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Triple-Negative or HER2-Positive Status Predicts Higher Rates of Locoregional Recurrence in Node-Positive Breast Cancer Patients After Mastectomy
Int. J. Radiation Oncology Biol. Phys., Vol. 80, No. 4, pp. 1095–1101, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter
doi:10.1016/j.ijrobp.2010.03.038
CLINICAL INVESTIGATION
Breast
TRIPLE-NEGATIVE OR HER2-POSITIVE STATUS PREDICTS HIGHER RATES OF LOCOREGIONAL RECURRENCE IN NODE-POSITIVE BREAST CANCER PATIENTS AFTER MASTECTOMY SHU-LIAN WANG, M.D., YE-XIONG LI, M.D., YONG-WEN SONG, M.D., WEI-HU WANG, M.D., JING JIN, M.D., YUE-PING LIU, M.D., XIN-FAN LIU, M.D., AND ZI-HAO YU, M.D. Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China Purpose: To evaluate the prognostic value of determining estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression in node-positive breast cancer patients treated with mastectomy. Methods and Materials: The records of 835 node-positive breast cancer patients who had undergone mastectomy between January 2000 and December 2004 were analyzed retrospectively. Of these, 764 patients (91.5%) received chemotherapy; 68 of 398 patients (20.9%) with T1–2N1 disease and 352 of 437 patients (80.5%) with T3–4 or N2–3 disease received postoperative radiotherapy. Patients were classified into four subgroups according to hormone receptor (Rec+ or Rec-) and HER2 expression profiles: Rec-/HER2- (triple negative; n = 141), Rec-/HER2+ (n = 99), Rec+/HER2+ (n = 157), and Rec+/HER2- (n = 438). The endpoints were the duration of locoregional recurrence–free survival, distant metastasis–free survival, disease-free survival, and overall survival. Results: Patients with triple-negative, Rec-/HER2+, and Rec+/HER2+ expression profiles had a significantly lower 5-year locoregional recurrence-free survival than those with Rec+/HER2- profiles (86.5% vs. 93.6%, p = 0.002). Compared with those with Rec+/HER2+ and Rec+/HER2- profiles, patients with Rec-/HER2- and Rec-/HER2+ profiles had significantly lower 5-year distant metastasis–free survival (69.1% vs. 78.5%, p = 0.000), lower disease-free survival (66.6% vs. 75.6%, p = 0.000), and lower overall survival (71.4% vs. 84.2%, p = 0.000). Triple-negative or Rec-/HER2+ breast cancers had an increased likelihood of relapse and death within the first 3 years after treatment. Conclusions: Triple-negative and HER2-positive profiles are useful markers of prognosis for locoregional recurrence and survival in node-positive breast cancer patients treated with mastectomy. Ó 2011 Elsevier Inc. Breast neoplasm, Prognosis, Estrogen receptor, Progesterone receptor, Human epidermal growth factor 2.
these patients, they all seem to agree with the outcome prediction for this subtype (4). For these observations to be used in large-scale clinical applications or retrospective studies, the immunohistochemical (IHC) staining profile can be a useful surrogate of gene expression analysis with the use of formalin-fixed, paraffinembedded samples. Basal-like tumors are usually triplenegative (TN) tumors because they lack the expression of both hormone receptors (ER and progesterone receptors [PR]; Rec-) and HER2. The HER2-overexpressing subtypes refer to predominantly hormone receptor–negative tumors with HER2 gene expression (Rec-/HER2+). Luminal subtypes make up the hormone receptor–expressing tumors (Rec+). Therefore, a simplified method of classification based on IHC staining of ER, PR, and HER2 is useful clinically.
INTRODUCTION Breast cancer is a heterogeneous disease, which has been classified into five distinct molecular subgroups with different prognoses by gene expression profiling (1). These molecular subgroups include basal-like and human epidermal growth factor 2 (HER2)-overexpressing breast cancers, which have poor outcomes, and the luminal-type of breast cancer that has a favorable prognosis (1–3). A recent comparison between cancers with different gene expression prognostic signatures has revealed that almost all patients with basal-like or HER2+ and estrogen receptor negative (ER-) breast cancers have high recurrence scores, poor 70gene profiles, and activated wound response signatures. Regardless of the different gene sets that were used to classify Reprint requests to: Ye-Xiong Li, M.D., Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Tel: (+86) 10-87788860; Fax: (+86) 10-67706153; E-mail: yexiong@ yahoo.com
Presented in poster form at the 51st Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 31– November 4, 2009, Chicago, IL. Conflict of interest: none. Received Feb 4, 2010, and in revised form March 17, 2010. Accepted for publication March 29, 2010. 1095
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Although basal-like TN tumors have been reported to have higher rates of distant metastases and mortality (1, 3, 5–8), there are only limited and controversial data of their impact on the rate of locoregional recurrence (LRR) (6, 8–10). The purpose of the present study was to investigate the impact of ER, PR, and HER2 expression by the tumor on the prognosis of node-positive breast cancer patients treated with mastectomy, with particular regard to the rate of LRR. METHODS AND MATERIALS Patient selection and evaluation The medical records of all consecutive breast cancer patients treated at the Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College between January 2000 and December 2004 were analyzed retrospectively. Patients were eligible for the present study if they met the following inclusion criteria: pathologically confirmed invasive breast cancer by mastectomy with available data for ER, PR, and HER2 expression from IHC staining techniques, with positive lymph nodes. The exclusion criteria included the presence of distant metastases. A total of 835 patients satisfied the inclusion criteria and were included in the cohort of the study. Pretreatment evaluations included a complete medical history and physical examination, complete blood count and biochemistry profiles, mammography and/or breast ultrasonography, chest X-ray, an abdominopelvic computed tomography scan and/or ultrasonography, and a bone scan if indicated. The 2002 American Joint Committee on Cancer Manual for Staging of Cancer was used for staging (11).
Treatment All patients were treated with mastectomy and axillary dissection. Adjuvant chemotherapy and/or radiotherapy were based on the National Comprehensive Cancer Network practice guideline. All patients with hormone receptor–positive tumors received hormone therapy. Postmastectomy radiotherapy was recommended for patients with T3–T4 and/or N2–N3 tumors, whereas it was optional for patients with T1–T2N1 tumors. Overall, 764 patients (91.5%) received chemotherapy, whereas 352 of 437 patients (80.5%) with T3–4 or N2–3 disease and 68 of 398 patients (20.9%) with T1–2N1 disease received postoperative radiotherapy. Chemotherapy regimens were anthracycline-based for 415 patients, anthracycline plus taxanes for 263, taxane-based for 4 patients, other regimens for 29, and unknown in the case of 53 patients. Four hundred sixty-four patients (55.6%) received hormonal therapy as well. Trastuzumab was administered to 8 patients (1%). Radiotherapy was given with a 6-MV linear accelerator. Radiotherapy was mainly delivered to the ipsilateral chest wall and supraclavicular region of lymph nodes, with a total dose of 50 Gy, 2 Gy per fraction, over a 5-week period.
Definition of TN tumors The IHC staining results of ER, PR, and HER2 were collected from pathology reports. Patients were classified into four subgroups according to the staining positivity or negativity for hormone receptors (ER and PR: Receptors [Rec]) and HER2: (1) Rec-/HER2(TN), (2) Rec-/HER2+, (3) Rec+/HER2+, and (4) Rec+/HER2-. Rec- was defined as both ER- and PR-, whereas Rec+ was defined as ER+ and/or PR+. Positive HER2 was either IHC HER2 3+ or 2+ staining, regardless of the expression of ER and PR.
