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Accompanying DCIS in breast cancer patients with invasive ductal carcinoma is predictive of improved local recurrence-free survival
The Breast xxx (2014) 1e6
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Original article
Accompanying DCIS in breast cancer patients with invasive ductal carcinoma is predictive of improved local recurrence-free survival M. Dieterich a, *, F. Hartwig a, J. Stubert a, S. Klöcking b, G. Kundt c, B. Stengel d, T. Reimer a, B. Gerber a a
Department of Obstetrics and Gynecology, Breast Unit, University of Rostock, Suedring 81, 18059 Rostock, Germany Cancer Registry Rostock, Department of Radiotherapy, University of Rostock, Suedring 75, 18059 Rostock, Germany Institute for Biostatistics and Informatics in Medicine, University of Rostock, Ernst-Heydemann-Str. 8, 18057 Rostock, Germany d Institute for Pathology, Hospital Suedstadt, Suedring 81, 18059 Rostock, Germany b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 March 2013 Received in revised form 28 October 2013 Accepted 19 January 2014
Background: Ductal carcinoma in situ (DCIS) often accompanies invasive ductal carcinoma (IDC). The presence of co-existing DCIS is postulated to present as a less aggressive phenotype than IDC alone. Patients and methods: Patients diagnosed with hormone receptor-positive breast cancer receiving mastectomy were evaluated. Only patients without adjuvant radio- and chemotherapy were included to decrease treatment bias on local recurrence (LR). Results: Of 2239 breast cancer patients, 198 fulfilled the inclusion criteria. The overall LR rate was 11.6%. Tumor stage (p ¼ 0.002), nodal status (pN2 vs. pN0, p ¼ 0.023) and pure IDC compared with IDC-DCIS (p ¼ 0.029) were multivariate independent factors for increased LR risk. Patients with IDC-DCIS were significantly younger (p < 0.001), had smaller tumors (p ¼ 0.001), less lymph node involvement (p ¼ 0.012). The LR rate was significantly increased in patients with pure IDC (p ¼ 0.012). The time to distant metastases was decreased in patients with pure IDC compared with that observed in patients with IDC-DCIS (log rank ¼ 0.030). Conclusion: Invasive ductal carcinoma accompanied by DCIS is associated with lower LR. The prognostic value of co-existing DCIS in the adjuvant decision-making process may be considered a new independent prognostic marker. This finding needs further studies to evaluate its usefulness in premenopausal women. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: Accompanying DCIS Breast cancer DCIS Invasive carcinoma Local recurrence Prognosis
Background Ductal carcinoma in situ (DCIS) is recognized as a precursor of invasive ductal carcinoma (IDC) and is associated with different clinical courses and treatment strategies [1]. In patients with IDC alone, IDC is postulated to arise de novo, whereas in patients with IDC and accompanying DCIS (IDC-DCIS), IDC is assumed to arise from a preexisting DCIS lesion, a recognized precursor for IDC [2]. Until now, it remains unclear to what extent and within what time frame DCIS might develop into IDC. In 30e60% of patients with IDC, accompanying DCIS is diagnosed [3,4]. Discussions regarding the biologic aggressiveness of pure IDC and IDC-DCIS exist [2]. Contradictory data exist regarding the transition from normal
* Corresponding author. University of Rostock, Department of Obstetrics and Gynecology and Interdisciplinary Breast Center, Suedring 81, 18059 Rostock, Germany. Tel.: þ49 381 4401 4536; fax: þ49 381 4401 4599. E-mail address: [email protected] (M. Dieterich).
epithelium to DCIS and the transition from DCIS to IDC. On the one hand, breast cancer (BC) is believed to be a linear transformation from pre-malignant changes (hyperplasia or atypical hyperplasia), to carcinoma in situ and IDC [5e8]. Castro et al. found a substantial number of differentially expressed genes in pure DCIS compared with those expressed in IDC-DCIS [9]. It is postulated that these similar genomic profiles and molecular changes precede the morphologic progression from pure DCIS to IDC-DCIS [10]. On the other hand, some studies have proposed that DCIS may not be a precursor for IDC [11,12]. Major changes in gene expression are suggested to occur during the transition from normal breast tissue to DCIS rather than during the transition from DCIS to IDC [13e15]. Other studies argue that the presence of DCIS is associated with a change in the microenvironment and neoplastic epithelial cells surrounding the DCIS, playing an important role in tumor progression as well [16,17]. This cell-mediated immunological response might lead to an improved prognosis for patients with concomitant DCIS [18].
0960-9776/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2014.01.015
Please cite this article in press as: Dieterich M, et al., Accompanying DCIS in breast cancer patients with invasive ductal carcinoma is predictive of improved local recurrence-free survival, The Breast (2014), http://dx.doi.org/10.1016/j.breast.2014.01.015
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M. Dieterich et al. / The Breast xxx (2014) 1e6
The aim of the present study was based on the assumption that IDC-DCIS arises directly from DCIS, whereas IDC develops de novo. We therefore compared the clinical behavior, in terms of local recurrence (LR), in patients with IDC or IDC-DCIS undergoing modified radical mastectomy without adjuvant radio- or chemotherapy.
p-value less than 0.1 were evaluated by multivariate Cox regression analysis. A p-value less than 0.05 was deemed to be statistically significant. Survival analysis was not performed because survival was based on all possible reasons for death and because active follow up is not practiced by the Cancer Registry of Rostock. The time to distant metastasis was used as an indicator of tumor aggressiveness.
