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Rates of residual disease with close but negative margins in breast cancer surgery
The Breast 24 (2015) 413e417
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Rates of residual disease with close but negative margins in breast cancer surgery Erin M. Garvey a, Derek A. Senior a, Barbara A. Pockaj a, Nabil Wasif a, Amylou C. Dueck b, Ann E. McCullough c, Idris T. Ocal c, Richard J. Gray a, * a b c
Department of Surgery, Division of Surgical Oncology, Mayo Clinic, Phoenix, AZ, USA Section of Biostatistics, Mayo Clinic, Scottsdale, AZ, USA Department of Pathology and Laboratory Medicine, Mayo Clinic, Scottsdale, AZ, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 February 2014 Received in revised form 11 January 2015 Accepted 15 March 2015 Available online 4 April 2015
Objectives: A recent multidisciplinary consensus defined an adequate breast cancer margin as no ink on tumor. The purpose of this study was to analyze rates of residual disease at re-excision by margin width. Materials and methods: A prospective database at a single institution was reviewed from 2000 to 2012. Institutional protocol had been to perform re-excision surgery when margins were <2 millimeters (mm). Results: There were 2520 procedures. Re-excision surgery was performed for 12% of breast conserving therapy (BCT) procedures and 2% of mastectomies; residual disease was present in 38% and 26%, respectively. The rates of residual disease for all patients with positive, 0.1e0.9 mm, and 1.0e1.9 mm margins were 40%, 38%, and 33%, respectively. Age, race, menopause status, width of closest final margin, tumor histology, hormone receptor status, triple-negative disease and presence of lymphovascular invasion (LVI) were not significantly associated with the presence of residual disease. The presence of multiple margins <2 mm trended toward significance (p ¼ 0.06). Median follow-up was 43 months. The five-year local recurrence rates (5-year LR) were 1.1% for mastectomy patients and 1.9% for BCT patients. Conclusions: Breast cancer patients with margins of excision <2 mm have a substantial risk of residual disease but the rates far exceed LR rates. These findings suggest that using residual disease rates to determine the appropriate margin width is not reliable, but also serve as a note of caution to track LR rates as institutions conform to new national guidelines for margin management. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer surgery Margins Breast conserving therapy Mastectomy Residual disease Local recurrence
Introduction The definition for adequate margin width for breast cancer surgery has long been controversial. A recent survey of surgeons found a wide variation in what margin width was thought to be adequate ranging from no tumor touching ink to >1 centimeter (cm) [1]. A similar study of radiation oncologists had a more narrow range of no tumor touching ink to >2 mm, but no particular margin width was favored by greater than 50% of survey respondents in
Abbreviations: mm, millimeters; BCT, breast conserving therapy; 5-yr LR, five year local recurrence; cm, centimeter; vs., versus; IDC, invasive ductal carcinoma; DCIS, ductal carcinoma in situ; ER, estrogen receptor; LVI, lympovascular invasion; CI, confidence interval; HR, hazard ratio. * Corresponding author. Mayo Clinic Hospital, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA. Tel.: þ1 480 301 2849; fax: þ1 480 342 2170. E-mail address: [email protected] (R.J. Gray). http://dx.doi.org/10.1016/j.breast.2015.03.005 0960-9776/© 2015 Elsevier Ltd. All rights reserved.
either study [1,2]. Previous studies have identified a positive margin as a risk factor for residual disease [3e8], though a 2010 metaanalysis of 21 retrospective studies encompassing 14,571 early stage breast cancer patients treated with BCT showed no significant association between local recurrence rate and margins >1 mm versus (vs.) >2 mm vs. >5 mm [8]. It is difficult to isolate the influence of margin width on local therapy success since many other patient and disease factors are associated with the presence of residual disease and local recurrence (LR) such as age, tumor size, tumor histology, hormone receptor status, multifocal disease, extensive in-situ component and axillary lymph node metastases [4,5,7,9e12]. In 2014, after convening another meta-analysis of 33 studies [13], the Society of Surgical Oncology and the American Society for Radiation Oncology developed consensus guidelines on margins for breast-conserving surgery for patients undergoing whole-breast irradiation for stages I and II invasive breast cancer [14]. These
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guidelines were also endorsed by the American Society of Clinical Oncology [15]. According to the guidelines, a positive margin is the presence of ink on invasive carcinoma or ductal carcinoma in situ and re-excision was not recommended for patients with no ink on tumor. There remains some controversy, however, as the metaanalysis that served as the primary evidence for the guideline panel demonstrated that positive margins were associated with an odds-ratio (OR) for LR of 2.44 (p < 0.001), but “close margins” versus negative margins was also associated with significant increase in LR risk (OR 1.74, p < 0.001) [13]. When the model was limited to only those studies that quantified “close” margins with measurements, there was little to no statistical evidence that the odds of LR decreased as the distance for declaring negative margins increased, adjusting for follow-up time. The guideline panel concluded that the finding of increased risk of LR with “close” margins in the model was not reliable. Many surgeons and pathologists remain concerned about the possibility of leaving residual disease when margins are close and that LR rates could increase. While the presence of residual disease does not necessarily produce a LR, logic suggests that those patients with residual disease at the end of their breast cancer surgery would be at higher risk for LR than those without residual disease. Therefore knowledge of whether patients with “close” but negative margins have a substantial risk of residual disease can help inform us as institutions implement the new guidelines on margin management in BCT. In addition, if one