Journal of Surgical Oncology 2014;110:75–81
Breast Conserving Therapy for DCIS—Does Size Matter? OLGA KANTOR, 1
1 MD AND
DAVID J. WINCHESTER,
MD, FACS
1,2
*
University of Chicago, Pritzker School of Medicine, Chicago, Illinois 2 NorthShore University HealthSystem, Evanston, Illinois
The incidence of ductal carcinoma in situ has increased dramatically with the use of screening mammography. Most patients can be considered for breast conserving therapy, depending upon patient and pathologic variables. In addition to other factors, tumor size is important to provide proper patient selection for breast conserving surgery and predict risk of local recurrence.
J. Surg. Oncol. 2014;110:75–81. ß 2014 Wiley Periodicals, Inc.
KEY WORDS: mammography; breast‐conserving surgery; local recurrence
INTRODUCTION Ductal carcinoma in situ (DCIS) now comprises 25% of all newly diagnosed breast cancers. The incidence of DCIS has grown from 1.87/ 100,000 women in 1973–1975 to 32.5/100,000 in 2004 (a 17.4 time increase), mostly accounted for by the increase in mammographic screening. Approximately 80% of DCIS is screen detected, while the remaining 20% is detected on physical exam [1]. Interestingly, the incidence of comedo DCIS has remained stable while the incidence of noncomedo DCIS has increased [2]. From 1983 to 1992, there was a marked decline in the number of patients with DCIS treated by mastectomy (from 71% to 43.8% in), although highly variable by geographic region [3]. There has been a subsequent increase in the utilization of mastectomy to 41% in 2006 [4]. DCIS is a pre‐invasive cancer and left untreated may progress to invasive cancer. DCIS diagnosed on core needle biopsy can also be upgraded to invasive carcinoma in approximately 25% of cases (ranging from 10% to 49%) [5]. Thus, DCIS is treated with surgical excision with intent to cure. The diverse biologic heterogeneity of DCIS leads to challenges in defining optimal therapy.
Risk Factors for DCIS The risk factors for developing DCIS are similar to those of invasive ductal cancer (IDC). In a large multicenter study in England and Scotland, information on genetic and environmental risk factors was analyzed for 1,131,924 postmenopausal women aged 50–64. Over a median 8.9‐year follow‐up, 3,715 cases of DCIS and 21,137 cases of IDC occurred. There were no statistically significant differences in age at menarche, parity, age at first birth, age at menopause, BMI, family history of breast cancer, alcohol intake, or HRT use between the DCIS and IDC groups, suggesting that the environmental risk factors are similar for both [6]. In patients with DCIS, BRCA1/2 mutations are increased in comparison to the general population. In a case–control trial of 875 patients with DCIS, patients were significantly more likely to report a first‐degree history of breast cancer (OR ¼ 1.6), especially of both a mother and sister with cancer (OR ¼ 2.4). The estimated risk of BRCA 1 and 2 in this population of patients with DCIS was 1.9% and 3.7%, respectively [7]. In a study of 118 high‐risk patients with DCIS who underwent genetic testing, 27% tested positive. In a multivariate model, only patients with two or more relatives with ovarian cancer (OR ¼ 8.81) and who had a high score on the BRCAPRO model (incorporating age, age at death, breast cancer and ovarian cancer
ß 2014 Wiley Periodicals, Inc.
diagnoses, and ages at diagnoses) to predict probability of a family member carrying a BRCA mutation were independent risk factors for BRCA mutation [8]. A 2010 review of risk factors on DCIS by Virnig et al. [9] named older age and positive family history as risk factors affecting DCIS incidence. Case–control trials of exercise activity [10] and OCP use [11] did not show either as a significant risk factor for DCIS.