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Endpoints and statistical analysis The clinical endpoints of this study were LRR-free survival (LRFS), distant metastasis–free survival (DMFS), disease-free survival (DFS), and overall survival (OS). Locoregional recurrence was defined as any relapse that occurred in the ipsilateral chest wall, supraclavicular lymph nodes, axillary nodes, and the intramammary chain. Distant metastasis (DM) was defined as any relapse outside the locoregional region. The event of DFS was defined as any relapse, and the event of OS was defined as any death during the observation period. Kaplan-Meier probability curves were calculated and tested for statistical differences by the log–rank test. Except for the four subgroups, the following factors were evaluated for the endpoints by a univariate analysis: menopausal status (pre-/perimenopausal vs. postmenopausal), tumor site (inner quadrant/central vs. outer quadrant), histologic grade (Grade 3 vs. 1/2), lymphovascular invasion (LVI), T stage (T4 vs. T1–3), N stage (N3 vs. N1–2), postmastectomy radiotherapy (yes vs. no), chemotherapy (yes vs. no), and hormonal therapy (yes vs. no). Factors having a p value of <0.05 on univariate analysis were subjected to Cox multivariate regression analyses. A comparison of the clinical variables between the four subgroups based on the presence of hormone receptors and HER2 was made using Pearson’s c2 test.
RESULTS Patient characteristics The clinical characteristics of all patients and the four subgroups are shown in Table 1. The median age of the group was 49 years (range, 21–85 years). The median number of axillary nodes dissected was 18 (range, 4–57). Four hundred twenty-nine patients (51.3%) had 1–3 positive nodes, 226 (27.1%) had 4–9, and 180 (21.6%) had $10 positive nodes. According to the IHC results for hormone receptors and HER2, 141 patients (16.9%) were Rec-/HER2- (TN), 99 patients (11.9%) were Rec-/HER2+, 157 patients (18.8%) were Rec+/HER2+, and 438 patients (52.4%) were Rec+/ HER2-. The mean age was 51, 51, 50, and 50 years for the patients in these four subgroups, respectively (p = 0.622). Compared with non-TN breast cancer, TN breast cancer correlated with a higher histologic grade (34.0% vs. 21.3%, p = 0.001). Compared with other subgroups, Rec-/HER2+ breast cancer had a higher incidence of lymphovascular invasion (32.3% vs. 22.3%, p = 0.027) and a higher percentage of N2-N3 disease (60.6% vs. 47.1%, p = 0.011) and Stage III disease (62.6% vs. 51.0%, p = 0.029). Survival and prognosis The median duration of follow-up was 47 months (range, 5–92 months). The rates of 5-year OS, DFS, DMFS, and LRFS for all patients were 80.5%, 72.7%, 75.5%, and 90.2%, respectively (Fig. 1), and the corresponding results for the four subgroups are shown in Table 2 and Figs. 2–5. There was a lower rate of 5-year LRFS for patients with TN or HER2-positive tumors (TN, Rec-/HER2+, or Rec+/ HER2+) than for those with Rec+/HER2- tumors (86.5% vs. 93.6%, p = 0.002). Patients with TN or Rec-/HER2+ breast cancer had a decreased 5-year DMFS (69.1% vs. 78.5%, p = 0.000), DFS (66.6% vs. 75.6%, p = 0.000), and
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Table 1. Clinical characteristics of all patients and in each of the four subgroups according to hormone receptors and HER2 expression
Menopausal status PrePostUnknown Pathology IDC ILC Medullary Others Grade 1–2 3 Unknown LVI Yes No T stage T1–2 T3–4 Tx N stage N1 N2 N3 Stage II III Chemotherapy Yes No Unknown Radiotherapy Yes No Unknown Hormone therapy Yes No Unknown
All
TN
Rec-/HER2+
Rec+/HER2+
Rec+/HER2-
483 (57.8) 325 (38.9) 27 (3.2)
71 (50.4) 65 (46.1) 5 (3.5)
51 (51.5) 44 (44.1) 4 (0.4)
96 (61.1) 60 (38.2) 1 (0.7)
265 (60.5) 156 (35.6) 17 (3.9)
775 (92.8) 29 (3.5) 3 (0.4) 28 (3.3)
127 (90.1) 8 (5.7) 1 (0.7) 5 (3.5)
91 (91.9) 1 (1.0) 0 (0) 7 (7.1)
147 (93.6) 4 (2.6) 0 (0) 6 (3.8)
410 (93.6) 16 (13.6) 2 (0.5) 10 (2.3)
451 (54.0) 196 (23.5) 188 (22.5)
61 (43.3) 48 (34.0) 32 (22.7)
49 (49.5) 16 (16.2) 34 (34.3)
87 (55.4) 33 (21.0) 37 (23.6)
254 (58.0) 99 (22.6) 85 (19.4)
196 (23.5) 639 (76.5)
35 (24.8) 106 (75.2)
32 (32.3) 67 (67.7)
39 (24.8) 118 (75.2)
90 (21.0) 348 (79.5)
709 (84.9) 101 (12.1) 25 (3.0)
119(84.4) 18 (12.8) 4 (2.4)
79 (79.8) 17 (17.2) 3 (3.0)
139 (88.5) 16 (10.2) 2 (1.3)
372 (84.9) 50 (11.4) 16 (3.7)
427 (51.1) 228 (27.3) 180 (21.6)
80 (56.7) 34 (24.1) 27 (19.2)
39 (39.4) 29 (29.3) 31 (31.3)
71 (45.2) 51 (32.5) 35 (22.3)
237 (54.1) 114 (26.0) 87 (19.9)
398 (47.7) 437 (52.3)
72 (51.1) 69 (48.9)
37 (37.4) 62 (62.6)
68 (43.3) 89 (56.7)
221 (50.5) 217 (49.5)
764 (91.5) 64 (7.7) 7 (0.8)
131 (92.9) 8 (5.7) 2 (1.4)
92 (92.9) 7 (7.1) 0 (0)
143 (91.1) 13 (8.3) 1 (0.6)
398 (90.9) 36 (8.2) 4 (0.9)
420 (50.3) 399 (47.8) 16 (1.9)
72 (51.1) 66 (46.8) 3 (2.1)
55 (55.6) 44 (44.4) 0 (0)
87 (55.4) 68 (43.3) 2 (1.3)
206 (47.0) 221 (50.5) 11 (2.5)
464 (55.6) 322 (38.6) 48 (5.8)
15 (10.6) 116 (82.3) 10 (7.1)
8 (8.1) 88 (88.9) 3 (3.0)
109 (69.4) 40 (25.5) 8 (5.1)
332 (75.8) 78 (17.8) 28 (6.4)
p 0.093
0.243
0.001
0.082 0.475
0.040
0.060 0.857
0.325
0.000
Abbreviations: HER2 = human epidermal growth factor 2; TN = triple negative; Rec = hormone receptor; IDC = invasive ductal carcinoma; ILC = invasive lobular carcinoma; LVI = lymphovascular invasion. Values are number (percentage).