could combine margin width with other clinical and pathologic factors to refine which patients are at higher or lower risk of residual disease, one could make more individualized judgments about re-excision. Previously, our institutional guideline was to perform re-excision surgery for breast cancer margins <2 mm. This gives us the opportunity to examine the rates of residual disease for a population that will no longer undergo reexcision if the new guidelines are adopted, at least for those patients undergoing BCT with planned whole-breast radiation. Thus, the purpose of this study was to determine the rates of residual disease at re-excision based on original width of margin. Although the new guidelines deal only with BCT and invasive cancer, we elected to examine the broad population of patients with invasive and in-situ carcinoma and those undergoing mastectomy as well as BCT in order to have a comprehensive view of this issue. Materials and methods Institutional review board approval was obtained. A prospective breast cancer database was reviewed including all BCT and mastectomy patients from January 2000 through May 2012. Patients with invasive breast cancer or ductal carcinoma in situ (DCIS) were included. Patients undergoing neoadjuvant therapy were also included. An extensive in-situ component was defined as an invasive tumor with 25% DCIS. Re-excision surgery was defined as a separate operation for margins found to be inadequate on final histology. Institutional protocol was to perform re-excision surgery for patients with either invasive cancer or DCIS within 2 mm of one or more margin for either BCT or mastectomy. Exceptions were made for patients who have undergone a mastectomy with a posterior margin that is negative by at least 1 mm for DCIS. The methods for intraoperative handling and pathology processing of specimens with respect to margins were previously described [16]. In brief, all patients have specimens oriented by the surgeon and six standardized ink colors applied by the pathologist for both BCT and mastectomy specimens. Each specimen is subjected to intraoperative sectioning and gross examination with selective frozen section analysis with intraoperative re-excision for any margin deemed inadequate. Patients are routinely presented at a
multidisciplinary management conference and undergo consultation with radiation and medical oncology to educate them on and offer appropriate adjuvant therapy. All patients 70 years of age with invasive cancer have radiation therapy recommended, and those patients >70 years of age have radiation therapy discussed and offered. All estrogren receptor (ER) and/or progesterone receptor (PR) positive patients have hormonal therapy recommended. Follow up information is obtained through a tumor registry via mailings and phone interviews. Statistical analysis was performed with SAS version 9 (SAS Institute). Chi-square tests were used for categorical variables. Wilcoxon rank sum test were used for continuous variables. Time to event endpoints were estimated using KaplaneMeier curves and compared between groups using Cox proportional hazards regression. All p-values were two-sided and considered statistically significant if <0.05. Results There were 2520 procedures performed on 2377 patients, for which BCT was performed in 1588 cases (63%). The mean tumor size was 1.3 ± 0.9 cm for BCT, 1.4 ± 0.9 cm for BCT requiring reexcision and 2.6 ± 2.3 for BCT requiring conversion to mastectomy. For mastectomy, the mean tumor size was 2.4 ± 2.3 cm versus 4.6 ± 5.5 cm for mastectomy requiring re-excision. In total, 204 procedures (8%) resulted in re-excision at a second operation for inadequate margins, including 185 (12%) patients undergoing BCT and 19 (2%) patients undergoing mastectomy. Twenty seven of the 1588 BCT cases (2%) were converted to mastectomy. Positive margins on final histology were present in 3% of all procedures while an additional 3% had margins 0.1e0.99 mm and 2% had margins 1.0e1.99 mm. Among patients who underwent re-excision, the mean age was 64 years (range 31e94 years), 194/204 (95%) were white and 161/ 204 (79%) were postmenopausal. Thirty of 204 patients (15%) had only DCIS at their first surgery and the remaining 174 (85%) had invasive breast cancer. Four patients (2%) had neoadjuvant therapy prior to their surgical procedure. Residual disease was present in 5/ 19 patients (26%) who underwent re-excision after mastectomy and in 70/185 (38%) of BCT patients who underwent re-excision: 50/158 of those who completed BCT (32%) and 20/27 of those who were converted to mastectomy (74%). Overall, 75/204 patients (37%) who underwent re-excision had residual disease (Fig. 1). Forty-four of the 75 (59%) patients had quantitative data on the degree of residual disease ranging from foci to 28 mm with 27/44 (61%) patients with 5 mm residual disease, 6/44 (14%) with 5e10 mm residual disease and 11/44 (25%) with >10 mm residual disease. Age, race, menopausal status, width of closest final margin, tumor histology, ER status, triple-negative disease and presence of LVI were not associated with the presence of residual disease on reexcision (Table 1). Patients with DCIS had a 39% rate of residual disease at re-excision, while those with invasive cancer had a rate of 36%. Patients with invasive lobular carcinoma had a 52% rate of residual disease versus 35% rate for patients with IDC, and 13% rate for patients with other carcinoma subtypes such as colloid and tubular carcinoma. Nonetheless, histologic type was not a significant predictor of recurrent disease (p ¼ 0.26). When separating patients into those whose final margin was positive, those whose closest final margin was 0.1e0.9 mm in width, and those whose closest final margin was 1.0e1.9 mm in width, there was no significant difference in the rate of residual disease present at re-excision (p ¼ 0.78). The rates of residual disease for all patients with positive, 0.1e0.9 mm, and 1.0e1.9 mm margins were 40%, 38% and 33%, respectively. Among BCT patients, the rates of residual disease by margin width were 39% for positive
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415
Fig. 1. Flow chart for patient cohort by type of procedure performed, re-excision and presence of residual disease. BCT, breast conserving therapy; 5 yr. LR, 5-year local recurrence.