TREATMENT OPTIONS The National Comprehensive Cancer Network (NCCN) guidelines for the treatment of DCIS (Tis, Stage 0) involve three options—simple mastectomy, breast conserving surgery (BCS) followed by radiation therapy (RT), or BCS without RT (in a specific subset of low‐risk patients) [12]. Multiple randomized control trials have demonstrated the efficacy and safety of breast conserving therapy as an option for invasive breast cancer; however, there have not been any randomized clinical trials comparing BCT to mastectomy for patients with DCIS. The National Surgical Adjuvant Breast and Bowel Project (NASBP) B‐06 trial included 1,851 women with stage I or II invasive breast cancer who were randomly assigned treatment of total mastectomy, BCS þ RT, or BCS alone, with all patients receiving axillary dissection. The 5‐year results, published in 1985, demonstrated the rates of disease free, distant disease free, and overall survival for BCS were no worse than those with total mastectomy, and there was a borderline significant trend towards improved overall survival in BCS [13]. The 20‐year results, published in 2002, showed an ipsilateral recurrence rate of 14.3% in women who underwent BCS þ RT and 39.2% in those that underwent BCS alone, but there were no significant differences among the three groups in respect to disease‐free survival, distant disease free survival, or overall survival [14].
*Correspondence to: David J. Winchester, MD, FACS, Chair of Surgical Oncology, NorthShore University HealthSystem, Clinical Professor of Surgery, University of Chicago, Pritzker School of Medicine, Evanston, IL. Fax: 773‐702‐2140. E‐mail: [email protected] Received 22 April 2014; Accepted 26 April 2014 DOI 10.1002/jso.23657 Published online 27 May 2014 in Wiley Online Library (wileyonlinelibrary.com).
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The European Organization for Research and Treatment of Cancer (EORTC) 10,801 prospective randomized control trial demonstrated no statistically different rates of local recurrence of survival in 903 patients who were randomized to either modified radical mastectomy or lumpectomy with axillary dissection and RT [15]. Twenty‐year follow‐up of the EORTC 10801 trial showed similar distant metastasis rates of 42% in the mastectomy group versus 46% in the BCS group, with no differences in time to distant metastases or overall survival by age [16]. The Danish Breast Cancer Cooperative randomized control trial of 1,133 patients demonstrated a 6‐year recurrence‐free survival of 70% with BCS versus 66% with mastectomy in patients with invasive carcinoma [17], with most recently reported 20‐year follow‐up showing no significant difference between the two treatments in either 10‐year recurrence‐free survival or 20‐year overall survival in a series including 1,133 patients [18].
The Swedish trial was conducted from 1987 to 1999, and included 1,046 women randomized to observation or RT after lumpectomy, followed for a mean of 8 years. This study revealed similar findings with a relative risk of local recurrence of 0.40 (95% CI, 0.30–0.54) for those receiving radiation. This observation was not affected by focality, lesion size, completeness of excision, or detection mode, although younger patients (younger than 50) had decreased benefit as compared to women older than 60 [30]. A collective review of these four RCT by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) included 3,729 women treated with BCS alone or with RT. The addition of RT reduced the 10‐ year risk of ipsilateral breast recurrence by 15.2%. RT was effective regardless of tumor factors but when stratified by tumor size, RT reduced the risk of ipsilateral recurrence by 15.8% for tumors 1–20 mm and by 26% for tumors measuring 20–50 mm in size [31].
