Breast Cancer Res Treat DOI 10.1007/s10549-014-3025-4
CLINICAL TRIAL
Influence of boost radiotherapy in patients with ductal carcinoma in situ breast cancer: a multicenter, retrospective study in Korea (KROG 11-04) Jin Hee Kim • Doo Ho Choi • Won Park • Seung Do Ahn • Su Ssan Kim • Sung Whan Ha • Kyubo Kim • Yong Bae Kim • Ji Woon Yea • Min Kyu Kang Kyung Hwan Shin • Dong Won Kim • Ji Hae Lee • Chang-Ok Suh
•
Received: 30 May 2014 / Accepted: 2 June 2014 Ó Springer Science+Business Media New York 2014
Abstract To estimate the effect of boost radiotherapy on local recurrence-free survival (LRFS) in patients with ductal carcinoma in situ (DCIS) breast cancer. We included patients from nine institutions who met the following criteria: having Tis, age 18 years or older, having breast conserving surgery (BCS) and radiotherapy within 12 weeks after surgery. From 1995 through 2006, 728 patients were analyzed retrospectively by the Korean Radiation Oncology Group. All patients received wholebreast radiation therapy (WBRT) after BCS. 232 patients (31.9 %) also received boost radiation therapy (RT) (median 10 Gy). After median follow-up of 82 months, 5-year LRFS was 98.4 % and 10-year LRFS was 95.8 %
This article presented at the 36th Annual San Antonio Breast Cancer Symposium, December 10–14, 2013, San Antonio, TX.
for all patients. There was no statistically significant difference of LRFS between the boost and no-boost groups. Nineteen (2.6 %) patients had ipsilateral breast recurrences, including 12 of invasive recurrence and 7 DCIS. The presence of the HER2 receptor was associated with more invasive recurrences. Nine (1.2 %) patients developed contralateral breast cancer, including six invasive breast cancer and three DCIS. In the multivariate analysis, only the margin status was a significant prognostic factor for LRFS. Boost RT was not associated with further improvement of local control in DCIS after BCS and WBRT. HER2 receptor-positive patients may need further treatment with the anti-HER2 agents. Keywords Breast cancer Ductal carcinoma in situ Radiation therapy Boost HER2
J. H. Kim (&) Department of Radiation Oncology, Dongsan Medical Center, Keimyung University School of Medicine, 56 Dalseong-Ro, Jung-Gu, Daegu, Korea e-mail: [email protected]
S. W. Ha K. Kim Seoul National University Hospital, Seoul, Korea e-mail: [email protected]
D. H. Choi (&) W. Park Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro Gangnam-gu, Seoul, Korea e-mail: [email protected]
Y. B. Kim C.-O. Suh Severance Hospital, Yonsei University College of Medicine, Seoul, Korea e-mail: [email protected]
W. Park e-mail: [email protected] S. D. Ahn S. S. Kim Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea e-mail: [email protected] S. S. Kim e-mail: [email protected]
K. Kim e-mail: [email protected]
C.-O. Suh e-mail: [email protected] J. W. Yea M. K. Kang Yeungnam University College of Medicine, Daegu, Korea e-mail: [email protected] M. K. Kang e-mail: [email protected]
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Introduction The incidence of ductal carcinoma in situ (DCIS) has been continuously increasing worldwide, even in Korea, a country with the widespread use of screening mammography; DCIS is estimated to represent 7–30 % of all diagnosed breast cancers [1, 2]. DCIS of the breast is associated with low mortality rates, but local recurrence (LR) is a problem of concern in this cancer [3]. In DCIS of the breast, breast-conserving treatment has been recommended since 1999 [4]. Whole-breast radiation therapy (WBRT) following breast conserving surgery (BCS) for DCIS significantly reduces the risk of LR in comparison with breast-conserving surgery alone [5]. Four prospective trials showed an improvement of local control in WBRT prescribed as adjuvant treatment after BCS [5–9]. Metaanalyses of randomized trials confirmed significant benefits of radiation therapy (RT) after BCS [10, 11]. Boost RT delivered to the surgical bed improved outcomes for patients with invasive breast cancer [12]. However, the role of boost RT has never been prospectively reported for DCIS and is still controversial. Only several retrospective studies have been published, and boost RT is usually administered at radiation oncologist’s discretion. Two multi-institutional randomized trials evaluating the role of boost RT in DCIS are ongoing: the Trans Tasman Radiation Oncology Group (TROG) 07.01 and the multicenter French INCA-BONBIS studies. Therefore, we studied Korean multicenter experiences in DCIS treatment retrospectively with respect to the effect of boost RT on local recurrence-free survival (LRFS).
