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Ductal Carcinoma in Situ: A French National Survey. Analysis of 2125 Patients

Open AccessPublished:August 22, 2019DOI:https://doi.org/10.1016/j.clbc.2019.08.002

      Abstract

      Background

      Ductal carcinoma in situ (DCIS) represents 15% of all breast cancers in France. The first national survey was conducted in 2003. The present multi-center real-life practice survey aimed at assessing possible changes in demographic, clinical, pathologic, and treatment features.

      Material and Methods

      From March 2014 to September 2015, patients diagnosed with DCIS from 71 centers with complete information about age, diagnostic features, and treatment modalities were prospectively included.

      Results

      A total of 2125 patients with a median age of 58.6 years from 71 centers were studied. DCIS was diagnosed by mammography in 87.5% of cases. Preoperative biopsy was performed in 96% of cases. The median tumor size was 15 mm. Nuclear grade was low, intermediate, and high in 12%, 36%, and 47% of cases, respectively. Margins were considered to be negative in 83% of cases. Overall mastectomy and lumpectomy rates were 25% and 75%, respectively. The immediate breast reconstruction rate was 50%. Sentinel node biopsy and axillary dissection rates were 41% and 2.6%, respectively. After lumpectomy, 97% of patients underwent radiotherapy, and 32% received a boost dose. Only 1% of patients received endocrine therapy. Compared with our previous survey, the median tumor size remained the same, and the proportion of high-grade lesions increased by 9%. The mastectomy rate decreased by 4%.

      Conclusions

      The clinical practice identified in this survey complies with French DCIS guidelines. About 10% of patients with low-grade DCIS may be eligible to participate in treatment de-escalation trials.

      Keywords

      Introduction

      Pure ductal carcinoma in situ (DCIS) now represents about 15% of all breast cancers (BCs) in Western countries,
      • Bleicher R.J.
      Ductal carcinoma in situ.
      • Ward E.M.
      • DeSantis C.E.
      • Lin C.C.
      • et al.
      Cancer statistics: breast cancer in situ.
      but with different types of lesions characterized by their morphology and prognostic features.
      • Allred D.C.
      Ductal carcinoma in situ: terminology, classification, and natural history.
      Prognosis is favorable in most cases, but invasive local recurrences (LRs) can lead to metastasis in 10% to 15% of cases.
      • Fu F.
      • Gilmore R.C.
      • Jacobs L.K.
      Ductal carcinoma in situ.
      • Wapnir I.L.
      • Dignam J.J.
      • Fisher B.
      • et al.
      Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized trials for DCIS.
      • Donker M.1
      • Litière S.
      • Werutsky G.
      • et al.
      Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ: 15-year recurrence rates and outcomes after a recurrence rates and outcome after a recurrence, from EORTC 10583 randomized phase III trial.
      • Cutuli B.
      • Lemanski C.
      • Le Blanc-Onfroy M.
      • et al.
      Local recurrence after ductal carcinoma in situ breast conserving treatment. Analysis of 195 cases.
      The treatment modalities for DCIS have been widely debated for many years, with several major questions concerning the role of mastectomy, sentinel node biopsy (SNB), whole breast radiotherapy (RT) with or without boost after breast-conserving surgery (BCS), and the real impact of tamoxifen.
      • Cutuli B.
      • Lemanski C.
      • Fourquet A.
      • et al.
      Breast conserving surgery with or without radiotherapy versus mastectomy for ductal carcinoma in situ. French survey experience.
      • Rakovitch E.
      • Nofech-Mozes S.
      • Narod S.A.
      • et al.
      Can we select individuals with low risk ductal carcinoma in situ (DCIS)? A population-based outcomes analysis.
      • Thompson A.M.
      • Clements K.
      • Cheung S.
      • et al.
      Sloane Project Steering Group (NHS Prospective Study of Screen-Detected Non-invasive Neoplasias)
      Management and 5-year outcomes in 9938 women with screen-detected ductal carcinoma in situ: the UK Sloane Project.
      In order to analyze real-life clinical practice, a first national prospective survey was performed in France from March 2003 to April 2004 to assess the epidemiologic data, diagnosis, and treatment modalities in 1289 patients with pure DCIS.
      • Cutuli B.
      • Lemanski C.
      • Fourquet A.
      • et al.
      Breast conserving surgery with or without radiotherapy versus mastectomy for ductal carcinoma in situ. French survey experience.
      In late 2004, the national screening program was applied throughout France, and the French DCIS guidelines were published in October 2009 (www.e-cancer).
      With the support of the French Society of Senology (SFSPM) and the National Cancer Institute (INCa), we conducted a new national prospective survey to assess any changes in the demographic, radiologic, and clinicopathologic features and treatment options in patients with DCIS treated from March 2014 to September 2015 compared with the previous survey. This study was also designed to analyze compliance with French DCIS guidelines and to compare our results with those reported in other countries. Treatment results will be evaluated at 3, 5, and 10 years.

      Materials and Methods

       Patient Inclusion

      This prospective observational study was conducted from March 2014 to September 2015 in a total of 71 centers comprising comprehensive cancer centres and private clinics, as well as general and/or university hospitals.
      Eligibility criteria were female patients with a diagnosis of pure DCIS. Women with microinvasive lesions, previous or synchronous contralateral invasive BC, or other cancers were excluded.
      We collected demographic characteristics (age, family history of breast cancer, menopausal status, hormone replacement therapy), clinical or mammographic findings, biopsy procedures, specimen pathology characteristics (tumor subtype, size, grade, excision quality, and hormone receptor status), and treatments: type of surgery for breast ± axilla, number of surgical procedures, and adjuvant RT with or without boost to the tumor bed, as well as tamoxifen use. The study was approved by the French data protection authority (CNIL).

