© 2005 Foundation for Promotion of Cancer Research
Treatment Results and Prognostic Factors of Early Breast Cancer Treated with a Breast Conserving Operation and Radiotherapy
Departments of 1 Radiation Oncology and 2 Surgery, Samsung Medical Center, Department of 3 Surgery, Samsung Cheil Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
For reprints and all correspondence: Seung Jae Huh, Samsung Medical Center, Department of Radiation Oncology, Ilwon-Dong 50, Kangnam-ku, Seoul, 135-710, Korea. E-mail: sjhuh{at}smc.samsung.co.kr
Received November 4, 2004; accepted January 2, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: The purpose of this study was to analyze the prognostic factors affecting local control and survival rates for patients with early breast cancer who received breast conserving treatment (BCT) and to find out the optimal treatment according to their risk factors.
Methods: From October 1994 to December 2001, 605 patients with 611 stage I and II breast cancers received BCT, and the results were analyzed retrospectively. BCT consists of breast conserving surgery and whole breast irradiation. All the patients underwent lumpectomy or quadrantectomy. Axillary lymph node dissection or sentinel lymph node biopsy was performed in 608 cases (99.5%). The radiation dose to the whole breast was 50.4 Gy over 5 weeks with a 1.8 Gy daily fraction and with boost doses of 9–14.4 Gy administered to the tumor bed. Adjuvant chemotherapy was performed in most of the patients with axillary lymph node metastasis or tumors larger than 1 cm. The median follow-up period was 47 months.
Results: Local relapse, regional relapse and distant metastasis occurred in 15 (2.5%), 16 (2.6%) and 43 patients (7.1%), respectively. The 5-year overall survival, local-relapse-free survival, distant-metastasis-free survival and disease-free survival rates were 95.3%, 97.2%, 91.3% and 88.5%, respectively. On multivariate analysis, age (P = 0.02), number of involved axillary lymph nodes (P = 0.01) and nuclear grade (P = 0.01) affected the local-relapse-free survival. The factors associated with disease-free survival were the T stage (P = 0.05), number of involved axillary lymph nodes (P = 0.01) and nuclear grade (P = 0.001). Overall survival was associated with the T stage (P = 0.02), number of involved axillary lymph nodes (P = 0.01) and c-erb B2 overexpression (P = 0.05). Patients with more than two factors among (i) age 
35 years, (ii) positive lymph node metastasis and (iii) high nuclear grade showed a poor 5-year local-relapse-free survival rate compared with others (P = 0.001). Also, patients with more than two factors among (i) tumor size >1 cm, (ii) positive lymph node metastasis and (iii) high nuclear grade showed an inferior 5-year disease-free survival rate compared with others (P = 0.0005).
Conclusions: The most important prognostic factor affecting local control, disease-free survival and overall survival was axillary lymph node metastasis. The nuclear grade influenced local control and disease relapse. Patients with multiple unfavorable risk factors such as positive axillary lymph nodes, high nuclear grade, young age and large tumor showed poorer local control and disease-free survival than patients without any risk factors, and so more aggressive treatment is required for these patients.
Key Words: breast conserving treatment • invasive ductal carcinoma • prognostic factors
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INTRODUCTION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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According to a 2002 annual report of the Korean Central Registry, breast cancer is the most common cancer of women and comprises 16.8% of all reported cancers in Korea (1). The incidence of early stage breast cancer is increasing with the use of screening mammography. In Korea, 25.3% of breast cancer victims were diagnosed as having stage I disease, and the proportion of stage II was 52.8% (2). The treatment of early breast cancer has changed with time. Several phase III randomized trials have shown that survival after breast conserving treatment (BCT) consisting of local excision and whole breast irradiation was equal to the survival rate after radical mastectomy, and BCT is now generally accepted as the optimal treatment for early breast cancer (3–6). The majority of patients with early breast cancer are cured by BCT; however, 30% of patients will die of breast cancer within 10 years (7). Over the past 30 years, various systemic adjuvant therapies have been studied to improve survival. Axillary nodal metastasis is the most important prognostic factor, and systemic chemotherapy has improved overall survival by 11% for patients aged <50 years with positive axillary lymph nodes (8). During the past several decades, many prognostic factors such as axillary lymph node metastasis, tumor size, nuclear grade, hormonal receptor status, etc. have been proposed to provide an estimate for the risk of recurrence in patients with early breast cancer after BCT. The direction for further research is to develop a risk factor profile system to allow identification of the subgroups that have low or high risks of recurrence, and to find out the most appropriate treatment for the subgroups. In this study, we analyzed the prognostic factors affecting loco-regional relapse, disease control and survival, and we intended to identify the subgroups with a low or high risk of recurrence.
