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Introduction
Breast cancer management strategies during the last decade have tended toward less radical surgeries. Accordingly, efforts to limit redundant axillary management have continued. The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial randomized women with up to two positive lymph nodes (LNs) detected after breast-conserving surgery (BCS) and sentinel node biopsy (SNB) to either the axillary lymph node dissection (ALND) or observation arm [1,2]. In that trial, the regional recurrence rates of < 1% were equivalent between the arms. However, it remains unclear whether this result is safely applicable to patients after mastectomy. Particularly, radiation is not routinely administered after mastectomy, and therefore post-mastectomy axillary management should different from that after BCS. Currently, about 91% of women with clinically node-negative but SNB-positive LNs underwent completion ALND, while 9% underwent SNB alone, after mastectomy [3]. Several relevant retrospective analyses have yielded conflicting results [3,4]; while no randomized controlled trials has compared SNB alone vs. ALND, particularly in pN1 stage.
The benefit of post-mastectomy radiotherapy (PMRT) in these patients also remains controversial [5]. According to the 2009 St. Gallen recommendations, PMRT is indicated for patients with ≥ 4 involved axillary LN [6]; however, indications for its use in patients with 1-3 affected nodes were more restricted and particularly applicable to young patients and those with other poor prognostic features. Accordingly, it remains unclear how these results should be incorporated into clinical practice, given the broad potential for selection bias in breast cancer treatment.
We therefore conducted this study to compare the benefits of ALND vs. SNB alone for breast cancer patients who underwent mastectomy and had 1-3 metastatic LNs. We adjusted for confounding factors to verify our findings. We additionally evaluated the contribution of PMRT to survival outcomes.
Materials and Methods
1. Patients
From 2000 to 2015, 1,768 women with breast cancer underwent total mastectomy and were diagnosed with N1 disease. The patient enrollment algorithm is shown in Fig. 1.
All patients were clinically staged according to the seventh edition of the American Joint Committee on Cancer staging guidelines. Patients were assessed at presentation using the clinical history and findings from the physical examination, mammography, ultrasonography, breast magnetic resonance imaging, and biopsies of the breast and suspicious LNs.
2. Treatment
Until 2002, patients were treated with regimens comprising cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, doxorubicin, and fluorouracil; since 2003, a taxane-based regimen has been used. Hormone suppression therapy was administered to patients with estrogen receptor–positive or progesterone receptor–positive breast cancer. An anti–human epidermal growth factor receptor 2 (HER-2) targeted agent was administered to patients with a positive HER-2/neu receptor status.
For pathologic T3 (pT3) tumors, radiotherapy (RT) was administered to the chest wall and regional lymphatics, including the ipsilateral axillary apex and supraclavicular fossa compartment. Radiation was delivered using a 4-15 MV X-ray and/or 6-16 MeV electron beam from a linear accelerator (Varian Medical Systems, Palo Alto, CA). Total radiation doses of 4,500-5,080 cGy in fractions of 180-250 cGy were typically administered, and boost doses of 540-2,540 cGy were directed to the tumor bed or gross tumor. For T1/2 tumors, the use of RT and irradiation field differed in terms of the treating physician’s preferences regarding the patient and pathologic characteristics. In this study patients, eight patients with T1/2 tumors received RT after SNB. Radiation field was chest wall and regional lymphatics in four patients, chest wall only in two patients, and unidentified in two patients.
3. Statistics
The extent of axillary operation was determined primarily according to the surgical record. However, the number of examined nodes was also considered. Patients were considered to have undergone an SNB alone if ≤ 5 nodes were examined. Completed ALND was defined as the examination of ≥ 10 nodes. This concept was also used in a previous study by the American College of Surgeons [3].
Locoregional failure was defined as recurrent or progressive disease of the ipsilateral chest wall or the regional nodal station (ipsilateral axillary, supraclavicular, or internal mammary LNs). Locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model. Inter-group comparisons of patient characteristics were performed using the chi-square test. All analyses were 2-tailed, and a p-value of < 0.05 was considered significant. All statistical analyses were performed using the SPSS statistical package, ver. 22.0 (IBM Corp., Armonk, NY).