       Statistical Methods

      All summaries and statistical analyses were generated using SAS software (version 9.4, SAS Institute Inc, Cary, NC).
      The following statistical tests were used to compare 2 groups: the Student t test or nonparametric Mann-Whitney test, when the assumption of normality was not met, for continuous data, and the χ2 test or Fisher exact test for categorical data. When more than 2 groups were compared, we used the χ2 test for categorical variables and the Kruskal-Wallis test for continuous variables.
      All statistical analyses were performed at a limit of significance of 5% using 2-sided tests, except for normality, which was tested at a limit of 1% (Shapiro-Wilk test).

      Results

       Study Population

      A total of 2125 patients (corresponding to 2141 treated breasts) in 71 centers (4 centers included more than 100 patients, another 4 centers included 50-100 patients, 19 centers included 30-50 patients, and 48 centers included less than 30 patients) were prospectively included. Forty-eight percent of patients were treated in comprehensive cancer centers, 33% were treated in private clinics, 11.5% were treated in university hospitals, and 7.5% were treated in general hospitals.

       Demographic Data

      The median age was 58.6 years (range, 30-93 years); 3% of the women were younger than 40, 20% were between 41 and 50 years, 64% were between 51 and 70 years, and 13% were over 70 years. A family history of BC (first- and/or second-degree relative) was identified in 37.5% of all patients. Young age was significantly correlated with a family history of BC, as follows: 48% in patients younger than 40 and 45% in women aged 41-50 (P < .0004).
      A total of 1424 (69%) patients were postmenopausal. The median age of menopause was 50 years.
      Twenty-eight percent of the study population had received hormone replacement therapy for a median of 8 years.

       Mode of Detection

      DCIS was diagnosed by mammographic abnormality in 87.5% of cases, whereas 12.5% of the patients presented with clinical symptoms, such as a mass, Paget's disease, serosanguinous nipple discharge, or nipple retraction. Forty-six percent of women under the age of 40 presented clinical symptoms, whereas symptoms were present in 18% of patients between the ages of 40 and 50 years and 18% of patients over the age of 70, and only 8% of women diagnosed between the ages of 50 to 70 years presented clinical symptoms. This difference was statistically significant (P < .0001).

       Mammographic Features and Preoperative Biopsy

      Mammograms were available for 2078 (97%) of the 2141 breasts; 87% showed the presence of microcalcifications, together with round opacity in 7% of cases, increased density in 5% of cases, and other images and/or combinations in 7% of cases.
      A total of 1877 mammograms were evaluated according to the Breast Imaging Reporting and Data System from American College of Radiology (BI-RADS) classification
      • Bent C.K.
      • Bassett L.W.
      • D'Orsi C.J.
      • Sayre J.W.
      The positive predictive value of BI-RADS microcalcification descriptors and final assessment categories.
      and were classified as follows: 58 (3.2%) BI-RADS 2, 115 (6%) BI-RADS 3, 1372 (73%) BI-RADS 4, and 327 (17.5%) BI-RADS 5. Multicentricity or multifocality was identified in 14.3% of 1929 evaluable cases, mostly in young patients: 23.8% in patients younger than 40 and 18.3% in patients aged 41 to 50 (P = .0056). Preoperative needle biopsy was performed in 96% of patients. Vacuum-assisted needle biopsy (8-11 gauge) was performed in 79% of cases, and stereotactic core-needle biopsy (14-16 gauge) was performed in 21% of cases.

       Surgery

       Breast Surgery

      All patients underwent surgery. Among 71 centers, twenty did not include the patients treated by mastectomy (n = 350, all treated by lumpectomy or quadrantectomy). Among the remaining 1781 patients treated for DCIS, primary surgery consisted of lumpectomy or quadrantectomy in 1530 (85.8%) cases, whereas in 165 (9.4%) and 86 (4.8%) cases, simple or subcutaneous mastectomy was performed, respectively.
      Owing to incomplete resection or close resection margins and/or multifocal or large lesions, second surgery was performed in 414 (22.6%) of 1781 cases, consisting of second conservative surgery in 278 (68%) cases, simple mastectomy in 101 (24%) cases, and subcutaneous mastectomy in 35 (8%) cases. A third operation was performed in 59 of 414 cases: 38 were simple mastectomy, 18 were subcutaneous mastectomy, and only 3 cases were lumpectomy.
      The final overall mastectomy rate was 21.7% after the second operation and 24.8% after the third operation.
      Residual disease was present at the second operation in 47% of cases. Predictive factors for residual disease were nuclear grade (NG) and tumor size. Low, intermediate, and high NG rates were 33%, 44%, and 53%, respectively (P = .014), and 32% of lesions were smaller than 20 mm versus 57% of lesions that were larger than 20 mm (P = .0001).
      Immediate breast reconstruction was performed in 50% of cases: 44% after simple mastectomy and 86% after subcutaneous mastectomy (P < .0001). Various types of implants were used in 52% of cases, followed by musculoglandular flaps in 30% of cases, a combination of the 2 in 8% of cases, and other techniques in 10% of cases.