OS (71.4% vs. 84.2%, p = 0.000) compared with those with Rec+/HER2+ or Rec+/HER2- tumors. Moreover, there was a lower rate of 5-year LRFS for patients with HER2positive tumors than for those with HER2-negative tumors (86.0% vs. 92.1%, p = 0.061). Figures 2–5 show that there was a significant difference in the timing of relapse and death between the four groups. Patients with TN or Rec-/HER2+ breast cancers had an increased likelihood of LRR, DM, and death within the first 3 years after treatment but not after 3 years; the peak of all events occurred at approximately 3 years. The risk of LRR, DM, and death was steady for Rec+/HER2+ or Rec+/HER2- breast cancers, and this trend continued for the first 5 years after treatment. Because of the uncertainty in the appropriate classification of HER2 2+ patients by IHC, because they could fall into either a positive or negative category with further accurate
measurement such as the fluorescence in situ hybridization (FISH) test, a second statistical analysis was performed for the whole group of patients when HER2 2+ patients were classified as HER2 negative. Using this strategy, consistent results with regard to OS, DFS, DMFS, and LRFS were observed (data not shown). Postmastectomy radiotherapy or hormone therapy significantly reduced LRR for the whole group. The 5-year LRFS was 91.9% and 87.1% for those with and without hormone therapy (p = 0.003), respectively. The impact of radiotherapy on 5-year LRR for all patients and subgroups of patients is shown in Table 3. There was no difference in 5-year LRFS between those with and without chemotherapy (90.3% vs. 88.9%, p = 0.433). In the group of patients treated with radiotherapy, there was no difference in 5-year LRFS between HER2-negative and HER2-positive diseases (94.9% vs. 91.4%, p = 0.451).
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Fig. 1. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRFS) curves of the whole cohort of patients in this study.
Fig. 2. Locoregional recurrence-free survival (LRFS) as a function of the tumor subgroup. TN = triple negative.
In the multivariate analysis, Rec+/HER2- was an independent favorable factor for LRFS (p = 0.000). Rec- (TN or Rec-/ HER2+) was independently associated with dismally short periods for DMFS (p = 0.001), DFS (p = 0.000), and OS (p = 0.000).
Patterns of distant metastasis According to the site of DM that occurred after treatment, the percentages of visceral and bone/soft-tissue metastases of all patients and in the four subgroups are shown in Table 4. Patients with TN, Rec-/HER2+, or Rec+/HER2- breast tumors were significantly more likely to develop visceral metastases than those with Rec+/HER2- tumors (73.3% vs. 54.8%, p = 0.014).
LRFS in T1–T2N1 patients Predictive factors for LRFS were evaluated in 319 patients with T1–T2N1 diseases who did not receive postmastectomy radiotherapy. The median number of nodes dissected was 17 (range, 6–45), and 6.3% patients (20 of 319) had fewer than 10 nodes dissected. The 5-year LRFS for patients with TN, Rec-/HER2+, Rec+/HER2+, and Rec+/HER2- breast cancers were 88.4%, 82.6%, 81.8%, and 91.1%, respectively (p = 0.205; Fig. 6). Patients with T2 diseases had significantly lower LRFS than those with T1 diseases (86.0% vs. 92.6%, p = 0.077), whereas patients with three positive nodes had a lower LRFS than those with one to two positive nodes (78.6% vs. 90.8%, p = 0.029). A HER2-positive profile was associated with a lower LRFS compared with HER2negative tumors (82.2% vs. 91.1%, p = 0.052). Other factors, such as age, menopausal status, histologic grade, LVI, percentage of positive nodes, total number of nodes dissected, and status of ER or PR were not associated with significant changes in LRFS. Postmastectomy radiotherapy reduced LRR for HER2positive patients with T1–T2N1 diseases: the 5-year LRFS for patients with radiotherapy (21 patients) and without radiotherapy (82 patients) was 100% and 82.2%, respectively (p = 0.052).
DISCUSSION Although the prognosis and risk of DM have been studied extensively for patients with TN tumors (1, 3, 5–8), the data with regard to the risk of LRR in breast cancer are controversial (6, 8–10). It remains less clear whether TN tumors or HER2-overexpressing breast cancers have a negative impact on locoregional control and overall survival in node-positive patients treated with mastectomy. This study is a comprehensive study that was designed to address the clinical features, failure patterns, and prognosis in patients with node-positive breast cancer. Similar to the other studies (5, 7), patients with TN and HER2-like breast cancer in this series were clinically characterized by high tumor grades, a large proportion of patients with N2–3 disease and LVI, and an unfavorable prognosis. Furthermore, the present study
Table 2. Five-year outcomes as a function of the tumor subgroup Parameter TN Rec-/HER2+ Rec+/HER2+ Rec+/HER2LRFS (%) DMFS (%) DFS (%) OS (%)
87.6 72.3 68.8 72.7
87.0 64.8 63.6 70.2
85.2 75.1 68.6 84.2
93.6 79.8 77.6 84.2
p 0.018 0.000 0.000 0.000
Abbreviations: LRFS = locoregional recurrence–free survival; DMFS = distant metastasis–free survival; DFS = disease-free survival; OS = overall survival. Other abbreviations as in Table 1.
Fig. 3. Distant metastasis-free survival (DMFS) as a function of the tumor subgroup. TN = triple negative.
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Table 3. Impact of postmastectomy radiotherapy on locoregional recurrence for the whole and the subgroup of patients Five-year LRFS (%)
Fig. 4. Disease-free survival (DFS) as a function of the tumor subgroup. TN = triple negative.
also showed that patients with TN, Rec-/HER2+, or Rec+/ HER2+ breast cancers were at an increased risk of LRR, whereas patients with Rec+/HER2- breast cancers had the lowest risk of LRR. To our knowledge, there are five other large studies that have provided information on LRR by histologic tumor subtype (6, 8–10, 12); two of these showed an increased risk of LRR with TN or Rec-/HER2+ breast cancers, whereas three other studies showed no such association. Kyndi et al. (10) studied 1000 patients who had undergone mastectomy (94% were node positive) and found that TN tumors and Rec-/HER2+ tumors were the two parameters that were most strongly associated with an increased probability for LRR; these parameters substantially outranked the risk incurred by both nodal status and tumor size. Nguyen et al. (8) found that TN or Rec-/Her2+ tumor was associated with an increased 5-year risk of local recurrence in 793 patients with breast-conservative surgery and radiation. The 5-year local recurrence rate was 7.1% for patients with TN tumors and 8.4% for patients with Rec-/Her2+ tumors, compared with 1.8% for patients with Rec+/HER2- tumors and 1.5% for those with Rec+/HER2+ tumors. In contrast, Freedman et al. (9) found that the 5-year LRR of patients with TN, Rec-/Her2+, and Rec+ was 3.2%, 4.6%, and 2.3%, respectively (p = 0.36), in 753 patients who underwent breast-conservative surgery and radiotherapy. Haffty et al. (6) reported that there was no significant difference in local
Fig. 5. Overall survival (OS) as a function of the tumor subgroup. TN = triple negative.