To adjust for potential selection bias regarding axillary operation, we used an inverse probability of treatment weighted (IPTW) method [7]. The IPTW approach is a propensity score (PS)–based method used to control for confounding factors. This method simulates a sample with balanced characteristics between the two therapy groups, independent of the treatment decision. The PS was derived using a multivariable logistic regression model in which the axillary operation (ALND/SNB alone) was set as the outcome variable. The model included covariates such as the characteristics of the patients and primary tumor, as specified in Table 1. The t test was used to evaluate continuous variables, and the chi-square test or Fisher exact test was used for categorical variables.
Table 1.
Patient characteristics
| Variable | Total (n=1,697) | ALND (n=1,539) | SNB (n=158) | p-value |
SDM |
|
|---|---|---|---|---|---|---|
| Before weighting | After weighting | |||||
| Age (yr) | 47.70 | 47.59 | 48.77 | 0.153 | 0.120 | 0.092 |
| BMI (kg/m2) | 23.42 | 23.44 | 23.18 | 0.395 | 0.075 | 0.105 |
| Histology | ||||||
| IDC | 1,628 (95.9) | 1,477 (96.0) | 151 (95.57) | 0.808 | 0.020 | 0.067 |
| ILC | 69 (4.1) | 62 (4.0) | 7 (4.43) | |||
| No. of tumors | ||||||
| 1 | 1,367 (80.6) | 1,237 (80.4) | 130 (82.3) | 0.502 | 0.108 | 0.171 |
| 2 | 243 (14.3) | 220 (14.3) | 23 (14.6) | |||
| ≥ 3 | 87 (5.1) | 82 (5.3) | 5 (3.2) | |||
| Locationa) | ||||||
| UOQ/LOQ | 951 (56.5) | 861 (56.5) | 90 (57.0) | 0.559 | 0.105 | 0.107 |
| Central | 394 (23.4) | 356 (23.3) | 38 (24.1) | |||
| UIQ/LIQ | 322 (19.1) | 295 (19.3) | 27 (17.1) | |||
| Whole | 16 (1.0) | 13 (0.9) | 3 (1.9) | |||
| Histologic gradeb) | ||||||
| G1 | 61 (3.8) | 55 (3.8) | 6 (3.9) | 0.021 | 0.242 | 0.132 |
| G2 | 928 (57.6) | 823 (56.5) | 105 (67.7) | |||
| G3 | 622 (38.6) | 578 (39.7) | 44 (28.4) | |||
| Tumor size (mm) | 28.26 | 28.73 | 23.70 | 0.002 | 0.283 | 0.055 |
| T category | ||||||
| T1/2 | 1,561 (92.0) | 1,413 (91.8) | 148 (93.7) | 0.413 | 0.072 | 0.064 |
| T3/4 | 136 (8.0) | 126 (8.2) | 10 (6.3) | |||
| Positive LN | ||||||
| 1 | 887 (52.3) | 758 (49.3) | 129 (81.7) | < 0.001 | 0.772 | 0.175 |
| 2 | 513 (30.2) | 488 (31.7) | 25 (15.8) | |||
| 3 | 297 (17.5) | 293 (19.0) | 4 (2.5) | |||
| Hormone receptorsc) | ||||||
| Positive | 1,201 (71.0) | 1,079 (70.3) | 122 (78.2) | 0.038 | 0.182 | 0.039 |
| Negative | 490 (29.0) | 456 (29.7) | 34 (21.8) | |||
| c-Erb B2d) | ||||||
| Negative | 995 (59.3) | 900 (59.1) | 95 (60.9) | 0.002 | 0.369 | 0.116 |
| Equivocal | 162 (9.7) | 159 (10.5) | 3 (1.9) | |||
| Positive | 521 (31.1) | 463 (30.4) | 58 (37.2) | |||
| Luminal typee) | ||||||
| Luminal | 1,201 (71.2) | 1,079 (70.5) | 122 (78.2) | 0.042 | ||
| Non-luminal | 486 (28.8) | 452 (29.5) | 34 (21.8) | |||
| p53f) | ||||||
| 0/1+/2+ | 1,249 (80.1) | 1,131 (80.0) | 118 (80.8) | 0.810 | 0.021 | 0.001 |
| 3+ | 311 (19.9) | 283 (20.0) | 28 (19.2) | |||
Values are presented as mean or number (%). ALND, axillary lymph node dissection; SNB, sentinel node biopsy; SDM, standardized difference of means; BMI, body-mass index; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; UOQ, upper outer quadrant; LOQ, lower outer quadrant; UIQ, upper inner quadrant; LIQ, lower inner quadrant; LN, lymph node.
