Width of excision margins after breast conserving surgery for invasive breast cancer and distant recurrence and survivalBMJ 2022; 378 doi: https://doi.org/10.1136/bmj.o2077 (Published 21 September 2022) Cite this as: BMJ 2022;378:o2077
- N J Bundred, professor of surgery1 2,
- J R Bundred, surgical trainee3 4,
- R I Cutress, professor of breast surgery5 6,
- D Dodwell, professor of oncology7
- 1Manchester University NHS Foundation Trust, Wythenshawe, Manchester, UK
- 2Division of Cancer Studies University of Manchester, Manchester, UK
- 3Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
- 4Leeds Institute of Emergency Surgery, St James University Hospital, Leeds, UK
- 5Cancer Sciences, University of Southampton, Southampton, UK
- 6University Hospital Southampton, Southampton, UK
- 7Nuffield Department of Population Health, University of Oxford, Oxford, UK
- Correspondence to: N J Bundred
Importance of tumour removal
In many cancers, such as colorectal cancer, attention to ensuring meticulous removal of the cancer with an encompassing cuff of normal tissue (ie, no tumour at the pathological margin) results in improved outcomes. The association between margin involvement and poorer recurrence and survival outcomes12 led to studies that showed a strong association between the width of tumour from the margin in colorectal cancer and subsequent outcomes.2
Most patients with early breast cancer are treated with breast conserving surgery. Removing cancers without leaving malignant cells at a surgical margin reduces local recurrence34567 but the effects of margin involvement on distant recurrence and mortality are unclear. How far the tumour should be from the specimen margin to ensure optimum oncological outcomes is contentious.
The definition of a clear margin matters
When cancer is surgically removed, the tumour is subject to pathological examination. The edges of the removed cancer specimens, known as the margins, can be either microscopically involved, in that the tumour is at the edge of the specimen, or not involved, that is, no tumour is seen at the edge. The distance from the edge of the margin to the tumour is measured. A close margin occurs when the tumour is not at the edge but within a given distance; usually 1 mm or 2 mm. Close margins are important because pathological assessment provides a representative sample of material examined. Involved or close margins are associated with between 39% and 85% patients having residual cancer after re-excision surgery.4 Occult foci of disease occur beyond the apparent edge of cancers and might not be adequately treated by adjuvant treatment.
Internationally, proportions of surgical margins involvement for breast cancer vary from 9.4% to 17.8% depending on definition of involvement.3589 A meta-analysis of 14 571 patients reported findings that a 1 mm margin of normal tissue around invasive cancer after breast conserving surgery was reasonable.3 In 2009, UK British Association of Surgical Oncology guidelines5 did not recommend a specific width of clearance around invasive cancers, and 21% of patients had tumours with less than 1 mm from margins in a large UK study.9 In 2014, an authoritative US guideline advised that avoiding the presence of cancer touching the margin (known as tumour on ink) was sufficient to minimise local recurrence.36 The National Institute for Health and Care Excellence (known as NICE) did not define a minimum margin distance but suggested that the benefits of further surgery should be discussed with the patient where margins were close but not on the edge.7 Differences in guidelines have led to confusion about the correct approach to surgical margins.
Local recurrence is associated with higher rates of death from breast cancer.10 Globally, local recurrence rates after breast surgery have reduced from 20% before widespread adjuvant treatment use to 5% or lower currently.4 The effect of both adjuvant systemic treatment and radiotherapy in reducing local and distant recurrence has probably influenced the interpretation of the significance of margin proximity.
To answer the questions of whether involved or close margins are associated with increased distant recurrence and decreased overall survival, we conducted a prospectively registered systematic review of all the available literature according to PRISMA guidelines (doi:10.1136/bmj-2022-070346).8 Patient pathology specimens were categorised as tumour at the margin (involved), close margins (tumour <2 mm from the margin, but not at the margin), and negative margins (tumour ≥2 mm from the margin).
We included 68 studies comprising 112 140 patients undergoing breast conserving surgery. Overall, 9.4% (95% confidence interval 6.8% to 12.8%) of patients had tumour at the margin and 17.8% (13.0% to 23.9%) had tumours at or close to the margin. The rate of distant recurrence was 25.4% (14.5% to 40.6%) in patients with tumour at the margin, 8.4% (4.4% to 15.5%) with tumours at or close to margins, and 7.4% (3.9% to 13.6%) patients with negative margins.
On multivariable analyses, importantly taking into account postoperative chemotherapy and radiotherapy, involved margins compared with negative margins were associated with increased distant recurrence (hazard ratio 2.10 (95% confidence interval 1.65 to 2.69), P<0.001) and local recurrence (1.98 (1.66 to 2.36)). Compared with negative margins, close margins were associated with increased distant recurrence (1.38 (1.13 to 1.69), P<0.001) and local recurrence (2.09 (1.39 to 3.13), P<0.001), after adjusting for receipt of adjuvant chemotherapy and radiotherapy.
This review collates data from more than five times the number of patients in the 2014 US consensus guideline addressing local recurrence and surgical margins.6 As with previous analyses, most of these data are from cohort studies, not randomised trials, thus a causal association between margin proximity and distant recurrence cannot be proven. Given the unavoidable absence of randomised evidence on the consequences of margin proximity, these findings plausibly indicate that clearance of margins in invasive breast cancer should remain a priority to reduce both distant and local recurrence irrespective of the increased use of adjuvant treatments.
Why surgical tumour margins matter
Current international guidelines need revision to account for these findings. Recognising that wider margins might require further surgery, decisions about re-excision should be the product of an informed discussion between clinicians and patients. The issue of involved margins after breast conservation might not be routinely discussed with patients but patient advocates believed that complete surgical excision to prevent distant recurrence was more important to them than cosmesis. In multidisciplinary team meetings, opinions vary about what margin width is acceptable for invasive and in situ cancer. International guidelines on the optimal width for margin clearance should be based on the width to prevent distant recurrence as a primary aim. Wider margins should not necessarily increase mastectomy rates but might require more specific preoperative multidisciplinary team planning of surgical incisions and operations.
These comprehensive data indicate the likelihood that inadequate margin width results in higher risks of distant recurrence and breast cancer mortality, as well as increased local recurrence. Involving patients with cancer in discussions about margin clearance before surgery should be an essential part of informed consent for surgery. Increased surgical focus on adequacy of margin excision would improve breast cancer survival worldwide.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; NJB received a National Institute for Health and Care Research, Research for Patient Benefit grant investigating a margin device. the authors declare no other relationships or activities that could appear to have influenced the submitted work. DD received funding from Cancer Research UK (C8225/A21133).
Provenance and peer review: Commissioned; not externally peer reviewed.