Group
RT
no RT
p
All TN Rec-/HER2+ Rec+/HER2+ Rec+/HER2HER2 positive
93.7 89.1 92.1 90.7 96.9 91.4
86.3 85.2 80.5 77.6 90.6 78.4
0.001 0.521 0.086 0.026 0.016 0.004
Abbreviation: RT = radiotherapy. Other abbreviations as in Tables 1 and 2.
control of breast cancer between the TN and other subtypes (83% vs. 83%, respectively) among 482 patients with breast-conservative surgery and radiation. However, between 70% and 75% of patients in the latter two studies were node negative, which is a different cohort of patients from that of our present study, in which all patients were node positive. Patients with HER2-positive tumors had an increased LRR compared with HER2-negative tumors in the whole group of patients and in the subgroup with T1–2N1 disease without radiotherapy. Radiotherapy significantly reduced LRR in patients with HER2-positive tumors. When we analyze only the patients treated with radiotherapy, there was no difference in LRR rate between HER2-positive and HER2negative tumors, suggesting that the application of radiotherapy overcame the value of HER2 positivity as a predictor of LRR. It is known that there are some controversies in the application of postmastectomy radiotherapy in T1–T2 and one to three node-positive patients. The percentage of patients with LRR by 10 years was <15% for these patients who did not receive radiation (13–15). It has been reported that postmastectomy radiotherapy improves the OS rate in retrospective analyses (16, 17) or subanalyses of randomized trials (18–20). However, randomized studies specifically designed to test the use of postmastectomy radiation in Stage II breast cancer patients have not
Fig. 6. Locoregional recurrence-free survival (LRFS) as a function of the tumor subgroup for 319 patients with T1/2N1M0 breast cancer who did not receive postmastectomy radiotherapy. TN = triple negative.
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Table 4. Patterns of distant metastases Site of distant metastases
All patients
TN
Rec-/HER2+
Rec+/HER2+
Rec+/HER2-
p
Visceral Bone or soft tissue
106 (65.0) 57 (35.0)
26 (76.5) 8 (23.5)
20 (71.4) 8 (28.6)
20 (71.4) 8 (28.6)
40 (54.8) 33 (45.2)
0.097
Abbreviations as in Table 1. Values are number (percentage).
demonstrated survival benefits (21). To identify high-risk subgroups within this cohort, we analyzed 319 patients with T1–T2N1 diseases who did not receive postmastectomy radiotherapy. We found that there were no differences in the incidence of LRR among the four subgroups, and only patients with three positive nodes had a significantly increased risk of LRR, of more than 20%. The present study also shows that patients with TN or Rec-/HER2+ breast cancers are at an increased risk for DM and have a poor DFS and OS. These findings are consistent with the literature already published (4, 5). Bauer et al. (22) found that 6370 women with TN breast cancers had a consistently poorer duration of survival when compared with 44,707 women with other breast cancer subtypes at each stage and within each racial group. Cheang et al. (23) and Carey et al. (5) reported that the TN subtype conveys a worse breast cancer–specific survival, but the Rec-/ HER2+ subtype has the worst among all patients. Because we also found that TN breast cancers were more likely to be Grade 3, whereas Rec-/HER2+ breast cancers were more likely to have LVI with more positive nodes and a greater incidence of Stage III disease, a multivariate analysis was performed. This showed that Rec+/HER2- was an independent favorable factor for LRFS, and either TN or Rec-/ HER2+ was independently associated with a dismal duration of OS, DFS, and DMFS. The present study also showed there was a significant difference with regard to the timing of relapse. Triple-negative or Rec-/HER2+ breast cancers have an increased likelihood of LRR, DM, and death within the first 3 years after treatment, but this risk does not persist beyond 3 years after mastectomy; the peak of all events was at approximately 3 years. The risk of LRR, DM, and death for Rec+/HER2+ or Rec+/HER2- breast tumors was consistent over the first 5 years after treatment. A similar early relapse pattern has been described by other studies (24–27). Dent et al. (24) reported that patients with TN breast cancers experienced high rates of relapse only in the period from 1 to 4 years after diagnosis; the risk declined rapidly thereafter, and no recurrences occurred after 8 years of follow-up. Another study, by Tischkowitz et al. (25), demonstrated a difference in OS between TN and non-TN breast
cancers that was most obvious at 3 years and decreased to no difference at all by 10 years after diagnosis. Consistent with other reports that the patient with a TN breast cancer is more likely to develop intrapulmonary, brain, or visceral metastases (26, 28, 29) and that HER2-positive tumors lead to a lower risk of developing bony metastases (26), the present study found that TN, Rec-/HER2+, or Rec+/ HER2- breast cancers were more likely to lead to visceral metastases. Accordingly, Dent et al. (26) found that the excess risk of DM in TN breast cancers vs. other forms of cancer was attributable in large part to an excess of visceral metastases in the first 5 years after diagnosis. There are some potential limitations to this study. First, the HER2 data were obtained through IHC testing because the FISH test was not available. Although there is agreement that HER2 3+ patients are positive and 0 to 1+ are negative, those patients who are 2+ should be tested with FISH. Our subset analysis, which demonstrated that the statistical significance of the results were consistent regardless of whether HER2 2+ tumors were classified as HER2-positive or -negative, provides some reassurance. Second, the short duration of the follow-up means that a long-term survival comparison is unavailable, and longer follow-up to fully evaluate the rate of LRR is also warranted. It has been reported that trastuzumab has significantly reduced locoregional and distant relapses and improved overall survival in patients with HER2-positive tumors (30), and it is widely used in the treatment of HER2-positive breast cancers, but it was used in only 8 patients (1%) in the present study. Future studies will need to assess the impact of trastuzumab on LRR and reassess the prognostic implications of HER2positive tumors with targeted therapy. In conclusion, we found that node-positive breast cancer patients who undergo mastectomy have a relatively poor prognosis if simple commonly available markers of ER, PR, and HER2 show the tumors to be TN or Rec-/HER2+. Patients with TN, Rec-/HER2+, or Rec+/HER2+ breast cancers are at an increased risk of LRR. Further prospective studies with a longer duration of follow-up are warranted to confirm these findings, and new localized and systemic therapeutic strategies should be investigated to improve the outcome of patients with TN and HER2+ breast cancers.
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receptor-negative invasive breast cancers. Hum Pathol 2008;39: 167–174. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006;295:2492–2502. Haffty BG, Yang Q, Reiss M, et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 2006;24:5652–5657. Kim MJ, Ro JY, Ahn SH, et al. Clinicopathologic significance of the basal-like subtype of breast cancer: A comparison with hormone receptor and Her2/neu-overexpressing phenotypes. Hum Pathol 2006;37:1217–1226. Nguyen PL, Taghian AG, Katz MS, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol 2008;26:2373–2378. Freedman GM, Anderson PR, Li T, et al. Locoregional recurrence of triple-negative breast cancer after breast-conserving surgery and radiation. Cancer 2009;115:946–951. Kyndi M, Sorensen FB, Knudsen H, et al. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: The Danish Breast Cancer Cooperative Group. J Clin Oncol 2008;26:1419–1426. Singletary SE, Connolly JL. Breast cancer staging: Working with the sixth edition of the AJCC Cancer Staging Manual. CA Cancer J Clin 2006;56:37–47. quiz 50–31. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673–1684. Recht A, Gray R, Davidson NE, et al. Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: Experience of the Eastern Cooperative Oncology Group. J Clin Oncol 1999;17: 1689–1700. Katz A, Strom EA, Buchholz TA, et al. Locoregional recurrence patterns after mastectomy and doxorubicin-based chemotherapy: Implications for postoperative irradiation. J Clin Oncol 2000;18:2817–2827. Taghian A, Jeong JH, Mamounas E, et al. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: Results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol 2004;22:4247–4254. van der Hage JA, Putter H, Bonnema J, et al. Impact of locoregional treatment on the early-stage breast cancer patients: A retrospective analysis. Eur J Cancer 2003;39:2192–2199. Voordeckers M, Vinh-Hung V, Lamote J, et al. Survival benefit with radiation therapy in node-positive breast carcinoma patients. Strahlenther Onkol 2009;185:656–662.