Methods Patients’ characteristics The records of patients with DCIS of breast cancer treated at nine institutions in Korea from 1995 to 2006 were retrospectively analyzed. We included patients who met the following inclusion criteria: having Tis tumors, age 18 years or older at diagnosis, having had BCS and WBRT
K. H. Shin National Cancer Center, Ilsan, Korea e-mail: [email protected] D. W. Kim Pusan National University Hospital, Pusan, Korea e-mail: [email protected] J. H. Lee Ewha Womans University Mokdong Hospital, Seoul, Korea e-mail: [email protected]
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within 12 weeks after surgery. A total of 728 patients were enrolled. Table 1 summarizes the patient and tumor characteristics for both groups (with boost or without boost). Age distribution was 19–72 years old with a median age of 46. The surgical procedures were wide excision in 448 (61.5 %), quadrantectomy in 248 (34.1 %), excisional biopsy in 30 (4.1 %) and unknown in 2 (0.3 %) patients. Discrimination of excision and quadrantectomy was at the discretion of surgical oncologist in every institution. Median tumor size was 12 mm (range 1–105 mm). The surgical margin status were \2 mm in 212 (29.1 %), C2 mm in 395 (54.3 %) and unknown in 121 (16.6 %) patients. Estrogen receptor (ER), progesterone receptor (PR) and HER2 receptor were present in 458 (62.9 %), 421 (57.8 %) and 309 (42.4 %) patients, respectively. Tamoxifen was administered in 395 (54.3 %) patients. ER, PR, HER2 status were established by immunohistochemistry (IHC) using the Ventana BenchMarkÒ XT automated slide stainer (Ventana Medical Systems, Tucson, AZ, USA) according to the manufacturer’s recommendations. The median follow up periods was 82 months (range 2–200). Radiation therapy All patients underwent WBRT to a median dose of 50.4 Gy (range 44–50.4 Gy), with 1.8–2 Gy per fraction, five times a week. The median interval between surgery and RT was 34 days (range 5–84 days). Patients were treated in the supine position with tangential fields using 6-MV or mixed 6–/15-MV photons. Boost RT was performed with a median dose of 10 Gy (range 6–20 Gy) by electron beams. Indication and field’s size and volume of boost RT was at the discretion of every radiation oncologist. For the electron boost, patients underwent radiographic localization of the surgical clips to delineate the field. If the clips were absent, the tissue defect from the surgery and the scar with an adequate margin were used to delineate the field. The energy of the electron boost varied according to the depth of the tumor bed as measured on radiotherapy planning CT scan. Statistics The differences of the patients’ distribution and patterns of LR between the two groups (boost vs. no boost) according to selected parameters were estimated by the Chi square test or Fisher’s exact test. For survival analyses, the date of surgery was used as the start of the observation. LRFS was calculated by using the Kaplan–Meier method and the difference between patient groups was assessed by the log rank test. Multivariate Cox regression with stepwise selection was performed to identify the major significant predictors of LR. The estimated relative risk of LR
Breast Cancer Res Treat
occurrence was expressed as hazard ratios and their 95 % confidence intervals. A variable was entered if the significance level of its probability-to-enter was less than the entry value (P \ 0.10), and was removed if the significance level was greater than the removal value (P = 0.10). The results were considered statistically significant at a P \ 0.05. All statistical tests were performed by using the SPSS for Windows software (version 20.0; SPSS Inc., Chicago, IL, USA).