Patient and methods Patients Data from the Cancer Registry of Rostock, Germany were retrospectively evaluated using the Gieben Tumor Documentation System (GTDS, WILEY-VCH-Verlag, Weinheim, Germany). Patients diagnosed with BC between September 1997 and December 2007 were evaluated. Surgeries were identified using the International Classification of Procedures in Medicine (ICPM) code. Follow up was performed by the Cancer Registry of Rostock using the GTDS. The last known information of follow up was recorded in May 2011. Tumor stage was classified according to the TNM or AJCC classification system [19]. Menopause status could not be obtained from the GTDS. Inclusion criteria Inclusion criteria were as follows: patients undergoing modified radical mastectomy (MRM) with pure IDC or IDC-DCIS (DCIS alone or DCIS with combined lobular carcinoma in situ (LCIS)), unilateral BC, no course of adjuvant radio- or chemotherapy, positive hormone receptor (HR) status (estrogen and/or progesterone positive) and R0-resection (>1 mm). Exclusion criteria Exclusion criteria were as follows: patients with adjuvant radioor chemotherapy, other histological BC than stated, local recurrences, bilateral BC, breast conserving therapy (BCT), DCIS or LCIS alone, negative HR (estrogen and progesterone) status, a hormonal status that could not be obtained and metastasis at the point of diagnosis. After surgery all mastectomy specimens were formalin-fixed and evaluated by a pathologist specialized in breast cancer. Patients were defined as hormone receptor positive if the estimated estrogen and/or progesterone receptor content of the primary tumor was 10% of the tumor cells assessed by immunohistochemical evaluation. Overexpression of HER2 was defined as 3 þ staining by immunohistochemistry or HER2 amplification (ratio >2) by FISH or an equivalent method. Local recurrence was defined as tumor recurrences either unilateral, contralateral or as regional node recurrence. Statistical analysis Statistics were performed using IBMÒ SPSSÒ 19.0. Descriptive statistics were computed for continuous and categorical variables. Testing for differences in continuous variables between the study groups was accomplished using the 2-sample t-test for independent samples and were expressed as mean values standard deviation. Chi-squared test was performed to compare frequencies between groups for larger contingency tables, and Fisher’s exact test was performed for 2 2 contingency tables. Disease-free survival was defined as the time from surgery to recurrence and was further classified into local and distant disease-free survival. Patients who did not experience relapse were censored at the last follow up. The KaplaneMeier log-rank test was used for univariate recurrence analysis. Univariate Cox regression analysis was performed for the adjustment of confounders. Confounders yielding a
Results Patients, histology and local recurrence Out of an initial 2239 patients treated for BC during the study period, 198 fulfilled the inclusion criteria. The median follow up was 77 months (range 6e139 months). Of the 198 patients, 177 (89.4%) were >50 years old and were considered postmenopausal. Ninety patients (45.5%) had IDC-DCIS, and 108 (54.5%) patients revealed IDC alone. Nearly all patients (n ¼ 190) had IDC, whereas 8 patients presented with concurrent invasive ductal and invasive lobular carcinomas. The overall LR rate was 11.6%. Patient characteristics are shown in Table 1. All tumor specimens were estrogen and/or progesterone positive, corresponding to luminal A and B subtypes. No triple-negative tumors or patients with estrogen negative, progesterone negative and HER2 positive tumors were observed. Receptor expression profile was comparable in pure IDC vs. IDC-DICS for estrogen positive (93.5% vs. 94.4%, p ¼ 0.51), progesterone positive (78.7% vs 80.0%, p ¼ 0.48%) and/or HER2 positive (56.5% vs 44.8%, p ¼ 0.12) tumors. Overall metastasis occurred in 15 (7.6%) patients and was distributed as follows: four patients with pulmonary, five with bone metastases, three patients with metastasis in the liver, two with skin and one with lymphatic metastasis (contralateral axillary metastasis). IDC versus IDC-DCIS Local recurrence was significantly increased in patients with pure IDC (Table 2). Patients with IDC-DCIS were significantly younger (p < 0.001), had smaller tumors (p ¼ 0.001) and had less lymph node involvement (p ¼ 0.010) compared with patients with IDC alone (Table 3). The occurrence of distant metastases was increased in patients with IDC alone (Logerank test ¼ 0.030; Fig. 1). A univariate Cox regression analysis confirmed IDC alone compared with IDC-DCIS (HR: 3.69; 95% CI: 1.04e13.12; p ¼ 0.043) and lymph node involvement (HR: 3.38; 95% CI: 1.22e9.32; p ¼ 0.019) as risk factors for developing distant metastases. However, multivariate Cox regression could not confirm IDC alone (HR: 3.24; 95% CI: 0.37e 28.08; p ¼ 0.29) or lymph node involvement (HR: 1.52; 95% CI: 0.29e8.03; p ¼ 0.62) as an independent risk factor for distant metastases due to limited case numbers. Local recurrence risk factors A log-rank test indicated that tumor stage (p ¼ 0.005), nodal status (p < 0.001) and IDC compared with IDC-DCIS (p ¼ 0.014, Fig. 2) were univariate prognostic factors for increased LR risk (Table 4). A multivariate Cox regression confirmed IDC alone compared with IDC-DCIS, tumor size and lymph node status as independent prognostic factors for increased LR (Table 5). Discussion In the present study, the impact of pure IDC vs. IDC-DCIS as a predictor of LR was demonstrated. A multivariate analysis
Please cite this article in press as: Dieterich M, et al., Accompanying DCIS in breast cancer patients with invasive ductal carcinoma is predictive of improved local recurrence-free survival, The Breast (2014), http://dx.doi.org/10.1016/j.breast.2014.01.015
M. Dieterich et al. / The Breast xxx (2014) 1e6 Table 1 Patient characteristics.
Table 3 Clinico-pathologic variables of patients with IDC-DCIS vs. IDC alone.
