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Comparison of failure patterns between tubular breast carcinoma and invasive ductal carcinoma (KROG 14–25)
The Breast 38 (2018) 165e170
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Original article
Comparison of failure patterns between tubular breast carcinoma and invasive ductal carcinoma (KROG 14e25) Won Kyung Cho a, Doo Ho Choi a, *, Jieun Lee b, Won Park a, Yong Bae Kim c, Chang-Ok Suh c, Kyung Hwan Shin d, Seung Hyuck Jeon d, Kyubo Kim d, e, Kyung Ran Park e, Jin Hee Kim f, Sung Ja Ahn g, Won Sup Yoon h, Dae Sik Yang i, Juree Kim j, Jong Hoon Lee k, Ji Woon Yea l a
Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Graduate School of Korea University, Seoul, Republic of Korea c Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea d Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea e Department of Radiation Oncology, Ewha Womans University School of Medicine, Seoul, Republic of Korea f Department of Radiation Oncology, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Republic of Korea g Department of Radiation Oncology, Chonnam National University Medical School, Gwangju, Republic of Korea h Department of Radiation Oncology, Ansan Hospital, Korea University, Ansan, Republic of Korea i Department of Radiation Oncology, Guro Hospital, Korea University, Seoul, Republic of Korea j Department of Radiation Oncology, Cheil General Hospital and Women's Healthcare Center, Dankook University College of Medicine, Seoul, Republic of Korea k Department of Radiation Oncology, St. Vincent's Hospital, The Catholic University of Korea College of Medicine, Suwon, Republic of Korea l Department of Radiation Oncology, Yeungnam University Medical Center, Daegu, Republic of Korea b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 6 October 2017 Received in revised form 3 January 2018 Accepted 21 January 2018
Purpose: Information on tubular carcinoma (TC) of breast is limited due to its rarity. A multi-institutional study was performed to investigate the prognosis and failure patterns of TC compared to invasive ductal carcinoma (IDC). Materials and methods: We collected retrospective data on 205 patients with TC from eleven institutions. For each TC case, 3 cases with IDC were matched according to similar size, t-stage, and n-stage from the same institution. Patterns of failure, disease free survival (DFS) and overall survival (OS) were assessed and compared between the groups. Results: DFS at 5 years was 98.8% and 97.3% and OS at 5 years was 99.5% and 99.6% in TC and IDC, respectively. Among the patients with TC, 5 patients (2.4%) developed contralateral breast cancer, while 3 patients (0.5%) presented with contralateral breast cancer in patients with IDC. Conclusions: The TC of breast presents an excellent prognosis, but the contralateral breast cancer tends to be more frequently observed compared to IDC in Korean women. © 2018 Elsevier Ltd. All rights reserved.
Keywords: Tubular carcinoma Breast cancer Radiotherapy
1. Introduction Tubular carcinoma (TC) is a rare histologic subtype of breast cancer comprising 2%e5% of all breast carcinomas [1]. Pathologically, TC appears like necklace formed by a string of beads and
* Corresponding author. Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, #81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea. E-mail address: [email protected] (D.H. Choi). https://doi.org/10.1016/j.breast.2018.01.004 0960-9776/© 2018 Elsevier Ltd. All rights reserved.
presents with stellate infiltration [2e5]. It has been reported that over 90 percent of tumors with tubular carcinoma present hormone receptor positive and HER2 negative which indicates favorable oncologic outcomes [6]. Moreover, TC is detected at higher frequency in screening mammography leading to greater detection at earlier stages [7]. Clinically, TC has a low incidence of axillary metastasis, low recurrence rate, and high survival rate compared to invasive ductal carcinoma (IDC) [8,9]. As recently as several years ago, there was no difference between recommended management of TC and IDC in general
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guidelines. However, updated guidelines now recommend considering adjuvant endocrine therapy for TC less than 3 cm and adjuvant chemotherapy is considered for node positive TC [10]. As for axillary management and adjuvant radiotherapy, there is still no specific recommendation for TC but management is usually performed in the same way as with IDC. Recently, several investigators have also examined whether the patients with tubular carcinoma can avoid axillary dissection or even omit radiotherapy. However, the evidence is limited and somewhat inconsistent due to its infrequency of presentation. In this study, we have investigated tumor characteristics, failure patterns, prognostic factors, and optimal treatment of TC compared to IDC using data collected from the Korean Radiation Oncology Group (KROG).
2. Materials and methods 2.1. Patients This study retrospectively reviewed the patients treated in institutions of KROG from January 1999 to December 2012. All participating institutions were approved by their institutional review boards. Female breast cancer patients with pure or mixed (>75%) pathology who received curative treatment were included. Cases involving in situ lesions, distant metastasis (DM) before surgery, and usage of neoadjuvant chemotherapy were excluded.
2.2. TC and IDC matching Counterfactual patients were selected among IDC patients who underwent surgery at the same institution and within the same time period. To minimize the effect of confounding factors: age, tumor size, pathologic tumor stage (pT), and node stage (pN) were matched between IDC and TC. Type of surgery and radiotherapy (RT) were also matched, while axillary lymph node (LN) dissection and sentinel LN biopsy were not divided in cases of pN0. Each case of TC was matched with three control cases of IDC. If there were 5 or more potential controls that matched, the control subjects were arranged in order according to the date of surgery and numbered. A random number generator (www.random.org/integers/) was used to match the patients without further interventions.
2.3. Evaluation and statistical analysis Local recurrence was defined as any recurrence in the ipsilateral breast or chest wall. Regional recurrence was defined as recurrence in the ipsilateral axilla, internal mammary, infraclavicular, or supraclavicular areas. Locoregional recurrence (LRR) was defined as local or regional recurrence and any other recurrence was defined as DM. The distributions of tumor characteristics and treatments between TC and IDC were compared using Chi-square tests. Disease free survival (DFS) was defined as the interval from the date of surgery to the date of recurrence or date of last follow-up. Overall survival (OS) was defined as the interval from the date of surgery to death or last follow-up date. Survival rates were calculated by Kaplan-Meier method and compared by log-rank test for univariate analysis. Multivariate analysis was described by hazard ratio (HR) and 95% confidence interval (CI) was derived from a Cox proportional hazards model. A P-value of 0.05 or less was considered statistically significant. All analyses were conducted using SPSS Statistics version 20 (SPSS Inc., an IBM Company, Chicago, IL).
