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Background: International guidelines state that any post-surgical tumour margin wider than tumour on ink following breast conserving surgery (BCS) for early invasive breast cancer is acceptable, based on analyses of margin width and local recurrence(LR). The aim of this review is to determine if margin involvement is associated with distant recurrence and secondarily to determine a minimum surgical margin to minimize both LR and distant recurrence (DR). Methods: A systematic review of literature published up to January 2021 was conducted according to PRISMA guidelines (PROSPERO: CRD42021232115). Unpublished data were sought from authors. The association between pathological margin status and distant and local recurrence were considered using random effects modelling. Results: Sixty-nine studies comprising 103,806 breast cancer patients were included. Across all studies, 9.7% of patients had tumour on ink and 13.9% had tumour on ink or a close margin (2mm) (HR: 1.38, 95%CI: 1.13-1.69, p Distant recurrence models by margin statusDistant RecurrenceHazard ratio95% CIp-valuePositive versus Negative margins2.101.65-2.69 Citation Format: James R Bundred, David Dodwell, Ramsay Cuttress, Sarah Michael, Beth Stuart, Bernd Holleczek, Kerri Beckmann, Jane Dahlstrom, Nigel J Bundred. Margin involvement in invasive breast cancer leads to increased distant recurrence after breast conservation: Systematic review [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-18-07.

Involved margins after surgery for early breast cancer increase the risk of local recurrence (LR), but international guidelines suggest that’ no tumour’ on ink is sufficient margin clearance after breast conserving surgery (BCS). Data on the effect of margin clearance on distant recurrence (DR) are lacking. Our aim was to determine the association between margin involvement, recurrence (DR) and breast cancer deaths. Methods Data from breast cancer units in Greater Manchester (GM) and the UK National Cancer Registry (NCRAS) were analysed. Margin status was prospectively recorded after surgery according to National Health Service Breast Screening Pathology (NHSBSP) minimum pathology data standards All patients underwent curative surgery and received adjuvant therapy according to local guidelines. Patients not undergoing curative surgery(T4, inflammatory or metastatic cancer) were excluded .Cox-proportional hazards models investigated factors associated with LR, DR and risk of breast cancer death.NCRAS records breast cancer deaths . Results GM analysis included 3270 patients from 2010 to 2014, 2295 (70.2%) had margins (>2mm) ,302 (9.2%) close (1-2mm) margin clearance and 673 (20.6%) involved (2mm. For Breast Conservation margins1mm (67.5%) and 3,935 (9.6%) were classed as “clear margins” and 9,325 (22.8%) cancer patients had involved margins 1mm were associated with reduced DR and should be essential surgical management. Current guidelines about surgical margins need to be re-evaluated to achieve reduced DR and cancer deaths. Citation Format: Nigel James Bundred, Sarah Michael, John Broggio, Anne Armstrong, Glen Martin, Mohamed Absar, Jane Ooi. Increased distant recurrence following margin involvement in early invasive breast cancer in two large UK cohorts [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-20-01.