Results Patients who received boost RT had higher-grade tumors. Other patients’ or tumor characteristics were not statistically different between the boost and no boost groups (Table 1). The actuarial 5 and 10-year LRFS was 98.4 and 95.8 %, respectively; the actuarial 5 and 10-year overall survival was 99.7 % for all patients. The actuarial 5 and 10-year LRFS was 98.4 and 96.5 %, respectively, in the boost group and 98.5 and 95.4 % in the no-boost group (P = 0.704). There was no statistically significant difference in LRFS between the two groups (Fig. 1). Nineteen (2.6 %) patients had ipsilateral breast recurrence after 19-123 months (median, 58 months). Among them, 12 patients had invasive breast cancer and 7 had DCIS (Table 2). Ipsilateral recurrent sites were tumor bed in 14 patients and other segment in 4 and unknown in 1. Nine (1.2 %) patients had contralateral breast cancer after 6-178 months (median, 49 months), including 6 cases of invasive breast cancer and 3 cases of DCIS (Table 2). HER2-positive patients had more ipsilateral breast recurrences (11/309, 3.6 %) than HER2-negative patients (1/ 242, 0.4 %). Positive HER2 receptor was also associated with higher invasive recurrences (Table 3).
Local recurrence free survival (%)
100
80
60
40 Boost
20
5-yr LRFS: 98.4%, 10-yr LRFS: 96.5%
No Boost 5-yr LRFS: 98.5%, 10-yr LRFS: 95.4% P = 0.704
0 0
24
48
72
96
120
144
168
192
Months after surgery
Fig. 1 Local recurrence-free survival (LRFS) with and without boost radiotherapy
Univariate analysis of LRFS revealed that younger age, surgical margin below 2 mm and the presence of HER2 receptor were statistically significant poor prognostic factors (Table 4). Patients with a surgical margin below 2 mm had significantly lower 5-year LRFS than those with C2 mm (P = 0.014). HER2-positive patients had lower 5-year LRFS than HER2-negative patients (P = 0.013). In the multivariate analysis, only the margin status was a significant prognostic factor for LRFS (Table 4). The presence of HER2 receptor had a borderline significance (P = 0.063). There was no significant difference regardless of boost RT in patients with risk factors of recurrence. In patients with surgical margin below 2 mm, 64 patients received boost RT compared with 148 who did not, and LRFS was 96.2 and 98.5 %, respectively (P = 0.317). In positive HER2 receptor, 80 patients received boost RT compared with 229 who did not, and LRFS was 97.1 and 98.1 %, respectively (P = 0.310). For patients under 40 years old, 46 patients underwent boost RT, whereas 100 patients did not receive boost RT, and LRFS was 91.9 and 98.9 %, respectively (P = 0.211).