Table 1 Patient characteristics. Characteristic Age (years) Median (range) Multiplicity Yes No Surgery Total mastectomy Partial mastectomy Axillary LN evaluation Sentinel biopsy Dissection No dissection Tumor size Pathologic T stage T1 T2 Pathologic N stage N0 Nþ Number of dissected LNs Median (range) Resection margin Clear (>1 mm) Close (1 mm) Positive Histologic grade I II-III Unknown Nuclear grade I I-III Unknown LVI Positive Negative Not reported Estrogen receptor Positive Negative Unknown Progesterone receptor Positive Negative Unknown HER2 Positive Negative Unknown Subtype HRþ HER2HRþ HER2þ riple negative HR HER2þ Unknown Radiotherapy Done Not done Chemotherapy Yes No Endocrine therapy Yes No
TC (n ¼ 205)
IDC (n ¼ 615)
48 (35e73)
48 (34e73)
181 (88.3) 24 (11.7)
553 (89.9) 62 (10.1)
31 (15.1) 174 (85.9)
94 (15.3) 521 (84.7)
102 (49.8) 102 (49.8) 1 (0.5) 0.9 (0.2e4.5)
381 (62.0) 230 (37.4) 4 (0.7) 1.0 (0.1e4.3)
199 (97.1) 6 (2.9)
596 (96.9) 19 (3.1)
192 (93.7) 13 (6.3)
585 (95.1) 30 (4.9)
5 (1e33)
5 (0e46)
196 (95.6) 9 (4.4) 0
546(88.8) 59 (9.6) 10 (1.6)
170 (82.9) 3 (1.5) 32 (15.6)
217 (35.3) 384 (62.4) 14 (2.3)
149 (72.7) 33 (16.1) 23 (11.2)
126 (20.5) 173 (79.9) 16 (2.6)
4 (2.0) 162 (79.0) 39 (19.0)
61 (9.9) 458 (74.5) 96 (15.6)
190 (92.7) 15 (7.3) 0
497 (80.8) 117 (19.0) 1 (0.2)
173 (84.4) 32 (15.6) 0
436 (70.9) 117 (19.0) 1 (0.2)
11 (5.4) 187 (91.2) 0
107 (17.4) 478 (77.7) 3 (0.5)
189 (92.2) 11 (5.4) 5 (2.4) 0 0
440 (71.0) 70 (11.4) 64 (10.4) 38 (6.2) 3 (0.5)
167 (81.6) 38 (18.5)
508 (82.6) 107 (17.4)
33 (16.1) 172 (83.9)
297 (48.3) 318 (51.7)
192 (93.7) 13 (6.3)
510 (82.9) 105 (17.1)
p-value
0.511
0.955
0.008
0.907
0.848
0.010
<0.001
<0.001
0.001
<0.001
0.001
<0.001
<0.001
0.451
<0.001
<0.001
TC, tubular carcinoma; IDC, invasive ductal carcinoma; LN, lymph node; HR, hormone receptor.
3. Results 3.1. Patient characteristics A total of 207 women with TC who received curative treatment
W.K. Cho et al. / The Breast 38 (2018) 165e170
167
Table 2 Characteristics and management of patients with lymph node positive tubular carcinoma. Patient No.
Primary tumor size (cm)
Subtypes
Axillary dissection
Number of positive LN
Dissected LNs
SCN RT
1 2 3 4 5 6 7 8 9 10 11 12 13
0.3 4.5 0.9 2.5 0.9 0.9 1.9 1.0 1.0 1.2 0.9 0.7 1.2
HR(þ)Her2() HR(þ)Her2() HR(þ)Her2() HR(þ)Her2() HR(þ)Her2() HR(þ)Her2() Triple negative HR(þ)Her2() HR(þ)Her2() HR(þ)Her2() HR(þ)Her2() HR(þ)Her2() HR(þ)Her2()
ALND ALND ALND ALND ALND SLNB only ALND ALND ALND ALND ALND SLNB only ALND
1 21 1 4 1 2 1 1 1 1 1 2 1
23 21 2 20 9 13 15 1 23 20 9 18 21
0 1 0 1 0 0 0 0 1 1 0 0 0
LN, lymph node; HR, hormone receptor; SCN, supraclavicular node; RT, radiation therapy; ALND, axillary lymph node dissection; SLNB, sentinel lymph node biopsy.
were identified at eleven institutions. Two patients could not be matched with IDC patients. Therefore, a total of 820 patients including 205 with TC and 615 with IDC were ultimately enrolled and analyzed. Patient characteristics according to pathology are described in Table 1. Median age for patients with TC and IDC was 48 (range 35e73) and 48 (range 34e73) years, respectively. Median tumor size was 0.9 cm in TC and 1.0 cm in IDC. No significant differences were observed in the distributions of type of primary tumor surgery, multiplicity, pT stage, and pN stage among groups. While most TC (82.9%) was histologic grade I, only 35.3% of IDC was histologic grade I (p < 0.001). Nuclear grade I was also more frequent in TC than IDC (72.7% vs. 20.5%, p < 0.001). Lymphovascular invasion (LVI) was more frequent in IDC than TC (9.9% vs. 2.0%, p ¼ 0.001). Estrogen receptor (ER) positive and progesterone receptor (PR) positive was more frequent in TC than IDC (ER 92.7% vs.80.8%, p < 0.001 and PR 84.4% vs. 70.9%, p < 0.001) while HER2 positive tumors occurred less frequently in TC than in IDC (5.4% vs. 17.4%, p < 0.001). Finally, among TC patients, 189 (92.2%) patients were HR þ HER2-, 11 (5.4%) were HR þ HER2þ, and 5 (2.4%) were HR þ HER2 while among IDC patients, the subtype distribution was 440 patients in HR þ HER2-, 70 in HR þ HER2þ, 64 in HR-HER2-, 38 in HR-HER2þ, respectively (p < 0.001).