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SUBJECTS AND METHODS |
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From October 1994 to December 2001, 605 patients with 611 stage I and II breast cancers who received BCT were analyzed retrospectively. The patient characteristics are listed in Table 1. The age of the patients ranged from 27 to 73 years (median, 45 years). According to the 1997 American Joint Committee on Cancer (AJCC) tumor staging system, 454 cases (74.3%) were T1 stage and 157 cases (25.7%) were T2 stage. One hundred and thirty-eight cases (22.6%) had lymph node metastasis and the number of involved lymph nodes was less than 4 in 113 cases (18.5%), 4–9 in 18 cases (2.9%) and more than 9 in seven cases (1.1%). Three hundred and sixty-seven cases had stage I disease (60.1%), 193 cases had stage IIA disease (31.6%) and 51 cases had stage IIB disease (8.3%). The pathological findings are shown in Table 2. The tumor histology showed 523 cases (85.6%) with invasive ductal cell carcinoma, 23 cases (3.8%) with invasive lobular carcinoma and 65 cases (10.6%) were other histologic a types of cancer. The final pathological margin was considered to be negative when no tumor was identified in the excision specimen. Inked surgical resection margins were evaluated for the presence of close proximity of carcinoma; ‘negative’ was defined when all tumor was identified >2 mm from the inked margin, ‘close’, when tumor was identified
2 mm from the inked margin, but not at the inked margin and ‘positive’ when tumor was identified at the inked margin. Resection margin was positive in 10 cases (1.6%) and close in 83 cases (13.6%). The nuclear grade was low in 90 cases (14.7%), intermediate in 254 cases (41.6%) and high in 145 cases (23.7%). Estrogen receptor was positive in 340 cases (55.6%) and progesterone receptor was positive in 262 cases (42.9%). One hundred and fifty-six (25.5%) cases showed p53 positivity and 225 (36.8%) cases showed Her-2 positivity. Estrogen and progesterone receptor immunostainings were scored using the scoring method, which is a microscopic method conveying the estimated proportion (0, nil; 1, <1%; 2, <10%; 3, <33%; 4, <67%; 5 >67%) and intensity (0, no staining; 1, weak; 2, intermediate; 3, strong) of positive tumor cells. Positive cases were determined when the total score was 3 or more. Her-2 immunostaining was scored by the intensity of membrane staining on a scale of 0–3 (0, no staining; 1, weak; 2, intermediate; 3, strong). We determined positive cases when the intensity of staining was intermediate or strong. The p53 immunostaining was assessed by point counting 500–1000 cells and was reported as percentage of positive cells. We used the cut-off value to define a positive result as >5% of positive cells.
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All patients underwent lumpectomy or quadrantectomy, and whole breast irradiation. Axillary lymph node dissection or sentinel lymph node biopsy was performed in 608 cases (99.5%) except for three cases of microinvasive ductal cell carcinoma. Nine patients had bilateral breast cancer at the time of their initial diagnosis; seven of these underwent breast conserving surgery (BCS) on both breasts and the others received modified radical mastectomy on the contralateral breast.