Tamoxifen Lumpectomy for DCIS Followed by Radiation Therapy Randomized clinical trials have compared outcomes for patients treated with BCT with or without external beam radiation therapy. All of these trials have demonstrated a decrease in local recurrence for those patients treated with radiation therapy. Prospective nonrandomized studies have also confirmed that low rates of local recurrence may be achieved with proper patient selection [19,20]. Debate has focused on the ability to select patients and avoid the use of radiation therapy. Much of this debate has focused on the size of the DCIS, as well as margin distance, age, and grade as selection criteria [21,22]. NSABP B‐17 was a RCT of 818 women receiving BCS with or without RT. At 8 years, there was a statistically significant decrease in ipsilateral breast recurrence with both invasive (3.9% with RT, 13.4% without RT) and noninvasive disease (8.2% with RT, 13.4% without RT). This benefit was seen in all cohorts, regardless of patient or tumor characteristics, including size [23]. At fifteen‐year follow‐up, radiation reduced ipsilateral breast recurrence by 52%. The incidence of invasive local recurrence was 19.4% for BCS only and 8.9% for BCS with RT. Women younger than 45 showed a 2.1 time increased risk of recurrence compared to those over 65, with no statistically significant treatment effect difference [24,25]. EORTC 10853 was a RCT of 1010 women with DCIS less than 5 cm assigned to BCS with or without RT with a median follow‐up of 15.8 years. The inclusion of RT reduced the risk of local recurrence by 48% (hazard ratio (HR) of 0.52), however this did not affect breast cancer specific survival (HR 1.07) or overall survival (HR 1.02) [26]. All subsets of patients benefited from inclusion of radiation therapy. There was a trend towards statistical significance for increased risk of local recurrence for patients with tumors greater than 20 mm as compared to those less than or equal to 10 mm (2.37 [1.02–5.47]; P ¼ 0.12). The United Kingdom, Australia, and New Zealand (UK/ANZ) trial was a randomized controlled trial of 1,701 women receiving BCS alone, BCS with RT, BCS with tamoxifen, or BCS with RT and tamoxifen. RT reduced the incidence of ipsilateral invasive breast cancer (0.45 [0.24– 0.85]; P ¼ 0.01) and ipsilateral DCIS (0.36 [0.19–0.66]; P ¼0.0004) with no effect on contralateral disease [27]. With a median follow‐up of 12.7 years, RT continued to have a reduced incidence of all new breast cancers (0.41 [0.30–0.56]; P < 0.0001) with no effect on contralateral breast cancer [28]. In a subsequent analysis of 1,224 (72.3%) patients, complete data on DCIS size, histological grade/sub‐type, presence and degree of comedo‐type necrosis, presence and degree of inflammation, and excision status were analyzed to predict local recurrence. Amongst other predictive variables, size was associated with risk of local recurrence. Patients with tumors greater than 20 mm had an increased risk of local recurrence as compared to those patients with tumors less than 10 mm (1.55 [1.08–2.22]; P < 0.0001) [29]. Journal of Surgical Oncology
Tamoxifen has been shown to reduce the risk of local recurrence as well as distant in invasive cancer as well as reduce the incidence of new primary tumors [32]. Its use has also been studied in the setting of ductal carcinoma in situ. NSABP B‐24 was a double blind RCT consisting of 902 women randomized to BCS þ RT þ tamoxifen versus BCS þ RT þ placebo. At 5 years, women in the tamoxifen group had fewer breast cancer events than those in the control group (8.2% vs. 13.4%, respectively) [33]. At 15 years, tamoxifen decreased the rate of all breast cancer events, with a cumulative incidence of invasive ipsilateral recurrence 8.5% in the tamoxifen group versus 10.0% in the placebo group. The rate of contralateral breast cancers was 7.3% for the tamoxifen group in comparison to 10.8% for the placebo (comparable to contralateral cancer risk with RT alone in B‐17 trial) [25]. The UK/AMZ trial initially demonstrated that tamoxifen reduced ipsilateral DCIS recurrence (HR 0.68) with no effect on invasive recurrence [27]. At 12.7‐year follow‐up, tamoxifen continued to show no significant effect on ipsilateral invasive recurrence, however, it did reduce the overall incidence of new breast events (HR 0.71), with reduction of both ipsilateral DCIS (HR 0.7) and contralateral tumors (HR 0.44) [28].