Background: Leaving involved margins after mastectomy for breast cancer has been associated with an increased risk of local recurrence. Current guidelines endorse a policy that negative margins of no ink on tumour represent sufficient margin for local control and that the routine practice of obtaining a more widely negative margin is not indicated. We performed a systematic review of the literature and meta-analysis of studies analysing the impact of margin involvement after mastectomy on subsequent local recurrence. Methods: A systematic review was carried out searching MedLine, EmBase and ProQuest databases using the terms ‘mastectomy’, ‘resection margin’, ‘deep margin’, ‘margin status’ ‘fascia’ and ‘muscle invasion or infiltration’ from 1980 - 2019. In total 2,199 papers were screened and 33 studies were included in the quantitative synthesis. Statistical Methods: Meta-analysis was conducted using random effects modelling, pooling hazard ratios (HR), and odds ratios (OR) from binary outcome data. The associations between positive margins and local recurrence were stratified by positive margin distance and analysed according to use of adjuvant radiotherapy and follow up duration. Results: In total 37,738 patients, with a median age of 54.5 years, were included in the quantitative synthesis. Positive margins were associated with increased local recurrence on univariable analyses (HR 2.99, 95%CI: 2.99, 2.15 - 4.15), multivariable adjusted analyses (HR, 2.61, (95%CI 2.03-3.35) (which included Molecular Phenotype, Stage and Node status) as well as binary outcome data (OR, 95%CI: 2.75, 1.94-3.88). Positive margins were consistently associated with increased local recurrence, regardless of the distance of the tumour from the margin defined as positive (HR, 95%CI, tumour at ink: 2.39, 1.53-3.72; margin 5 years compared to 5 years OR 3.50, 2.13 - 5.75). Data were available from five studies for patients not receiving radiotherapy. In this subgroup positive margins were associated with a 3-fold risk of local recurrence (OR: 3.01, 1.96-4.61). Conclusions: On meta-analysis the risk of local recurrence after mastectomy is associated with margin proximity. Most data on margin status has related to breast conserving surgery. Adequate surgical margin clearance greater than 2mm margin after mastectomy is required to prevent local recurrence and International guidelines should reflect this finding. Citation Format: James Bundred, Sarah Michael, Sarah Bowers, Nicola Barnes, David Dodwell, Yasmin Jauhari, Nigel Bundred. Do surgical margins matter after mastectomy? A meta-analysis of 37,738 breast cancer patients in 33 studies [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-20-07.

Background: Leaving involved margins after surgery for early breast cancer is associated with an increased risk of local recurrence but the effect on distant recurrence is controversial. ASCO and ASTRO endorsed a policy that negative margins of no ink on tumour represented sufficient margin for local control and that the routine practice of obtaining a more widely negative margin was not indicated. We aimed to assess margin status (2mm) on local and distant control of breast cancer in a consecutive UK patient audit of Breast Cancer Units. Methods: Patients (n = 2795) undergoing surgery for early breast cancer (Tis, T1-3) in 3 Greater Manchester Breast Units had margin status prospectively recorded (reported by micrometer according to NHSBSP pathology guidelines) and local and distant recurrence recorded. All patients received adjuvant therapy according to local guidelines. Statistical analysis using cox proportional hazard regression was used to identify clinicopathological factors predicting recurrence in the multivariate analysis. Results: Overall 575 women (19.3%) had involved (≤1mm clearance) and 235 (8.5%) close (≤2mm clearance) and 1895 clear surgical margins. 1652 patients underwent breast conserving surgery and 1143 mastectomy. Median follow-up is 63.7 months. Overall local recurrence rate was 3.8% and distant recurrence 4.9% by a median of 5 years follow-up. Local and distant recurrence was higher after mastectomy at 7% and 7.8%, respectively. Margin 2mm. In multivariate analysis, two factors: molecular phenotype (other phenotypes versus Luminal A HR 1.79) and close / involved margins less than 2mm clearance (versus clear >2mm) [HR 1.76 (95% confidence intervals 1.06 - 2.92)], predicted local recurrence and the same factors together with mastectomy (compared to breast conservation), T and N stage predicted distant recurrence (see table 1). Table 1. Multivariate analysis of factors predicting cancer recurrenceLocal Recurrence (HR)Distant Recurrence (HR)Margin categorical 2mm1.84 (1.05 - 3.22, p=0.031)1.82 (1.1 – 3.02, p= 0.019)Margin 2mm)1.76 (1.06-2.92, p=0.027)1.86 (1.16-2.27, p=0.009)T Stage 2 vs 11.55 (0.88 – 2.73, p=0.129)4.35 (2.07 – 9.14, p Conclusion: Clearing surgical margins improves recurrence free survival (both local and distant). Leaving margins ≤2mm increases distant cancer recurrence and clearance of margins should be essential surgical management, particularly in oestrogen receptor (ER) negative breast cancer. Current guidelines accepting margins ≤1mm will increase distant recurrence and deaths from breast cancer. Citation Format: Sarah Michael, Sarah Bowers, Jane Ooi, Mo Absar, James Bundred, Nigel Bundred. Surgical margin involvement (