For radiation treatment planning, a virtual computed tomography (CT) simulation was performed for all patients. The dose distribution was calculated using a computerized three-dimensional conformal radiotherapy planning system. Except for one case of ductal carcinoma in situ, a total of 605 patients with 611 invasive carcinomas received whole breast radiotherapy after BCS. The whole breast was irradiated by two tangential fields using 4–6 MV X-rays at a dose of 50.4 Gy in 5.5 weeks with a dose per fraction of 1.8 Gy. Additional boost doses of 9–14.4 Gy were administered to 97.2% of the cases (594/611). In patients with more than four involved axillary lymph nodes, 50.4 Gy in 5.5 weeks was given to the supraclavicular fossa in 90% of cases (23/25). The supraclavicular fossa was irradiated and the axillary and internal mammary nodal areas were not treated. Adjuvant chemotherapy was performed in 420 patients (69.4%) having axillary lymph node metastasis or a tumor larger than 1 cm. One hundred and thirty-two out of 138 patients having a positive axillary lymph node (95.7%) received chemotherapy. The regimen of chemotherapy was CMF (cyclophosphamide 600 mg/m2 i.v., methotrexate 40 mg/m2 i.v. and fluorouracil 600 mg/m2 i.v.; days 1 and 8 every 4 weeks, six cycles) in 365 patients (86.5%), AC (adriamycin 60 mg/m2 i.v., cyclophosphamide 600 mg/m2 i.v.; day 1 every 3 weeks, four cycles) in 20 patients (4.7%), CAF (cyclophosphamide 600 mg/m2 i.v. day 1, adriamycin 60 mg/m2 i.v. day 1, and fluorouracil 600 mg/m2 i.v.; days 1 and 8 every 4 weeks, six cycles) in nine patients (2.1%) and other or unknown regimen in 28 patients (6.6%). Hormone therapy with tamoxifen (20 mg per day) for 5 years was performed for 289 patients (47.8%).
Local relapse was defined as relapse within the irradiated breast. Regional relapse was defined as relapse in the ipsilateral axillary, supraclavicular and internal mammary nodal areas. Distant metastasis was defined as failure beyond the local or regional area. The overall survival, local-relapse-free survival, distant-metastasis-free survival and disease-free survival rates were calculated from the date of surgery until the date of death or up to the last follow-up, the date of the local relapse or up to the last follow-up, the date of the distant metastasis or up to the last follow-up, and the date of the first relapse or up to the last follow-up, respectively. The survival rates were calculated using the Kaplan–Meier method, and the comparison of the survival rates was done using the log-rank test. Multivariate analyses of the independent prognostic factors were performed using the Cox proportional hazards regression model.
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RESULTS |
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PATTERNS OF FAILURE
The median follow-up period was 47 months and this ranged from 7 to 107 months. The types of events occurring during the follow-up period are listed in Table 3. Failure occurred in 57 patients (9.4%). Fifteen patients (2.5%) had recurrent disease in the ipsilateral breast, 12 patients (2.0%) had recurrent disease in the same quadrant, two patients (0.3%) had recurrent disease in another quadrant and one patient (0.2%) had recurrent disease in multiple quadrants. Regional nodal recurrence occurred in 16 patients (2.7%) and seven of them also had local recurrence or distant metastases. The site of regional recurrence was the axillary lymph nodes in six patients (1%), the supraclavicular lymph nodes in 12 patients (2%) and the internal mammary lymph nodes in four patients (0.7%). Forty-three patients (7.1%) developed distant metastasis. Ten patients (1.7%) developed subsequent contralateral breast cancer, and these patients were not regarded as failures. A total of 57 patients experienced treatment failure in any site(s) after treatment and 20 of these patients (3.3%) died of disease. Of the remaining 37 patients, 10 patients with local recurrence and one patient with regional recurrence are still alive with no evidence of disease after salvage surgery. All patients having a solitary recurrence in the treated breast were salvaged with mastectomy and two patients developed subsequent regional recurrence and distant metastasis, respectively. Twenty-six patients with regional or distant disease are still alive with disease.
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SURVIVAL RATES AND PROGNOSTIC FACTORS
The 5-year overall survival, local-relapse-free survival, distant-metastasis-free survival and disease-free survival rates were 95.3%, 97.2%, 91.3% and 88.5%, respectively (Fig. 1). The clinical and pathological factors that potentially affected the local-recurrence-free, distant-metastasis-free, disease-free and overall survival rates were analyzed. On univariate analysis, the factors that affected the local-relapse-free survival rate were the nuclear grade (P = 0.01) and the presence of extensive intraductal component (EIC) (P = 0.04) (Table 4). However, on multivariate analysis, age (P = 0.02), the number of involved axillary lymph nodes (P = 0.01) and the nuclear grade (P = 0.01) affected the local-recurrence-free survival rate (Table 5). The T stage did not affect local recurrence. The distant-metastasis-free survival was affected by the T stage (P < 0.001), the N stage (P < 0.001), the number of involved axillary lymph nodes (P < 0.001), the AJCC stage (P < 0.001), the nuclear grade (P = 0.001), and c-erb B2 overexpression (P = 0.02) on the univariate analysis. On multivariate analysis, the T stage (P = 0.01), the number of involved lymph nodes (P = 0.01), nuclear grade (P = 0.01), c-erb B2 overexpression (P = 0.04) and EIC (P = 0.03) affected the distant-metastasis-free survival rate. The factors associated with disease-free survival according to univariate analysis were age (P = 0.05), T stage (P < 0.001), N stage (P < 0.001), the number of involved axillary lymph nodes (P < 0.001), stage (P < 0.001) and the nuclear grade (P < 0.001). On multivariate analysis, the T stage (P = 0.05), the number of involved axillary lymph nodes (P = 0.01) and the nuclear grade (P = 0.001) were associated with the disease-free survival. The factors affecting the overall survival rate were the T stage (P = 0.02), the number of involved axillary lymph nodes (P = 0.01) and c-erb B2 overexpression (P = 0.05), as was seen on multivariate analysis.
