Abstract
Aim: Triple-negative breast cancer (TNBC) has a relatively poor prognosis compared to other molecular subtypes of breast cancer. This study aimed to evaluate the role of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-negative TNBC and to identify patients who could benefit from this therapy. Patients and Methods: We retrospectively reviewed the clinicopathological features and outcomes of patients with node-negative TNBC after surgery followed by either adjuvant chemotherapy with CMF or observation only. Results: Between January 2000 and December 2006, 276 patients with node-negative TNBC were eligible for inclusion in this study. The median follow-up time was 85.0 months by the end of 2010. The CMF (N=211) and observation (N=65) groups did not significantly differ with regard to T-stage, lymphovascular invasion (LVI), and tumour grade, but patients in the former group were on average younger (p<0.01). Adjuvant CMF was associated with favourable disease-free survival (DFS) (p=0.04). The CMF group also had a significantly lower locoregional recurrence rate than the observation group (0.4% vs. 9.2%, p=0.02). Subgroup analysis revealed that patients in the CMF group had significantly better DFS than those in the observation group among those with tumours larger than 2 cm (hazard ratio=0.38, p=0.02) and those who underwent partial mastectomy (hazard ratio=0.28, p=0.01). Conclusion: Adjuvant CMF chemotherapy was effective in reducing locoregional recurrence rate and prolong DFS in patients with node-negative TNBC, particularly in those with tumours of more than 2 cm or who had undergone partial mastectomy.
- Tiple-negative breast cancer
- node-negative breast cancer
- adjuvant chemotherapy
- CMF
- locoregional recurrence
Triple-negative breast cancer (TNBC), a subtype distinguished by negative immunohistochemical (IHC) assays for the expression of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2), accounts for approximately 12%-17% of women with breast cancer (1). TNBC has a relatively poor prognosis compared to other molecular subtypes of breast cancer (2) and cannot be treated with endocrine therapy or agents that target HER2. The treatment choices for TNBC include anthracyclines, taxanes, platinum, and alkylating agents (3-6). However, there is no standard chemotherapy regimen for node-negative TNBC.
The efficacy of adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) was first reported by Bonadonna et al. (7) for node-positive breast cancer in 1976 and, subsequently, for high-risk node-negative breast cancer (8). The National Surgical Adjuvant Breast and Bowel Project (NASBP)-B20 trial showed that the benefit of CMF combined with tamoxifen is inversely related to the expression of ER on tumour cells (9). Furthermore, the efficacy of adjuvant CMF was shown to be greater for patients without HER2 overexpression on tumour cells (10) and to be of at least equal efficacy to anthracycline-containing therapy in patients with HER2-negative breast cancer (11). Therefore, CMF is considered an optional regimen as adjuvant chemotherapy for patients with TNBC.
To evaluate the role of CMF for breast cancer adjuvant therapy, we retrospectively reviewed our database of patients with breast cancer to evaluate its efficacy in an adjuvant setting for node-negative TNBC and to identify factors that could predict which patients benefit from adjuvant CMF chemotherapy.
Patients and Methods
Patients. Between January 2000 and December 2006, a total of 3884 patients with breast cancer who underwent breast cancer surgery at the Linkou Chang Gung Memorial Hospital (CGMH) were registered in the Hospital's breast cancer databank. Data on patient demographics, tumour characteristics, surgical procedure, adjuvant chemotherapy, radiotherapy, hormonal therapy, disease status, and survival outcomes were prospectively collected. Among 3,884 patients, 509 (13.1%) patients had TNBC, and 304 (59.7%) of these 509 had node-negative TNBC. The present analysis enrolled patients who had node-negative TNBC and received either adjuvant CMF or who were monitored without further therapy. TNBC was defined as a pathological confirmation of invasive carcinoma with negative ER (<10%), PR (<10%), and HER2 (0, 1+) expression by IHC staining. The pathological features were also reviewed by an experienced pathologist (HS). Our study was approved by the Hospital's Institutional review board (approval number: 101-4030B).
Treatment. A subset of patients underwent primary surgery consisting of either modified radical mastectomy or partial mastectomy with axillary lymph node dissection. Adjuvant radiotherapy was performed for patients who underwent partial mastectomy or who had a tumour greater than 5 cm after modified radical mastectomy (12). Adjuvant chemotherapy with CMF consisted of cyclophosphamide at 600 mg/m2, methotrexate at 40 mg/m2, and fluorouracil at 600 mg/m2 every three weeks for nine cycles. After completion of therapy, the patients were followed-up at the Outpatient Department with physical examination every three months for the first two years, every six months for the next three years, and every 12 months thereafter; breast mammography or ultrasonography every 12 months; chest radiography every 12 months; and a complete blood count, biochemistry tests, and measurements of serum levels of carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) every six months for the first three years and every 12 months thereafter. Other examinations, such as bone scanning and abdominal ultrasonography, were performed at the physician's discretion. Medical information was obtained by a periodic review of the charts and telephone interviews. The last follow-up date was 31 December 2010.