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18. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 1997; 337:949–955. 19. Overgaard M, Nielsen HM, Overgaard J. Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b&c randomized trials. Radiother Oncol 2007;82:247–253. 20. Ragaz J, Olivotto IA, Spinelli JJ, et al. Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst 2005;97:116–126. 21. Killander F, Anderson H, Ryden S, et al. Efficient reduction of loco-regional recurrences but no effect on mortality twenty years after postmastectomy radiation in premenopausal women with stage II breast cancer—a randomized trial from the South Sweden Breast Cancer Group. Breast 2009;18:309–315. 22. Bauer KR, Brown M, Cress RD, et al. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: A population-based study from the California cancer Registry. Cancer 2007;109:1721–1728. 23. Cheang MC, Voduc D, Bajdik C, et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 2008;14: 1368–1376. 24. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: Clinical features and patterns of recurrence. Clin Cancer Res 2007;13:4429–4434. 25. Tischkowitz M, Brunet JS, Begin LR, et al. Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer 2007;7:134. 26. Dent R, Hanna WM, Trudeau M, et al. Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat 2009;115:423–428. 27. Yin WJ, Lu JS, Di GH, et al. Clinicopathological features of the triple-negative tumors in Chinese breast cancer patients. Breast Cancer Res Treat 2009;115:325–333. 28. Luck AA, Evans AJ, Green AR, et al. The influence of basal phenotype on the metastatic pattern of breast cancer. Clin Oncol (R Coll Radiol) 2008;20:40–45. 29. Fulford LG, Reis-Filho JS, Ryder K, et al. Basal-like grade III invasive ductal carcinoma of the breast: Patterns of metastasis and long-term survival. Breast Cancer Res 2007;9:R4. 30. Dahabreh IJ, Linardou H, Siannis F, et al. Trastuzumab in the adjuvant treatment of early-stage breast cancer: A systematic review and meta-analysis of randomized controlled trials. Oncologist 2008;13:620–630.
doi:10.1016/j.ijrobp.2010.03.038
CLINICAL INVESTIGATION
Breast
TRIPLE-NEGATIVE OR HER2-POSITIVE STATUS PREDICTS HIGHER RATES OF LOCOREGIONAL RECURRENCE IN NODE-POSITIVE BREAST CANCER PATIENTS AFTER MASTECTOMY SHU-LIAN WANG, M.D., YE-XIONG LI, M.D., YONG-WEN SONG, M.D., WEI-HU WANG, M.D., JING JIN, M.D., YUE-PING LIU, M.D., XIN-FAN LIU, M.D., AND ZI-HAO YU, M.D. Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China Purpose: To evaluate the prognostic value of determining estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression in node-positive breast cancer patients treated with mastectomy. Methods and Materials: The records of 835 node-positive breast cancer patients who had undergone mastectomy between January 2000 and December 2004 were analyzed retrospectively. Of these, 764 patients (91.5%) received chemotherapy; 68 of 398 patients (20.9%) with T1–2N1 disease and 352 of 437 patients (80.5%) with T3–4 or N2–3 disease received postoperative radiotherapy. Patients were classified into four subgroups according to hormone receptor (Rec+ or Rec-) and HER2 expression profiles: Rec-/HER2- (triple negative; n = 141), Rec-/HER2+ (n = 99), Rec+/HER2+ (n = 157), and Rec+/HER2- (n = 438). The endpoints were the duration of locoregional recurrence–free survival, distant metastasis–free survival, disease-free survival, and overall survival. Results: Patients with triple-negative, Rec-/HER2+, and Rec+/HER2+ expression profiles had a significantly lower 5-year locoregional recurrence-free survival than those with Rec+/HER2- profiles (86.5% vs. 93.6%, p = 0.002). Compared with those with Rec+/HER2+ and Rec+/HER2- profiles, patients with Rec-/HER2- and Rec-/HER2+ profiles had significantly lower 5-year distant metastasis–free survival (69.1% vs. 78.5%, p = 0.000), lower disease-free survival (66.6% vs. 75.6%, p = 0.000), and lower overall survival (71.4% vs. 84.2%, p = 0.000). Triple-negative or Rec-/HER2+ breast cancers had an increased likelihood of relapse and death within the first 3 years after treatment. Conclusions: Triple-negative and HER2-positive profiles are useful markers of prognosis for locoregional recurrence and survival in node-positive breast cancer patients treated with mastectomy. Ó 2011 Elsevier Inc. Breast neoplasm, Prognosis, Estrogen receptor, Progesterone receptor, Human epidermal growth factor 2.
these patients, they all seem to agree with the outcome prediction for this subtype (4). For these observations to be used in large-scale clinical applications or retrospective studies, the immunohistochemical (IHC) staining profile can be a useful surrogate of gene expression analysis with the use of formalin-fixed, paraffinembedded samples. Basal-like tumors are usually triplenegative (TN) tumors because they lack the expression of both hormone receptors (ER and progesterone receptors [PR]; Rec-) and HER2. The HER2-overexpressing subtypes refer to predominantly hormone receptor–negative tumors with HER2 gene expression (Rec-/HER2+). Luminal subtypes make up the hormone receptor–expressing tumors (Rec+). Therefore, a simplified method of classification based on IHC staining of ER, PR, and HER2 is useful clinically.
INTRODUCTION Breast cancer is a heterogeneous disease, which has been classified into five distinct molecular subgroups with different prognoses by gene expression profiling (1). These molecular subgroups include basal-like and human epidermal growth factor 2 (HER2)-overexpressing breast cancers, which have poor outcomes, and the luminal-type of breast cancer that has a favorable prognosis (1–3). A recent comparison between cancers with different gene expression prognostic signatures has revealed that almost all patients with basal-like or HER2+ and estrogen receptor negative (ER-) breast cancers have high recurrence scores, poor 70gene profiles, and activated wound response signatures. Regardless of the different gene sets that were used to classify Reprint requests to: Ye-Xiong Li, M.D., Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Tel: (+86) 10-87788860; Fax: (+86) 10-67706153; E-mail: yexiong@ yahoo.com
Presented in poster form at the 51st Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 31– November 4, 2009, Chicago, IL. Conflict of interest: none. Received Feb 4, 2010, and in revised form March 17, 2010. Accepted for publication March 29, 2010. 1095
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Although basal-like TN tumors have been reported to have higher rates of distant metastases and mortality (1, 3, 5–8), there are only limited and controversial data of their impact on the rate of locoregional recurrence (LRR) (6, 8–10). The purpose of the present study was to investigate the impact of ER, PR, and HER2 expression by the tumor on the prognosis of node-positive breast cancer patients treated with mastectomy, with particular regard to the rate of LRR. METHODS AND MATERIALS Patient selection and evaluation The medical records of all consecutive breast cancer patients treated at the Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College between January 2000 and December 2004 were analyzed retrospectively. Patients were eligible for the present study if they met the following inclusion criteria: pathologically confirmed invasive breast cancer by mastectomy with available data for ER, PR, and HER2 expression from IHC staining techniques, with positive lymph nodes. The exclusion criteria included the presence of distant metastases. A total of 835 patients satisfied the inclusion criteria and were included in the cohort of the study. Pretreatment evaluations included a complete medical history and physical examination, complete blood count and biochemistry profiles, mammography and/or breast ultrasonography, chest X-ray, an abdominopelvic computed tomography scan and/or ultrasonography, and a bone scan if indicated. The 2002 American Joint Committee on Cancer Manual for Staging of Cancer was used for staging (11).