Treatment Trends With the abundance of data demonstrating the safety of BCS, it is no surprise that between 1991 and 2005, decreasing mastectomy rates were observed for women diagnosed with DCIS [34]. However, since 2004 there has been an increasing mastectomy rate. A study of 21,869 women from the Kentucky Cancer Registry diagnosed between 1998 and 2007 demonstrated an overall decrease mastectomy rates from 53.1% in 1998 to 38.8% in 2005. However, from 2005 to 2007, higher mastectomy rates were noted in all age groups (75% increase in women 70). Multivariate analysis demonstrated that factors associated with mastectomy over BCS included early stage breast cancer, increasing grade, unusual histology, rural location, uninsured or government‐insured status, receptor negative disease, and age >70 [35]. A study of 5,865 patients at a single institution from 1994 to 2007 also demonstrated increased mastectomy rates from 2004 to 2007 (44%) in comparison to 1994 to 1998 (33%) and 1999 to 2003 (33%). Gender, age 2 mm (OR 0.46) [48]. Margin definitions varied widely among surveyed surgeons in a 2010 survey of 318 surgeons in two large metropolitan areas. Breast specialization (>50% of practice devoted to breast surgery) was found to be an independent predictor of margin preferences, with breast specialists favoring smaller margins in a scenario of invasive cancer treated with BCS and RT and larger margins in a scenario of DCIS treated with BCS without RT [67]. Numerous factors contribute to the success or failure of breast conserving surgery for DCIS, many of which have been reviewed above. Size, because of its impact on local recurrence risk, as well as dictating surgical options due to extent of resection, is a frequently considered factor in surgical decision making in the management of DCIS. Table I summarizes the effect of size in published reports. Even among studies that do find size a significant factor, there is a lack of consensus of size criteria. While review of the literature does not consistently reflect the significance of size, there is certainly a trend in the literature towards its significance, and there is clear clinical significance in surgical decisions and planning.
Guides for Therapy Size has been described as a surrogate marker for margin involvement. There have been many methods described to optimize negative margins including intraoperative pathology or ultrasound guidance. Intraoperative frozen section has reported accuracy rates between 84% and 98%, while touch prep and imprint cytology are comparable with accuracy rates between 85% and 94%. However, pathological methods are time and labor intensive and increase the duration of anesthesia. Intraoperative ultrasound has variable accuracy of margin assessment, with sensitivity ranging from 25% to 100% and
Breast Conserving Therapy for DCIS—Does Size Matter?
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TABLE I. Impact of Size on Local Recurrence Refs. Silverstein et al. [19] Wapnir et al. [25] Cuzick et al. [28] EBCTCG [31] Vicini et al. [39] Collins et al. [44] Bailes et al. [46] Melstrom et al. [49] Thomas et al. [50] Holmes et al. [51] Dillon et al. [52] Goldstein et al. [53] O’Sullivan et al. [54] MacDonald et al. [56] Kerlikowske et al. [57] Wai et al. [58] Hughes et al. [59] Ringberg et al. [60] Solin et al. [61] Bijker et al. [68]
# Patients
Type
Size a significant factor?
Size of significance
333 2,622 1,694 3,729 145 2,995 1,902 546 2,564 141 135 132 2,770 455 1,036 460 671 161 268 1,010
SIC RCT RCT RCT review SIC MIC SIC SIC MIC SIC SIC SIC SIC SIC MIC MIC MIC SIC MIC RCT
Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes (reverse effect) Yes Yes Yes No No No No
>1.5 cm Not specified Not specified Not specified >7 mm >15 low powered fields Not specified Not specified >1.5 cm Not specified >3 cm Not specified Not specified Not specified >1 cm >4 cm Not specified Not specified Not specified Not specified
SIC, single institution cohort; MIC, multi‐institution cohort; RCT, randomized control trial.
specificity ranging from 74% to 95%. However, ultrasound has a more limited role for DCIS due to the lack of an ultrasound correlate for most presentations [68]. There are two tools described in the literature to help in treatment decisions for DCIS. The first is the University of Southern California Van Nuys Index. The index is based on a multi‐institution analysis of 949 patients with DCIS who underwent BCS alone or BCS with RT. The index gives a score of 1–3 (best to worst) for each of 5 measurable prognostic factors. The index initiated with just two factors in 1995– grade and necrosis, with size and margins added in 1996 and age added in 2002 [19,69,70]. A recently described DCIS nomogram attempts to predict 5‐ and 10‐year ipsilateral breast tumor recurrence rates based upon a single‐institution cohort of 1,681 women with DCIS treated with BCS. The nomogram integrates 10 clinical and pathological variables: age at diagnosis, family history, initial presentation, adjuvant RT, adjuvant endocrine therapy, nuclear grade, presence of necrosis, margin size, number of re‐excisions, and the time period of surgery. The study shows good internal validation and is a potentially very useful tool in predicting risk in individual patients to help guide surgical planning [71]. In conclusion, tumor size is an important factor for patient selection for breast conservation therapy as it been determined to be a predictor of positive margins, re‐excision, and local recurrence in randomized clinical trials and retrospective studies.