4. Ethical statement
Our institutional review board approved the retrospective use of clinical data for this study (2017-1234). As this was a retrospective analysis of routine clinical data, a waiver of the requirement for individual informed consent was granted by the institutional ethics committee.
Results
1. Patient and tumor characteristics
A total of 1,697 patients were included in the analysis. The patient and tumor characteristics are shown in Table 1. The median age was 47.7 years (range, 23 to 81 years). The majority of patients (95.9%) had ductal carcinoma and underwent ALND (91%).
2. Patterns of the first failure
The patterns of the first failure are summarized in Table 2. Most of the 256 patients who experienced recurrence had distant metastases (205/256). Isolated local and regional recurrences were detected in 19 and 23 patients, respectively. The most frequent sites of distant metastasis were the bone and lung. In 34 patients, the first recurrence involved metastases at > 3 sites. Regional recurrences of the axillary, supraclavicular, and internal mammary LNs were diagnosed in 41, 47, and 36 patients, respectively. The sites of recurrence are specified in S1 Table.
Table 2.
The pattern of first failure sites
3. Prognostic factors for survival
The median follow-up period was 93 months (range, 3 to 212 months). The 10-year LRRFS, DMFS, DFS, and OS rates were 92%, 86%, 83%, and 84%, respectively (Fig. 2). The results of a prognostic factor analysis of LRRFS and DMFS are shown in Table 3. In the multivariate analysis, age, location, tumor size, and hormone therapy were identified as significant factors for LRRFS, whereas the body mass index, location, size, number of positive LNs, and hormone receptor status were significant factors for DMFS. The analyses of DFS and OS are summarized in Table 4. The tumor location, size, number of metastatic LNs, and hormone receptor status were identified as poor prognostic factors for DFS and OS. Additionally, the histologic grade was predictive of DFS while the body mass index and chemotherapy were predictive of OS.
Fig. 2.
Kaplan-Meier survival curves of the total patients. LRRFS, lcoregional recurrence-free survival; DMFS, distant metastasis-free survival; DFS, disease-free survival; OS, overall survival.
Table 3.
Univariate and multivariate analyses of LRRFS and DMFS
LRRFS, locoregional recurrence-free survival; DMFS, distant metastasis-free survival; HR, hazard ratio; BMI, body mass index; UOQ, upper outer quadrant; LOQ, lower outer quadrant; UIQ, upper inner quadrant; LIQ, lower inner quadrant; LN, lymph node; ILC, invasive lobular carcinoma; IDC, invasive ductal carcinoma.
Table 4.
Univariate and multivariate analyses of DFS and OS
4. Inverse probability of treatment weighted
To account for the effects of confounding factors, we calculated a PS and used this value in an IPTW analysis. Based on the prognostic factor analysis, our covariates included age, body mass index, number of breast tumors (1 vs. 2 vs. ≥ 3), tumor location (outer quadrant vs. inner quadrant vs. central vs. whole breast), size, number of metastatic LNs (1 vs. 2 vs. 3), T category (T1/2 vs. T3/4), histologic grade (1 vs. 2 vs. 3), histologic type (invasive ductal carcinoma vs. invasive lobular carcinoma), hormone receptor status (positive vs. negative), HER-2/neu receptor status (positive vs. negative), luminal type (luminal vs. non-luminal), and p53 expre-ssion (negative/weak/intermediate vs. strong). We additionally adjusted for the following known postoperative prognostic factors: number of harvested LNs, N category (N1 vs. N1mi), use of adjuvant chemotherapy, adjuvant RT, adjuvant hormone therapy, and trastuzumab therapy. A numeric distribution of patients is shown in S2 Table. A median of 15.2 LNs were retrieved. Fifty-two patients (3%) were diagnosed with N1mi stage disease.
The hazard ratios of locoregional recurrence, distant metastasis, progression, and death for the SNB group relative to the ALND group are shown in Table 5. After IPTW correction and additional adjustments of postoperative covariates, we observed no differences in LRRFS, DFS, and OS between the SNB and ALND groups. Rather, only the risk of distant metastasis was significantly lower in the SNB group after IPTW correction. Specifically, the hazard ratio for distant metastasis was 0.35 (95% confidence interval, 0.12 to 0.97; p=0.043). This difference was lost after additional adjustments of postoperative covariates. The results are shown in Fig. 3.