Discussion Boost radiotherapy In the previous reported randomized trials, boost RT was used at the physician’s discretion [6], not recommended [7, 9], or was not addressed [11]. To our knowledge, only eight retrospective studies have reported the effect of boost RT in DCIS treatment [13–20]. The results of these reports and our present study are summarized in Table 5. A positive role of boost RT was found in five studies [13–15, 18, 19] but not in the other three [16, 17, 20]. Omlin et al. [13] reported an international multicenter (18 institutions) retrospective study on 373 DCIS patients aged 45 years or less. The differences of LRFS were statistically significant with an overall risk reduction for LR of 66 % with WBRT and 85 % with WBRT and boost. The margin status and the radiation dose were the only two independent factors for LRFS in the multivariate analysis. Julian et al. [18] reviewed retrospectively the data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 trial, in which 692 out of 1,569 patients with DCIS received a boost after conventional RT. There were no differences of ipsilateral breast tumor recurrence between the both groups (boost: 13.8 % vs no boost: 14.3 %), but the authors showed a higher number of patients with positive margins in the boost group (21 vs. 15 %), suggesting that the boost may have compensated for close or positive margins. However, our study found no statistically
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significant difference of LRFS between the boost and noboost groups, but the patients who received boost RT had higher grade tumors (Table 1). A relatively large proportion (54.3 %) of patients received tamoxifen compared to many institutional or population-based studies. This and slight high rate (34.1 %) of ‘quadrantectomy’ may contribute to a low rate of 5-year LR. The effect of boost RT to the tumor bed has never been prospectively assessed, and the results from prospective phase III studies would be necessary to verify the effect of boost RT in DCIS patients. Two ongoing randomized controlled trials addressing this issue should help to individualize patients who may benefit from this treatment. Prognostic factors for local recurrence Among the risk factors for LR, the adequacy of excision seems to be crucial, but there is controversy regarding the amount of uninvolved breast tissue adjacent to the surgical margin necessary to define a complete excision. Some authors suggested 2 mm as a sufficient margin [21–23], but others require 5–10 mm margins [24]. In our study, the surgical margin status was revealed as an independent prognostic factor for LRFS in multivariate analysis; surgical margins of \2 mm were associated with a worse LRFS (P = 0.043). Therefore, careful evaluation of the margin status is warranted during surgery rather than considering boost RT after surgery. Also, younger age (P = 0.027) was a significant prognostic factor of LRFS in the univariate analysis in line with the published studies [13, 14]. In HER2-positive patients, more ipsilateral breast recurrences occurred than in HER2-negative patients. The presence of HER2 was associated with higher invasive recurrences. HER2- positive patients had lower 5-year LRFS than HER2 negative patients, and this effect was marginally significant in the multivariate analysis. HER-2 has a potential role in tumor proliferation, invasion, or migration [25]. Park et al. [26] reported that the intraductal component of invasive ductal carcinoma (IDC) may differ biologically from pure DCIS. HER2 appears not to play a critical role in the progression from DCIS to IDC, and the HER2 status is maintained in metastatic lesions. Noh et al. [27] reported no significant difference in ipsilateral breast tumor recurrence (invasive or DCIS) according to HER-2 expression, but time to recurrence was shorter in HER-2 positive tumors. In the present study, the univariate analysis also suggested HER2 to be a prognostic factor in the LRFS of DCIS. Thus, targeting HER-2 could have potential therapeutic implications. Trastuzumab, a monoclonal antibody against HER-2, improves the clinical outcomes in HER-2 overexpressing invasive breast cancer [28, 29]. Yet, there is no proven HER2-targeting therapy for HER-2 positive DCIS. A phase II trial reported that trastuzumab
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augmented antibody-dependent cell-mediated cytotoxicity whereas it did not cause significant histologic, antiproliferative, or apoptotic changes [30]. Von Minckwitz and colleagues examined the effect of neoadjuvant chemotherapy and trastuzumab on adjacent DCIS in invasive ductal carcinoma, and found that trastuzumab could reduce or eradicate adjacent DCIS, but the result was not specific for trastuzumab [31]. The NSABP B-43 trial, which compares whole-breast irradiation with or without concurrent trastuzumab in HER2-positive DCIS, will determine whether trastuzumab is beneficial in preventing subsequent ipsilateral breast tumor recurrence. In conclusion, within the limitations of this study’s retrospective design and relatively low 5-year local recurrence rate, the addition of a tumor bed boost to standard whole breast RT was not associated with further improvement in local control. The results from ongoing prospective phase III studies will be necessary in order to verify the usefulness of boost RT in DCIS of the breast treated by BCS and WBRT. In addition, careful evaluation of the margin status is needed. Patients with positive for HER2 receptor status may need further treatment with HER2 targeting agents such as trastuzumab. The NSABP B-43 trial results are expected to clarify whether the late treatment is beneficial. Conflict of interest
None.