9 patients received whole breast RT. 3.4. Treatment outcomes Of 205 patients with TC, 7 patients developed a recurrence; one patient developed local recurrence in the tumor bed, 1 developed bone metastasis, and 5 patients developed contralateral breast cancer (Table 3). Among the IDC group, 27 patients experienced recurrence; 2 patients developed LRR, 12 developed DM, and 3 patients developed contralateral breast cancer. Excluding the development of contralateral breast cancer, 2 of 205 (1%) of patients developed a recurrence among TC. After a median 69.8 months follow-up period, survival was not different between TC and IDC (5year DFS 98.8% vs. 97.3%, p ¼ 0.506, and 5-year OS 99.5% vs. 99.6%, p ¼ 0.645, Fig. 1A and B). However, if the patients presenting with contralateral breast cancer were categorized as having a new primary cancer, and therefore excluded, DFS was higher in TC than IDC (5-year DFS 100.0% vs. 97.3%, p ¼ 0.038, Fig. 1C). Table 5 shows the characteristics of patients with TC who developed a recurrence. Among the 5 patients who developed contralateral cancer, 4 patients presented with IDC while one patient developed TC, 13.9 months after diagnosis of primary tumor. None of the patients with contralateral tumors had a family history of breast cancer.
3.2. Treatment 3.5. Prognostic factors for tubular carcinoma Among the all patients, 125 patients received total mastectomy while 695 patients received partial mastectomy. There was no difference between TC and IDC based on primary tumor surgical treatment. As for axillary management, TC patients were treated more frequently with axillary dissection than patients with IDC (49.8% vs. 37.4%, p ¼ 0.008). Administration of RT was not different between TC and IDC and neither was tumor bed boost. Chemotherapy was administrated at higher frequency in IDC while hormone therapy was more utilized in TC. Radiotherapy following curative surgery was used for 81.6% of TC and 82.6% of IDC patients (Table 1). 3.3. Lymph node involvement in tubular carcinoma The characteristics and treatment modalities of TC patients with LN involvement is described in Table 2. The median tumor size was 1.0 cm. Only one patient was triple negative and all others were hormone receptor positive and had HER2 negative tumors. 11 of 13 patients underwent axillary LN dissection, while 2 patients received sentinel LN biopsy. The number of positive LNs was one in 9 patients, 2e4 in 3 patients, and 21 in 1 patient. Regional irradiation to the supraclavicular area was performed in 4 patients while
The prognostic significance for disease free survival (DFS) was analyzed for age, pT stage, pN stage, resection margin, histologic grade, nuclear grade, LVI, hormone receptor, radiotherapy, hormone therapy and chemotherapy (Table 4). Univariate analysis for DFS found that age younger than 40 years (p ¼ 0.042) and no administration of hormone therapy (p ¼ 0.006) were unfavorable prognostic factors. 4. Discussion On the basis of a typically favorable prognosis for TC, efforts have been made to diminish unnecessary treatment [11]. Whether axillary dissection is even necessary has been investigated in several studies. Furthermore, some investigators have suggested that surgical staging of axilla may not be necessary for TC of 1 cm or less [11,12]. In contrast, others have proposed that axillary staging should be considered for all patients with TC since small tumors of less than 1 cm also showed nodal involvement [8,13]. This study found that among 13 patients with LN involvement, 6 patients had primary tumors of less than 1 cm. It seems therefore that we should not correlate LN involvement with primary tumor size in TC.
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W.K. Cho et al. / The Breast 38 (2018) 165e170 Table 3 Patterns of failure: tubular carcinoma vs. invasive ductal carcinoma.
Loco regional recurrence Distant metastasis Contralateral breast cancer Total recurrence
Tubular carcinoma (n ¼ 205)
Invasive ductal carcinoma (n ¼ 615)
1 1 5 7
2 (0.3%) 22 (3.6%) 3 (0.5%) 27 (4.3%)
(0.5%) (0.5%) (2.4%) (3.4%)
Fig. 1. (A) Disease free survival of tubular carcinoma and invasive ductal carcinoma when development of contralateral breast cancer is considered as an event. (B) Overall survival of tubular carcinoma and invasive ductal carcinoma. (C) Disease free survival of tubular carcinoma and invasive ductal carcinoma when the contralateral breast cancer is excluded from disease recurrence.