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Breast Conserving Therapy for DCIS—Does Size Matter? OLGA KANTOR, 1
1 MD AND
DAVID J. WINCHESTER,
MD, FACS
1,2
*
University of Chicago, Pritzker School of Medicine, Chicago, Illinois 2 NorthShore University HealthSystem, Evanston, Illinois
The incidence of ductal carcinoma in situ has increased dramatically with the use of screening mammography. Most patients can be considered for breast conserving therapy, depending upon patient and pathologic variables. In addition to other factors, tumor size is important to provide proper patient selection for breast conserving surgery and predict risk of local recurrence.
J. Surg. Oncol. 2014;110:75–81. ß 2014 Wiley Periodicals, Inc.
KEY WORDS: mammography; breast‐conserving surgery; local recurrence
INTRODUCTION Ductal carcinoma in situ (DCIS) now comprises 25% of all newly diagnosed breast cancers. The incidence of DCIS has grown from 1.87/ 100,000 women in 1973–1975 to 32.5/100,000 in 2004 (a 17.4 time increase), mostly accounted for by the increase in mammographic screening. Approximately 80% of DCIS is screen detected, while the remaining 20% is detected on physical exam [1]. Interestingly, the incidence of comedo DCIS has remained stable while the incidence of noncomedo DCIS has increased [2]. From 1983 to 1992, there was a marked decline in the number of patients with DCIS treated by mastectomy (from 71% to 43.8% in), although highly variable by geographic region [3]. There has been a subsequent increase in the utilization of mastectomy to 41% in 2006 [4]. DCIS is a pre‐invasive cancer and left untreated may progress to invasive cancer. DCIS diagnosed on core needle biopsy can also be upgraded to invasive carcinoma in approximately 25% of cases (ranging from 10% to 49%) [5]. Thus, DCIS is treated with surgical excision with intent to cure. The diverse biologic heterogeneity of DCIS leads to challenges in defining optimal therapy.
Risk Factors for DCIS The risk factors for developing DCIS are similar to those of invasive ductal cancer (IDC). In a large multicenter study in England and Scotland, information on genetic and environmental risk factors was analyzed for 1,131,924 postmenopausal women aged 50–64. Over a median 8.9‐year follow‐up, 3,715 cases of DCIS and 21,137 cases of IDC occurred. There were no statistically significant differences in age at menarche, parity, age at first birth, age at menopause, BMI, family history of breast cancer, alcohol intake, or HRT use between the DCIS and IDC groups, suggesting that the environmental risk factors are similar for both [6]. In patients with DCIS, BRCA1/2 mutations are increased in comparison to the general population. In a case–control trial of 875 patients with DCIS, patients were significantly more likely to report a first‐degree history of breast cancer (OR ¼ 1.6), especially of both a mother and sister with cancer (OR ¼ 2.4). The estimated risk of BRCA 1 and 2 in this population of patients with DCIS was 1.9% and 3.7%, respectively [7]. In a study of 118 high‐risk patients with DCIS who underwent genetic testing, 27% tested positive. In a multivariate model, only patients with two or more relatives with ovarian cancer (OR ¼ 8.81) and who had a high score on the BRCAPRO model (incorporating age, age at death, breast cancer and ovarian cancer
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diagnoses, and ages at diagnoses) to predict probability of a family member carrying a BRCA mutation were independent risk factors for BRCA mutation [8]. A 2010 review of risk factors on DCIS by Virnig et al. [9] named older age and positive family history as risk factors affecting DCIS incidence. Case–control trials of exercise activity [10] and OCP use [11] did not show either as a significant risk factor for DCIS.