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CLINICAL TRIAL
Influence of boost radiotherapy in patients with ductal carcinoma in situ breast cancer: a multicenter, retrospective study in Korea (KROG 11-04) Jin Hee Kim • Doo Ho Choi • Won Park • Seung Do Ahn • Su Ssan Kim • Sung Whan Ha • Kyubo Kim • Yong Bae Kim • Ji Woon Yea • Min Kyu Kang Kyung Hwan Shin • Dong Won Kim • Ji Hae Lee • Chang-Ok Suh
•
Received: 30 May 2014 / Accepted: 2 June 2014 Ó Springer Science+Business Media New York 2014
Abstract To estimate the effect of boost radiotherapy on local recurrence-free survival (LRFS) in patients with ductal carcinoma in situ (DCIS) breast cancer. We included patients from nine institutions who met the following criteria: having Tis, age 18 years or older, having breast conserving surgery (BCS) and radiotherapy within 12 weeks after surgery. From 1995 through 2006, 728 patients were analyzed retrospectively by the Korean Radiation Oncology Group. All patients received wholebreast radiation therapy (WBRT) after BCS. 232 patients (31.9 %) also received boost radiation therapy (RT) (median 10 Gy). After median follow-up of 82 months, 5-year LRFS was 98.4 % and 10-year LRFS was 95.8 %
This article presented at the 36th Annual San Antonio Breast Cancer Symposium, December 10–14, 2013, San Antonio, TX.
for all patients. There was no statistically significant difference of LRFS between the boost and no-boost groups. Nineteen (2.6 %) patients had ipsilateral breast recurrences, including 12 of invasive recurrence and 7 DCIS. The presence of the HER2 receptor was associated with more invasive recurrences. Nine (1.2 %) patients developed contralateral breast cancer, including six invasive breast cancer and three DCIS. In the multivariate analysis, only the margin status was a significant prognostic factor for LRFS. Boost RT was not associated with further improvement of local control in DCIS after BCS and WBRT. HER2 receptor-positive patients may need further treatment with the anti-HER2 agents. Keywords Breast cancer Ductal carcinoma in situ Radiation therapy Boost HER2
J. H. Kim (&) Department of Radiation Oncology, Dongsan Medical Center, Keimyung University School of Medicine, 56 Dalseong-Ro, Jung-Gu, Daegu, Korea e-mail: [email protected]
S. W. Ha K. Kim Seoul National University Hospital, Seoul, Korea e-mail: [email protected]
D. H. Choi (&) W. Park Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro Gangnam-gu, Seoul, Korea e-mail: [email protected]
Y. B. Kim C.-O. Suh Severance Hospital, Yonsei University College of Medicine, Seoul, Korea e-mail: [email protected]
W. Park e-mail: [email protected] S. D. Ahn S. S. Kim Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea e-mail: [email protected] S. S. Kim e-mail: [email protected]
K. Kim e-mail: [email protected]
C.-O. Suh e-mail: [email protected] J. W. Yea M. K. Kang Yeungnam University College of Medicine, Daegu, Korea e-mail: [email protected] M. K. Kang e-mail: [email protected]
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Introduction The incidence of ductal carcinoma in situ (DCIS) has been continuously increasing worldwide, even in Korea, a country with the widespread use of screening mammography; DCIS is estimated to represent 7–30 % of all diagnosed breast cancers [1, 2]. DCIS of the breast is associated with low mortality rates, but local recurrence (LR) is a problem of concern in this cancer [3]. In DCIS of the breast, breast-conserving treatment has been recommended since 1999 [4]. Whole-breast radiation therapy (WBRT) following breast conserving surgery (BCS) for DCIS significantly reduces the risk of LR in comparison with breast-conserving surgery alone [5]. Four prospective trials showed an improvement of local control in WBRT prescribed as adjuvant treatment after BCS [5–9]. Metaanalyses of randomized trials confirmed significant benefits of radiation therapy (RT) after BCS [10, 11]. Boost RT delivered to the surgical bed improved outcomes for patients with invasive breast cancer [12]. However, the role of boost RT has never been prospectively reported for DCIS and is still controversial. Only several retrospective studies have been published, and boost RT is usually administered at radiation oncologist’s discretion. Two multi-institutional randomized trials evaluating the role of boost RT in DCIS are ongoing: the Trans Tasman Radiation Oncology Group (TROG) 07.01 and the multicenter French INCA-BONBIS studies. Therefore, we studied Korean multicenter experiences in DCIS treatment retrospectively with respect to the effect of boost RT on local recurrence-free survival (LRFS).