However, the question of whether axillary dissection would be mandatory is still debatable since most node positive TC still exhibited good prognosis. Lea et al. analyzed 146 patients with TC and reported that nodal status was not a prognostic factor for recurrence, in the light of all 8 recurrent patients being node negative [14,15]. Likewise, no patient with LN involvement in this study developed a recurrence and LN positivity was not a prognostic factor. Administration of RT is often considered beneficial in TC. Irradiated patients showed higher 10 year survival rate compared to a non-irradiated group (85.9% vs. 76.3%, p ¼ 0.035) [16]. Sullivan et al. indicated that adjuvant RT in younger TC patients was beneficial for local control while in patients over 65 it was not [13]. In the current study, RT was not a significant factor for recurrence. Neither regional irradiation nor tumor bed boost was associated with better local control. However, the majority of patients (82.3%) received RT, and patients underwent both partial mastectomy and total mastectomy, so we cannot conclude that we can omit RT in TC based on this analysis. Rather, in further study, we can try to examine if less aggressive RT such as omission of regional RT or tumor bed boost, or partial breast irradiation would be possible for TC. We should not offer chemotherapy routinely in TC patients since there was only one patient who presented with a distant metastasis even though over 83.9% of patients had no adjuvant chemotherapy [9]. On the other hand, hormone therapy is considered to be mandatory for hormone receptor positive TC. Among 8 patients who had positive hormone receptor but did not receive hormone therapy, 3 developed a recurrence and hormone therapy was a prognostic factor for recurrence in univariate analysis although it was not significant in multivariate analysis (p ¼ 0.064). Several studies have reported that adjuvant hormone therapy is not beneficial for TC [9,15e17]. On the other hand, a prospective study which evaluated hormone therapy showed that the benefit of tamoxifen was most prominent in TC [18]. Notably, this study showed that 5 of 7 recurrent patients presented with contralateral breast cancer (Table 5). Contralateral breast malignancy is defined as a new primary cancer when either
in situ lesions or different histological types are identified in the contralateral breast of breast cancer patients [19]. Otherwise, if there is no evidence of LRR or DM of primary breast cancer, the contralateral breast cancer is also considered to be second primary cancer [20]. Since 4 of 5 recurrent TC patients developed as IDC and all of these cases exhibited an absence of recurrence of the primary cancer, we considered them to be a new primary cancer. Possible risk factors for contralateral breast cancer are family history, age under 45, and use of hormonal therapy [21]. Among various
Table 4 Prognostic factors for recurrence free survival in tubular carcinoma in univariate analysis. Factors
Variables
5 year DFS
p
Age
40 years >40 years pT1 pT2 pN0 pNþ >1 mm 1 mm I II-II I II-III Positive Negative Positive Negative Positive Negative Positive Negative Done Not done Done Not done Done Not done
90.2% 97.0% 98.8% 100% 98.8% 100% 98.8% 100% 98.2% 100% 99.3% 96.3% 100% 99.4% 98.8% 100.0% 99.3% 96.8% 100.0% 98.8% 98.7% 100.0% 99.3% 92.3% 100.0% 98.7%
0.042
pT stage pN stage Resection margin Histologic grade Nuclear grade LVI Estrogen receptor Progesterone receptor HER2 Radiation therapy Hormone therapy Chemotherapy
DFS, disease free survival; LVI, lymphovascular invasion.
0.651 0.579 0.589 0.933 0.211 0.807 0.246 0.523 0.300 0.294 0.006 0.574
W.K. Cho et al. / The Breast 38 (2018) 165e170
169
Table 5 Characteristics and treatment of patients with tubular carcinoma who developed recurrence. Patient No.
Age
FHx
Initial tumor stage
Subtype
HT
RT
Type of recurrence
Pathology of recurrent tumor
Time to recurrence (months)
1 2 3 4
37 38 40 56
0 0 1 0
pT1(1.0)N0 pT1(0.8)N0 pT1(0.8)N0 pT1(1.0)N0
HR(þ)Her2(þ) HR(þ)Her2() HR(þ)Her2(þ) HR(þ)Her2()
0 0 0 1
1 1 1 1
IDC TC IDC IDC
162.9 13.9 104.5 131.2
5
50
0
pT1(1.5)N0
HR(þ)Her2()
1
1
IDC
62.0
6
43
0
pT1(1.1)N0
HR(þ)Her2()
1
1
IDC
43.1
7
44
e
pT1(1.2)N0
HR(þ)Her2()
1
1
Contralateral breast Contralateral breast Ipsilateral breast Contralateral breast Contralateral breast Contralateral breast Bone
e
83.7
FHx, family history; HT, hormone therapy; RT, radiation therapy; HR, hormone receptor; IDC, invasive ductal carcinoma; TC, tubular carcinoma.
histologic types of breast cancer, lobular carcinoma or medullary carcinoma are usually reported to be at higher risk of contralateral breast cancer while there is no established relationship between tubular subtype and contralateral breast cancer [22,23]. A previous study reported that there was no difference in the risk of contralateral breast cancer between IDC and TC [24]. However, a recent study indicated that patients with TC are at risk of developing malignancy in the contralateral breast and reported that 5 of 13 recurrent TC were in contralateral breast [9]. Gunham et al. analyzed 32 patients with TC and among them, four patients developed contralateral breast cancer at follow-up [25]. A possible reason for higher incidence of contralateral breast cancer in TC patients is less intensive endocrine therapy or chemotherapy in view of favorable prognosis of TC. In this study, only two patients having hormone receptor positive TC omitted hormone therapy, all of whom developed contralateral recurrence. Genetic background is another conceivable explanation. BRCA mutation, which presents mainly in IDC and have been reported to be frequent in medullary carcinoma, is a risk factor for the increased risk of contralateral breast cancer. On the other hand, the BRCA mutation is not frequently reported in TC and there might be other genetic factors associated with contralateral breast cancer in TC. However, first of all, more concrete evidence to validate the higher incidence of contralateral breast cancer in TC compared to IDC needs to be accumulated by further studies. This study has a few limitations. Firstly, central review of pathology was not performed. However, all seven institutions of KROG are academic hospitals in which highly experienced pathologists review the slides. Secondly, subtype classification was not based on gene expression and Ki-67 but stratified according to ER/ PR and HER2 status. Nevertheless, the current study included a large cohort with tubular carcinoma and detailed information. The largest study of TC is SEER data but it lacks information such as HER2-status, use of endocrine therapy, or chemotherapy. One wellreviewed study from a single institution compared 102 TC patients with 212 low grade IDC patients and showed results consistent with this study, reporting that TC patients achieved higher survival rates and higher incidence of contralateral breast cancer compared with low grade IDC [9]. With a larger cohort of 215 patients, we also revealed the frequent development of contralateral breast cancer in TC. In summary, TC has an extremely low recurrence rate and high survival rates even including those with LN positive tumors. However, contralateral breast cancer tends to be more frequently observed compared to IDC in Korean women. Further studies to endorse the result are warranted. Conflicts of interest There are no conflicts of interest relevant to this article.