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SUBGROUP ANALYSIS
To find out the low- or high-risk groups for recurrence and to individualize the treatment according to the prognosis, we performed a subgroup analysis. Because age, number of lymph nodes and nuclear grade affected the local-relapse-free survival on multivariate analysis, the patients were divided into three subgroups according to the number of these risk factors that they had. Patients who had no risk factors among young age (
35 years), positive lymph nodes and high nuclear grade were classified into the low-risk group, patients with one risk factor were classified into the intermediate-risk group and patients with two or more risk factors were classified into the high-risk group. Patients with tumor(s) of unknown nuclear grade were excluded from the analysis. As a result, the 5-year local-relapse-free survival rates for the low-, intermediate- and high-risk groups were 99%, 98% and 87%, respectively (Table 6), and the differences for these groups were statistically significant (P = 0.001). Local-relapse-free survival between the low- and intermediate-risk groups was not different (P = 0.84). Survival difference between the low/intermediate- and high-risk groups is shown in Figure 2. Disease-free survival was affected by the T stage, the number of metastatic lymph nodes and the nuclear grade, so the risk group was also divided according to these factors. For the T stage, T1c (tumor >1 cm) and T2 were regarded as high-risk factors. Patients who had none of the three risk factors of tumor >1 cm, a positive lymph node and high nuclear grade were classified into the low-risk group, patients with one of these risk factors were classified into the intermediate-risk group and patients with two or more of these risk factors were classified into the high-risk group. The 5-year disease-free survival rates of the low-, intermediate- and high-risk groups were 93%, 94% and 81%, respectively (Table 7), and the differences were significantly different (P = 0.0005). Disease-free survival between the low- and intermediate-risk groups was not different (P = 0.89). Survival difference between low/intermediate- and high-risk groups is shown in Figure 3.
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DISCUSSION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Over the past two decades, BCT has become an alternative treatment to mastectomy for early breast cancer. Since several phase III randomized trials have shown the same survival rates with satisfactory local control after BCT compared with radical mastectomy, the use of BCT has progressively increased for the treatment of early breast cancer (9). In the USA, 58% of patients with stage I breast cancer and 36.2% of patients with stage II breast cancer underwent BCS (10). The incidence of breast cancer in Korea has continuously increased, although it is still quite low compared with its incidence in European countries and the USA. According to the cancer registration report issued by the Ministry of Health and Welfare, breast cancer ranks as the most common cancer in Korean women (1). In Korea, BCS has been performed in 27.1% of patients with breast cancer (2).