margins, 35% for margins 0.1e0.9 mm, and 37% for margins 1.0e1.9 mm (Fig. 2). The presence of more than one margin <2 mm trended toward being associated with residual disease (45% rate of residual disease for multiple close margins versus 31% for single close margin, p ¼ 0.06). When considering only those patients undergoing BCT, 45% of patients with multiple inadequate margins had residual disease as compared to 26% of patients with a single inadequate margin. Six of 16 patients (38%) with IDC without an extensive in-situ component and final margins 1.0e1.9 mm in width had residual disease on re-excision. The residual pathologic
Table 1 Clinical and pathologic characteristics of patients with and without residual disease. Factor
Mean age (SD) Race ¼ White Postmenopausal Closest final margin 0 mm 0.1e0.99 mm 1e1.99 mm Number of close margins Single Multiple Histology DCIS Invasive Ductal Carcinoma Invasive Lobular Carcinoma Mixed Invasive Ductal/Lobular Other Estrogen receptor Positive Negative Triple-negative tumor No Yes Lymphovascular invasion No Yes
Disease present at Re-Excision No
Yes
65 (11.85) 96% 79%
64 (12.44) 93% 79%
60% 62% 67%
40% 38% 33%
69% 55%
31% 45%
61% 65% 48% 75% 88%
39% 35% 52% 25% 12%
54% 65%
46% 35%
63% 60%
37% 40%
64% 58%
36% 42%
P value
0.85a 0.39b 0.99b 0.78b
finding was pure DCIS in 74% of all patients with residual disease, including 69% of the patients treated for invasive disease at their initial operation. The median follow-up time was 43 months. The 5-year LR rates were 1.9% (95% confidence interval [CI] ¼ 1.1e2.7) for BCT and 1.1% (95% CI ¼ 0.5e2.5) for mastectomy patients. Among mastectomy patients, the 5-year LR rate was 1.1% (95% CI ¼ 0.5e2.5) in patients that did not undergo re-excision, and those patients who did undergo re-excision had no observed local recurrences. Among patients initially treated with BCT, the 5-year LR rate for those who did not undergo re-excision was 1.8% (95% CI ¼ 1.1e2.9) and was 3.6% (95% CI ¼ 1.3e9.3, p ¼ 0.09) for those who did undergo re-excision. Discussion The presence of positive margins has been shown to increase the risk for local recurrence thus highlighting the importance of adequate surgical margins in breast cancer surgery [8]. Surgical practices for re-excision have varied widely so national guidelines
0.06b
0.26b
0.67b
0.81b
0.60b
SD, standard deviation; mm, millimeter. a Wilcoxon. b Chi-Square.
Fig. 2. Rates of residual disease among BCT patients by margin width. BCT, breast conserving therapy; mm, millimeter.