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Original article
Comparison of failure patterns between tubular breast carcinoma and invasive ductal carcinoma (KROG 14e25) Won Kyung Cho a, Doo Ho Choi a, *, Jieun Lee b, Won Park a, Yong Bae Kim c, Chang-Ok Suh c, Kyung Hwan Shin d, Seung Hyuck Jeon d, Kyubo Kim d, e, Kyung Ran Park e, Jin Hee Kim f, Sung Ja Ahn g, Won Sup Yoon h, Dae Sik Yang i, Juree Kim j, Jong Hoon Lee k, Ji Woon Yea l a
Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Graduate School of Korea University, Seoul, Republic of Korea c Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea d Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea e Department of Radiation Oncology, Ewha Womans University School of Medicine, Seoul, Republic of Korea f Department of Radiation Oncology, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Republic of Korea g Department of Radiation Oncology, Chonnam National University Medical School, Gwangju, Republic of Korea h Department of Radiation Oncology, Ansan Hospital, Korea University, Ansan, Republic of Korea i Department of Radiation Oncology, Guro Hospital, Korea University, Seoul, Republic of Korea j Department of Radiation Oncology, Cheil General Hospital and Women's Healthcare Center, Dankook University College of Medicine, Seoul, Republic of Korea k Department of Radiation Oncology, St. Vincent's Hospital, The Catholic University of Korea College of Medicine, Suwon, Republic of Korea l Department of Radiation Oncology, Yeungnam University Medical Center, Daegu, Republic of Korea b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 6 October 2017 Received in revised form 3 January 2018 Accepted 21 January 2018
Purpose: Information on tubular carcinoma (TC) of breast is limited due to its rarity. A multi-institutional study was performed to investigate the prognosis and failure patterns of TC compared to invasive ductal carcinoma (IDC). Materials and methods: We collected retrospective data on 205 patients with TC from eleven institutions. For each TC case, 3 cases with IDC were matched according to similar size, t-stage, and n-stage from the same institution. Patterns of failure, disease free survival (DFS) and overall survival (OS) were assessed and compared between the groups. Results: DFS at 5 years was 98.8% and 97.3% and OS at 5 years was 99.5% and 99.6% in TC and IDC, respectively. Among the patients with TC, 5 patients (2.4%) developed contralateral breast cancer, while 3 patients (0.5%) presented with contralateral breast cancer in patients with IDC. Conclusions: The TC of breast presents an excellent prognosis, but the contralateral breast cancer tends to be more frequently observed compared to IDC in Korean women. © 2018 Elsevier Ltd. All rights reserved.
Keywords: Tubular carcinoma Breast cancer Radiotherapy
1. Introduction Tubular carcinoma (TC) is a rare histologic subtype of breast cancer comprising 2%e5% of all breast carcinomas [1]. Pathologically, TC appears like necklace formed by a string of beads and
* Corresponding author. Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, #81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea. E-mail address: [email protected] (D.H. Choi). https://doi.org/10.1016/j.breast.2018.01.004 0960-9776/© 2018 Elsevier Ltd. All rights reserved.
presents with stellate infiltration [2e5]. It has been reported that over 90 percent of tumors with tubular carcinoma present hormone receptor positive and HER2 negative which indicates favorable oncologic outcomes [6]. Moreover, TC is detected at higher frequency in screening mammography leading to greater detection at earlier stages [7]. Clinically, TC has a low incidence of axillary metastasis, low recurrence rate, and high survival rate compared to invasive ductal carcinoma (IDC) [8,9]. As recently as several years ago, there was no difference between recommended management of TC and IDC in general
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guidelines. However, updated guidelines now recommend considering adjuvant endocrine therapy for TC less than 3 cm and adjuvant chemotherapy is considered for node positive TC [10]. As for axillary management and adjuvant radiotherapy, there is still no specific recommendation for TC but management is usually performed in the same way as with IDC. Recently, several investigators have also examined whether the patients with tubular carcinoma can avoid axillary dissection or even omit radiotherapy. However, the evidence is limited and somewhat inconsistent due to its infrequency of presentation. In this study, we have investigated tumor characteristics, failure patterns, prognostic factors, and optimal treatment of TC compared to IDC using data collected from the Korean Radiation Oncology Group (KROG).
2. Materials and methods 2.1. Patients This study retrospectively reviewed the patients treated in institutions of KROG from January 1999 to December 2012. All participating institutions were approved by their institutional review boards. Female breast cancer patients with pure or mixed (>75%) pathology who received curative treatment were included. Cases involving in situ lesions, distant metastasis (DM) before surgery, and usage of neoadjuvant chemotherapy were excluded.
2.2. TC and IDC matching Counterfactual patients were selected among IDC patients who underwent surgery at the same institution and within the same time period. To minimize the effect of confounding factors: age, tumor size, pathologic tumor stage (pT), and node stage (pN) were matched between IDC and TC. Type of surgery and radiotherapy (RT) were also matched, while axillary lymph node (LN) dissection and sentinel LN biopsy were not divided in cases of pN0. Each case of TC was matched with three control cases of IDC. If there were 5 or more potential controls that matched, the control subjects were arranged in order according to the date of surgery and numbered. A random number generator (www.random.org/integers/) was used to match the patients without further interventions.
2.3. Evaluation and statistical analysis Local recurrence was defined as any recurrence in the ipsilateral breast or chest wall. Regional recurrence was defined as recurrence in the ipsilateral axilla, internal mammary, infraclavicular, or supraclavicular areas. Locoregional recurrence (LRR) was defined as local or regional recurrence and any other recurrence was defined as DM. The distributions of tumor characteristics and treatments between TC and IDC were compared using Chi-square tests. Disease free survival (DFS) was defined as the interval from the date of surgery to the date of recurrence or date of last follow-up. Overall survival (OS) was defined as the interval from the date of surgery to death or last follow-up date. Survival rates were calculated by Kaplan-Meier method and compared by log-rank test for univariate analysis. Multivariate analysis was described by hazard ratio (HR) and 95% confidence interval (CI) was derived from a Cox proportional hazards model. A P-value of 0.05 or less was considered statistically significant. All analyses were conducted using SPSS Statistics version 20 (SPSS Inc., an IBM Company, Chicago, IL).