       Axillary Surgery

      Sentinel node biopsy (SNB) was performed in 863 (41%) cases, mostly after mastectomy. The SNB rate was significantly influenced by the type of surgery, the mode of detection, and, more particularly, grade and size (Table 1). Axillary dissection (AD) was performed in only 54 (2.6%) patients; 5.2% of cases of mastectomy and 2.2% of cases of conservative surgery (P = .01).
      Table 1Factors Influencing SNB Use
      nSNB %P
      Type of surgery (n = 2103)
       Mastectomy30275
       Subcutaneous mastectomy13887<.0001
       Conservative surgery166331
      Discovery modalities (n = 2073)
       Clinical26251.0003
       Radiologic181139
      Grade (n = 1950)
       Low24818
       Intermediate73229<.0001
       High97057
      Tumor size, mm (n = 1728)
       ≤532023
       6-1033329
       11-2046741<.0001
       21-4038051
       >4022868
      Abbreviation: SNB = sentinal node biopsy.

       Histopathology

      The median tumor size of the 1732 evaluable lesions was 15 mm; 66% of tumors were smaller than 20 mm (Table 2). NG was low in 12%, intermediate in 36%, and high in 47% of cases (5% of cases were not evaluable). Low NG was more frequently observed in small lesions and high NGs more frequently observed in larger tumors, especially those larger than 40 mm (P < .0001). After BCS, excision was considered to be complete (with margins ≥ 2 mm) in 83% of cases. The detailed tumor-free margin status is shown in Table 2.
      Table 2Histopathologic Features
      Featuren%
      Tumor size, mm (n = 1733)
       ≤531019
       6-1034020
       11-2046827
       21-4038021
       >4022513
      Nuclear grade (n = 2094)
       Low24912
       Intermediate74636
       High98747
       Not specified1125
      Final margins, mm (n = 1536
      Breast-conserving surgery.
      )
       ≤126017
       2-333021
       4-522415
       6-915710
       ≥1032421
       Not specified24116
      Hormone receptors (n = 343
      Assessed in only 19% of the cases.
      )
       Positive ER34378
       Positive PgR33464
      Abbreviations: ER = estrogen receptor; PgR = progesterone receptor.
      a Breast-conserving surgery.
      b Assessed in only 19% of the cases.

       RT

      Of the 1658 women treated by BCS, 1608 (97.2%) received whole breast irradiation with a median dose of 50 Gy. A 10 to 16 Gy boost was delivered to 32% of patients. Two factors influenced the use of boost radiation: NG (24%, 31%, and 36.5% for low, intermediate, and high grade, respectively; P = .019) and margin status (37.5% ≤ 1 mm, 33% 2-9 mm, and 25% ≥ 10 mm, respectively; P = .021). Age and tumor size were not significantly associated with boost radiation. Of the 415 patients who underwent mastectomy, 29 (7%) received RT owing to very extensive disease, deep margins ≤ 1 mm, and/or wide multicentricity.

       Hormone Therapy

      Only 20 (1%) of the 1896 evaluable patients received hormone therapy, mostly tamoxifen.