Fig. 3.
Forest plot demonstrating the risks of death, locoregional recurrence, distant metastasis, and disease recurrences for sentinel node biopsy (SNB) relative to axillary lymph node dissection (ALND). HR, hazard ratio; CI, confidence interval; IPTW, inverse probability of treatment weighted.
Table 5.
Outcome analysis based on the IPTW method
| Outcome | HRa) | 95% CI | p-value |
|---|---|---|---|
| Overall survival (event=237/1,697) | |||
| Univariate | 0.457 | 0.225-0.926 | 0.030 |
| Multivariable adjusted | 0.675 | 0.330-1.380 | 0.281 |
| IPTW methodb) | 0.537 | 0.212-1.356 | 0.188 |
| IPTW and adjusted by covariatesc) | 0.566 | 0.219-1.464 | 0.240 |
| Locoregional recurrence-free survival | |||
| Univariate | 0.499 | 0.203-1.224 | 0.129 |
| Multivariable adjusted | 0.624 | 0.254-1.537 | 0.306 |
| IPTW methodb) | 0.698 | 0.248-1.967 | 0.497 |
| IPTW and adjusted by covariatesc) | 0.775 | 0.251-2.394 | 0.658 |
| Distant metastasis-free survival | |||
| Univariate | 0.444 | 0.219-0.901 | 0.025 |
| Multivariable adjusted | 0.622 | 0.304-1.275 | 0.195 |
| IPTW methodb) | 0.346 | 0.124-0.965 | 0.043 |
| IPTW and adjusted by covariatesc) | 0.374 | 0.131-1.063 | 0.065 |
| Disease-free survival | |||
| Univariate | 0.530 | 0.297-0.947 | 0.032 |
| Multivariable adjusted | 0.752 | 0.417-1.357 | 0.344 |
| IPTW methodb) | 0.552 | 0.254-1.200 | 0.134 |
| IPTW and adjusted by covariatesc) | 0.619 | 0.327-1.172 | 0.141 |
Discussion
In this study, we reviewed patients who had undergone mastectomy at our institution and were determined to have pN1 or pN1mi disease. After a median follow-up of 93 months, we observed no significant differences in the LRRFS, DMFS, DFS, and OS rates of patients who underwent SNB vs. those who underwent ALND. We observed a clear bias toward smaller tumors, lower histologic grade, lower number of metastatic LNs, and better immunohistochemical findings among patients who underwent a limited axillary operation. To correct this, we applied the IPTW method. Subsequently, we observed no differences in OS, DFS, and LRRFS between the groups. The corrected DMFS rate was higher in the SNB group relative to the ALND group, however, after adjusting for postoperative factors, the statistical power was lost.
Despite ongoing controversy, the avoidance of axillary node dissection in selected patients with micrometastatic disease or isolated tumor cells in the sentinel node is considered adequate [3,8]. However, the issue of whether to complete ALND after a notification of nodal macrometastases remains controversial. The results of the ACOSOG Z0011 trial suggest that ALND can be avoided safely in patients with up to 2 macroscopically positive sentinel nodes [2]. The long-term follow-up also showed excellent regional control, despite the potential for residual axillary disease [9]. Additionally, ALND could be avoided in a large majority of Z0011-eligible patients, regardless of the use of routine nodal radiation [10]. However, the applicability of these findings to patients undergoing total mastectomy has not been established. Several publications from single-institutional studies have reported the outcomes of mastectomy cases. The majority of these studies suggest that omitting ALND or replacing it with RT does not worsen DFS [4,11]. Accordingly, the pattern of axillary management has shifted toward less radical surgery (Fig. 4) [3,4,8,10].