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are welcomed but continue to be based on retrospective data. Appropriate margin width is a controversy not likely to be addressed with a gold standard prospective, randomized trial given the increasingly low LR event rates and the difficulty of controlling for the many patient, disease and treatment factors that play an important role in disease recurrence. While the consequences of poor margin management can be quite serious, this is increasingly being balanced against the financial, cosmetic and emotional costs of re-excision. Re-operation can result in increased health care costs, societal loss from decreased patient and surgeon productivity, increased risk of operative complications and poor cosmesis, and increased emotional distress for patients having to endure another procedure. The present study represents a large patient population from a single institution with a standardized approach of re-excision for inadequate margins defined as <2 mm for both mastectomy and BCT patients among whom we can assess the relative influences of margin width and other patient factors on the presence of residual disease at re-excision. In addition, this group of patients is unique in including mastectomy patients as prior studies of margin management have included only BCT patients. In this cohort of more than 2300 patients, including more than 200 who underwent re-excision for margin management, there was no difference in the risk of residual disease when breaking down margins into positive, 0.1e0.9 mm, and 1.0e1.9 mm categories. In addition, no particular patient or disease factor including age, race, menopause status, tumor histology, ER status, triplenegative disease or LVI was predictive of residual disease. Only four patients of the patients (2%) undergoing re-excision had undergone neoadjuvant therapy, so there are too few to conclude whether such preoperative therapy influences rates of residual disease. These patients were included in the overall cohort as their rates of residual disease (25%) were in line with the patients who did not undergo neoadjuvant therapy. The presence of multiple (versus single) margins <2 mm was the only factor which trended toward a significant association with residual disease, but even patients with a single close margin had a 31% rate of residual disease on re-excision. The lack of a clear association of residual disease with any of these characteristics in our study calls into question the reliability of using such factors for physician-directed indicators for selecting patients for re-excision. The major problem of residual disease is clearly DCIS. Of all patients with residual disease at re-excision, 74% had DCIS only, including 69% of patients initially treated for invasive disease. Efforts to improve the efficiency of initial margin control should therefore be most focused on the preoperative and intraoperative identification of the extent of in-situ disease in patients with breast carcinoma. Patients with margins of excision 2 mm did not routinely undergo re-excision in this cohort, and therefore, we cannot determine if a greater width margin criterion would have resulted in lower rates of residual disease than those seen at up to 2 mm. Combining margin widths narrower than 2 mm with other clinical factors did not allow for the identification of a subset of patients with minimal risk of residual disease. We hypothesized patients with IDC without an extensive in-situ component and with at least 1 mm margins would be such a minimal risk group. However, 38% of such patients were found to have residual disease on re-excision, which is in line with the rates of the group as a whole. This serves as a caution to the physician basing the need for re-excision on a judgment of which combination of factors should put patients at low risk. The 5-year LR rates for our patients were low, including 1.1% for mastectomy patients and 1.9% for BCT patients. LR is influenced not just by surgery but also by adjuvant therapies. Our patient population consistently has radiation therapy recommended and
adjuvant systemic therapy as appropriate which certainly contributes to lower rates of LR. While the rates of adjuvant therapy are not available for this entire cohort, our institution monitors quality data that demonstrates high rates of adjuvant therapy. For example, in 2011, receipt of radiation therapy among our BCT patients 70 years of age was 94.1%. For patients of all ages with hormone receptor positive T1c tumors, the rate of hormonal therapy in 2011 was 92.7%. And the rate of receipt of chemotherapy for hormone receptor negative T1c tumors in patients 70 years of age in 2011 was 100%. The 10e20 year local recurrence rates from the six randomized controlled trials conducted in the 1970s and 1980s comparing the outcomes of mastectomy versus BCT ranged from 8.8 to 22% for BCT and 0e12% for mastectomy [17e22]. More recent trials, however, have shown that advances in breast imaging, surgical technique, pathological processing of specimens and adjuvant therapies have substantially lowered local recurrence rates to a level more in line with the rates in our cohort [22e25]. Achieving excellent local control has many influences beyond margin width and adjuvant therapy, including preoperative planning, operative execution, and meticulous intraoperative and postoperative pathologic assessment. In addition, it is known that patient factors such as young age [26e28], and several adverse disease markers [17e21,26,29e32] are associated with a higher risk of local recurrence. Punglia et al. cited a number of risk factors for local recurrence and ranked them in order of importance: positive margins, young age, lack of systemic therapy, close margins, LVI and axillarynode involvement for BCT; and increasing number of positive axillary nodes, lack of systemic therapy, positive margins, close margins, tumor size, young age and LVI for mastectomy [33]. Therefore, margin width and the risk of residual disease must be placed within the context of these other factors when considering the ultimate goal of preventing local recurrences. In doing so, one must take care to not reduce the importance of margin management as one considers the other points in assessing the overall patient risk for recurrence. The suggestion to standardize the cutoff for adequate margin width at no tumor on ink is certainly reasonable given the multiple influences on local recurrence. The lack of substantial decrease in the rates of residual disease as original margin widths increased in this cohort, along with the observation that the rates of residual disease were far from approaching zero as we approached our 2 mm previous standard, suggest that rates of residual disease are not reliable in setting a threshold for acceptable margin widths. The fact the LR rates were so low despite these findings reiterates the multiple factors beyond rates of and bulk of residual disease in causing LR. Nonetheless, the substantial rates of residual disease and our inability to predict it should serve as a caution to closely track LR rates as institutions adopt the new no ink on tumor guideline to assure continued quality outcomes.
Conclusions Breast cancer patients with margins of excision <2 mm have a substantial risk of residual disease but the rates far exceed LR rates. The residual disease is overwhelmingly in the form of DCIS. These findings suggest that using residual disease rates to determine the appropriate margin width is not reliable, but also serve as a note of caution to track LR rates as institutions conform to new national guidelines for margin management.
Conflict of interest statement All authors declare they have no conflicts of interest.