TREATMENT OPTIONS The National Comprehensive Cancer Network (NCCN) guidelines for the treatment of DCIS (Tis, Stage 0) involve three options—simple mastectomy, breast conserving surgery (BCS) followed by radiation therapy (RT), or BCS without RT (in a specific subset of low‐risk patients) [12]. Multiple randomized control trials have demonstrated the efficacy and safety of breast conserving therapy as an option for invasive breast cancer; however, there have not been any randomized clinical trials comparing BCT to mastectomy for patients with DCIS. The National Surgical Adjuvant Breast and Bowel Project (NASBP) B‐06 trial included 1,851 women with stage I or II invasive breast cancer who were randomly assigned treatment of total mastectomy, BCS þ RT, or BCS alone, with all patients receiving axillary dissection. The 5‐year results, published in 1985, demonstrated the rates of disease free, distant disease free, and overall survival for BCS were no worse than those with total mastectomy, and there was a borderline significant trend towards improved overall survival in BCS [13]. The 20‐year results, published in 2002, showed an ipsilateral recurrence rate of 14.3% in women who underwent BCS þ RT and 39.2% in those that underwent BCS alone, but there were no significant differences among the three groups in respect to disease‐free survival, distant disease free survival, or overall survival [14].
*Correspondence to: David J. Winchester, MD, FACS, Chair of Surgical Oncology, NorthShore University HealthSystem, Clinical Professor of Surgery, University of Chicago, Pritzker School of Medicine, Evanston, IL. Fax: 773‐702‐2140. E‐mail: [email protected] Received 22 April 2014; Accepted 26 April 2014 DOI 10.1002/jso.23657 Published online 27 May 2014 in Wiley Online Library (wileyonlinelibrary.com).
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The European Organization for Research and Treatment of Cancer (EORTC) 10,801 prospective randomized control trial demonstrated no statistically different rates of local recurrence of survival in 903 patients who were randomized to either modified radical mastectomy or lumpectomy with axillary dissection and RT [15]. Twenty‐year follow‐up of the EORTC 10801 trial showed similar distant metastasis rates of 42% in the mastectomy group versus 46% in the BCS group, with no differences in time to distant metastases or overall survival by age [16]. The Danish Breast Cancer Cooperative randomized control trial of 1,133 patients demonstrated a 6‐year recurrence‐free survival of 70% with BCS versus 66% with mastectomy in patients with invasive carcinoma [17], with most recently reported 20‐year follow‐up showing no significant difference between the two treatments in either 10‐year recurrence‐free survival or 20‐year overall survival in a series including 1,133 patients [18].
The Swedish trial was conducted from 1987 to 1999, and included 1,046 women randomized to observation or RT after lumpectomy, followed for a mean of 8 years. This study revealed similar findings with a relative risk of local recurrence of 0.40 (95% CI, 0.30–0.54) for those receiving radiation. This observation was not affected by focality, lesion size, completeness of excision, or detection mode, although younger patients (younger than 50) had decreased benefit as compared to women older than 60 [30]. A collective review of these four RCT by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) included 3,729 women treated with BCS alone or with RT. The addition of RT reduced the 10‐ year risk of ipsilateral breast recurrence by 15.2%. RT was effective regardless of tumor factors but when stratified by tumor size, RT reduced the risk of ipsilateral recurrence by 15.8% for tumors 1–20 mm and by 26% for tumors measuring 20–50 mm in size [31].