Characteristic
Mean age (in years)a Tumor stagec pT1 pT2 pT3 pT4 Nodal statusc Positive Negative Unknown Vascular invasion V1 V0 Unknown Lymphatic invasion L1 L0 Unknown IDC grade G1 G2 G3 Unknown Accompanying DCIS IDC alone IDC-DCIS Tumor focality Unifocal Multifocal Estrogen receptor status Positive Negative Progesterone receptor status Positive Negative HER2 receptor status Positive Negative Unknown Global anti-hormonal therapy Treatment received Treatment denied Anti-hormonal therapy agent Tamoxifen Aromatase inhibitor Unknown a b c d e
No local recurrence (n ¼ 175)
Local recurrence (n ¼ 23)
p-Value
72.9 10.3 (range, 35e92)
65.4 13.5 (range, 32e92)
<0.001b
105 (60.0%) 58 (33.2%) 3 (1.7%) 9 (5.1%)
11 (47.8%) 8 (34.8%) 3 (13.1%) 1 (4.3%)
Mean age (in years)a
0.027d
0.053e 33 (18.8%) 141 (80.6%) 1 (0.6%)
9 (39.1%) 14 (60.9%) e
53 (30.3%) 11 (6.3%) 111 (63.4%)
7 (30.4%) 0 16 (69.6%)
80 (45.7%) 69 (39.4%) 26 (14.9%)
5 (21.7%) 12 (52.2%) 6 (26.1%)
0.586e
0.074e
0.318d 40 (22.9%) 115 (65.7%) 20 (11.4%) e
4 (17.4%) 13 (56.5%) 5 (21.8%) 1 (4.3%)
90 (51.4%) 85 (48.6%)
18 (78.3%) 5 (21.7%)
130 (74.3%) 45 25.7%)
19 (82.6%) 4 (17.4%)
166 (94.9%) 9 5.1%)
20 (86.9%) 3 (13.1%)
141 (80.6%) 34 (19.4%)
17 (73.9%) 6 (26.1%)
58 (33.1%) 63 (36.0%) 54 (30.9%)
11 (47.8%) 4 (17.4%) 8 (34.8%)
159 (90.9%) 16 (9.1%)
23 (100%) 0
0.024e
0.453e
0.150e
0.423d
0.099e
Mean tumor size (cm)a Tumor stage pT1 pT2 pT3/4 Nodal status in general Node pos. Node neg. Lymphovascular invasion (L) Yes No Unknown IDC grade G1 G2 G3 Hormone receptor statuse Estrogen pos. Progesterone pos. HER2 receptor status Positive Negative Unknown DCIS grade G1 G2 G3 Unknown
IDC (n ¼ 108)
IDC-DCIS (n ¼ 90)
p-Value
72.9 10.3 (range, 35e92) 2.3 1.3 (range, 0.5e8.0)
65.4 13.5 (range, 32e92) 1.7 1.4 (range, 0.1e8.0)
<0.001b
54 (50.0%) 42 (38.9%) 12 (11.1%)
62 (68.9%) 24 (26.7%) 4 (4.4%)
31 (28.7%) 77 (71.3%)
12 (13.3%) 78 (86.7%)
50 (46.3%) 42 (38.9%) 16 (14.8%)
31 (34.4%) 43 (47.8%) 16 (17.8%)
18 (16.7%) 76 (60.4%) 14 (12.9%)
26 (28.9%) 53 (58.9%) 11 (12.2%)
101 85
85 72
39 (36.1%) 30 (27.8%) 39 (36.1)
30 (33.3%) 37 (41.1%) 23 (25.6%)
e e e e
26 13 15 36
0.001b 0.043c
0.010d
0.121d
0.125c
0.786d 0.482d 0.230d
e (28.9%) (14.4%) (26.7%) (40.0%)
Data are expressed as the number of patients (except for age and tumor size). IDC: invasive ductal carcinoma; DCIS: ductal carcinoma in situ. Tumor stage was classified according to TNM or AJCC [19]. a Data are expressed as the means SD. b t-test used to compare means of groups. c Pearson’s chi-squared test. d Fisher’s exact test. e Numbers exceed n ¼ 108 and n ¼ 90, respectively. Because estrogen and/or progesterone receptors were present in each patient, the percentage was not calculated.
0.225e
0.351e 56 (32.0%) 54 (30.9%) 65 (37.1%)
14 (60.9%) 8 (34.8%) 1 (4.3%)
Data are given as means SD. t-test used to compare means of groups. According to TNM or AJCC [19]. Pearson’s chi-squared test. Fisher’s exact test.
illustrated the independent prognostic value of pure IDC compared with IDC-DCIS as a risk factor for increased LR. Relatively few studies have investigated the role of co-existing DCIS in patients with IDC. Recently, Wong et al. postulated a divergent clinical behavior of pure IDC compared with IDC-DCIS [2]. In their study, IDCs were increasingly self detected
Table 2 Local recurrence and distant metastases.
Local recurrence Distant metastases
3
IDC N (%)
IDC-DCIS N (%)
p-Valuea
18 (16.7) 12 (11.1)
5 (5.6) 3 (3.3)
0.024 0.057
IDC: invasive ductal carcinoma; DCIS: ductal carcinoma in situ. a Fisher’s exact test.
compared with IDC-DCIS lesions, which were detected by patient screening, implicating the higher tumor aggressiveness of IDCs. These finding were supported by increased Ki-67 levels in pure IDC compared with those in IDC-DCIS of comparable invasive size [2]. Their data corroborate our findings showing that patients with pure IDC had increased LN involvement and an advanced tumor size. Presently, the intrinsic molecular subtypes of BC are known to influence disease and distant metastasis-free survival [20]. Patients with luminal A tumors (either ER or PR positive, Ki-67 < 14%, and HER2 negative) have the most favorable prognosis; therefore, adjuvant chemotherapy is not recommended [21]. In patients with luminal B tumors (either ER or PR positive, Ki-67 14%, and HER2 negative or positive), decisions on further treatment regarding chemotherapy are often difficult and are assessed in accordance with other histological findings, such as grading, lymphovascular or vascular invasion, Ki-67 levels, tumor size and lymph node status [22]. Expensive gene arrays are increasingly used to assess the need for adjuvant chemotherapy [23]. Nevertheless, using immunohistological data for molecular subtyping can provide almost identical information to that obtained by gene arrays and are used for adjuvant treatment decisions [24,25]. Because recommendations in luminal B (HER2-negative) patients are particularly challenging, our data suggest including IDC vs. IDC-DCIS in the decision-making process for adjuvant systemic treatment recommendations because concomitant DCIS in IDC is not yet
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Fig. 1. KaplaneMeier survival curve for IDC vs. IDC-DCIS (time to distant metastases).
Fig. 2. KaplaneMeier survival curve for IDC vs. IDC-DCIS (time to local recurrence).
relevant for making systemic treatment decisions. We identified pure IDC as an independent risk factor for LR and an increased risk for distant metastasis, although only low-risk BC patients with unknown Ki-67 status (luminal A and B, HER2 negative) were included. A biological difference between pure IDC and IDC-DCIS with decreased tumor aggressiveness for IDC-DCIS can be
Table 4 KaplaneMeier log-rank test of factors influencing the time to local recurrence. Characteristic
p-Value (log rank)
IDC vs. IDC-DCIS (Fig. 1) Tumor stagea Nodal statusa IDC grade Vascular invasion (yes vs. no)b Lymphatic invasion (yes vs. no) HER2 receptor status (positive vs. negative) Tamoxifen vs. aromatase inhibitor Unifocality vs. multifocality
0.014 0.005 <0.001 0.161 e 0.096 0.249 0.920 0.249
IDC: invasive ductal carcinoma; DCIS: ductal carcinoma in situ. a Tumor stage according to TNM or AJCC [19]. b No statistics available: all cases are censored.