Statistical considerations. The description of the cohort used median and range values for categorical variables. We evaluated clinicopathological features including age, tumour size, tumour grade, lymphovascular invasion (LVI), and the primary surgical method. Disease-free survival (DFS) was defined as the duration from surgery to the diagnosis of recurrence or a second primary malignancy. Data on patients who died without evidence of recurrence, or who were lost to follow-up, were censored at the date of death or their last visit, respectively. Overall survival (OS) was defined as the duration from surgery to death due to any cause. Cancer-specific survival was defined as the duration from surgery to death resulting from breast cancer. Prognostic factors included age, tumour size, Scarff-Bloom-Richardson (SBR) grade, primary surgical method, and use of adjuvant chemotherapy. Survival was analyzed using the Kaplan–Meier method. Univariate and multivariate analysis of the association between the prognostic factors and survival was performed using the Cox proportional hazard model.
Patients' characteristics (N=276).
Results
Patients' characteristics. Among patients with node-negative TNBC, 211 received adjuvant chemotherapy with CMF and 65 patients were monitored but received no additional therapy (observation group). The patients in the CMF group were on average younger (p<0.01) than those in the observation group. There was no significant difference in T-stage, tumour grade, LVI, and surgical methods between the two groups. Details of patient characteristics are provided in Table I.
DFS and OS. The median follow-up period was 85.0 months, and the 5-year and estimated 10-year DFS rates of node-negative TNBC were 88.7% and 77.9%, respectively, with 5-year and estimated 10-year OS rates of node-negative TNBC of 94.2% and 92.5%, respectively. The estimated 5-year and 10-year DFS rates were 90.0% and 83.7% in the CMF group and 84.5% and 54.4% in the observation group, respectively. The median DFS was not reached in either group. The adjuvant CMF group had significantly better DFS than the observation group (p=0.04; Figure 1). The 5-year and estimated 10-year OS rates were 94.0% and 93.3% in the CMF group and 95.0% and 89.8% in the observation group, respectively, and the estimated 10-year cancer-specific survival rate was 94.4% in the CMF group and 95.0% in the observation group. OS and cancer-specific survival did not differ between groups (Figure 2).
Kaplan-Meier survival curve of disease-free survival. Patients who received cyclophosphamide, methotrexate, and fluorouracil (CMF) adjuvant chemotherapy had better disease-free survival than those who did not (p=0.04).
In univariate analysis, only adjuvant CMF was associated with favourable DFS [hazard ratio (HR)=0.52; 95% confidence interval (CI)=0.27-0.98, p=0.04]. DFS was also significantly better in the CMF group (adjusted HR=0.43; 95% CI=0.20-0.94, p=0.04) after adjusting for age, grade, tumour size, and LVI.
Patterns of first recurrence. We further analyzed the patterns of the first incidence of recurrence in both groups. Patients who received adjuvant CMF regimen had a significantly lower locoregional recurrence rate (0.4% vs. 9.2%, p=0.02), although there was no significant difference in the frequency of distant recurrence or second primary malignancy (Table II). All seven patients with locoregional recurrence were treated with salvage surgery. Among patients with locoregional recurrence, five are currently disease-free for 5.1, 15.6, 25.3, 43.3, and 70.7 months (measured at the last follow-up) after salvage surgery and the other two patients have died of breast cancer (6.5 and 39.3 months after salvage surgery).
Six patients in the CMF group had second primary malignancies, including contralateral breast cancer (N=1), colorectal cancer (N=2), ovarian cancer (N=1), lung cancer (N=1), and hepatocellular carcinoma (N=1). All three patients with a second primary malignancy in the observation group had contralateral breast cancer. No therapy-related myeloid neoplasms were noted.
Subgroup analysis. We further performed subgroup analysis to identify for patients who had better DFS after adjuvant CMF. Patients in the CMF group with tumours greater than 2 cm (HR=0.38, 95% CI=0.16-0.87, p=0.02) and those who had undergone partial mastectomy (HR=0.28, 95% CI=0.10-0.73, p=0.01) had significantly better DFS than those in the observation group (Table III).
Kaplan-Meier survival curve of overall survival. There was no statistically significant difference in overall survival between patients who received cyclophosphamide, methotrexate, and fluorouracil (CMF) and those who did not (p=0.60).
We stratified the 276 patients into two distinct groups according to tumour size and type of primary surgery. Patients with tumours of 2 cm or less and who had undergone modified radical mastectomy were placed in the low-risk group (80 patients), while the remainder (including those with tumours of more than 2 cm, or those who underwent partial mastectomy) were placed in the average-risk group (196 patients). In the average-risk group, patients who received CMF had a better DFS than those who received no adjuvant chemotherapy (HR=0.35, 95% CI=0.17-0.74, p<0.01) (Table III, Figure 3).