Table 1 Patient characteristics. Characteristic Age (years) Median (range) Multiplicity Yes No Surgery Total mastectomy Partial mastectomy Axillary LN evaluation Sentinel biopsy Dissection No dissection Tumor size Pathologic T stage T1 T2 Pathologic N stage N0 Nþ Number of dissected LNs Median (range) Resection margin Clear (>1 mm) Close (1 mm) Positive Histologic grade I II-III Unknown Nuclear grade I I-III Unknown LVI Positive Negative Not reported Estrogen receptor Positive Negative Unknown Progesterone receptor Positive Negative Unknown HER2 Positive Negative Unknown Subtype HRþ HER2HRþ HER2þ riple negative HR HER2þ Unknown Radiotherapy Done Not done Chemotherapy Yes No Endocrine therapy Yes No
TC (n ¼ 205)
IDC (n ¼ 615)
48 (35e73)
48 (34e73)
181 (88.3) 24 (11.7)
553 (89.9) 62 (10.1)
31 (15.1) 174 (85.9)
94 (15.3) 521 (84.7)
102 (49.8) 102 (49.8) 1 (0.5) 0.9 (0.2e4.5)
381 (62.0) 230 (37.4) 4 (0.7) 1.0 (0.1e4.3)
199 (97.1) 6 (2.9)
596 (96.9) 19 (3.1)
192 (93.7) 13 (6.3)
585 (95.1) 30 (4.9)
5 (1e33)
5 (0e46)
196 (95.6) 9 (4.4) 0
546(88.8) 59 (9.6) 10 (1.6)
170 (82.9) 3 (1.5) 32 (15.6)
217 (35.3) 384 (62.4) 14 (2.3)
149 (72.7) 33 (16.1) 23 (11.2)
126 (20.5) 173 (79.9) 16 (2.6)
4 (2.0) 162 (79.0) 39 (19.0)
61 (9.9) 458 (74.5) 96 (15.6)
190 (92.7) 15 (7.3) 0
497 (80.8) 117 (19.0) 1 (0.2)
173 (84.4) 32 (15.6) 0
436 (70.9) 117 (19.0) 1 (0.2)
11 (5.4) 187 (91.2) 0
107 (17.4) 478 (77.7) 3 (0.5)
189 (92.2) 11 (5.4) 5 (2.4) 0 0
440 (71.0) 70 (11.4) 64 (10.4) 38 (6.2) 3 (0.5)
167 (81.6) 38 (18.5)
508 (82.6) 107 (17.4)
33 (16.1) 172 (83.9)
297 (48.3) 318 (51.7)
192 (93.7) 13 (6.3)
510 (82.9) 105 (17.1)
p-value
0.511
0.955
0.008
0.907
0.848
0.010
<0.001
<0.001
0.001
<0.001
0.001
<0.001
<0.001
0.451
<0.001
<0.001
TC, tubular carcinoma; IDC, invasive ductal carcinoma; LN, lymph node; HR, hormone receptor.
3. Results 3.1. Patient characteristics A total of 207 women with TC who received curative treatment
W.K. Cho et al. / The Breast 38 (2018) 165e170
167
Table 2 Characteristics and management of patients with lymph node positive tubular carcinoma. Patient No.
Primary tumor size (cm)
Subtypes
Axillary dissection
Number of positive LN
Dissected LNs
SCN RT
1 2 3 4 5 6 7 8 9 10 11 12 13
0.3 4.5 0.9 2.5 0.9 0.9 1.9 1.0 1.0 1.2 0.9 0.7 1.2
HR(þ)Her2() HR(þ)Her2() HR(þ)Her2() HR(þ)Her2() HR(þ)Her2() HR(þ)Her2() Triple negative HR(þ)Her2() HR(þ)Her2() HR(þ)Her2() HR(þ)Her2() HR(þ)Her2() HR(þ)Her2()
ALND ALND ALND ALND ALND SLNB only ALND ALND ALND ALND ALND SLNB only ALND
1 21 1 4 1 2 1 1 1 1 1 2 1
23 21 2 20 9 13 15 1 23 20 9 18 21
0 1 0 1 0 0 0 0 1 1 0 0 0
LN, lymph node; HR, hormone receptor; SCN, supraclavicular node; RT, radiation therapy; ALND, axillary lymph node dissection; SLNB, sentinel lymph node biopsy.
were identified at eleven institutions. Two patients could not be matched with IDC patients. Therefore, a total of 820 patients including 205 with TC and 615 with IDC were ultimately enrolled and analyzed. Patient characteristics according to pathology are described in Table 1. Median age for patients with TC and IDC was 48 (range 35e73) and 48 (range 34e73) years, respectively. Median tumor size was 0.9 cm in TC and 1.0 cm in IDC. No significant differences were observed in the distributions of type of primary tumor surgery, multiplicity, pT stage, and pN stage among groups. While most TC (82.9%) was histologic grade I, only 35.3% of IDC was histologic grade I (p < 0.001). Nuclear grade I was also more frequent in TC than IDC (72.7% vs. 20.5%, p < 0.001). Lymphovascular invasion (LVI) was more frequent in IDC than TC (9.9% vs. 2.0%, p ¼ 0.001). Estrogen receptor (ER) positive and progesterone receptor (PR) positive was more frequent in TC than IDC (ER 92.7% vs.80.8%, p < 0.001 and PR 84.4% vs. 70.9%, p < 0.001) while HER2 positive tumors occurred less frequently in TC than in IDC (5.4% vs. 17.4%, p < 0.001). Finally, among TC patients, 189 (92.2%) patients were HR þ HER2-, 11 (5.4%) were HR þ HER2þ, and 5 (2.4%) were HR þ HER2 while among IDC patients, the subtype distribution was 440 patients in HR þ HER2-, 70 in HR þ HER2þ, 64 in HR-HER2-, 38 in HR-HER2þ, respectively (p < 0.001).