assumed. Mylonas et al. compared differential expression of molecular markers of pure IDC and IDC-DCIS and found significantly increased HER2 amplification and Ki-67 expression in patients with pure IDC, suggesting an increased malignant behavior for pure IDCs [26]. Presently, the progression from DCIS to IDC-DCIS remains unclear. Favorable data exist for a linear progression model from DCIS to IDC [9,27,28]. Other cancer progression pathways, such as de novo development of pure IDC due to heterogenetic changes in DCIS compared with IDC, oppose a linear progression model [2,29,30]. Increasing evidence is available for several progression routes leading to IDC [31,32]. Our data support the hypothesis of two pathways for the development of HR-positive IDC: de novo non-linear growth of IDC unaffected by co-existing DCIS and less aggressive BC progressing from pre-existing DCIS to IDC-DCIS. Data concerning the role of co-existing DCIS vary. Logullo et al. showed that the presence of a co-existing DCIS component was negatively related to tumor recurrence [33]. Others have found a trend on univariate analysis toward improved survival in patients with IDC-DCIS compared with pure IDC [34,35]. Conversely, Merchera et al. found on univariate analysis an increased risk of LR for patients with concomitant DCIS that was no longer persistent on multivariate analysis. Not only tumor biology but also adjuvant treatment influences the LR rate and overall survival (OAS) [36e38]. The effect of adjuvant radiotherapy, chemotherapy or antibody therapy on LR and OAS might have biased previous clinical investigations because patients were treated with different adjuvant therapeutic strategies. Our study model seemed appropriate for evaluating the effect of concomitant DCIS on the prognosis of patients with IDC because all patients were homogeneously treated. All patients had hormonal treatment and received the identical surgical procedure. Our local recurrence rate of 11.6% in 77 months was relatively high compared with that reported in the literature [39,40]. The cause may be that patients with T3/T4 tumors and pN2/pN3 lymph node status were included, for whom post mastectomy radiation or chemotherapy would be indicated, but not offered due to co-morbidity or advanced age. A limitation to our study is its retrospective approach and data regarding the grade or extent of DCIS that were incomplete and inevaluable. The low rates of events have to be considered when interpreting the statistical data, particularly distant event analysis. However, the results are meaningful and are comparable with previous studies. Because most of the patients were >50 years, the data are only appropriate and limited to postmenopausal HR-positive patients. The strength of our study lies in its homogeneous study population and the statistical significance of the results that were confirmed by multivariate analyses. The same pathological institute evaluated all pathological slides, reducing the possibility that some patients with concomitant DCIS did not have this information available in the final pathological report. Conclusion In our series, we found an increased LR risk for BC patients with pure IDC compared with that for patients with IDC-DCIS. The prognostic value of co-existing DCIS may prove useful in the adjuvant decision-making process. However, its use in routine clinical practice cannot yet be recommended, and further data are needed to evaluate its role in future guidelines. Co-existing DCIS in postmenopausal patients with IDC may be considered a new independent prognostic marker.
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M. Dieterich et al. / The Breast xxx (2014) 1e6
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Table 5 Univariate and multivariate Cox regression analysis of risk factors for local recurrence. Parameter
Histological type IDC vs. IDC-DCISa BMI 25 vs. >30a 25e30 vs. >30a Tumor size 1e2.5 cm vs. <1 cma >2.5 cm vs. <1 cma Age in years >50 vs. 50a pTb 2 vs. 1a 3 vs. 1a 4 vs. 1a pNb in general Positive vs. negativea Vascular invasion 1 vs. 0a (statistical analysis)c Lymphatic invasion 1 vs. 0a IDC grade 2 vs. 1a 3 vs. 1a ER receptor status Negative vs. positivea PR Receptor status Negative vs. positivea HER2 receptor status Positive vs. negativea Treatment Tamoxifen vs. aromatase inhibitora Carcinoma focality Unifocal vs. multifocala
Univariate Cox regression
Multivariate Cox regression
Unadjusted HR
95% CI
p-Value
3.24
1.20e8.73
1.79 2.10
0.39e8.29 0.44e9.92
5.52 8.66
0.73e42.0 1.06e70.5
0.020 0.645 0.458 0.349 0.121 0.099 0.044
1.14
0.26e4.96
1.41 7.60 1.99
0.56e3.51 2.11e27.4 0.25e15.6
0.858 0.021 0.486 0.002 0.512
2.37
1.03e5.48
0.043
e
e
e
2.36
0.83e6.70
1.33 3.11
0.43e4.14 0.81e12.0
0.107 0.184 0.627 0.098
1.93
0.57e6.56
0.294
1.48
0.58e3.80
0.410
1.94
0.62e6.11
0.258
1.05
0.44e2.52
0.920
1.88
0.63e5.55
0.257
Adjusted HR
95% CI
p-Value
4.81
1.08e21.4
0.039
1.71 21.3 1.18
0.62e4.75 4.20e108 0.11e12.8
0.002 0.304 <0.001 0.892
BMI: body mass index. IDC: invasive ductal carcinoma; DCIS: ductal carcinoma in situ. No statistics available: no real event in “intermediate grade DCIS” due to incomplete histological data on grading in DCIS patients / statistical artifact remains in the analysis, therefore data cannot be evaluated. a Reference category. b Tumor stage according to TNM or AJCC [19]. c No statistics available: all cases are censored.
Ethical approval Not required.