Methods Patients’ characteristics The records of patients with DCIS of breast cancer treated at nine institutions in Korea from 1995 to 2006 were retrospectively analyzed. We included patients who met the following inclusion criteria: having Tis tumors, age 18 years or older at diagnosis, having had BCS and WBRT
K. H. Shin National Cancer Center, Ilsan, Korea e-mail: [email protected] D. W. Kim Pusan National University Hospital, Pusan, Korea e-mail: [email protected] J. H. Lee Ewha Womans University Mokdong Hospital, Seoul, Korea e-mail: [email protected]
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within 12 weeks after surgery. A total of 728 patients were enrolled. Table 1 summarizes the patient and tumor characteristics for both groups (with boost or without boost). Age distribution was 19–72 years old with a median age of 46. The surgical procedures were wide excision in 448 (61.5 %), quadrantectomy in 248 (34.1 %), excisional biopsy in 30 (4.1 %) and unknown in 2 (0.3 %) patients. Discrimination of excision and quadrantectomy was at the discretion of surgical oncologist in every institution. Median tumor size was 12 mm (range 1–105 mm). The surgical margin status were \2 mm in 212 (29.1 %), C2 mm in 395 (54.3 %) and unknown in 121 (16.6 %) patients. Estrogen receptor (ER), progesterone receptor (PR) and HER2 receptor were present in 458 (62.9 %), 421 (57.8 %) and 309 (42.4 %) patients, respectively. Tamoxifen was administered in 395 (54.3 %) patients. ER, PR, HER2 status were established by immunohistochemistry (IHC) using the Ventana BenchMarkÒ XT automated slide stainer (Ventana Medical Systems, Tucson, AZ, USA) according to the manufacturer’s recommendations. The median follow up periods was 82 months (range 2–200). Radiation therapy All patients underwent WBRT to a median dose of 50.4 Gy (range 44–50.4 Gy), with 1.8–2 Gy per fraction, five times a week. The median interval between surgery and RT was 34 days (range 5–84 days). Patients were treated in the supine position with tangential fields using 6-MV or mixed 6–/15-MV photons. Boost RT was performed with a median dose of 10 Gy (range 6–20 Gy) by electron beams. Indication and field’s size and volume of boost RT was at the discretion of every radiation oncologist. For the electron boost, patients underwent radiographic localization of the surgical clips to delineate the field. If the clips were absent, the tissue defect from the surgery and the scar with an adequate margin were used to delineate the field. The energy of the electron boost varied according to the depth of the tumor bed as measured on radiotherapy planning CT scan. Statistics The differences of the patients’ distribution and patterns of LR between the two groups (boost vs. no boost) according to selected parameters were estimated by the Chi square test or Fisher’s exact test. For survival analyses, the date of surgery was used as the start of the observation. LRFS was calculated by using the Kaplan–Meier method and the difference between patient groups was assessed by the log rank test. Multivariate Cox regression with stepwise selection was performed to identify the major significant predictors of LR. The estimated relative risk of LR
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occurrence was expressed as hazard ratios and their 95 % confidence intervals. A variable was entered if the significance level of its probability-to-enter was less than the entry value (P \ 0.10), and was removed if the significance level was greater than the removal value (P = 0.10). The results were considered statistically significant at a P \ 0.05. All statistical tests were performed by using the SPSS for Windows software (version 20.0; SPSS Inc., Chicago, IL, USA).