Treatment All patients were treated with mastectomy and axillary dissection. Adjuvant chemotherapy and/or radiotherapy were based on the National Comprehensive Cancer Network practice guideline. All patients with hormone receptor–positive tumors received hormone therapy. Postmastectomy radiotherapy was recommended for patients with T3–T4 and/or N2–N3 tumors, whereas it was optional for patients with T1–T2N1 tumors. Overall, 764 patients (91.5%) received chemotherapy, whereas 352 of 437 patients (80.5%) with T3–4 or N2–3 disease and 68 of 398 patients (20.9%) with T1–2N1 disease received postoperative radiotherapy. Chemotherapy regimens were anthracycline-based for 415 patients, anthracycline plus taxanes for 263, taxane-based for 4 patients, other regimens for 29, and unknown in the case of 53 patients. Four hundred sixty-four patients (55.6%) received hormonal therapy as well. Trastuzumab was administered to 8 patients (1%). Radiotherapy was given with a 6-MV linear accelerator. Radiotherapy was mainly delivered to the ipsilateral chest wall and supraclavicular region of lymph nodes, with a total dose of 50 Gy, 2 Gy per fraction, over a 5-week period.
Definition of TN tumors The IHC staining results of ER, PR, and HER2 were collected from pathology reports. Patients were classified into four subgroups according to the staining positivity or negativity for hormone receptors (ER and PR: Receptors [Rec]) and HER2: (1) Rec-/HER2(TN), (2) Rec-/HER2+, (3) Rec+/HER2+, and (4) Rec+/HER2-. Rec- was defined as both ER- and PR-, whereas Rec+ was defined as ER+ and/or PR+. Positive HER2 was either IHC HER2 3+ or 2+ staining, regardless of the expression of ER and PR.
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Endpoints and statistical analysis The clinical endpoints of this study were LRR-free survival (LRFS), distant metastasis–free survival (DMFS), disease-free survival (DFS), and overall survival (OS). Locoregional recurrence was defined as any relapse that occurred in the ipsilateral chest wall, supraclavicular lymph nodes, axillary nodes, and the intramammary chain. Distant metastasis (DM) was defined as any relapse outside the locoregional region. The event of DFS was defined as any relapse, and the event of OS was defined as any death during the observation period. Kaplan-Meier probability curves were calculated and tested for statistical differences by the log–rank test. Except for the four subgroups, the following factors were evaluated for the endpoints by a univariate analysis: menopausal status (pre-/perimenopausal vs. postmenopausal), tumor site (inner quadrant/central vs. outer quadrant), histologic grade (Grade 3 vs. 1/2), lymphovascular invasion (LVI), T stage (T4 vs. T1–3), N stage (N3 vs. N1–2), postmastectomy radiotherapy (yes vs. no), chemotherapy (yes vs. no), and hormonal therapy (yes vs. no). Factors having a p value of <0.05 on univariate analysis were subjected to Cox multivariate regression analyses. A comparison of the clinical variables between the four subgroups based on the presence of hormone receptors and HER2 was made using Pearson’s c2 test.
RESULTS Patient characteristics The clinical characteristics of all patients and the four subgroups are shown in Table 1. The median age of the group was 49 years (range, 21–85 years). The median number of axillary nodes dissected was 18 (range, 4–57). Four hundred twenty-nine patients (51.3%) had 1–3 positive nodes, 226 (27.1%) had 4–9, and 180 (21.6%) had $10 positive nodes. According to the IHC results for hormone receptors and HER2, 141 patients (16.9%) were Rec-/HER2- (TN), 99 patients (11.9%) were Rec-/HER2+, 157 patients (18.8%) were Rec+/HER2+, and 438 patients (52.4%) were Rec+/ HER2-. The mean age was 51, 51, 50, and 50 years for the patients in these four subgroups, respectively (p = 0.622). Compared with non-TN breast cancer, TN breast cancer correlated with a higher histologic grade (34.0% vs. 21.3%, p = 0.001). Compared with other subgroups, Rec-/HER2+ breast cancer had a higher incidence of lymphovascular invasion (32.3% vs. 22.3%, p = 0.027) and a higher percentage of N2-N3 disease (60.6% vs. 47.1%, p = 0.011) and Stage III disease (62.6% vs. 51.0%, p = 0.029). Survival and prognosis The median duration of follow-up was 47 months (range, 5–92 months). The rates of 5-year OS, DFS, DMFS, and LRFS for all patients were 80.5%, 72.7%, 75.5%, and 90.2%, respectively (Fig. 1), and the corresponding results for the four subgroups are shown in Table 2 and Figs. 2–5. There was a lower rate of 5-year LRFS for patients with TN or HER2-positive tumors (TN, Rec-/HER2+, or Rec+/ HER2+) than for those with Rec+/HER2- tumors (86.5% vs. 93.6%, p = 0.002). Patients with TN or Rec-/HER2+ breast cancer had a decreased 5-year DMFS (69.1% vs. 78.5%, p = 0.000), DFS (66.6% vs. 75.6%, p = 0.000), and
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Table 1. Clinical characteristics of all patients and in each of the four subgroups according to hormone receptors and HER2 expression
Menopausal status PrePostUnknown Pathology IDC ILC Medullary Others Grade 1–2 3 Unknown LVI Yes No T stage T1–2 T3–4 Tx N stage N1 N2 N3 Stage II III Chemotherapy Yes No Unknown Radiotherapy Yes No Unknown Hormone therapy Yes No Unknown
All
TN
Rec-/HER2+
Rec+/HER2+
Rec+/HER2-
483 (57.8) 325 (38.9) 27 (3.2)
71 (50.4) 65 (46.1) 5 (3.5)
51 (51.5) 44 (44.1) 4 (0.4)
96 (61.1) 60 (38.2) 1 (0.7)
265 (60.5) 156 (35.6) 17 (3.9)
775 (92.8) 29 (3.5) 3 (0.4) 28 (3.3)
127 (90.1) 8 (5.7) 1 (0.7) 5 (3.5)
91 (91.9) 1 (1.0) 0 (0) 7 (7.1)
147 (93.6) 4 (2.6) 0 (0) 6 (3.8)
410 (93.6) 16 (13.6) 2 (0.5) 10 (2.3)
451 (54.0) 196 (23.5) 188 (22.5)
61 (43.3) 48 (34.0) 32 (22.7)
49 (49.5) 16 (16.2) 34 (34.3)
87 (55.4) 33 (21.0) 37 (23.6)
254 (58.0) 99 (22.6) 85 (19.4)
196 (23.5) 639 (76.5)
35 (24.8) 106 (75.2)
32 (32.3) 67 (67.7)
39 (24.8) 118 (75.2)
90 (21.0) 348 (79.5)
709 (84.9) 101 (12.1) 25 (3.0)
119(84.4) 18 (12.8) 4 (2.4)
79 (79.8) 17 (17.2) 3 (3.0)
139 (88.5) 16 (10.2) 2 (1.3)
372 (84.9) 50 (11.4) 16 (3.7)
427 (51.1) 228 (27.3) 180 (21.6)
80 (56.7) 34 (24.1) 27 (19.2)
39 (39.4) 29 (29.3) 31 (31.3)
71 (45.2) 51 (32.5) 35 (22.3)
237 (54.1) 114 (26.0) 87 (19.9)
398 (47.7) 437 (52.3)
72 (51.1) 69 (48.9)
37 (37.4) 62 (62.6)
68 (43.3) 89 (56.7)
221 (50.5) 217 (49.5)
764 (91.5) 64 (7.7) 7 (0.8)
131 (92.9) 8 (5.7) 2 (1.4)
92 (92.9) 7 (7.1) 0 (0)
143 (91.1) 13 (8.3) 1 (0.6)
398 (90.9) 36 (8.2) 4 (0.9)
420 (50.3) 399 (47.8) 16 (1.9)
72 (51.1) 66 (46.8) 3 (2.1)
55 (55.6) 44 (44.4) 0 (0)
87 (55.4) 68 (43.3) 2 (1.3)
206 (47.0) 221 (50.5) 11 (2.5)
464 (55.6) 322 (38.6) 48 (5.8)
15 (10.6) 116 (82.3) 10 (7.1)
8 (8.1) 88 (88.9) 3 (3.0)
109 (69.4) 40 (25.5) 8 (5.1)
332 (75.8) 78 (17.8) 28 (6.4)
p 0.093
0.243
0.001
0.082 0.475
0.040
0.060 0.857
0.325
0.000
Abbreviations: HER2 = human epidermal growth factor 2; TN = triple negative; Rec = hormone receptor; IDC = invasive ductal carcinoma; ILC = invasive lobular carcinoma; LVI = lymphovascular invasion. Values are number (percentage).