[5] [6]
Funding sources [7]
All financial support was provided by the authors themselves and the University Hospital Rostock. [8]
Conflict of interest statement [9]
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[28] Lee S, Stewart S, Nagtegaal I, Luo J, Wu Y, Colditz G, et al. Differentially expressed genes regulating the progression of ductal carcinoma in situ to invasive breast cancer. Cancer Res 2012 Sep 1;72(17):4574e86. [29] Gao Y, Niu Y, Wang X, Wei L, Lu S. Genetic changes at specific stages of breast cancer progression detected by comparative genomic hybridization. J Mol Med (Berl) 2009 Feb;87(2):145e52. [30] Bombonati A, Sgroi DC. The molecular pathology of breast cancer progression. J Pathol 2011 Jan;223(2):307e17. [31] Lakhani SR. The transition from hyperplasia to invasive carcinoma of the breast. J Pathol 1999 Feb;187(3):272e8. [32] Menard S, Fortis S, Castiglioni F, Agresti R, Balsari A. HER2 as a prognostic factor in breast cancer. Oncology 2001;61:67e72. Suppl. 2. [33] Logullo AF, Godoy AB, Mourao-Neto M, Simpson AJ, Nishimoto IN, Brentani MM. Presence of ductal carcinoma in situ confers an improved prognosis for patients with T1N0M0 invasive breast carcinoma. Braz J Med Biol Res 2002 Aug;35(8):913e9. [34] Matsukuma A, Enjoji M, Toyoshima S. Ductal carcinoma of the breast. an analysis of proportions of intraductal and invasive components. Pathol Res Pract 1991 Jan;187(1):62e7. [35] Chagpar AB, McMasters KM, Sahoo S, Edwards MJ. Does ductal carcinoma in situ accompanying invasive carcinoma affect prognosis? Surgery 2009 Oct;146(4):561e7. discussion 7e8. [36] Rowell NP. Radiotherapy to the chest wall following mastectomy for nodenegative breast cancer: a systematic review. Radiother Oncol 2009 Apr;91(1): 23e32. [37] Killander F, Anderson H, Ryden S, Moller T, Hafstrom LO, Malmstrom P. Efficient reduction of loco-regional recurrences but no effect on mortality twenty years after postmastectomy radiation in premenopausal women with stage II breast cancer e a randomized trial from the South Sweden Breast Cancer Group. Breast 2009 Oct;18(5):309e15. [38] EBCTCG EBCTCG. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005 May 14e20;365(9472):1687e717. [39] Karlsson P, Cole BF, Chua BH, Price KN, Lindtner J, Collins JP, et al. Patterns and risk factors for locoregional failures after mastectomy for breast cancer: an International Breast Cancer Study Group report. Ann Oncol 2012 Nov;23(11): 2852e8. [40] Botteri E, Gentilini O, Rotmensz N, Veronesi P, Ratini S, Fraga-Guedes C, et al. Mastectomy without radiotherapy: outcome analysis after 10 years of follow-up in a single institution. Breast Cancer Res Treat 2012 Aug;134(3): 1221e8.
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Original article
Accompanying DCIS in breast cancer patients with invasive ductal carcinoma is predictive of improved local recurrence-free survival M. Dieterich a, *, F. Hartwig a, J. Stubert a, S. Klöcking b, G. Kundt c, B. Stengel d, T. Reimer a, B. Gerber a a
Department of Obstetrics and Gynecology, Breast Unit, University of Rostock, Suedring 81, 18059 Rostock, Germany Cancer Registry Rostock, Department of Radiotherapy, University of Rostock, Suedring 75, 18059 Rostock, Germany Institute for Biostatistics and Informatics in Medicine, University of Rostock, Ernst-Heydemann-Str. 8, 18057 Rostock, Germany d Institute for Pathology, Hospital Suedstadt, Suedring 81, 18059 Rostock, Germany b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 March 2013 Received in revised form 28 October 2013 Accepted 19 January 2014
Background: Ductal carcinoma in situ (DCIS) often accompanies invasive ductal carcinoma (IDC). The presence of co-existing DCIS is postulated to present as a less aggressive phenotype than IDC alone. Patients and methods: Patients diagnosed with hormone receptor-positive breast cancer receiving mastectomy were evaluated. Only patients without adjuvant radio- and chemotherapy were included to decrease treatment bias on local recurrence (LR). Results: Of 2239 breast cancer patients, 198 fulfilled the inclusion criteria. The overall LR rate was 11.6%. Tumor stage (p ¼ 0.002), nodal status (pN2 vs. pN0, p ¼ 0.023) and pure IDC compared with IDC-DCIS (p ¼ 0.029) were multivariate independent factors for increased LR risk. Patients with IDC-DCIS were significantly younger (p < 0.001), had smaller tumors (p ¼ 0.001), less lymph node involvement (p ¼ 0.012). The LR rate was significantly increased in patients with pure IDC (p ¼ 0.012). The time to distant metastases was decreased in patients with pure IDC compared with that observed in patients with IDC-DCIS (log rank ¼ 0.030). Conclusion: Invasive ductal carcinoma accompanied by DCIS is associated with lower LR. The prognostic value of co-existing DCIS in the adjuvant decision-making process may be considered a new independent prognostic marker. This finding needs further studies to evaluate its usefulness in premenopausal women. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: Accompanying DCIS Breast cancer DCIS Invasive carcinoma Local recurrence Prognosis
Background Ductal carcinoma in situ (DCIS) is recognized as a precursor of invasive ductal carcinoma (IDC) and is associated with different clinical courses and treatment strategies [1]. In patients with IDC alone, IDC is postulated to arise de novo, whereas in patients with IDC and accompanying DCIS (IDC-DCIS), IDC is assumed to arise from a preexisting DCIS lesion, a recognized precursor for IDC [2]. Until now, it remains unclear to what extent and within what time frame DCIS might develop into IDC. In 30e60% of patients with IDC, accompanying DCIS is diagnosed [3,4]. Discussions regarding the biologic aggressiveness of pure IDC and IDC-DCIS exist [2]. Contradictory data exist regarding the transition from normal
* Corresponding author. University of Rostock, Department of Obstetrics and Gynecology and Interdisciplinary Breast Center, Suedring 81, 18059 Rostock, Germany. Tel.: þ49 381 4401 4536; fax: þ49 381 4401 4599. E-mail address: [email protected] (M. Dieterich).
epithelium to DCIS and the transition from DCIS to IDC. On the one hand, breast cancer (BC) is believed to be a linear transformation from pre-malignant changes (hyperplasia or atypical hyperplasia), to carcinoma in situ and IDC [5e8]. Castro et al. found a substantial number of differentially expressed genes in pure DCIS compared with those expressed in IDC-DCIS [9]. It is postulated that these similar genomic profiles and molecular changes precede the morphologic progression from pure DCIS to IDC-DCIS [10]. On the other hand, some studies have proposed that DCIS may not be a precursor for IDC [11,12]. Major changes in gene expression are suggested to occur during the transition from normal breast tissue to DCIS rather than during the transition from DCIS to IDC [13e15]. Other studies argue that the presence of DCIS is associated with a change in the microenvironment and neoplastic epithelial cells surrounding the DCIS, playing an important role in tumor progression as well [16,17]. This cell-mediated immunological response might lead to an improved prognosis for patients with concomitant DCIS [18].
0960-9776/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2014.01.015
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M. Dieterich et al. / The Breast xxx (2014) 1e6
The aim of the present study was based on the assumption that IDC-DCIS arises directly from DCIS, whereas IDC develops de novo. We therefore compared the clinical behavior, in terms of local recurrence (LR), in patients with IDC or IDC-DCIS undergoing modified radical mastectomy without adjuvant radio- or chemotherapy.
p-value less than 0.1 were evaluated by multivariate Cox regression analysis. A p-value less than 0.05 was deemed to be statistically significant. Survival analysis was not performed because survival was based on all possible reasons for death and because active follow up is not practiced by the Cancer Registry of Rostock. The time to distant metastasis was used as an indicator of tumor aggressiveness.