Results Patients who received boost RT had higher-grade tumors. Other patients’ or tumor characteristics were not statistically different between the boost and no boost groups (Table 1). The actuarial 5 and 10-year LRFS was 98.4 and 95.8 %, respectively; the actuarial 5 and 10-year overall survival was 99.7 % for all patients. The actuarial 5 and 10-year LRFS was 98.4 and 96.5 %, respectively, in the boost group and 98.5 and 95.4 % in the no-boost group (P = 0.704). There was no statistically significant difference in LRFS between the two groups (Fig. 1). Nineteen (2.6 %) patients had ipsilateral breast recurrence after 19-123 months (median, 58 months). Among them, 12 patients had invasive breast cancer and 7 had DCIS (Table 2). Ipsilateral recurrent sites were tumor bed in 14 patients and other segment in 4 and unknown in 1. Nine (1.2 %) patients had contralateral breast cancer after 6-178 months (median, 49 months), including 6 cases of invasive breast cancer and 3 cases of DCIS (Table 2). HER2-positive patients had more ipsilateral breast recurrences (11/309, 3.6 %) than HER2-negative patients (1/ 242, 0.4 %). Positive HER2 receptor was also associated with higher invasive recurrences (Table 3).
Local recurrence free survival (%)
100
80
60
40 Boost
20
5-yr LRFS: 98.4%, 10-yr LRFS: 96.5%
No Boost 5-yr LRFS: 98.5%, 10-yr LRFS: 95.4% P = 0.704
0 0
24
48
72
96
120
144
168
192
Months after surgery
Fig. 1 Local recurrence-free survival (LRFS) with and without boost radiotherapy
Univariate analysis of LRFS revealed that younger age, surgical margin below 2 mm and the presence of HER2 receptor were statistically significant poor prognostic factors (Table 4). Patients with a surgical margin below 2 mm had significantly lower 5-year LRFS than those with C2 mm (P = 0.014). HER2-positive patients had lower 5-year LRFS than HER2-negative patients (P = 0.013). In the multivariate analysis, only the margin status was a significant prognostic factor for LRFS (Table 4). The presence of HER2 receptor had a borderline significance (P = 0.063). There was no significant difference regardless of boost RT in patients with risk factors of recurrence. In patients with surgical margin below 2 mm, 64 patients received boost RT compared with 148 who did not, and LRFS was 96.2 and 98.5 %, respectively (P = 0.317). In positive HER2 receptor, 80 patients received boost RT compared with 229 who did not, and LRFS was 97.1 and 98.1 %, respectively (P = 0.310). For patients under 40 years old, 46 patients underwent boost RT, whereas 100 patients did not receive boost RT, and LRFS was 91.9 and 98.9 %, respectively (P = 0.211).