Tamoxifen Lumpectomy for DCIS Followed by Radiation Therapy Randomized clinical trials have compared outcomes for patients treated with BCT with or without external beam radiation therapy. All of these trials have demonstrated a decrease in local recurrence for those patients treated with radiation therapy. Prospective nonrandomized studies have also confirmed that low rates of local recurrence may be achieved with proper patient selection [19,20]. Debate has focused on the ability to select patients and avoid the use of radiation therapy. Much of this debate has focused on the size of the DCIS, as well as margin distance, age, and grade as selection criteria [21,22]. NSABP B‐17 was a RCT of 818 women receiving BCS with or without RT. At 8 years, there was a statistically significant decrease in ipsilateral breast recurrence with both invasive (3.9% with RT, 13.4% without RT) and noninvasive disease (8.2% with RT, 13.4% without RT). This benefit was seen in all cohorts, regardless of patient or tumor characteristics, including size [23]. At fifteen‐year follow‐up, radiation reduced ipsilateral breast recurrence by 52%. The incidence of invasive local recurrence was 19.4% for BCS only and 8.9% for BCS with RT. Women younger than 45 showed a 2.1 time increased risk of recurrence compared to those over 65, with no statistically significant treatment effect difference [24,25]. EORTC 10853 was a RCT of 1010 women with DCIS less than 5 cm assigned to BCS with or without RT with a median follow‐up of 15.8 years. The inclusion of RT reduced the risk of local recurrence by 48% (hazard ratio (HR) of 0.52), however this did not affect breast cancer specific survival (HR 1.07) or overall survival (HR 1.02) [26]. All subsets of patients benefited from inclusion of radiation therapy. There was a trend towards statistical significance for increased risk of local recurrence for patients with tumors greater than 20 mm as compared to those less than or equal to 10 mm (2.37 [1.02–5.47]; P ¼ 0.12). The United Kingdom, Australia, and New Zealand (UK/ANZ) trial was a randomized controlled trial of 1,701 women receiving BCS alone, BCS with RT, BCS with tamoxifen, or BCS with RT and tamoxifen. RT reduced the incidence of ipsilateral invasive breast cancer (0.45 [0.24– 0.85]; P ¼ 0.01) and ipsilateral DCIS (0.36 [0.19–0.66]; P ¼0.0004) with no effect on contralateral disease [27]. With a median follow‐up of 12.7 years, RT continued to have a reduced incidence of all new breast cancers (0.41 [0.30–0.56]; P < 0.0001) with no effect on contralateral breast cancer [28]. In a subsequent analysis of 1,224 (72.3%) patients, complete data on DCIS size, histological grade/sub‐type, presence and degree of comedo‐type necrosis, presence and degree of inflammation, and excision status were analyzed to predict local recurrence. Amongst other predictive variables, size was associated with risk of local recurrence. Patients with tumors greater than 20 mm had an increased risk of local recurrence as compared to those patients with tumors less than 10 mm (1.55 [1.08–2.22]; P < 0.0001) [29]. Journal of Surgical Oncology
Tamoxifen has been shown to reduce the risk of local recurrence as well as distant in invasive cancer as well as reduce the incidence of new primary tumors [32]. Its use has also been studied in the setting of ductal carcinoma in situ. NSABP B‐24 was a double blind RCT consisting of 902 women randomized to BCS þ RT þ tamoxifen versus BCS þ RT þ placebo. At 5 years, women in the tamoxifen group had fewer breast cancer events than those in the control group (8.2% vs. 13.4%, respectively) [33]. At 15 years, tamoxifen decreased the rate of all breast cancer events, with a cumulative incidence of invasive ipsilateral recurrence 8.5% in the tamoxifen group versus 10.0% in the placebo group. The rate of contralateral breast cancers was 7.3% for the tamoxifen group in comparison to 10.8% for the placebo (comparable to contralateral cancer risk with RT alone in B‐17 trial) [25]. The UK/AMZ trial initially demonstrated that tamoxifen reduced ipsilateral DCIS recurrence (HR 0.68) with no effect on invasive recurrence [27]. At 12.7‐year follow‐up, tamoxifen continued to show no significant effect on ipsilateral invasive recurrence, however, it did reduce the overall incidence of new breast events (HR 0.71), with reduction of both ipsilateral DCIS (HR 0.7) and contralateral tumors (HR 0.44) [28].