E.M. Garvey et al. / The Breast 24 (2015) 413e417
Funding sources The authors declare no funding was utilized for this study.
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Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Rates of residual disease with close but negative margins in breast cancer surgery Erin M. Garvey a, Derek A. Senior a, Barbara A. Pockaj a, Nabil Wasif a, Amylou C. Dueck b, Ann E. McCullough c, Idris T. Ocal c, Richard J. Gray a, * a b c
Department of Surgery, Division of Surgical Oncology, Mayo Clinic, Phoenix, AZ, USA Section of Biostatistics, Mayo Clinic, Scottsdale, AZ, USA Department of Pathology and Laboratory Medicine, Mayo Clinic, Scottsdale, AZ, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 February 2014 Received in revised form 11 January 2015 Accepted 15 March 2015 Available online 4 April 2015
Objectives: A recent multidisciplinary consensus defined an adequate breast cancer margin as no ink on tumor. The purpose of this study was to analyze rates of residual disease at re-excision by margin width. Materials and methods: A prospective database at a single institution was reviewed from 2000 to 2012. Institutional protocol had been to perform re-excision surgery when margins were <2 millimeters (mm). Results: There were 2520 procedures. Re-excision surgery was performed for 12% of breast conserving therapy (BCT) procedures and 2% of mastectomies; residual disease was present in 38% and 26%, respectively. The rates of residual disease for all patients with positive, 0.1e0.9 mm, and 1.0e1.9 mm margins were 40%, 38%, and 33%, respectively. Age, race, menopause status, width of closest final margin, tumor histology, hormone receptor status, triple-negative disease and presence of lymphovascular invasion (LVI) were not significantly associated with the presence of residual disease. The presence of multiple margins <2 mm trended toward significance (p ¼ 0.06). Median follow-up was 43 months. The five-year local recurrence rates (5-year LR) were 1.1% for mastectomy patients and 1.9% for BCT patients. Conclusions: Breast cancer patients with margins of excision <2 mm have a substantial risk of residual disease but the rates far exceed LR rates. These findings suggest that using residual disease rates to determine the appropriate margin width is not reliable, but also serve as a note of caution to track LR rates as institutions conform to new national guidelines for margin management. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer surgery Margins Breast conserving therapy Mastectomy Residual disease Local recurrence
Introduction The definition for adequate margin width for breast cancer surgery has long been controversial. A recent survey of surgeons found a wide variation in what margin width was thought to be adequate ranging from no tumor touching ink to >1 centimeter (cm) [1]. A similar study of radiation oncologists had a more narrow range of no tumor touching ink to >2 mm, but no particular margin width was favored by greater than 50% of survey respondents in
Abbreviations: mm, millimeters; BCT, breast conserving therapy; 5-yr LR, five year local recurrence; cm, centimeter; vs., versus; IDC, invasive ductal carcinoma; DCIS, ductal carcinoma in situ; ER, estrogen receptor; LVI, lympovascular invasion; CI, confidence interval; HR, hazard ratio. * Corresponding author. Mayo Clinic Hospital, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA. Tel.: þ1 480 301 2849; fax: þ1 480 342 2170. E-mail address: [email protected] (R.J. Gray). http://dx.doi.org/10.1016/j.breast.2015.03.005 0960-9776/© 2015 Elsevier Ltd. All rights reserved.
either study [1,2]. Previous studies have identified a positive margin as a risk factor for residual disease [3e8], though a 2010 metaanalysis of 21 retrospective studies encompassing 14,571 early stage breast cancer patients treated with BCT showed no significant association between local recurrence rate and margins >1 mm versus (vs.) >2 mm vs. >5 mm [8]. It is difficult to isolate the influence of margin width on local therapy success since many other patient and disease factors are associated with the presence of residual disease and local recurrence (LR) such as age, tumor size, tumor histology, hormone receptor status, multifocal disease, extensive in-situ component and axillary lymph node metastases [4,5,7,9e12]. In 2014, after convening another meta-analysis of 33 studies [13], the Society of Surgical Oncology and the American Society for Radiation Oncology developed consensus guidelines on margins for breast-conserving surgery for patients undergoing whole-breast irradiation for stages I and II invasive breast cancer [14]. These
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guidelines were also endorsed by the American Society of Clinical Oncology [15]. According to the guidelines, a positive margin is the presence of ink on invasive carcinoma or ductal carcinoma in situ and re-excision was not recommended for patients with no ink on tumor. There remains some controversy, however, as the metaanalysis that served as the primary evidence for the guideline panel demonstrated that positive margins were associated with an odds-ratio (OR) for LR of 2.44 (p < 0.001), but “close margins” versus negative margins was also associated with significant increase in LR risk (OR 1.74, p < 0.001) [13]. When the model was limited to only those studies that quantified “close” margins with measurements, there was little to no statistical evidence that the odds of LR decreased as the distance for declaring negative margins increased, adjusting for follow-up time. The guideline panel concluded that the finding of increased risk of LR with “close” margins in the model was not reliable. Many surgeons and pathologists remain concerned about the possibility of leaving residual disease when margins are close and that LR rates could increase. While the presence of residual disease does not necessarily produce a LR, logic suggests that those patients with residual disease at the end of their breast cancer surgery would be at higher risk for LR than those without residual disease. Therefore knowledge of whether patients with “close” but negative margins have a substantial risk of residual disease can help inform us as institutions implement the new guidelines on margin management in BCT. In addition, if