9 patients received whole breast RT. 3.4. Treatment outcomes Of 205 patients with TC, 7 patients developed a recurrence; one patient developed local recurrence in the tumor bed, 1 developed bone metastasis, and 5 patients developed contralateral breast cancer (Table 3). Among the IDC group, 27 patients experienced recurrence; 2 patients developed LRR, 12 developed DM, and 3 patients developed contralateral breast cancer. Excluding the development of contralateral breast cancer, 2 of 205 (1%) of patients developed a recurrence among TC. After a median 69.8 months follow-up period, survival was not different between TC and IDC (5year DFS 98.8% vs. 97.3%, p ¼ 0.506, and 5-year OS 99.5% vs. 99.6%, p ¼ 0.645, Fig. 1A and B). However, if the patients presenting with contralateral breast cancer were categorized as having a new primary cancer, and therefore excluded, DFS was higher in TC than IDC (5-year DFS 100.0% vs. 97.3%, p ¼ 0.038, Fig. 1C). Table 5 shows the characteristics of patients with TC who developed a recurrence. Among the 5 patients who developed contralateral cancer, 4 patients presented with IDC while one patient developed TC, 13.9 months after diagnosis of primary tumor. None of the patients with contralateral tumors had a family history of breast cancer.
3.2. Treatment 3.5. Prognostic factors for tubular carcinoma Among the all patients, 125 patients received total mastectomy while 695 patients received partial mastectomy. There was no difference between TC and IDC based on primary tumor surgical treatment. As for axillary management, TC patients were treated more frequently with axillary dissection than patients with IDC (49.8% vs. 37.4%, p ¼ 0.008). Administration of RT was not different between TC and IDC and neither was tumor bed boost. Chemotherapy was administrated at higher frequency in IDC while hormone therapy was more utilized in TC. Radiotherapy following curative surgery was used for 81.6% of TC and 82.6% of IDC patients (Table 1). 3.3. Lymph node involvement in tubular carcinoma The characteristics and treatment modalities of TC patients with LN involvement is described in Table 2. The median tumor size was 1.0 cm. Only one patient was triple negative and all others were hormone receptor positive and had HER2 negative tumors. 11 of 13 patients underwent axillary LN dissection, while 2 patients received sentinel LN biopsy. The number of positive LNs was one in 9 patients, 2e4 in 3 patients, and 21 in 1 patient. Regional irradiation to the supraclavicular area was performed in 4 patients while
The prognostic significance for disease free survival (DFS) was analyzed for age, pT stage, pN stage, resection margin, histologic grade, nuclear grade, LVI, hormone receptor, radiotherapy, hormone therapy and chemotherapy (Table 4). Univariate analysis for DFS found that age younger than 40 years (p ¼ 0.042) and no administration of hormone therapy (p ¼ 0.006) were unfavorable prognostic factors. 4. Discussion On the basis of a typically favorable prognosis for TC, efforts have been made to diminish unnecessary treatment [11]. Whether axillary dissection is even necessary has been investigated in several studies. Furthermore, some investigators have suggested that surgical staging of axilla may not be necessary for TC of 1 cm or less [11,12]. In contrast, others have proposed that axillary staging should be considered for all patients with TC since small tumors of less than 1 cm also showed nodal involvement [8,13]. This study found that among 13 patients with LN involvement, 6 patients had primary tumors of less than 1 cm. It seems therefore that we should not correlate LN involvement with primary tumor size in TC.
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W.K. Cho et al. / The Breast 38 (2018) 165e170 Table 3 Patterns of failure: tubular carcinoma vs. invasive ductal carcinoma.
Loco regional recurrence Distant metastasis Contralateral breast cancer Total recurrence
Tubular carcinoma (n ¼ 205)
Invasive ductal carcinoma (n ¼ 615)
1 1 5 7
2 (0.3%) 22 (3.6%) 3 (0.5%) 27 (4.3%)
(0.5%) (0.5%) (2.4%) (3.4%)
Fig. 1. (A) Disease free survival of tubular carcinoma and invasive ductal carcinoma when development of contralateral breast cancer is considered as an event. (B) Overall survival of tubular carcinoma and invasive ductal carcinoma. (C) Disease free survival of tubular carcinoma and invasive ductal carcinoma when the contralateral breast cancer is excluded from disease recurrence.