      Discussion

      This second national survey provides comprehensive and unselected data on DCIS characteristics and treatment modalities in France. We also compared the results of this survey with those of the first survey
      • Cutuli B.
      • Lemanski C.
      • Fourquet A.
      • et al.
      Breast conserving surgery with or without radiotherapy versus mastectomy for ductal carcinoma in situ. French survey experience.
      (Table 3) after widespread implementation of the national screening program (late 2004) and publication of the first national DCIS guidelines in October 2009 (www.e-cancer.fr/). These new data were also compared with data from other large studies performed in several countries, especially The Netherlands, the United Kingdom (UK), Canada, and the United States (US).
      • Ward E.M.
      • DeSantis C.E.
      • Lin C.C.
      • et al.
      Cancer statistics: breast cancer in situ.
      • Rakovitch E.
      • Nofech-Mozes S.
      • Narod S.A.
      • et al.
      Can we select individuals with low risk ductal carcinoma in situ (DCIS)? A population-based outcomes analysis.
      • Thompson A.M.
      • Clements K.
      • Cheung S.
      • et al.
      Sloane Project Steering Group (NHS Prospective Study of Screen-Detected Non-invasive Neoplasias)
      Management and 5-year outcomes in 9938 women with screen-detected ductal carcinoma in situ: the UK Sloane Project.
      • Elshof L.E.
      • Schmidt M.K.
      • Rutgers E.J.T.
      • van Leeuwen F.E.
      • Wesseling J.
      • Schaapveld M.
      Cause-specific mortality in a population-based cohort of 9799 women treated for ductal carcinoma in situ.
      • Punglia R.S.
      • Jiang W.
      • Lipsitz S.R.
      • et al.
      Clinical risk score to predict likelihood of recurrence after ductal carcinoma in situ treated with breast-conserving surgery.
      • Hassett M.J.
      • Jiang W.
      • Hughes M.E.
      • et al.
      Treating second breast events after breast conserving surgery for ductal carcinoma in situ.
      • Rakovitch E.
      • Nofech-Mozes S.
      • Hanna W.
      • et al.
      Omitting radiation therapy after lumpectomy for pure DCIS does not reduce the risk of salvage mastectomy.
      • van Maaren M.C.
      • Lagendijk M.
      • Tilanus-Linthorst M.M.A.
      • et al.
      Breast cancer-related deaths according to grade in ductal carcinoma in situ: a Dutch population-based study on patients diagnosed between 1999 and 2012.
      Table 3Comparison Between 2 French Surveys: Clinicopathologic Features and Treatment Modalities
      2003-2004, %2014-2015, %P
      Patients, n12892125
      Centers, n7771
      Median age, y (range)56 (30-84)58.6 (30-93)<.0001
      Family history of BC3037.5<.001
      Menopause63.569.0013
      HRT5228<.0001
      Diagnosis
       Mammography8888NS
       Clinical1212NS
      Biopsy (total)6296<.0001
       14-16 G3421<.0001
       8-11 G6679<.0001
      Median tumor size, mm14.515NS
      Grade
       Low2113<.0001
       Intermediate3938NS
       High4050<.0001
      Margins (<1 mm)1220<.0001
      Mastectomy30.525.2<.0001
      BCS7.72.8<.0001
      BCS + RT61.872<.0001
      Immediate reconstruction5549.26
      SNB2141<.0001
      Axillary dissection10.42.6<.0001
      Tamoxifen13.41<.0001
      Abbreviations: BC = breast cancer; BCS = breast-conserving surgery; HRT = hormone replacement therapy; NS = not significant; RT = radiotherapy; SNB = sentinel node biopsy.
      The overall rate of mammographically detected DCIS in both surveys was identical: 87.5%, in accordance with other series.
      • Yamada T.
      • Mori N.
      • Watanabe M.
      • et al.
      Radiologic-pathologic correlation of ductal carcinoma in situ.
      Microcalcifications remain the major abnormality (87% vs. 82.5% previously). The rate of BI-RADS III/IV classification was also very similar (88.5% vs. 90.8%). On the other hand, we observed a slight increase in the percentage of women presenting with “clinical symptoms” in women under the age of 40 (46% vs. 39% previously).
      The rate of biopsy-proven diagnosis increased dramatically from 61.8% to 96% (P < .0001), with a large predominance of vacuum-assisted needle biopsies (8-11 gauge) increasing from 66.4% to 79% of cases (P < .0001).
      Final tumor size was assessed in 81.5% of cases (82.4% in the initial survey). Median size was not significantly different between the 2 surveys (15 mm vs. 14.5 mm previously); lesions smaller than 10 mm were observed in 29% of our cases. In the UK study, 34.5% of the 7007 patients treated by BCS presented lesions < 10 mm.
      • Thompson A.M.
      • Clements K.
      • Cheung S.
      • et al.
      Sloane Project Steering Group (NHS Prospective Study of Screen-Detected Non-invasive Neoplasias)
      Management and 5-year outcomes in 9938 women with screen-detected ductal carcinoma in situ: the UK Sloane Project.
      The low NG DCIS rate decreased significantly (13% vs. 21%; P < .0001), whereas the “high grade” rate increased (50% vs. 41%; P < .0001). Almost identical results were reported in a recent large-scale Dutch study including 4901 cases of DCIS, showing 13%, 39%, and 48% of low, intermediate, and high NG, respectively.
      • van Dooijeweert C.
      • van Diest P.J.
      • Willems S.M.
      • Kuijpers C.C.H.J.
      • Overbeek L.I.H.
      • Deckers I.A.G.
      Significant inter- and intra-laboratory variation in grading of ductal carcinoma in situ of the breast: a nationwide study of 4901 patients in the Netherlands.
      Table 4 shows the NG distribution in other large-scale national studies. The rate of low-grade tumors varied from 8% to 13% and the rate of high-grade tumors varied from 34% to 57%. Several studies have reported discrepancies in grading accuracy between pathologists, partly owing to the frequency of “mixed forms.”
      • Allred D.C.
      Ductal carcinoma in situ: terminology, classification, and natural history.
      • van Dooijeweert C.
      • van Diest P.J.
      • Willems S.M.
      • Kuijpers C.C.H.J.
      • Overbeek L.I.H.
      • Deckers I.A.G.
      Significant inter- and intra-laboratory variation in grading of ductal carcinoma in situ of the breast: a nationwide study of 4901 patients in the Netherlands.
      Table 4Distribution of Nuclear Grade in 5 National Studies
      Grade, %PRACCIS II (Present Study)UK Sloane Project
      • Thompson A.M.
      • Clements K.
      • Cheung S.
      • et al.
      Sloane Project Steering Group (NHS Prospective Study of Screen-Detected Non-invasive Neoplasias)
      Management and 5-year outcomes in 9938 women with screen-detected ductal carcinoma in situ: the UK Sloane Project.
      NL Cancer Registry
      • van Maaren M.C.
      • Lagendijk M.
      • Tilanus-Linthorst M.M.A.
      • et al.
      Breast cancer-related deaths according to grade in ductal carcinoma in situ: a Dutch population-based study on patients diagnosed between 1999 and 2012.
      NL Palga Study
      • van Dooijeweert C.
      • van Diest P.J.
      • Willems S.M.
      • Kuijpers C.C.H.J.
      • Overbeek L.I.H.
      • Deckers I.A.G.
      Significant inter- and intra-laboratory variation in grading of ductal carcinoma in situ of the breast: a nationwide study of 4901 patients in the Netherlands.
      Ontario
      • Rakovitch E.
      • Nofech-Mozes S.
      • Hanna W.
      • et al.
      Omitting radiation therapy after lumpectomy for pure DCIS does not reduce the risk of salvage mastectomy.