Patient and methods Patients Data from the Cancer Registry of Rostock, Germany were retrospectively evaluated using the Gieben Tumor Documentation System (GTDS, WILEY-VCH-Verlag, Weinheim, Germany). Patients diagnosed with BC between September 1997 and December 2007 were evaluated. Surgeries were identified using the International Classification of Procedures in Medicine (ICPM) code. Follow up was performed by the Cancer Registry of Rostock using the GTDS. The last known information of follow up was recorded in May 2011. Tumor stage was classified according to the TNM or AJCC classification system [19]. Menopause status could not be obtained from the GTDS. Inclusion criteria Inclusion criteria were as follows: patients undergoing modified radical mastectomy (MRM) with pure IDC or IDC-DCIS (DCIS alone or DCIS with combined lobular carcinoma in situ (LCIS)), unilateral BC, no course of adjuvant radio- or chemotherapy, positive hormone receptor (HR) status (estrogen and/or progesterone positive) and R0-resection (>1 mm). Exclusion criteria Exclusion criteria were as follows: patients with adjuvant radioor chemotherapy, other histological BC than stated, local recurrences, bilateral BC, breast conserving therapy (BCT), DCIS or LCIS alone, negative HR (estrogen and progesterone) status, a hormonal status that could not be obtained and metastasis at the point of diagnosis. After surgery all mastectomy specimens were formalin-fixed and evaluated by a pathologist specialized in breast cancer. Patients were defined as hormone receptor positive if the estimated estrogen and/or progesterone receptor content of the primary tumor was 10% of the tumor cells assessed by immunohistochemical evaluation. Overexpression of HER2 was defined as 3 þ staining by immunohistochemistry or HER2 amplification (ratio >2) by FISH or an equivalent method. Local recurrence was defined as tumor recurrences either unilateral, contralateral or as regional node recurrence. Statistical analysis Statistics were performed using IBMÒ SPSSÒ 19.0. Descriptive statistics were computed for continuous and categorical variables. Testing for differences in continuous variables between the study groups was accomplished using the 2-sample t-test for independent samples and were expressed as mean values standard deviation. Chi-squared test was performed to compare frequencies between groups for larger contingency tables, and Fisher’s exact test was performed for 2 2 contingency tables. Disease-free survival was defined as the time from surgery to recurrence and was further classified into local and distant disease-free survival. Patients who did not experience relapse were censored at the last follow up. The KaplaneMeier log-rank test was used for univariate recurrence analysis. Univariate Cox regression analysis was performed for the adjustment of confounders. Confounders yielding a
Results Patients, histology and local recurrence Out of an initial 2239 patients treated for BC during the study period, 198 fulfilled the inclusion criteria. The median follow up was 77 months (range 6e139 months). Of the 198 patients, 177 (89.4%) were >50 years old and were considered postmenopausal. Ninety patients (45.5%) had IDC-DCIS, and 108 (54.5%) patients revealed IDC alone. Nearly all patients (n ¼ 190) had IDC, whereas 8 patients presented with concurrent invasive ductal and invasive lobular carcinomas. The overall LR rate was 11.6%. Patient characteristics are shown in Table 1. All tumor specimens were estrogen and/or progesterone positive, corresponding to luminal A and B subtypes. No triple-negative tumors or patients with estrogen negative, progesterone negative and HER2 positive tumors were observed. Receptor expression profile was comparable in pure IDC vs. IDC-DICS for estrogen positive (93.5% vs. 94.4%, p ¼ 0.51), progesterone positive (78.7% vs 80.0%, p ¼ 0.48%) and/or HER2 positive (56.5% vs 44.8%, p ¼ 0.12) tumors. Overall metastasis occurred in 15 (7.6%) patients and was distributed as follows: four patients with pulmonary, five with bone metastases, three patients with metastasis in the liver, two with skin and one with lymphatic metastasis (contralateral axillary metastasis). IDC versus IDC-DCIS Local recurrence was significantly increased in patients with pure IDC (Table 2). Patients with IDC-DCIS were significantly younger (p < 0.001), had smaller tumors (p ¼ 0.001) and had less lymph node involvement (p ¼ 0.010) compared with patients with IDC alone (Table 3). The occurrence of distant metastases was increased in patients with IDC alone (Logerank test ¼ 0.030; Fig. 1). A univariate Cox regression analysis confirmed IDC alone compared with IDC-DCIS (HR: 3.69; 95% CI: 1.04e13.12; p ¼ 0.043) and lymph node involvement (HR: 3.38; 95% CI: 1.22e9.32; p ¼ 0.019) as risk factors for developing distant metastases. However, multivariate Cox regression could not confirm IDC alone (HR: 3.24; 95% CI: 0.37e 28.08; p ¼ 0.29) or lymph node involvement (HR: 1.52; 95% CI: 0.29e8.03; p ¼ 0.62) as an independent risk factor for distant metastases due to limited case numbers. Local recurrence risk factors A log-rank test indicated that tumor stage (p ¼ 0.005), nodal status (p < 0.001) and IDC compared with IDC-DCIS (p ¼ 0.014, Fig. 2) were univariate prognostic factors for increased LR risk (Table 4). A multivariate Cox regression confirmed IDC alone compared with IDC-DCIS, tumor size and lymph node status as independent prognostic factors for increased LR (Table 5). Discussion In the present study, the impact of pure IDC vs. IDC-DCIS as a predictor of LR was demonstrated. A multivariate analysis
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M. Dieterich et al. / The Breast xxx (2014) 1e6 Table 1 Patient characteristics.
Table 3 Clinico-pathologic variables of patients with IDC-DCIS vs. IDC alone.