one could combine margin width with other clinical and pathologic factors to refine which patients are at higher or lower risk of residual disease, one could make more individualized judgments about re-excision. Previously, our institutional guideline was to perform re-excision surgery for breast cancer margins <2 mm. This gives us the opportunity to examine the rates of residual disease for a population that will no longer undergo reexcision if the new guidelines are adopted, at least for those patients undergoing BCT with planned whole-breast radiation. Thus, the purpose of this study was to determine the rates of residual disease at re-excision based on original width of margin. Although the new guidelines deal only with BCT and invasive cancer, we elected to examine the broad population of patients with invasive and in-situ carcinoma and those undergoing mastectomy as well as BCT in order to have a comprehensive view of this issue. Materials and methods Institutional review board approval was obtained. A prospective breast cancer database was reviewed including all BCT and mastectomy patients from January 2000 through May 2012. Patients with invasive breast cancer or ductal carcinoma in situ (DCIS) were included. Patients undergoing neoadjuvant therapy were also included. An extensive in-situ component was defined as an invasive tumor with 25% DCIS. Re-excision surgery was defined as a separate operation for margins found to be inadequate on final histology. Institutional protocol was to perform re-excision surgery for patients with either invasive cancer or DCIS within 2 mm of one or more margin for either BCT or mastectomy. Exceptions were made for patients who have undergone a mastectomy with a posterior margin that is negative by at least 1 mm for DCIS. The methods for intraoperative handling and pathology processing of specimens with respect to margins were previously described [16]. In brief, all patients have specimens oriented by the surgeon and six standardized ink colors applied by the pathologist for both BCT and mastectomy specimens. Each specimen is subjected to intraoperative sectioning and gross examination with selective frozen section analysis with intraoperative re-excision for any margin deemed inadequate. Patients are routinely presented at a
multidisciplinary management conference and undergo consultation with radiation and medical oncology to educate them on and offer appropriate adjuvant therapy. All patients 70 years of age with invasive cancer have radiation therapy recommended, and those patients >70 years of age have radiation therapy discussed and offered. All estrogren receptor (ER) and/or progesterone receptor (PR) positive patients have hormonal therapy recommended. Follow up information is obtained through a tumor registry via mailings and phone interviews. Statistical analysis was performed with SAS version 9 (SAS Institute). Chi-square tests were used for categorical variables. Wilcoxon rank sum test were used for continuous variables. Time to event endpoints were estimated using KaplaneMeier curves and compared between groups using Cox proportional hazards regression. All p-values were two-sided and considered statistically significant if <0.05. Results There were 2520 procedures performed on 2377 patients, for which BCT was performed in 1588 cases (63%). The mean tumor size was 1.3 ± 0.9 cm for BCT, 1.4 ± 0.9 cm for BCT requiring reexcision and 2.6 ± 2.3 for BCT requiring conversion to mastectomy. For mastectomy, the mean tumor size was 2.4 ± 2.3 cm versus 4.6 ± 5.5 cm for mastectomy requiring re-excision. In total, 204 procedures (8%) resulted in re-excision at a second operation for inadequate margins, including 185 (12%) patients undergoing BCT and 19 (2%) patients undergoing mastectomy. Twenty seven of the 1588 BCT cases (2%) were converted to mastectomy. Positive margins on final histology were present in 3% of all procedures while an additional 3% had margins 0.1e0.99 mm and 2% had margins 1.0e1.99 mm. Among patients who underwent re-excision, the mean age was 64 years (range 31e94 years), 194/204 (95%) were white and 161/ 204 (79%) were postmenopausal. Thirty of 204 patients (15%) had only DCIS at their first surgery and the remaining 174 (85%) had invasive breast cancer. Four patients (2%) had neoadjuvant therapy prior to their surgical procedure. Residual disease was present in 5/ 19 patients (26%) who underwent re-excision after mastectomy and in 70/185 (38%) of BCT patients who underwent re-excision: 50/158 of those who completed BCT (32%) and 20/27 of those who were converted to mastectomy (74%). Overall, 75/204 patients (37%) who underwent re-excision had residual disease (Fig. 1). Forty-four of the 75 (59%) patients had quantitative data on the degree of residual disease ranging from foci to 28 mm with 27/44 (61%) patients with 5 mm residual disease, 6/44 (14%) with 5e10 mm residual disease and 11/44 (25%) with >10 mm residual disease. Age, race, menopausal status, width of closest final margin, tumor histology, ER status, triple-negative disease and presence of LVI were not associated with the presence of residual disease on reexcision (Table 1). Patients with DCIS had a 39% rate of residual disease at re-excision, while those with invasive cancer had a rate of 36%. Patients with invasive lobular carcinoma had a 52% rate of residual disease versus 35% rate for patients with IDC, and 13% rate for patients with other carcinoma subtypes such as colloid and tubular carcinoma. Nonetheless, histologic type was not a significant predictor of recurrent disease (p ¼ 0.26). When separating patients into those whose final margin was positive, those whose closest final margin was 0.1e0.9 mm in width, and those whose closest final margin was 1.0e1.9 mm in width, there was no significant difference in the rate of residual disease present at re-excision (p ¼ 0.78). The rates of residual disease for all patients with positive, 0.1e0.9 mm, and 1.0e1.9 mm margins were 40%, 38% and 33%, respectively. Among BCT patients, the rates of residual disease by margin width were 39% for positive
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415
Fig. 1. Flow chart for patient cohort by type of procedure performed, re-excision and presence of residual disease. BCT, breast conserving therapy; 5 yr. LR, 5-year local recurrence.