OS (71.4% vs. 84.2%, p = 0.000) compared with those with Rec+/HER2+ or Rec+/HER2- tumors. Moreover, there was a lower rate of 5-year LRFS for patients with HER2positive tumors than for those with HER2-negative tumors (86.0% vs. 92.1%, p = 0.061). Figures 2–5 show that there was a significant difference in the timing of relapse and death between the four groups. Patients with TN or Rec-/HER2+ breast cancers had an increased likelihood of LRR, DM, and death within the first 3 years after treatment but not after 3 years; the peak of all events occurred at approximately 3 years. The risk of LRR, DM, and death was steady for Rec+/HER2+ or Rec+/HER2- breast cancers, and this trend continued for the first 5 years after treatment. Because of the uncertainty in the appropriate classification of HER2 2+ patients by IHC, because they could fall into either a positive or negative category with further accurate
measurement such as the fluorescence in situ hybridization (FISH) test, a second statistical analysis was performed for the whole group of patients when HER2 2+ patients were classified as HER2 negative. Using this strategy, consistent results with regard to OS, DFS, DMFS, and LRFS were observed (data not shown). Postmastectomy radiotherapy or hormone therapy significantly reduced LRR for the whole group. The 5-year LRFS was 91.9% and 87.1% for those with and without hormone therapy (p = 0.003), respectively. The impact of radiotherapy on 5-year LRR for all patients and subgroups of patients is shown in Table 3. There was no difference in 5-year LRFS between those with and without chemotherapy (90.3% vs. 88.9%, p = 0.433). In the group of patients treated with radiotherapy, there was no difference in 5-year LRFS between HER2-negative and HER2-positive diseases (94.9% vs. 91.4%, p = 0.451).
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Fig. 1. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRFS) curves of the whole cohort of patients in this study.
Fig. 2. Locoregional recurrence-free survival (LRFS) as a function of the tumor subgroup. TN = triple negative.
In the multivariate analysis, Rec+/HER2- was an independent favorable factor for LRFS (p = 0.000). Rec- (TN or Rec-/ HER2+) was independently associated with dismally short periods for DMFS (p = 0.001), DFS (p = 0.000), and OS (p = 0.000).
Patterns of distant metastasis According to the site of DM that occurred after treatment, the percentages of visceral and bone/soft-tissue metastases of all patients and in the four subgroups are shown in Table 4. Patients with TN, Rec-/HER2+, or Rec+/HER2- breast tumors were significantly more likely to develop visceral metastases than those with Rec+/HER2- tumors (73.3% vs. 54.8%, p = 0.014).
LRFS in T1–T2N1 patients Predictive factors for LRFS were evaluated in 319 patients with T1–T2N1 diseases who did not receive postmastectomy radiotherapy. The median number of nodes dissected was 17 (range, 6–45), and 6.3% patients (20 of 319) had fewer than 10 nodes dissected. The 5-year LRFS for patients with TN, Rec-/HER2+, Rec+/HER2+, and Rec+/HER2- breast cancers were 88.4%, 82.6%, 81.8%, and 91.1%, respectively (p = 0.205; Fig. 6). Patients with T2 diseases had significantly lower LRFS than those with T1 diseases (86.0% vs. 92.6%, p = 0.077), whereas patients with three positive nodes had a lower LRFS than those with one to two positive nodes (78.6% vs. 90.8%, p = 0.029). A HER2-positive profile was associated with a lower LRFS compared with HER2negative tumors (82.2% vs. 91.1%, p = 0.052). Other factors, such as age, menopausal status, histologic grade, LVI, percentage of positive nodes, total number of nodes dissected, and status of ER or PR were not associated with significant changes in LRFS. Postmastectomy radiotherapy reduced LRR for HER2positive patients with T1–T2N1 diseases: the 5-year LRFS for patients with radiotherapy (21 patients) and without radiotherapy (82 patients) was 100% and 82.2%, respectively (p = 0.052).
DISCUSSION Although the prognosis and risk of DM have been studied extensively for patients with TN tumors (1, 3, 5–8), the data with regard to the risk of LRR in breast cancer are controversial (6, 8–10). It remains less clear whether TN tumors or HER2-overexpressing breast cancers have a negative impact on locoregional control and overall survival in node-positive patients treated with mastectomy. This study is a comprehensive study that was designed to address the clinical features, failure patterns, and prognosis in patients with node-positive breast cancer. Similar to the other studies (5, 7), patients with TN and HER2-like breast cancer in this series were clinically characterized by high tumor grades, a large proportion of patients with N2–3 disease and LVI, and an unfavorable prognosis. Furthermore, the present study
Table 2. Five-year outcomes as a function of the tumor subgroup Parameter TN Rec-/HER2+ Rec+/HER2+ Rec+/HER2LRFS (%) DMFS (%) DFS (%) OS (%)
87.6 72.3 68.8 72.7
87.0 64.8 63.6 70.2
85.2 75.1 68.6 84.2
93.6 79.8 77.6 84.2
p 0.018 0.000 0.000 0.000
Abbreviations: LRFS = locoregional recurrence–free survival; DMFS = distant metastasis–free survival; DFS = disease-free survival; OS = overall survival. Other abbreviations as in Table 1.
Fig. 3. Distant metastasis-free survival (DMFS) as a function of the tumor subgroup. TN = triple negative.