      Low121112138
      Intermediate3632303946
      High4757504834
      Unknown5812
      Abbreviations: NL = Netherlands; UK = United Kingdom.
      Surprisingly, the rate of “suboptimal excision” with margins < 1 mm increased from 12% to 20% (P = .0001). International guidelines
      • Morrow M.
      • Van Zee K.J.
      • Solin L.J.
      • et al.
      Society of surgical oncology-American society for radiation oncology-American society of clinical oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ.
      define free margins as margins equal to or greater than 2 mm. Less detailed results are reported in the literature for “close” resection margins and focally involved margins. In these cases, most patients received a 16 to 20 Gy boost dose to tumor bed with good local control, as previously reported.
      • Monteau A.
      • Sigal-Zafrani B.
      • Kirova Y.M.
      • et al.
      Ductal carcinoma in situ of the breast with close or focally involved margins following breast-conserving surgery: treatment with reexcision or radiotherapy with increased dosage.
      This practice complies with the American consensus of specific “clinical judgement” in patients with negative margins less than 2 mm.
      • Morrow M.
      • Van Zee K.J.
      • Solin L.J.
      • et al.
      Society of surgical oncology-American society for radiation oncology-American society of clinical oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ.
      We observed several changes in the treatment strategy between this survey and the previous survey, reflecting the widespread implementation of the national DCIS guidelines (Table 3).
      The mastectomy rate decreased significantly from 30.5% to 25% (P < .0001). In a very large UK study (Sloane Project) including 9938 women treated from 2003 to 2012, the mastectomy rate was 29.5%.
      • Thompson A.M.
      • Clements K.
      • Cheung S.
      • et al.
      Sloane Project Steering Group (NHS Prospective Study of Screen-Detected Non-invasive Neoplasias)
      Management and 5-year outcomes in 9938 women with screen-detected ductal carcinoma in situ: the UK Sloane Project.
      In another study from the US (2007-2011)
      • Ward E.M.
      • DeSantis C.E.
      • Lin C.C.
      • et al.
      Cancer statistics: breast cancer in situ.
      and in an older one from Ontario (1994-2003),
      • Rakovitch E.
      • Nofech-Mozes S.
      • Hanna W.
      • et al.
      Omitting radiation therapy after lumpectomy for pure DCIS does not reduce the risk of salvage mastectomy.
      mastectomy rates were 27% and 35%, respectively. In the series of 12,256 patients collected by the Netherlands Cancer Registry from 1999 to 2012, 44.3% underwent mastectomy (33.5%, 39.3%, and 49.5% for grades I, II, and III, respectively).
      • van Maaren M.C.
      • Lagendijk M.
      • Tilanus-Linthorst M.M.A.
      • et al.
      Breast cancer-related deaths according to grade in ductal carcinoma in situ: a Dutch population-based study on patients diagnosed between 1999 and 2012.
      In our study, the mastectomy rate was 50% in women under the age of 40. Young age is associated with a high risk of LR related to well-known risk factors, such as extensive disease (> 4 cm), multicentric and high-grade lesions, and close or positive margins after BCS.
      • Vicini F.A.
      • Shaitelman S.
      • Wilkinson J.B.
      • et al.
      Long-term impact of young age at diagnosis on treatment outcome and patterns of failure in patients with ductal carcinoma in situ treated with breast conserving therapy.
      • VandenBussche C.J.
      • Elwood H.
      • Cimino-Mathews A.
      • Bittar Z.
      • Illei P.B.
      • Warzecha H.N.
      Clinicopathological features of ductal carcinoma in situ in young women with an emphasis on molecular subtype.
      In this study, AD was almost abandoned (2.6% vs. 10.4% in our previous study; P < .0001), whereas the SNB rate doubled (41% vs. 21%; P < .0001). Although the SNB rate of approximately 80% among patients treated by mastectomy complies with national and international guidelines, the 31% SNB rate in patients treated by BCS appears to be much higher than expected. In a retrospective Swedish study including 753 patients treated by mastectomy (40%) or BCS (60%) with SNB for pure DCIS in 2008 to 2009, only 5 (0.7%) positive SN were found (3 micrometastases and 2 macrometastases).
      • Zetterlund L.
      • Stemme S.
      • Arnrup H.
      • de Boniface J.
      Incidence and risk factors for sentinel node metastasis in patients with a postoperative diagnosis of ductal carcinoma in situ.
      In a large Danish population-based study in 2618 patients with DCIS, SNB was performed in 54% of cases (44% and 86% in the BCS and mastectomy groups, respectively) and, in 24% of cases, SNB did not comply with guidelines.
      • Holm-Rasmussen E.V.
      • Jensen M.B.
      • Balslev E.
      • Kroman N.
      • Tvedskov T.F.
      The use of sentinel lymph node biopsy in the treatment of breast ductal carcinoma in situ: a Danish population-based study.
      In another international survey (ICSN [International Cancer Screening Network]) studying 3831 screened patients between the ages of 50 and 69 years between 2003 and 2008 (30% of mastectomies), the overall AD and SNB rates were 8.4% and 35%, but with marked differences between countries.
      • Ponti A.
      • Lynge E.
      • James T.
      • et al.
      ICSN DCIS Working Group
      International variation in management of screen-detected ductal carcinoma in situ of the breast.
      In the US study based on the National Cancer Database including 88,083 patients diagnosed with DCIS between 1998 and 2011, 37% underwent mastectomy and 63% underwent BCS. The overall AD rate in the mastectomy group decreased from 50% in 1998 to 16% in 2011, whereas the SNB rate increased from 24% to 77%. In the BCS group, the AD rate decreased from 13% to 5% and the SNB rate increased from 7% to 39%.
      • Mitchell K.B.
      • Lin H.
      • Shen Y.
      • et al.
      DCIS and axillary nodal evaluation: compliance with national guidelines.
      A recently published literature review and meta-analysis based on 48 articles with a total of 9803 patients concluded that SNB should be routinely considered only in patients with large (> 2 cm) and high-grade DCIS.
      • El Hage Chehade H.
      • Headon H.
      • Wazir U.
      • Abtar H.
      • Kasem A.
      • Mokbel K.
      Is sentinel lymph node biopsy indicated in patients with a diagnosis of ductal carcinoma in situ? A systematic literature review and meta-analysis.
      The use of RT after BCS increased from 89% to 96% (P < .0001), reflecting good compliance with national guidelines (published in 2004) based on the updated results of 4 randomized trials as well as other large retrospective studies, all of which showed a 50% to 60% reduction of LRs (both invasive and in situ recurrences) related to the use of RT after BCS. Table 5 shows the results of randomized trials and several large retrospective studies confirming the place of RT in reduction of LR rates after BCS.
      • Wapnir I.L.
      • Dignam J.J.
      • Fisher B.
      • et al.
      Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized trials for DCIS.
      • Donker M.1
      • Litière S.
      • Werutsky G.
      • et al.
      Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ: 15-year recurrence rates and outcomes after a recurrence rates and outcome after a recurrence, from EORTC 10583 randomized phase III trial.
