Aim To determine whether margin involvement is associated with distant recurrence and determine the margin needed to minimize both local recurrence and distant recurrence in early-stage invasive breast cancer. Design Prospectively registered systematic review and meta-analysis of the literature. Data sources Online databases Medline (PubMed), Embase and Proquest. Unpublished data were requested from the authors of the studies. Eligibility criteria Eligible studies reported on patients undergoing breast-conserving surgery (for stage I-III breast cancer), allowed estimation of outcomes in relation to margin status, and followed patients for a minimum of 60 months. . Patients with ductal carcinoma in situ only or treated with neoadjuvant chemotherapy or mastectomy were excluded. When applicable, margins were classified as ink tumor (involved), closed margins (no ink tumor but <2 mm), and negative margins (≥2 mm). Results 68 studies were included from January 1, 1980 to December 31, 2021, with 112,140 breast cancer patients. Across all studies, 9.4% (95% confidence interval: 6.8% to 12.8%) of patients had involved margins (ink tumor) and 17.8% (13.0% % to 23.9%) had a tumor in the ink or a closed margin. The distant recurrence rate was 25.4% (14.5% to 40.6%) in patients with ink tumor, 8.4% (4.4% to 15.5%) in patients with ink tumor. ink or close, and 7.4% (3.9% to 13.6%) in patients with negative margins. Compared with negative margins, tumor in ink margins was associated with greater 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, P<0.001). Closed 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) compared with negative margins, after adjusting for receiving adjuvant chemotherapy and radiation therapy. In five studies published since 2010, tumor at the ink margins was associated with greater distant recurrence (2.41, 1.81 to 3.21, P < 0.001), as was tumor at the ink and closed margins (1.44, 1.22 to 1.71, P < 0.001) compared with negative ones. margins. Conclusions Pathologic involved or closed margins after breast-conserving surgery for early-stage invasive breast cancer are associated with increased distant recurrence and local recurrence. Surgeons should aim to achieve a minimum clear margin of at least 1 mm. Based on current evidence, international guidelines should be revised. Systematic review registration CRD42021232115. |
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Surgeons should aim to remove at least a 1mm-wide edge (margin) of healthy tissue around a breast tumor to reduce the risk of the cancer coming back and improve breast cancer survival worldwide, suggests the largest analysis of the evidence to date published by The BMJ.
The findings indicate that inadequate margin widths may result in increased risks of distant recurrence (cancer that returns in a different part of the body) and breast cancer mortality, as well as increased local recurrence (cancer that returns in the same place).
The researchers say current international guidelines need revision to account for these new findings.
After surgery, a pathologist measures the shortest distance between the tumor and the edge of the specimen to establish the width of the margin. The sample is usually "inked" at the edges with a special pen, so that the pathologist can clearly see the end of the tumor in relation to healthy tissue.
Cancer guidelines suggest that avoiding a tumor touching the margin of healthy tissue after breast cancer surgery reduces local recurrence, but there are no data on distant recurrence.
To address this knowledge gap, an international team of researchers searched for published studies reporting on patients who underwent breast-conserving surgery for early-stage invasive breast cancer who were followed for a minimum of five years.
A total of 68 observational studies published between 1980 and 2021 involving 112,140 breast cancer patients (average age 56 years) were included in the analysis. The studies were designed differently and were of variable quality, but the researchers were able to take that into account in their analysis.
Tumor samples were classified as "inked" tumor at the margin (involved), closed margins (tumor less than 2 mm from the margin, but not at the margin), and negative margins (tumor 2 mm or more from the margin). .
Across all studies, 9.4% of patients had involved margins (ink tumor) and 17.8% had an ink tumor or closed margin. The distant recurrence rate was 25.4% in patients with tumor at ink margins, 8.4% in patients with tumor at or near ink, and 7.4% in patients with negative margins.
Compared with negative margins, tumor at stained margins was associated with a two-fold increased risk of distant recurrence and local recurrence.
Close margins were associated with a 38% increased risk of distant recurrence and a two-fold increased risk of local recurrence compared with negative margins, after adjusting for chemotherapy and radiotherapy treatment after surgery.
In five studies published since 2010, tumor at stained margins was associated with a 2.4-fold increase in distant recurrence, as was tumor at stained and closed margins (1.4-fold increased risk ) compared to negative margins.
Two studies reported on overall survival, comparing patients with tumor in inked versus uninked margins. Tumors at ink margins were associated with a 61% increase in mortality rate, while positive or close margins versus wider (negative) margins were associated with a 32% increase in mortality rates. .
The researchers acknowledge that most of this data comes from observational studies with low to moderate quality evidence, so a causal association between margin proximity and distant recurrence cannot be proven.
However, they say this study collects data from about four times the number of patients included in a similar 2014 analysis, and is also the first to consider the association between distant recurrence and overall survival with margins.
As such, they say: "A tumor-free margin in the ink is inadequate and we recommend a minimum tumor-free distance of 1 mm from the margin for invasive disease or ductal carcinoma in situ to ensure optimal oncologic outcomes."
Recognizing that wider margins require additional surgery, they suggest that decisions about re-excision “should be the product of informed discussion between physicians and patients with full disclosure of the risks of increased distant recurrence associated with closed margins.” ”.
Differences between various international surgical guidelines on the best width for margin clearance should also be standardized with prevention of distant recurrence as the primary goal, they add.