margins, 35% for margins 0.1e0.9 mm, and 37% for margins 1.0e1.9 mm (Fig. 2). The presence of more than one margin <2 mm trended toward being associated with residual disease (45% rate of residual disease for multiple close margins versus 31% for single close margin, p ¼ 0.06). When considering only those patients undergoing BCT, 45% of patients with multiple inadequate margins had residual disease as compared to 26% of patients with a single inadequate margin. Six of 16 patients (38%) with IDC without an extensive in-situ component and final margins 1.0e1.9 mm in width had residual disease on re-excision. The residual pathologic
Table 1 Clinical and pathologic characteristics of patients with and without residual disease. Factor
Mean age (SD) Race ¼ White Postmenopausal Closest final margin 0 mm 0.1e0.99 mm 1e1.99 mm Number of close margins Single Multiple Histology DCIS Invasive Ductal Carcinoma Invasive Lobular Carcinoma Mixed Invasive Ductal/Lobular Other Estrogen receptor Positive Negative Triple-negative tumor No Yes Lymphovascular invasion No Yes
Disease present at Re-Excision No
Yes
65 (11.85) 96% 79%
64 (12.44) 93% 79%
60% 62% 67%
40% 38% 33%
69% 55%
31% 45%
61% 65% 48% 75% 88%
39% 35% 52% 25% 12%
54% 65%
46% 35%
63% 60%
37% 40%
64% 58%
36% 42%
P value
0.85a 0.39b 0.99b 0.78b
finding was pure DCIS in 74% of all patients with residual disease, including 69% of the patients treated for invasive disease at their initial operation. The median follow-up time was 43 months. The 5-year LR rates were 1.9% (95% confidence interval [CI] ¼ 1.1e2.7) for BCT and 1.1% (95% CI ¼ 0.5e2.5) for mastectomy patients. Among mastectomy patients, the 5-year LR rate was 1.1% (95% CI ¼ 0.5e2.5) in patients that did not undergo re-excision, and those patients who did undergo re-excision had no observed local recurrences. Among patients initially treated with BCT, the 5-year LR rate for those who did not undergo re-excision was 1.8% (95% CI ¼ 1.1e2.9) and was 3.6% (95% CI ¼ 1.3e9.3, p ¼ 0.09) for those who did undergo re-excision. Discussion The presence of positive margins has been shown to increase the risk for local recurrence thus highlighting the importance of adequate surgical margins in breast cancer surgery [8]. Surgical practices for re-excision have varied widely so national guidelines
0.06b
0.26b
0.67b
0.81b
0.60b
SD, standard deviation; mm, millimeter. a Wilcoxon. b Chi-Square.
Fig. 2. Rates of residual disease among BCT patients by margin width. BCT, breast conserving therapy; mm, millimeter.