Treatment Trends With the abundance of data demonstrating the safety of BCS, it is no surprise that between 1991 and 2005, decreasing mastectomy rates were observed for women diagnosed with DCIS [34]. However, since 2004 there has been an increasing mastectomy rate. A study of 21,869 women from the Kentucky Cancer Registry diagnosed between 1998 and 2007 demonstrated an overall decrease mastectomy rates from 53.1% in 1998 to 38.8% in 2005. However, from 2005 to 2007, higher mastectomy rates were noted in all age groups (75% increase in women 70). Multivariate analysis demonstrated that factors associated with mastectomy over BCS included early stage breast cancer, increasing grade, unusual histology, rural location, uninsured or government‐insured status, receptor negative disease, and age >70 [35]. A study of 5,865 patients at a single institution from 1994 to 2007 also demonstrated increased mastectomy rates from 2004 to 2007 (44%) in comparison to 1994 to 1998 (33%) and 1999 to 2003 (33%). Gender, age 2 mm (OR 0.46) [48]. Margin definitions varied widely among surveyed surgeons in a 2010 survey of 318 surgeons in two large metropolitan areas. Breast specialization (>50% of practice devoted to breast surgery) was found to be an independent predictor of margin preferences, with breast specialists favoring smaller margins in a scenario of invasive cancer treated with BCS and RT and larger margins in a scenario of DCIS treated with BCS without RT [67]. Numerous factors contribute to the success or failure of breast conserving surgery for DCIS, many of which have been reviewed above. Size, because of its impact on local recurrence risk, as well as dictating surgical options due to extent of resection, is a frequently considered factor in surgical decision making in the management of DCIS. Table I summarizes the effect of size in published reports. Even among studies that do find size a significant factor, there is a lack of consensus of size criteria. While review of the literature does not consistently reflect the significance of size, there is certainly a trend in the literature towards its significance, and there is clear clinical significance in surgical decisions and planning.
Guides for Therapy Size has been described as a surrogate marker for margin involvement. There have been many methods described to optimize negative margins including intraoperative pathology or ultrasound guidance. Intraoperative frozen section has reported accuracy rates between 84% and 98%, while touch prep and imprint cytology are comparable with accuracy rates between 85% and 94%. However, pathological methods are time and labor intensive and increase the duration of anesthesia. Intraoperative ultrasound has variable accuracy of margin assessment, with sensitivity ranging from 25% to 100% and
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TABLE I. Impact of Size on Local Recurrence Refs. Silverstein et al. [19] Wapnir et al. [25] Cuzick et al. [28] EBCTCG [31] Vicini et al. [39] Collins et al. [44] Bailes et al. [46] Melstrom et al. [49] Thomas et al. [50] Holmes et al. [51] Dillon et al. [52] Goldstein et al. [53] O’Sullivan et al. [54] MacDonald et al. [56] Kerlikowske et al. [57] Wai et al. [58] Hughes et al. [59] Ringberg et al. [60] Solin et al. [61] Bijker et al. [68]
# Patients
Type
Size a significant factor?
Size of significance
333 2,622 1,694 3,729 145 2,995 1,902 546 2,564 141 135 132 2,770 455 1,036 460 671 161 268 1,010
SIC RCT RCT RCT review SIC MIC SIC SIC MIC SIC SIC SIC SIC SIC MIC MIC MIC SIC MIC RCT
Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes (reverse effect) Yes Yes Yes No No No No
>1.5 cm Not specified Not specified Not specified >7 mm >15 low powered fields Not specified Not specified >1.5 cm Not specified >3 cm Not specified Not specified Not specified >1 cm >4 cm Not specified Not specified Not specified Not specified
SIC, single institution cohort; MIC, multi‐institution cohort; RCT, randomized control trial.
specificity ranging from 74% to 95%. However, ultrasound has a more limited role for DCIS due to the lack of an ultrasound correlate for most presentations [68]. There are two tools described in the literature to help in treatment decisions for DCIS. The first is the University of Southern California Van Nuys Index. The index is based on a multi‐institution analysis of 949 patients with DCIS who underwent BCS alone or BCS with RT. The index gives a score of 1–3 (best to worst) for each of 5 measurable prognostic factors. The index initiated with just two factors in 1995– grade and necrosis, with size and margins added in 1996 and age added in 2002 [19,69,70]. A recently described DCIS nomogram attempts to predict 5‐ and 10‐year ipsilateral breast tumor recurrence rates based upon a single‐institution cohort of 1,681 women with DCIS treated with BCS. The nomogram integrates 10 clinical and pathological variables: age at diagnosis, family history, initial presentation, adjuvant RT, adjuvant endocrine therapy, nuclear grade, presence of necrosis, margin size, number of re‐excisions, and the time period of surgery. The study shows good internal validation and is a potentially very useful tool in predicting risk in individual patients to help guide surgical planning [71]. In conclusion, tumor size is an important factor for patient selection for breast conservation therapy as it been determined to be a predictor of positive margins, re‐excision, and local recurrence in randomized clinical trials and retrospective studies.
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