Discussion Boost radiotherapy In the previous reported randomized trials, boost RT was used at the physician’s discretion [6], not recommended [7, 9], or was not addressed [11]. To our knowledge, only eight retrospective studies have reported the effect of boost RT in DCIS treatment [13–20]. The results of these reports and our present study are summarized in Table 5. A positive role of boost RT was found in five studies [13–15, 18, 19] but not in the other three [16, 17, 20]. Omlin et al. [13] reported an international multicenter (18 institutions) retrospective study on 373 DCIS patients aged 45 years or less. The differences of LRFS were statistically significant with an overall risk reduction for LR of 66 % with WBRT and 85 % with WBRT and boost. The margin status and the radiation dose were the only two independent factors for LRFS in the multivariate analysis. Julian et al. [18] reviewed retrospectively the data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 trial, in which 692 out of 1,569 patients with DCIS received a boost after conventional RT. There were no differences of ipsilateral breast tumor recurrence between the both groups (boost: 13.8 % vs no boost: 14.3 %), but the authors showed a higher number of patients with positive margins in the boost group (21 vs. 15 %), suggesting that the boost may have compensated for close or positive margins. However, our study found no statistically
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significant difference of LRFS between the boost and noboost groups, but the patients who received boost RT had higher grade tumors (Table 1). A relatively large proportion (54.3 %) of patients received tamoxifen compared to many institutional or population-based studies. This and slight high rate (34.1 %) of ‘quadrantectomy’ may contribute to a low rate of 5-year LR. The effect of boost RT to the tumor bed has never been prospectively assessed, and the results from prospective phase III studies would be necessary to verify the effect of boost RT in DCIS patients. Two ongoing randomized controlled trials addressing this issue should help to individualize patients who may benefit from this treatment. Prognostic factors for local recurrence Among the risk factors for LR, the adequacy of excision seems to be crucial, but there is controversy regarding the amount of uninvolved breast tissue adjacent to the surgical margin necessary to define a complete excision. Some authors suggested 2 mm as a sufficient margin [21–23], but others require 5–10 mm margins [24]. In our study, the surgical margin status was revealed as an independent prognostic factor for LRFS in multivariate analysis; surgical margins of \2 mm were associated with a worse LRFS (P = 0.043). Therefore, careful evaluation of the margin status is warranted during surgery rather than considering boost RT after surgery. Also, younger age (P = 0.027) was a significant prognostic factor of LRFS in the univariate analysis in line with the published studies [13, 14]. In HER2-positive patients, more ipsilateral breast recurrences occurred than in HER2-negative patients. The presence of HER2 was associated with higher invasive recurrences. HER2- positive patients had lower 5-year LRFS than HER2 negative patients, and this effect was marginally significant in the multivariate analysis. HER-2 has a potential role in tumor proliferation, invasion, or migration [25]. Park et al. [26] reported that the intraductal component of invasive ductal carcinoma (IDC) may differ biologically from pure DCIS. HER2 appears not to play a critical role in the progression from DCIS to IDC, and the HER2 status is maintained in metastatic lesions. Noh et al. [27] reported no significant difference in ipsilateral breast tumor recurrence (invasive or DCIS) according to HER-2 expression, but time to recurrence was shorter in HER-2 positive tumors. In the present study, the univariate analysis also suggested HER2 to be a prognostic factor in the LRFS of DCIS. Thus, targeting HER-2 could have potential therapeutic implications. Trastuzumab, a monoclonal antibody against HER-2, improves the clinical outcomes in HER-2 overexpressing invasive breast cancer [28, 29]. Yet, there is no proven HER2-targeting therapy for HER-2 positive DCIS. A phase II trial reported that trastuzumab
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augmented antibody-dependent cell-mediated cytotoxicity whereas it did not cause significant histologic, antiproliferative, or apoptotic changes [30]. Von Minckwitz and colleagues examined the effect of neoadjuvant chemotherapy and trastuzumab on adjacent DCIS in invasive ductal carcinoma, and found that trastuzumab could reduce or eradicate adjacent DCIS, but the result was not specific for trastuzumab [31]. The NSABP B-43 trial, which compares whole-breast irradiation with or without concurrent trastuzumab in HER2-positive DCIS, will determine whether trastuzumab is beneficial in preventing subsequent ipsilateral breast tumor recurrence. In conclusion, within the limitations of this study’s retrospective design and relatively low 5-year local recurrence rate, the addition of a tumor bed boost to standard whole breast RT was not associated with further improvement in local control. The results from ongoing prospective phase III studies will be necessary in order to verify the usefulness of boost RT in DCIS of the breast treated by BCS and WBRT. In addition, careful evaluation of the margin status is needed. Patients with positive for HER2 receptor status may need further treatment with HER2 targeting agents such as trastuzumab. The NSABP B-43 trial results are expected to clarify whether the late treatment is beneficial. Conflict of interest
None.
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