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are welcomed but continue to be based on retrospective data. Appropriate margin width is a controversy not likely to be addressed with a gold standard prospective, randomized trial given the increasingly low LR event rates and the difficulty of controlling for the many patient, disease and treatment factors that play an important role in disease recurrence. While the consequences of poor margin management can be quite serious, this is increasingly being balanced against the financial, cosmetic and emotional costs of re-excision. Re-operation can result in increased health care costs, societal loss from decreased patient and surgeon productivity, increased risk of operative complications and poor cosmesis, and increased emotional distress for patients having to endure another procedure. The present study represents a large patient population from a single institution with a standardized approach of re-excision for inadequate margins defined as <2 mm for both mastectomy and BCT patients among whom we can assess the relative influences of margin width and other patient factors on the presence of residual disease at re-excision. In addition, this group of patients is unique in including mastectomy patients as prior studies of margin management have included only BCT patients. In this cohort of more than 2300 patients, including more than 200 who underwent re-excision for margin management, there was no difference in the risk of residual disease when breaking down margins into positive, 0.1e0.9 mm, and 1.0e1.9 mm categories. In addition, no particular patient or disease factor including age, race, menopause status, tumor histology, ER status, triplenegative disease or LVI was predictive of residual disease. Only four patients of the patients (2%) undergoing re-excision had undergone neoadjuvant therapy, so there are too few to conclude whether such preoperative therapy influences rates of residual disease. These patients were included in the overall cohort as their rates of residual disease (25%) were in line with the patients who did not undergo neoadjuvant therapy. The presence of multiple (versus single) margins <2 mm was the only factor which trended toward a significant association with residual disease, but even patients with a single close margin had a 31% rate of residual disease on re-excision. The lack of a clear association of residual disease with any of these characteristics in our study calls into question the reliability of using such factors for physician-directed indicators for selecting patients for re-excision. The major problem of residual disease is clearly DCIS. Of all patients with residual disease at re-excision, 74% had DCIS only, including 69% of patients initially treated for invasive disease. Efforts to improve the efficiency of initial margin control should therefore be most focused on the preoperative and intraoperative identification of the extent of in-situ disease in patients with breast carcinoma. Patients with margins of excision 2 mm did not routinely undergo re-excision in this cohort, and therefore, we cannot determine if a greater width margin criterion would have resulted in lower rates of residual disease than those seen at up to 2 mm. Combining margin widths narrower than 2 mm with other clinical factors did not allow for the identification of a subset of patients with minimal risk of residual disease. We hypothesized patients with IDC without an extensive in-situ component and with at least 1 mm margins would be such a minimal risk group. However, 38% of such patients were found to have residual disease on re-excision, which is in line with the rates of the group as a whole. This serves as a caution to the physician basing the need for re-excision on a judgment of which combination of factors should put patients at low risk. The 5-year LR rates for our patients were low, including 1.1% for mastectomy patients and 1.9% for BCT patients. LR is influenced not just by surgery but also by adjuvant therapies. Our patient population consistently has radiation therapy recommended and
adjuvant systemic therapy as appropriate which certainly contributes to lower rates of LR. While the rates of adjuvant therapy are not available for this entire cohort, our institution monitors quality data that demonstrates high rates of adjuvant therapy. For example, in 2011, receipt of radiation therapy among our BCT patients 70 years of age was 94.1%. For patients of all ages with hormone receptor positive T1c tumors, the rate of hormonal therapy in 2011 was 92.7%. And the rate of receipt of chemotherapy for hormone receptor negative T1c tumors in patients 70 years of age in 2011 was 100%. The 10e20 year local recurrence rates from the six randomized controlled trials conducted in the 1970s and 1980s comparing the outcomes of mastectomy versus BCT ranged from 8.8 to 22% for BCT and 0e12% for mastectomy [17e22]. More recent trials, however, have shown that advances in breast imaging, surgical technique, pathological processing of specimens and adjuvant therapies have substantially lowered local recurrence rates to a level more in line with the rates in our cohort [22e25]. Achieving excellent local control has many influences beyond margin width and adjuvant therapy, including preoperative planning, operative execution, and meticulous intraoperative and postoperative pathologic assessment. In addition, it is known that patient factors such as young age [26e28], and several adverse disease markers [17e21,26,29e32] are associated with a higher risk of local recurrence. Punglia et al. cited a number of risk factors for local recurrence and ranked them in order of importance: positive margins, young age, lack of systemic therapy, close margins, LVI and axillarynode involvement for BCT; and increasing number of positive axillary nodes, lack of systemic therapy, positive margins, close margins, tumor size, young age and LVI for mastectomy [33]. Therefore, margin width and the risk of residual disease must be placed within the context of these other factors when considering the ultimate goal of preventing local recurrences. In doing so, one must take care to not reduce the importance of margin management as one considers the other points in assessing the overall patient risk for recurrence. The suggestion to standardize the cutoff for adequate margin width at no tumor on ink is certainly reasonable given the multiple influences on local recurrence. The lack of substantial decrease in the rates of residual disease as original margin widths increased in this cohort, along with the observation that the rates of residual disease were far from approaching zero as we approached our 2 mm previous standard, suggest that rates of residual disease are not reliable in setting a threshold for acceptable margin widths. The fact the LR rates were so low despite these findings reiterates the multiple factors beyond rates of and bulk of residual disease in causing LR. Nonetheless, the substantial rates of residual disease and our inability to predict it should serve as a caution to closely track LR rates as institutions adopt the new no ink on tumor guideline to assure continued quality outcomes.
Conclusions Breast cancer patients with margins of excision <2 mm have a substantial risk of residual disease but the rates far exceed LR rates. The residual disease is overwhelmingly in the form of DCIS. These findings suggest that using residual disease rates to determine the appropriate margin width is not reliable, but also serve as a note of caution to track LR rates as institutions conform to new national guidelines for margin management.
Conflict of interest statement All authors declare they have no conflicts of interest.
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Funding sources The authors declare no funding was utilized for this study.
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