BCT consists of BCS and whole breast radiotherapy. When performing BCT, radiotherapy is very important to reduce local relapse. Ipsilateral breast cancer recurrence occurs in 25–35% of patients undergoing BCS alone, but it is reduced to 
10% with the addition of radiotherapy (11–14). In our study, local relapse occurred in 15 patients (2.5%). This is very low compared with other studies that have reported 5–15% of local recurrence (11–14). Our low rate of local relapse may be related to the relatively short follow-up period of our study. Because not all patients have recurrent tumor after BCS, efforts to identify a subgroup of patients with a low risk of local recurrence after BCS alone have been made. The Joint Center for Radiation Therapy performed a single arm prospective clinical trial of BCS alone for the patients having a low risk of local recurrence (15). The criteria for trial entry were T1 tumor without lymphatic vessel invasion and an extensive intraductal component having wide excision with a negative margin of >1 cm, and negative axillary nodes. With a median follow-up of 86 months, 23% of these patients experienced a local recurrence as their first site of failure. These researchers concluded that even in this highly selected group of patients, there was a long-term risk of a local recurrence after BCS alone. While it is recognized that not all women require radiation following BCS, the subgroup of patients who do not benefit from the addition of radiotherapy has not been identified yet. As a result, BCS followed by radiotherapy is thought to be the standard and proper care for all patients receiving BCT. In our study, young age (35 years), a large number of metastatic axillary lymph nodes and a high nuclear grade were significantly correlated with a worse local-relapse-free survival rate. However, resection margin, one of the important prognostic factors affecting local control, did not affect local-relapse-free survival in our study. This finding may be caused by the relatively short follow-up period and the few cases with positive or close resection margins. In our study, re-excision was performed in most cases if the resection margin was positive, so the cases with a positive resection margin represent only a very small proportion. Park et al. (16) reported that a close resection margin is not likely to affect local relapse. They reported that patients with close margins and those with negative margins both had a rate of local recurrence of 7% at 8 years.
In this study, to find out the low- or high-risk groups with local recurrence after BCT, the patients were divided into three subgroups according to the number of risk factors that they had. Patients who had no risk factors among young age, positive lymph node and high nuclear grade were classified into the low-risk group, patients with one risk factor were classified into the intermediate-risk group and patients with two or more risk factors were classified into the high-risk group. As a result, the low- and intermediate-risk groups showed excellent 5-year local-relapse-free survival rates, but the high-risk group showed a much lower 5-year local-relapse-free survival rate (P = 0.001). Recently, partial breast irradiation (PBI) to reduce the treatment period has been investigated for patients with early stage breast cancer who are expected to have a good prognosis (17). The results of PBI are consistent and successful, but selecting patients that appear to be appropriate for PBI is very difficult and controversial.
Over the past 30 years, various systemic adjuvant therapies have been studied to improve survival. Axillary lymph node involvement is a strong predictor of metastasis and death, so those patients with axillary lymph node metastasis have received chemotherapy, hormonal therapy or both. In many randomized trials, it has been demonstrated that the rate of local and distant recurrence was decreased both by adjuvant chemotherapy and by adjuvant tamoxifen for patients with axillary lymph node metastasis (18). The majority of patients without nodal metastasis are cured by BCT; however, the 10-year disease-free survival rate in these patients is 70–80% without systemic therapy (19–22). Because the risk of recurrence increases with increasing tumor size, systemic therapy is generally recommended for those patients with node-negative cancers whose tumor size is >1 cm. An overview analysis used by the Early Breast Cancer Trialists' Collaborative Group showed that systemic adjuvant polychemotherapy produces a substantial reduction in recurrence and mortality. An absolute improvement of 7% in the 10-year survival for node-negative patients under age 50 and an improvement of 11% for the node-positive patients under age 50 were observed. However, only a 2% reduction in mortality for node-negative patients aged 50–59 and 3% reduction in mortality for node-positive patients aged 50–59 was seen (8). In our study, most of the patients with positive axillary lymph nodes or tumor >1 cm received systemic adjuvant chemotherapy. To estimate the risk of recurrence for patients with early stage breast cancer after BCT with or without systemic therapy, the prognostic factors were analyzed. On multivariate analysis, the T stage, the number of metastatic axillary lymph nodes and high nuclear grade were thought to be the most important prognostic factors. The T stage, the number of metastatic axillary lymph nodes and nuclear grade were shown to significantly affect disease-free survival. Survival was affected by the number of metastatic axillary lymph nodes, nuclear grade and the existence of c-erb B2.
BCT is confirmed to be the appropriate treatment for patients with early breast cancer. The treatment should be decided upon according to the risk of relapse for the patient and the possibility of improved disease control and survival by the treatment. In our study, the number of involved lymph nodes was the most important prognostic factor affecting local-relapse-free, disease-free, distant-metastasis-free and overall survival. The nuclear grade is also an important prognostic factor. Age affected the local control and T stage affected the disease-free survival. Therefore, patients with positive lymph nodes, high nuclear grade and large tumor(s) should be treated aggressively and patients without any of these risk factors may require less aggressive treatment.
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References |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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