Discussion
Identification of factors that can predict for outcome of adjuvant treatment of breast cancer has become an important clinical goal. This study showed that adjuvant chemotherapy with CMF was able to reduce the locoregional recurrence rate and prolong DFS in patients with node-negative TNBC, particularly in those with tumours greater than 2 cm or who had undergone partial mastectomy. We also identified a subgroup of low-risk patients (those with tumours of 2 cm or less and those who had undergone modified radical mastectomy) who derived no benefit from adjuvant chemotherapy with CMF compared to those in the observation group.
Patterns of first recurrence (N=276).
Colleoni et al. (13) retrospectively analyzed the role of adjuvant classical CMF in patients with node-negative breast cancer treated in two adjuvant trials and found that the benefit of CMF in prolonging DFS was most pronounced in patients with node-negative TNBC. The results of our study also support the use of a specific chemotherapy regimen (CMF) for a specific tumour subtype (TNBC).
Our results support the idea that patients with pT1N0 TNBC who underwent modified radical mastectomy may not benefit from adjuvant CMF. This adds to a growing number of studies that have shown tumour-related factors to be of potential prognostic value in breast cancer, most notably tumour size. It is recommended that most patients with node-negative TNBC receive postoperative adjuvant chemotherapy (14). In the earlier St. Gallen consensus (15, 16), TNBC negative for ER and PR was considered to have a high risk of recurrence, so adjuvant chemotherapy is indicated for all patients with TNBC. The most recent consensus of opinion is that patients with tumours less than 1 cm in size and without axillary lymph node involvement or other adverse features might not need adjuvant chemotherapy (14). We also found that some patients with node-negative TNBC and a very low risk of recurrence obtained only very limited benefit from adjuvant chemotherapy.
Partial mastectomy is an appropriate choice of surgeons for women with small breast tumours as, when combined with adjuvant radiotherapy, it confers the same long-term survival benefit as radical mastectomy (17, 18). However, the incidence of local recurrence was significantly higher in those treated by partial, as compared to radical mastectomy in some studies (17). The local recurrence rate after partial mastectomy was also higher in TNBC (19). Adjuvant chemotherapy with CMF can reduce locoregional recurrence in node-negative and ER-negative breast cancer patients and can also markedly reduce the incidence of ipsilateral breast tumour recurrences after lumpectomy and breast irradiation (20). Our finding that patients with node-negative TNBC benefited from adjuvant CMF only if they underwent partial rather than modified radical mastectomy are consistent with these reports.
Subgroup analyses of disease-free survival.
Although patients who received CMF had less locoregional recurrence and better DFS than those in the observation group, lengthened DFS does not necessarily correspond to increased OS. This may be because all patients with locoregional recurrence can be treated by salvage surgery and most of them were disease-free after this. The observation group in the present study had better survival than similar patient groups in previous reports (13, 20). Colleoni et al. reported that the 10-year OS rate was 79% in the CMF group and 70% in the observation group for patients with node-negative TNBC (13). Similarly, the NSABP-B13 trial showed that the 8-year survival rate for patients with node-negative, ER-negative breast cancer was 69% (20). In the present study, the estimated 10-year OS rate was 89.8% and the 10-year cancer-specific survival rate was 95% in the observation group. This is probably close to the maximum improvement in survival that can be achieved using adjuvant chemotherapy.
The present study had several limitations. Firstly, since this is a retrospective single-institution analysis, some bias may exist. Secondly, we did not assess the role of Ki-67, which might be a prognostic factor for breast cancer (21). However, some authors have suggested that Ki-67 status should not be considered a routine part of breast cancer evaluation because there are relatively few prospective studies or standardized assay reagents, procedures, and scoring systems (22, 23). Thirdly, the median follow-up of 85.0 months was not long enough to fully-evaluate survival and cancer relapse. However, in a previous study (24), disease recurrence was found to peak within one to four years of primary surgery in patients with TNBC, and was rare after eight years.
Analyses of disease-free survival in the average-risk and low-risk groups. A: Kaplan-Meier estimates of the probability of disease-free survival in the low-risk group (patients with tumours 2 cm or less and undergoing radical mastectomy). The unadjusted hazard ratio for disease recurrence in the CMF group compared with the observation group was 1.62 [95% CI=0.35–7.40, p=0.54). B: Kaplan-Meier estimates of the probability of disease-free survival in the average-risk group (patients with tumours greater than 2 cm or receiving partial mastectomy). The unadjusted hazard ratio for disease recurrence in the CMF group compared with the observation group was 0.35 (95% CI=0.17–0.74, p<0.01).
In conclusion, adjuvant chemotherapy with CMF plays a significant role in reducing locoregional recurrence and prolonging DFS in patients with node-negative TNBC. Patients with tumours greater than 2 cm or those who undergo partial mastectomy derive the most benefit from CMF.
Footnotes
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Conflicts of Interest
The Authors have no conflicts of interest to declare.
- Received September 9, 2013.
- Revision received October 11, 2013.
- Accepted October 15, 2013.
- Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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