes. Patients with positive margins were excluded from margin subgroup analyses.

The primary outcome was ipsilateral breast tumor recurrence (IBTR), defined as the first event of local recurrence. Data analysis was conducted from July 2024 to April 2025.

Key Findings

Among the 2707 patients included for analysis by the 1-mm margin partition, the 10-year unadjusted cumulative incidence of IBTR was 5.6% in patients with margins less than 1 mm compared to 4.0% for margins ≥1 mm (P = .04). Similarly, using a 2-mm cutoff among 2546 patients, the 10-year IBTR incidence was 5.3% for margins ≤2 mm versus 3.8% for margins >2 mm (P = .05).

Although statistically significant unadjusted differences suggest a slightly higher rate of IBTR with narrower margins, multivariate modeling adjusting for other clinical and tumor characteristics, including treatment with tamoxifen versus anastrozole, demonstrated that margin width did not significantly predict IBTR risk. The hazard ratio (HR) for margins ≤2 mm compared with >2 mm was 1.33 (95% CI, 0.86-2.06), indicating no statistically conclusive increased risk.

Notably, the overall IBTR rate was low in this cohort, underscoring the effectiveness of combined lumpectomy, WBI, and adjuvant endocrine therapy in HR-positive DCIS. These findings align with accumulating evidence that stringent margin width thresholds may not be universally necessary, avoiding reexcision procedures that carry risks and can impact cosmetic outcomes adversely.

Expert Commentary

The NSABP B-35 margin analysis contributes critical prospective evidence to a historically contentious surgical parameter in DCIS management. Dr. Isabel Wapnir and colleagues’ work challenges the convention that wider margins universally confer improved local control in this well-defined population receiving comprehensive adjuvant therapies.

While prior retrospective analyses and expert consensus often endorsed at least 2 mm margins for DCIS, this study’s prospective and randomized context provides more robust data supporting a tailored approach to margin management. Particularly, the lack of significance in adjusted models emphasizes that margin width, in isolation, should not be the sole determinant of additional surgery decisions.

Limitations include the exclusive enrollment of postmenopausal women with HR-positive tumors, potentially limiting generalizability to younger or HR-negative cases. Additionally, the low absolute IBTR rates indicate that longer follow-up and further exploration of molecular risk stratification may enhance personalized decision-making.

Conclusion

In conclusion, the ancillary analysis of the NRG Oncology/NSABP B-35 trial indicates that lumpectomy margin widths less than 1 mm or 2 mm are associated with only slight increases in ipsilateral breast tumor recurrence rates, which do not remain statistically significant after adjustment for other factors, in postmenopausal women with hormone receptor-positive DCIS treated with lumpectomy, whole-breast irradiation, and adjuvant endocrine therapy.

These findings support reconsidering the routine use of reexcision to achieve wider margins in selected patients, potentially reducing treatment morbidity without compromising local control. Clinical decisions should integrate patient preferences, tumor biology, and comprehensive treatment context rather than margin width alone.

Funding and Trial Registration

The NSABP B-35 trial was conducted by the NRG Oncology research organization and the National Surgical Adjuvant Breast and Bowel Project (NSABP). The study was registered on ClinicalTrials.gov under identifier NCT00053898.

References

1. Wapnir IL, Cecchini RS, Dignam JJ, et al. Lumpectomy Margins and Local Recurrence in DCIS: Results From the NRG Oncology/NSABP B-35 Randomized Clinical Trial. JAMA Surg. 2026 Jul 1. doi:10.1001/jamasurg.2026.42384406
2. Moran MS, Schnitt SJ, Giuliano AE, et al. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ. Ann Surg Oncol. 2016 Feb;23(2):380-391.
3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomized trials. Lancet. 2011 Nov 12;378(9804):1707-1716.