      • Rakovitch E.
      • Nofech-Mozes S.
      • Hanna W.
      • et al.
      Omitting radiation therapy after lumpectomy for pure DCIS does not reduce the risk of salvage mastectomy.
      • Wärnberg F.
      • Garmo H.
      • Emdin S.
      • et al.
      Effect radiotherapy after breast-conserving surgery for ductal carcinoma in situ: 20-years follow-up in the randomized SWEDCIS trial.
      • Cuzick J.
      • Sestak I.
      • Pinder S.E.
      • et al.
      Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial.
      • Corradini S.
      • Pazos M.
      • Schönecker S.
      • et al.
      Role of postoperative radiotherapy in reducing ipsilateral recurrence in DCIS: an observational study of 1048 cases.
      Table 5Impact of Whole Breast RT on Local Control After Breast-conserving Surgery
      NLR, %Absolute Benefit, %Follow-up, mo
      No RTRT
      NSABP B-17
      • Wapnir I.L.
      • Dignam J.J.
      • Fisher B.
      • et al.
      Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized trials for DCIS.
      Randomized trials.
      818352015204
      EORTC 10583
      • Donker M.1
      • Litière S.
      • Werutsky G.
      • et al.
      Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ: 15-year recurrence rates and outcomes after a recurrence rates and outcome after a recurrence, from EORTC 10583 randomized phase III trial.
      Randomized trials.
      1010301713190
      SWE-DCIS
      • Wärnberg F.
      • Garmo H.
      • Emdin S.
      • et al.
      Effect radiotherapy after breast-conserving surgery for ductal carcinoma in situ: 20-years follow-up in the randomized SWEDCIS trial.
      Randomized trials.
      1046321814202
      UK-ANZ DCIS
      • Cuzick J.
      • Sestak I.
      • Pinder S.E.
      • et al.
      Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial.
      Randomized trials.
      103019.5712.5120
      Ontario
      • Rakovitch E.
      • Nofech-Mozes S.
      • Hanna W.
      • et al.
      Omitting radiation therapy after lumpectomy for pure DCIS does not reduce the risk of salvage mastectomy.
      Retrospective studies.
      330320.815.55.3132
      Munich
      • Corradini S.
      • Pazos M.
      • Schönecker S.
      • et al.
      Role of postoperative radiotherapy in reducing ipsilateral recurrence in DCIS: an observational study of 1048 cases.
      Retrospective studies.
      10482013.56.588
      Abbreviations: LR = local recurrence; RT = radiotherapy.
      a Randomized trials.
      b Retrospective studies.
      The meta-analysis showed that approximately 50% of LRs were invasive.
      • Correa C.
      • McGale P.
      • Taylor C.
      • et al.
      Early Breast Cancer Trialists' Collaborative Group (EBCTCG)
      Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast.
      The benefit of RT increases with time, as the overall absolute LR reduction was 10.5% at 5 years and 15.2% at 10 years (from 28.1% to 12.9%; log rank P < .0001). Despite these results, the use of RT after BCS varies considerably between countries. For instance, a study in Japan showed only 41% of RT use after BCS, whereas other series in the UK,
      • Thompson A.M.
      • Clements K.
      • Cheung S.
      • et al.
      Sloane Project Steering Group (NHS Prospective Study of Screen-Detected Non-invasive Neoplasias)
      Management and 5-year outcomes in 9938 women with screen-detected ductal carcinoma in situ: the UK Sloane Project.
      Queensland,
      • Barbour S.
      • Moore J.
      • Dunn N.
      • et al.
      Patterns of care for ductal carcinoma in situ of the breast: Queensland's experience over a decade.
      and Munich
      • Corradini S.
      • Pazos M.
      • Schönecker S.
      • et al.
      Role of postoperative radiotherapy in reducing ipsilateral recurrence in DCIS: an observational study of 1048 cases.
      showed 62%, 62%, and 66% rates, respectively, with similar rates in the ICSN multicenter study.
      • Ponti A.
      • Lynge E.
      • James T.
      • et al.
      ICSN DCIS Working Group
      International variation in management of screen-detected ductal carcinoma in situ of the breast.
      A study conducted in the Navarra region of Spain reported a 100% RT rate.
      In 2 studies including “very low risk” DCIS, omission of RT led to a marked increase in local recurrence rates: in the ECOG (Eastern Cooperative Oncologic Group)-ACRIN (American College of Radiology Imaging Network) E5194 Study, with a 12-year follow-up, LR rates were 14.4% in cohort 1 (DCIS NG 1-2 < 2.5 cm) and 24.6% in cohort 2 (DCIS NG 3 < 1 cm). It should be noted that the median size of DCIS included in these 2 cohorts was only 6 mm, with very wide free margins in 80% of cases.
      • Solin L.J.
      • Gray R.
      • Hughes L.L.
      • et al.
      Surgical excision without radiation for ductal carcinoma in situ of the breast: 12-year results from the ECOG-ACRIN E5194 study.
      Similar results were observed in the RTOG (Radiation Therapy Oncology Group) 9804 trial, including low or intermediate DCIS (< 2.5 cm) with ≥ 3-mm free margins. With a 12-year follow-up, LR rates were 2.8% with RT and 11.4% without RT (P = .0001).
      • McCormick B.
      • Winter K.
      • Hudis C.
      • et al.
      RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation.
      In the present study, 32% of patients treated by BCS and whole breast RT received tumor bed boost. In the literature, boost rates are extremely heterogeneous (ranging from 25% to 71%), and boost radiation is mainly used in “high-risk” cases, including high-grade and extensive DCIS, close or focally positive margins, and young age. In a French-Italian study on 819 patients, boost radiation was used in 48% of cases (55% in France and 45% in Italy; P = .017).
      • Cutuli B.
      • Wiezzane N.
      • Palumbo I.
      • et al.
      Breast conserving treatment for ductal carcinoma in situ: impact of boost and tamoxifen on local recurrences.
      In another multicenter study in The Netherlands, boost radiation was used in 59% of 1248 patients, especially in the case of grade III tumors and/or positive or close (≤ 1 mm) margins.
      • Jobsen J.J.
      • Scheijmans L.J.E.E.
      • Smit W.G.J.M.
      • Stenfert Kroese M.C.
      • Struikmans H.
      • van der Palen J.
      Breast-conserving therapy for primary ductal carcinoma in situ in the Netherlands: a multicenter study and population-based analysis.
      The role of boost radiation was reported in a large international retrospective study including 4131 patients: boost radiation (performed in 62% of patients) reduced the 15-year LR rate from 12% to 8.4% (P = .04).
      • Moran M.S.
      • Zhao Y.
      • Ma S.
      • et al.
      Association of radiotherapy boost for ductal carcinoma in situ with local control after whole-breast radiotherapy.
      A subgroup of patients in which boost radiation is clearly beneficial should be identified in 2 randomized trials that are now closed for accrual.
      Besides, in our group of 361 patients (26%) treated by mastectomy, 29 (8%) underwent chest wall irradiation. As in other studies, very extensive disease, with or without multicentricity and/or deep margins ≤ 2 mm were the main indicators for chest wall irradiation.
      • Chadha M.
      • Portenoy J.
      • Boolbol S.K.
      • Gillego A.
      • Harrison L.B.
      Is there a role for postmastectomy radiation therapy in ductal carcinoma in situ?.