Characteristic
Mean age (in years)a Tumor stagec pT1 pT2 pT3 pT4 Nodal statusc Positive Negative Unknown Vascular invasion V1 V0 Unknown Lymphatic invasion L1 L0 Unknown IDC grade G1 G2 G3 Unknown Accompanying DCIS IDC alone IDC-DCIS Tumor focality Unifocal Multifocal Estrogen receptor status Positive Negative Progesterone receptor status Positive Negative HER2 receptor status Positive Negative Unknown Global anti-hormonal therapy Treatment received Treatment denied Anti-hormonal therapy agent Tamoxifen Aromatase inhibitor Unknown a b c d e
No local recurrence (n ¼ 175)
Local recurrence (n ¼ 23)
p-Value
72.9 10.3 (range, 35e92)
65.4 13.5 (range, 32e92)
<0.001b
105 (60.0%) 58 (33.2%) 3 (1.7%) 9 (5.1%)
11 (47.8%) 8 (34.8%) 3 (13.1%) 1 (4.3%)
Mean age (in years)a
0.027d
0.053e 33 (18.8%) 141 (80.6%) 1 (0.6%)
9 (39.1%) 14 (60.9%) e
53 (30.3%) 11 (6.3%) 111 (63.4%)
7 (30.4%) 0 16 (69.6%)
80 (45.7%) 69 (39.4%) 26 (14.9%)
5 (21.7%) 12 (52.2%) 6 (26.1%)
0.586e
0.074e
0.318d 40 (22.9%) 115 (65.7%) 20 (11.4%) e
4 (17.4%) 13 (56.5%) 5 (21.8%) 1 (4.3%)
90 (51.4%) 85 (48.6%)
18 (78.3%) 5 (21.7%)
130 (74.3%) 45 25.7%)
19 (82.6%) 4 (17.4%)
166 (94.9%) 9 5.1%)
20 (86.9%) 3 (13.1%)
141 (80.6%) 34 (19.4%)
17 (73.9%) 6 (26.1%)
58 (33.1%) 63 (36.0%) 54 (30.9%)
11 (47.8%) 4 (17.4%) 8 (34.8%)
159 (90.9%) 16 (9.1%)
23 (100%) 0
0.024e
0.453e
0.150e
0.423d
0.099e
Mean tumor size (cm)a Tumor stage pT1 pT2 pT3/4 Nodal status in general Node pos. Node neg. Lymphovascular invasion (L) Yes No Unknown IDC grade G1 G2 G3 Hormone receptor statuse Estrogen pos. Progesterone pos. HER2 receptor status Positive Negative Unknown DCIS grade G1 G2 G3 Unknown
IDC (n ¼ 108)
IDC-DCIS (n ¼ 90)
p-Value
72.9 10.3 (range, 35e92) 2.3 1.3 (range, 0.5e8.0)
65.4 13.5 (range, 32e92) 1.7 1.4 (range, 0.1e8.0)
<0.001b
54 (50.0%) 42 (38.9%) 12 (11.1%)
62 (68.9%) 24 (26.7%) 4 (4.4%)
31 (28.7%) 77 (71.3%)
12 (13.3%) 78 (86.7%)
50 (46.3%) 42 (38.9%) 16 (14.8%)
31 (34.4%) 43 (47.8%) 16 (17.8%)
18 (16.7%) 76 (60.4%) 14 (12.9%)
26 (28.9%) 53 (58.9%) 11 (12.2%)
101 85
85 72
39 (36.1%) 30 (27.8%) 39 (36.1)
30 (33.3%) 37 (41.1%) 23 (25.6%)
e e e e
26 13 15 36
0.001b 0.043c
0.010d
0.121d
0.125c
0.786d 0.482d 0.230d
e (28.9%) (14.4%) (26.7%) (40.0%)
Data are expressed as the number of patients (except for age and tumor size). IDC: invasive ductal carcinoma; DCIS: ductal carcinoma in situ. Tumor stage was classified according to TNM or AJCC [19]. a Data are expressed as the means SD. b t-test used to compare means of groups. c Pearson’s chi-squared test. d Fisher’s exact test. e Numbers exceed n ¼ 108 and n ¼ 90, respectively. Because estrogen and/or progesterone receptors were present in each patient, the percentage was not calculated.
0.225e
0.351e 56 (32.0%) 54 (30.9%) 65 (37.1%)
14 (60.9%) 8 (34.8%) 1 (4.3%)
Data are given as means SD. t-test used to compare means of groups. According to TNM or AJCC [19]. Pearson’s chi-squared test. Fisher’s exact test.
illustrated the independent prognostic value of pure IDC compared with IDC-DCIS as a risk factor for increased LR. Relatively few studies have investigated the role of co-existing DCIS in patients with IDC. Recently, Wong et al. postulated a divergent clinical behavior of pure IDC compared with IDC-DCIS [2]. In their study, IDCs were increasingly self detected
Table 2 Local recurrence and distant metastases.
Local recurrence Distant metastases
3
IDC N (%)
IDC-DCIS N (%)
p-Valuea
18 (16.7) 12 (11.1)
5 (5.6) 3 (3.3)
0.024 0.057
IDC: invasive ductal carcinoma; DCIS: ductal carcinoma in situ. a Fisher’s exact test.
compared with IDC-DCIS lesions, which were detected by patient screening, implicating the higher tumor aggressiveness of IDCs. These finding were supported by increased Ki-67 levels in pure IDC compared with those in IDC-DCIS of comparable invasive size [2]. Their data corroborate our findings showing that patients with pure IDC had increased LN involvement and an advanced tumor size. Presently, the intrinsic molecular subtypes of BC are known to influence disease and distant metastasis-free survival [20]. Patients with luminal A tumors (either ER or PR positive, Ki-67 < 14%, and HER2 negative) have the most favorable prognosis; therefore, adjuvant chemotherapy is not recommended [21]. In patients with luminal B tumors (either ER or PR positive, Ki-67 14%, and HER2 negative or positive), decisions on further treatment regarding chemotherapy are often difficult and are assessed in accordance with other histological findings, such as grading, lymphovascular or vascular invasion, Ki-67 levels, tumor size and lymph node status [22]. Expensive gene arrays are increasingly used to assess the need for adjuvant chemotherapy [23]. Nevertheless, using immunohistological data for molecular subtyping can provide almost identical information to that obtained by gene arrays and are used for adjuvant treatment decisions [24,25]. Because recommendations in luminal B (HER2-negative) patients are particularly challenging, our data suggest including IDC vs. IDC-DCIS in the decision-making process for adjuvant systemic treatment recommendations because concomitant DCIS in IDC is not yet
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M. Dieterich et al. / The Breast xxx (2014) 1e6
Fig. 1. KaplaneMeier survival curve for IDC vs. IDC-DCIS (time to distant metastases).