Nodal radiation is another alternative to ALND for LN-positive patients. In the current analysis, adjuvant RT did not improve LRRFS, DFS, or OS. In this study, we sought to identify a patient group that would benefit from RT. However, the retrospective nature of this study precluded such an analysis because most of the high-risk patients underwent ALND. Still, other researchers have attempted such an analysis. In the 2005 pooled analysis of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), PMRT yielded reductions in the risks of local recurrence and 15-year breast cancer mortality [12]. As RT led to similar proportional reductions in the rate of local recurrence among all women, large absolute reductions in local recurrence were only observed if the control risk was also large. Therefore, PMRT was indicated for N2 disease; however, the benefit of PMRT in N1 disease, which is assumed to confer a relatively low risk of absolute locoregional recurrence, remained debatable. Recently, a meta-analysis showed that a locoregional recurrence reduction in response to PMRT conferred a significant survival benefit upon patients with N1 disease [13]. Chang et al. [5] performed a retrospective study of patients who underwent mastectomy plus ALND [5]; in this group, 17.8% of patients also received PMRT. Here, PMRT did not significantly reduce the locoregional recurrence (1% vs. 3.8%, 5 years) but was associated with an improved DFS. As shown above, the evidence supports the use of PMRT for patients with N1 disease who did not undergo ALND. In contrast to cases involving BCS, for which adjuvant radiation is scheduled, post-mastectomy patients face a more complicated decision-making process regarding RT. The current American Society of Clinical Oncology (ASCO) guidelines recommend that “Clinicians should not recommend ALND for women with early-stage breast cancer who have one or two sentinel lymph node metastases and will receive breast-conserving surgery with conventionally fractionated whole-breast RT”; this recommendation is based on the ACOSOG Z0011 and International Breast Cancer Study Group (IBCSG)-2301 clinical trials [2,14]. This suggests that no definitive guidelines on axillary management exist for cases in which RT is not planned, such as mastectomy cases involving T1 or T2 breast cancer.
Previous research has identified age, tumor size, premenopausal status, and the numbers of positive and dissected LNs as predictors of locoregional failure in patients with node-positive breast cancer [15]. Recent studies that included patients treated with modern chemotherapy regimens reported that the presence of extensive intraductal components, lymphovascular invasion, histologic grade 3, and non-luminal subtype were also predictive of local control [16,17]. A current study revealed similar findings. Additionally, patients with inner quadrant tumors tended to had unfavorable outcomes, including LRRFS, DMFS, DFS, and OS. According to several studies conducted with respect to tumor location as a prognostic factor, inner quadrant tumors were associated with a lower OS rate and more frequent distant metastases, compared to outer quadrant tumors [18]. Although it remains unclear why patients with inner quadrant breast cancer have worse outcomes, a potential association with internal mammary node (IMN) involvement is generally accepted. More aggressive chemotherapy or PMRT that includes the IMN area can be considered in patients with inner quadrant tumors. In this study, which includes a large number of patients with N1 disease, at least three metastatic LNs was also identified as a poor prognosticator for DMFS, DFS, and OS. Metastatic LNs may be a source of early regional or distant recurrence; therefore, the extent of LN metastasis can serve as a prognosticator in breast cancer patients with metastatic LNs. A population-based study of more than 25,000 women found that the LN ratio (LNR, the ratio of positive LNs to the total number of removed LNs) was an important prognostic factor independent of traditional clinicopathological factors [19]. Some researchers have argued that the LNR may have a greater prognostic value than the absolute number of involved nodes. Moreover, the LNR has been identified as a significant predictor of outcomes in all stages of breast cancer [20]. Given the variability of factors related to the local recurrence of breast cancer, it is difficult to determine the need for PMRT using only ALND. Further research is needed to define the appropriate indications for PMRT. We suggest that less aggressive axillary procedures for N1 patients should be considered cautiously for those with inner quadrant tumors or metastasis to ≥ 3 LNs. Additionally, age, tumor size, and hormone receptor status should be considered when making decisions about adjuvant treatment.
Our study had several limitations of note, including those inherent to a retrospective analysis. First, the long study period led to heterogeneity in the use of chemotherapy regimens. Second, patients were not randomly allocated to undergo ALND vs. SNB alone or RT vs. no RT. We used IPTW-PS matching to adjust for these errors. However, it was difficult to draw any definitive conclusions regarding the efficacy of ALND or PMRT. A randomized clinical trial of this subject is currently ongoing in the Netherlands. Specifically, the Dutch Breast Cancer Research Group (BOOG) 2013-07 trial is conducting a randomized clinical trial to determine whether completion axillary treatment can be safely omitted in SNB-positive breast cancer patients treated with mastectomy. Until the results of that study are published, our findings could serve as a reference for treatment decisions.
In conclusion, ALND did not improved the survival outcomes, including locoregional control, of women with pN1 breast cancer who underwent mastectomy, even after adjusting for all histopathologic and treatment-related factors. Omitting ALND or replacing it with RT in these patient groups can be considered in the absence of high risk factors.
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