      Conclusions

      Finally, the DCIS prognosis remains favorable, with a breast cancer-specific mortality rate of 3% in a large Dutch study (3.9% and 2% for patients treated by BCS and BCS + RT, respectively, but 5.4% in women under the age of 40).
      • Elshof L.E.
      • Schmidt M.K.
      • Rutgers E.J.T.
      • van Leeuwen F.E.
      • Wesseling J.
      • Schaapveld M.
      Cause-specific mortality in a population-based cohort of 9799 women treated for ductal carcinoma in situ.
      Data derived from real-life clinical practice are very important to detect possible overtreatment or undertreatment. Our study showed several factors associated with SNB use and risk of residual disease, as well as boost use. We confirmed a small percentage (about 10%-12%) of low-grade DCIS, as in other studies (with also a high misinterpretation rate among pathologists).
      • Onega T.
      • Weaver D.L.
      • Frederick P.D.
      • et al.
      The diagnosic challenge of low-grade ductal carcinoma in situ.
      Similarly, DCIS smaller than 5 mm represent less than 20% of cases. Consequently, treatment de-escalation studies omitting RT after BCS, especially the “observational strategy,” appear to be suitable for only about 10% of selected patients.
      In the future, this very detailed real-life data-based study (with an already planned follow-up at 5 and 8 years) could allow for a better orientation of DCIS treatment modalities. This kind of approach has already been suggested.
      • Mannu G.S.
      • Dodwell D.
      Making progress in early breast cancer. Taking time or accepting risk?.

       Clinical Practice Points

      • DCIS represents about 15% of all breast cancers in France, with literature showing a heterogeneous management. A national survey conducted in 71 centers in 2014 to 2015 allowed us to analyze the real radiologic and pathologic features as well as treatments in daily practice without any selection.
      • Among 2125 patients, the median age was 58.5 years. The median tumor size was 15 mm; nuclear grade was low, intermediate and high in 12%, 36%, and 47% of cases, respectively. Margins were negative in 83% of cases. Mastectomy and lumpectomy rates were 25% and 75%, respectively. Sentinel node biopsy and axillary dissection rates were 41% and 2.6%, respectively. After lumpectomy, 97% of patients underwent whole breast irradiation (32% with a boost). Only 1% of patients received endocrine therapy.
      • These results are in accordance with the French guidelines published in 2009. Overall, less than 10% of DCIS treated in clinical practice seems eligible for “de-escalation” trials.