Fig. 2. KaplaneMeier survival curve for IDC vs. IDC-DCIS (time to local recurrence).
relevant for making systemic treatment decisions. We identified pure IDC as an independent risk factor for LR and an increased risk for distant metastasis, although only low-risk BC patients with unknown Ki-67 status (luminal A and B, HER2 negative) were included. A biological difference between pure IDC and IDC-DCIS with decreased tumor aggressiveness for IDC-DCIS can be
Table 4 KaplaneMeier log-rank test of factors influencing the time to local recurrence. Characteristic
p-Value (log rank)
IDC vs. IDC-DCIS (Fig. 1) Tumor stagea Nodal statusa IDC grade Vascular invasion (yes vs. no)b Lymphatic invasion (yes vs. no) HER2 receptor status (positive vs. negative) Tamoxifen vs. aromatase inhibitor Unifocality vs. multifocality
0.014 0.005 <0.001 0.161 e 0.096 0.249 0.920 0.249
IDC: invasive ductal carcinoma; DCIS: ductal carcinoma in situ. a Tumor stage according to TNM or AJCC [19]. b No statistics available: all cases are censored.
assumed. Mylonas et al. compared differential expression of molecular markers of pure IDC and IDC-DCIS and found significantly increased HER2 amplification and Ki-67 expression in patients with pure IDC, suggesting an increased malignant behavior for pure IDCs [26]. Presently, the progression from DCIS to IDC-DCIS remains unclear. Favorable data exist for a linear progression model from DCIS to IDC [9,27,28]. Other cancer progression pathways, such as de novo development of pure IDC due to heterogenetic changes in DCIS compared with IDC, oppose a linear progression model [2,29,30]. Increasing evidence is available for several progression routes leading to IDC [31,32]. Our data support the hypothesis of two pathways for the development of HR-positive IDC: de novo non-linear growth of IDC unaffected by co-existing DCIS and less aggressive BC progressing from pre-existing DCIS to IDC-DCIS. Data concerning the role of co-existing DCIS vary. Logullo et al. showed that the presence of a co-existing DCIS component was negatively related to tumor recurrence [33]. Others have found a trend on univariate analysis toward improved survival in patients with IDC-DCIS compared with pure IDC [34,35]. Conversely, Merchera et al. found on univariate analysis an increased risk of LR for patients with concomitant DCIS that was no longer persistent on multivariate analysis. Not only tumor biology but also adjuvant treatment influences the LR rate and overall survival (OAS) [36e38]. The effect of adjuvant radiotherapy, chemotherapy or antibody therapy on LR and OAS might have biased previous clinical investigations because patients were treated with different adjuvant therapeutic strategies. Our study model seemed appropriate for evaluating the effect of concomitant DCIS on the prognosis of patients with IDC because all patients were homogeneously treated. All patients had hormonal treatment and received the identical surgical procedure. Our local recurrence rate of 11.6% in 77 months was relatively high compared with that reported in the literature [39,40]. The cause may be that patients with T3/T4 tumors and pN2/pN3 lymph node status were included, for whom post mastectomy radiation or chemotherapy would be indicated, but not offered due to co-morbidity or advanced age. A limitation to our study is its retrospective approach and data regarding the grade or extent of DCIS that were incomplete and inevaluable. The low rates of events have to be considered when interpreting the statistical data, particularly distant event analysis. However, the results are meaningful and are comparable with previous studies. Because most of the patients were >50 years, the data are only appropriate and limited to postmenopausal HR-positive patients. The strength of our study lies in its homogeneous study population and the statistical significance of the results that were confirmed by multivariate analyses. The same pathological institute evaluated all pathological slides, reducing the possibility that some patients with concomitant DCIS did not have this information available in the final pathological report. Conclusion In our series, we found an increased LR risk for BC patients with pure IDC compared with that for patients with IDC-DCIS. The prognostic value of co-existing DCIS may prove useful in the adjuvant decision-making process. However, its use in routine clinical practice cannot yet be recommended, and further data are needed to evaluate its role in future guidelines. Co-existing DCIS in postmenopausal patients with IDC may be considered a new independent prognostic marker.
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M. Dieterich et al. / The Breast xxx (2014) 1e6
5
Table 5 Univariate and multivariate Cox regression analysis of risk factors for local recurrence. Parameter
Histological type IDC vs. IDC-DCISa BMI 25 vs. >30a 25e30 vs. >30a Tumor size 1e2.5 cm vs. <1 cma >2.5 cm vs. <1 cma Age in years >50 vs. 50a pTb 2 vs. 1a 3 vs. 1a 4 vs. 1a pNb in general Positive vs. negativea Vascular invasion 1 vs. 0a (statistical analysis)c Lymphatic invasion 1 vs. 0a IDC grade 2 vs. 1a 3 vs. 1a ER receptor status Negative vs. positivea PR Receptor status Negative vs. positivea HER2 receptor status Positive vs. negativea Treatment Tamoxifen vs. aromatase inhibitora Carcinoma focality Unifocal vs. multifocala
Univariate Cox regression
Multivariate Cox regression
Unadjusted HR
95% CI
p-Value
3.24
1.20e8.73
1.79 2.10
0.39e8.29 0.44e9.92
5.52 8.66
0.73e42.0 1.06e70.5
0.020 0.645 0.458 0.349 0.121 0.099 0.044
1.14
0.26e4.96
1.41 7.60 1.99
0.56e3.51 2.11e27.4 0.25e15.6
0.858 0.021 0.486 0.002 0.512
2.37
1.03e5.48
0.043
e
e
e
2.36
0.83e6.70
1.33 3.11
0.43e4.14 0.81e12.0
0.107 0.184 0.627 0.098
1.93
0.57e6.56
0.294
1.48
0.58e3.80
0.410
1.94
0.62e6.11
0.258
1.05
0.44e2.52
0.920
1.88
0.63e5.55
0.257
Adjusted HR
95% CI
p-Value
4.81
1.08e21.4
0.039
1.71 21.3 1.18
0.62e4.75 4.20e108 0.11e12.8
0.002 0.304 <0.001 0.892
BMI: body mass index. IDC: invasive ductal carcinoma; DCIS: ductal carcinoma in situ. No statistics available: no real event in “intermediate grade DCIS” due to incomplete histological data on grading in DCIS patients / statistical artifact remains in the analysis, therefore data cannot be evaluated. a Reference category. b Tumor stage according to TNM or AJCC [19]. c No statistics available: all cases are censored.
Ethical approval Not required.
[5] [6]
Funding sources [7]
All financial support was provided by the authors themselves and the University Hospital Rostock. [8]
Conflict of interest statement [9]
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Please cite this article in press as: Dieterich M, et al., Accompanying DCIS in breast cancer patients with invasive ductal carcinoma is predictive of improved local recurrence-free survival, The Breast (2014), http://dx.doi.org/10.1016/j.breast.2014.01.015