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Table 3. Impact of postmastectomy radiotherapy on locoregional recurrence for the whole and the subgroup of patients Five-year LRFS (%)
Fig. 4. Disease-free survival (DFS) as a function of the tumor subgroup. TN = triple negative.
also showed that patients with TN, Rec-/HER2+, or Rec+/ HER2+ breast cancers were at an increased risk of LRR, whereas patients with Rec+/HER2- breast cancers had the lowest risk of LRR. To our knowledge, there are five other large studies that have provided information on LRR by histologic tumor subtype (6, 8–10, 12); two of these showed an increased risk of LRR with TN or Rec-/HER2+ breast cancers, whereas three other studies showed no such association. Kyndi et al. (10) studied 1000 patients who had undergone mastectomy (94% were node positive) and found that TN tumors and Rec-/HER2+ tumors were the two parameters that were most strongly associated with an increased probability for LRR; these parameters substantially outranked the risk incurred by both nodal status and tumor size. Nguyen et al. (8) found that TN or Rec-/Her2+ tumor was associated with an increased 5-year risk of local recurrence in 793 patients with breast-conservative surgery and radiation. The 5-year local recurrence rate was 7.1% for patients with TN tumors and 8.4% for patients with Rec-/Her2+ tumors, compared with 1.8% for patients with Rec+/HER2- tumors and 1.5% for those with Rec+/HER2+ tumors. In contrast, Freedman et al. (9) found that the 5-year LRR of patients with TN, Rec-/Her2+, and Rec+ was 3.2%, 4.6%, and 2.3%, respectively (p = 0.36), in 753 patients who underwent breast-conservative surgery and radiotherapy. Haffty et al. (6) reported that there was no significant difference in local
Fig. 5. Overall survival (OS) as a function of the tumor subgroup. TN = triple negative.
Group
RT
no RT
p
All TN Rec-/HER2+ Rec+/HER2+ Rec+/HER2HER2 positive
93.7 89.1 92.1 90.7 96.9 91.4
86.3 85.2 80.5 77.6 90.6 78.4
0.001 0.521 0.086 0.026 0.016 0.004
Abbreviation: RT = radiotherapy. Other abbreviations as in Tables 1 and 2.
control of breast cancer between the TN and other subtypes (83% vs. 83%, respectively) among 482 patients with breast-conservative surgery and radiation. However, between 70% and 75% of patients in the latter two studies were node negative, which is a different cohort of patients from that of our present study, in which all patients were node positive. Patients with HER2-positive tumors had an increased LRR compared with HER2-negative tumors in the whole group of patients and in the subgroup with T1–2N1 disease without radiotherapy. Radiotherapy significantly reduced LRR in patients with HER2-positive tumors. When we analyze only the patients treated with radiotherapy, there was no difference in LRR rate between HER2-positive and HER2negative tumors, suggesting that the application of radiotherapy overcame the value of HER2 positivity as a predictor of LRR. It is known that there are some controversies in the application of postmastectomy radiotherapy in T1–T2 and one to three node-positive patients. The percentage of patients with LRR by 10 years was <15% for these patients who did not receive radiation (13–15). It has been reported that postmastectomy radiotherapy improves the OS rate in retrospective analyses (16, 17) or subanalyses of randomized trials (18–20). However, randomized studies specifically designed to test the use of postmastectomy radiation in Stage II breast cancer patients have not
Fig. 6. Locoregional recurrence-free survival (LRFS) as a function of the tumor subgroup for 319 patients with T1/2N1M0 breast cancer who did not receive postmastectomy radiotherapy. TN = triple negative.
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Table 4. Patterns of distant metastases Site of distant metastases
All patients
TN
Rec-/HER2+
Rec+/HER2+
Rec+/HER2-
p
Visceral Bone or soft tissue
106 (65.0) 57 (35.0)
26 (76.5) 8 (23.5)
20 (71.4) 8 (28.6)
20 (71.4) 8 (28.6)
40 (54.8) 33 (45.2)
0.097
Abbreviations as in Table 1. Values are number (percentage).
demonstrated survival benefits (21). To identify high-risk subgroups within this cohort, we analyzed 319 patients with T1–T2N1 diseases who did not receive postmastectomy radiotherapy. We found that there were no differences in the incidence of LRR among the four subgroups, and only patients with three positive nodes had a significantly increased risk of LRR, of more than 20%. The present study also shows that patients with TN or Rec-/HER2+ breast cancers are at an increased risk for DM and have a poor DFS and OS. These findings are consistent with the literature already published (4, 5). Bauer et al. (22) found that 6370 women with TN breast cancers had a consistently poorer duration of survival when compared with 44,707 women with other breast cancer subtypes at each stage and within each racial group. Cheang et al. (23) and Carey et al. (5) reported that the TN subtype conveys a worse breast cancer–specific survival, but the Rec-/ HER2+ subtype has the worst among all patients. Because we also found that TN breast cancers were more likely to be Grade 3, whereas Rec-/HER2+ breast cancers were more likely to have LVI with more positive nodes and a greater incidence of Stage III disease, a multivariate analysis was performed. This showed that Rec+/HER2- was an independent favorable factor for LRFS, and either TN or Rec-/ HER2+ was independently associated with a dismal duration of OS, DFS, and DMFS. The present study also showed there was a significant difference with regard to the timing of relapse. Triple-negative or Rec-/HER2+ breast cancers have an increased likelihood of LRR, DM, and death within the first 3 years after treatment, but this risk does not persist beyond 3 years after mastectomy; the peak of all events was at approximately 3 years. The risk of LRR, DM, and death for Rec+/HER2+ or Rec+/HER2- breast tumors was consistent over the first 5 years after treatment. A similar early relapse pattern has been described by other studies (24–27). Dent et al. (24) reported that patients with TN breast cancers experienced high rates of relapse only in the period from 1 to 4 years after diagnosis; the risk declined rapidly thereafter, and no recurrences occurred after 8 years of follow-up. Another study, by Tischkowitz et al. (25), demonstrated a difference in OS between TN and non-TN breast
cancers that was most obvious at 3 years and decreased to no difference at all by 10 years after diagnosis. Consistent with other reports that the patient with a TN breast cancer is more likely to develop intrapulmonary, brain, or visceral metastases (26, 28, 29) and that HER2-positive tumors lead to a lower risk of developing bony metastases (26), the present study found that TN, Rec-/HER2+, or Rec+/ HER2- breast cancers were more likely to lead to visceral metastases. Accordingly, Dent et al. (26) found that the excess risk of DM in TN breast cancers vs. other forms of cancer was attributable in large part to an excess of visceral metastases in the first 5 years after diagnosis. There are some potential limitations to this study. First, the HER2 data were obtained through IHC testing because the FISH test was not available. Although there is agreement that HER2 3+ patients are positive and 0 to 1+ are negative, those patients who are 2+ should be tested with FISH. Our subset analysis, which demonstrated that the statistical significance of the results were consistent regardless of whether HER2 2+ tumors were classified as HER2-positive or -negative, provides some reassurance. Second, the short duration of the follow-up means that a long-term survival comparison is unavailable, and longer follow-up to fully evaluate the rate of LRR is also warranted. It has been reported that trastuzumab has significantly reduced locoregional and distant relapses and improved overall survival in patients with HER2-positive tumors (30), and it is widely used in the treatment of HER2-positive breast cancers, but it was used in only 8 patients (1%) in the present study. Future studies will need to assess the impact of trastuzumab on LRR and reassess the prognostic implications of HER2positive tumors with targeted therapy. In conclusion, we found that node-positive breast cancer patients who undergo mastectomy have a relatively poor prognosis if simple commonly available markers of ER, PR, and HER2 show the tumors to be TN or Rec-/HER2+. Patients with TN, Rec-/HER2+, or Rec+/HER2+ breast cancers are at an increased risk of LRR. Further prospective studies with a longer duration of follow-up are warranted to confirm these findings, and new localized and systemic therapeutic strategies should be investigated to improve the outcome of patients with TN and HER2+ breast cancers.
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