However, the question of whether axillary dissection would be mandatory is still debatable since most node positive TC still exhibited good prognosis. Lea et al. analyzed 146 patients with TC and reported that nodal status was not a prognostic factor for recurrence, in the light of all 8 recurrent patients being node negative [14,15]. Likewise, no patient with LN involvement in this study developed a recurrence and LN positivity was not a prognostic factor. Administration of RT is often considered beneficial in TC. Irradiated patients showed higher 10 year survival rate compared to a non-irradiated group (85.9% vs. 76.3%, p ¼ 0.035) [16]. Sullivan et al. indicated that adjuvant RT in younger TC patients was beneficial for local control while in patients over 65 it was not [13]. In the current study, RT was not a significant factor for recurrence. Neither regional irradiation nor tumor bed boost was associated with better local control. However, the majority of patients (82.3%) received RT, and patients underwent both partial mastectomy and total mastectomy, so we cannot conclude that we can omit RT in TC based on this analysis. Rather, in further study, we can try to examine if less aggressive RT such as omission of regional RT or tumor bed boost, or partial breast irradiation would be possible for TC. We should not offer chemotherapy routinely in TC patients since there was only one patient who presented with a distant metastasis even though over 83.9% of patients had no adjuvant chemotherapy [9]. On the other hand, hormone therapy is considered to be mandatory for hormone receptor positive TC. Among 8 patients who had positive hormone receptor but did not receive hormone therapy, 3 developed a recurrence and hormone therapy was a prognostic factor for recurrence in univariate analysis although it was not significant in multivariate analysis (p ¼ 0.064). Several studies have reported that adjuvant hormone therapy is not beneficial for TC [9,15e17]. On the other hand, a prospective study which evaluated hormone therapy showed that the benefit of tamoxifen was most prominent in TC [18]. Notably, this study showed that 5 of 7 recurrent patients presented with contralateral breast cancer (Table 5). Contralateral breast malignancy is defined as a new primary cancer when either
in situ lesions or different histological types are identified in the contralateral breast of breast cancer patients [19]. Otherwise, if there is no evidence of LRR or DM of primary breast cancer, the contralateral breast cancer is also considered to be second primary cancer [20]. Since 4 of 5 recurrent TC patients developed as IDC and all of these cases exhibited an absence of recurrence of the primary cancer, we considered them to be a new primary cancer. Possible risk factors for contralateral breast cancer are family history, age under 45, and use of hormonal therapy [21]. Among various
Table 4 Prognostic factors for recurrence free survival in tubular carcinoma in univariate analysis. Factors
Variables
5 year DFS
p
Age
40 years >40 years pT1 pT2 pN0 pNþ >1 mm 1 mm I II-II I II-III Positive Negative Positive Negative Positive Negative Positive Negative Done Not done Done Not done Done Not done
90.2% 97.0% 98.8% 100% 98.8% 100% 98.8% 100% 98.2% 100% 99.3% 96.3% 100% 99.4% 98.8% 100.0% 99.3% 96.8% 100.0% 98.8% 98.7% 100.0% 99.3% 92.3% 100.0% 98.7%
0.042
pT stage pN stage Resection margin Histologic grade Nuclear grade LVI Estrogen receptor Progesterone receptor HER2 Radiation therapy Hormone therapy Chemotherapy
DFS, disease free survival; LVI, lymphovascular invasion.
0.651 0.579 0.589 0.933 0.211 0.807 0.246 0.523 0.300 0.294 0.006 0.574
W.K. Cho et al. / The Breast 38 (2018) 165e170
169
Table 5 Characteristics and treatment of patients with tubular carcinoma who developed recurrence. Patient No.
Age
FHx
Initial tumor stage
Subtype
HT
RT
Type of recurrence
Pathology of recurrent tumor
Time to recurrence (months)
1 2 3 4
37 38 40 56
0 0 1 0
pT1(1.0)N0 pT1(0.8)N0 pT1(0.8)N0 pT1(1.0)N0
HR(þ)Her2(þ) HR(þ)Her2() HR(þ)Her2(þ) HR(þ)Her2()
0 0 0 1
1 1 1 1
IDC TC IDC IDC
162.9 13.9 104.5 131.2
5
50
0
pT1(1.5)N0
HR(þ)Her2()
1
1
IDC
62.0
6
43
0
pT1(1.1)N0
HR(þ)Her2()
1
1
IDC
43.1
7
44
e
pT1(1.2)N0
HR(þ)Her2()
1
1
Contralateral breast Contralateral breast Ipsilateral breast Contralateral breast Contralateral breast Contralateral breast Bone
e
83.7
FHx, family history; HT, hormone therapy; RT, radiation therapy; HR, hormone receptor; IDC, invasive ductal carcinoma; TC, tubular carcinoma.
histologic types of breast cancer, lobular carcinoma or medullary carcinoma are usually reported to be at higher risk of contralateral breast cancer while there is no established relationship between tubular subtype and contralateral breast cancer [22,23]. A previous study reported that there was no difference in the risk of contralateral breast cancer between IDC and TC [24]. However, a recent study indicated that patients with TC are at risk of developing malignancy in the contralateral breast and reported that 5 of 13 recurrent TC were in contralateral breast [9]. Gunham et al. analyzed 32 patients with TC and among them, four patients developed contralateral breast cancer at follow-up [25]. A possible reason for higher incidence of contralateral breast cancer in TC patients is less intensive endocrine therapy or chemotherapy in view of favorable prognosis of TC. In this study, only two patients having hormone receptor positive TC omitted hormone therapy, all of whom developed contralateral recurrence. Genetic background is another conceivable explanation. BRCA mutation, which presents mainly in IDC and have been reported to be frequent in medullary carcinoma, is a risk factor for the increased risk of contralateral breast cancer. On the other hand, the BRCA mutation is not frequently reported in TC and there might be other genetic factors associated with contralateral breast cancer in TC. However, first of all, more concrete evidence to validate the higher incidence of contralateral breast cancer in TC compared to IDC needs to be accumulated by further studies. This study has a few limitations. Firstly, central review of pathology was not performed. However, all seven institutions of KROG are academic hospitals in which highly experienced pathologists review the slides. Secondly, subtype classification was not based on gene expression and Ki-67 but stratified according to ER/ PR and HER2 status. Nevertheless, the current study included a large cohort with tubular carcinoma and detailed information. The largest study of TC is SEER data but it lacks information such as HER2-status, use of endocrine therapy, or chemotherapy. One wellreviewed study from a single institution compared 102 TC patients with 212 low grade IDC patients and showed results consistent with this study, reporting that TC patients achieved higher survival rates and higher incidence of contralateral breast cancer compared with low grade IDC [9]. With a larger cohort of 215 patients, we also revealed the frequent development of contralateral breast cancer in TC. In summary, TC has an extremely low recurrence rate and high survival rates even including those with LN positive tumors. However, contralateral breast cancer tends to be more frequently observed compared to IDC in Korean women. Further studies to endorse the result are warranted. Conflicts of interest There are no conflicts of interest relevant to this article.
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