      Disclosure

      The authors have stated that they have no conflicts of interest.

      Acknowledgments

      The authors are grateful to Diane Penet for her help in preparing this manuscript and to Dr Antonio Ponti for his valuable suggestions.
      This study was supported by a grant from the French National Cancer Institute (INCa) and the logistical support of the French National Society of Senology (SFSPM).

      Appendix

      Tabled 1Complementary Investigator List
      InvestigatorCenterCity
      Dr Delphine AntoniCentre Paul StraussStrasbourg
      Dr Delphine Argo-LeignelCH de Bretagne SudLorient
      Dr Jean-Sébastien AucouturierGroupe Hospitalier La RochelleLa Rochelle
      Dr Sandrine AvigdorCHR d’OrléansOrleans
      Dr Marc BaronClinique MathildeRouen
      Dr Isabelle BartholomotClinique Mutualiste de l'EstuaireSaint-Nazaire
      Dr Pierre BaumannCentre d'Oncologie de GentillyNancy
      Dr Deborah BelemsaghaCentre Médical de ForcillesFerolles-Attily
      Dr Aurélie Bellière-CalandryCentre Jean-PerrinClermont Ferrand
      Dr Marc BolletClinique HartmannLevallois-Perret
      Dr Marie-Christine Bone-LepinoyCentre de Radiothérapie du ParcDijon
      Dr Patrick BontempsCHU de BesançonBesancon
      Dr Fatiha BoulbairCentre hospitalier de Belfort-MontbéliardMontbeliard
      Dr Claire BrunaudInstitut de Cancérologie de LorraineVandoeuvre-les-Nancy
      Dr Louis-Michel CaquotInstitut Jean GodinotReims
      Dr Christian ChevelleClinique PasteurToulouse
      Dr Vanessa ConriCHU BordeauxBordeaux
      Dr Anne-Catherine Courtecuisse-DegrendelCentre Joliot CurieSaint Martin Boulogne
      Pr Didier CowenHôpital de la TimoneMarseille
      Dr Francesco Del PianoHôpitaux du LémanThonon les Bains
      Dr Elisabeth Deniaud-AlexandreCH Départemental La Roche-sur-YonLa Roche sur Yon
      Dr Nadine DohollouPolyclinique Bordeaux NordBordeaux
      Dr Virginie DoridotClinique du SeinClermont-Ferrand
      Dr Patrick DubéClinique de l'EuropeAmiens
      Dr Catherine FerrerCHU de NîmesNimes
      Dr Virginie FichetClinique de l'OrmeauTarbes
      Dr Alain FignonClinique de l'AllianceSaint-Cyr-sur-Loire
      Dr Alain FourquetInstitut CurieParis
      Dr Sophie GirardCentre Hospitalier Alpes LémanContamine sur Arve
      Dr Dominique GoudersCH de CornouailleQuimper
      Pr Olivier GraesslinCHU de ReimsReims
      Pr Jean-Michel Hannoun-LeviCentre Antoine LacassagneNice
      Dr Anne KarstCentre libéral de radiothérapieStrasbourg
      Dr Hortense Laharie-MineurClinique TivoliBordeaux
      Dr Julien Langrand-EscureInstitut de cancérologie Lucien NeuwirthSaint Priest en Jarez
      Dr Sandrine Lavau-DenesCHU de LimogesLimoges
      Dr Julie LeseurCentre Eugène MarquisRennes
      Dr Christelle LevyCentre François BaclesseCaen
      Dr Francis LipinskiCentre d'Oncologie et de RadiothérapieBayonne
      Dr Valérie MagninCHU La RéunionSaint Pierre
      Dr Jacques MedioniHopital Européen Georges PompidouParis
      Dr Jacques MermetMédipôle de SavoieChalles-les-Eaux
      Dr Eliane MeryGustave RoussyVillejuif
      Dr Erik MontpetitCentre Saint YvesVannes
      Dr Matthieu MullerCH de MORLAIXMorlaix
      Dr Lobna OuldamerCHU de ToursTours
      Dr Karine PeignauxCentre Georges François LeclercDijon
      Dr Philippe QuetinCHR de MetzMetz
      Dr Aurélie RevauxGH Diaconesses Croix St SimonParis
      Dr Jean-Louis ReynoardCentre ClinicalSoyaux
      Dr Pascale RomestaingCentre Radiothérapie CharcotSainte Foy les Lyon
      Dr Naoum SaderCH de Saint-QuentinSaint-Quentin
      Dr François SensenbrennerHôpital Privé Drôme ArdècheGuilherand-Granges
      Dr Hélène SimonCHU de BrestBrest
      Dr Agnès TalletInstitut Paoli-CalmettesMarseille
      Dr Pierrick TheretCHU d'AmiensAmiens
      Dr Caroline ToussaintCentre Hospitalier Marne-la-Vallée-JossignyJossigny
      Dr Véronique Vaini-CowenPolyclinique du Parc RambotAix-en-Provence
      Dr Brigitte VieClinique ArmoricaineSaint Brieuc
      Dr Anne Vincent-SalomonInstitut CurieParis
      Dr Delphine WeitbruchHôpital PasteurColmar
      Dr Cécile ZinzindohouéClinique ClémentvilleMontpellier
      Dr Amira ZiouecheHôpital de la Croix Rouge FrançaiseToulon

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