10.1245/ASO.2006.03.010
Annals of Surgical Oncology 13:685-691 (2006)
© 2006 Society of Surgical Oncology
Size of Residual Lymph Node Metastasis After Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer Patients Is Prognostic
Nancy Klauber-DeMore, MD1,2,
David W. Ollila, MD1,2,
Dominic T. Moore, M.S, M.P.H.2,3,
Chad Livasy, MD4,
Benjamin F. Calvo, MD1,2,
Hong Jin Kim, MD1,2,
E. Claire Dees, MD2,5,
Carolyn I. Sartor, MD2,6,
Lynda R. Sawyer, M.F.A.2,
Mark Graham, II, MD2,5 and
Lisa A. Carey, MD2,5
1 Department of Surgery, University of North Carolina at Chapel Hill, 3010 Old Clinic Building, CB #7213, Chapel Hill, North Carolina 27599
2 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 102 Mason Farm Road, CB #7295, Chapel Hill, North Carolina 27599
3 Department of Biostatistics, University of North Carolina at Chapel Hill, McGavran-Greenberg Hall, CB #7420, Chapel Hill, North Carolina 27599
4 Department of Pathology and Lab Medicine, University of North Carolina at Chapel Hill, 30145 Women and Children’s Hospital, CB #7525, Chapel Hill, North Carolina 27599
5 Department of Medicine, University of North Carolina at Chapel Hill, 3009 Old Clinic Building, CB #7305, Chapel Hill, North Carolina 27599
6 Department of Radiation Oncology, University of North Carolina at Chapel Hill, 101 Manning Drive, CB #7512, Chapel Hill, North Carolina 27599
Correspondence: Address correspondence and reprint requests to: Nancy Klauber-DeMore, MD; E-mail: nancy_demore{at}med.unc.edu.
 |
ABSTRACT
|
|---|
Background: The prognostic significance of micrometastasis after neoadjuvant chemotherapy for locally advanced breast cancer is unknown. We examined the residual lymph node metastasis size in patients after treatment with neoadjuvant chemotherapy to determine the relevance of metastasis size on outcome.
Methods: Stage II/III breast cancer patients treated with neoadjuvant chemotherapy at our institution from 1991 to 2002 were included. We examined the relationship of postneoadjuvant chemotherapy lymph node metastasis size and number with distant disease-free survival (DDFS) and overall survival (OS).
Results: In 122 patients with a median follow-up of 5.4 years, we found not only that patients with an increasing number of residual positive nodes had progressively worse DDFS and OS (P < .0001 for both) compared with patients with negative nodes, but also that the size of the largest lymph node metastasis was associated with worse DDFS and OS (P < .0001 for both) in both univariate and multivariate analysis. Compared with negative nodes, even lymph node micrometastasis (<2 mm) was associated with worsened DDFS and OS (adjusted P = .02 and P = .005, respectively).
Conclusions: Residual micrometastatic disease in the axillary lymph nodes after neoadjuvant chemotherapy is predictive of worse prognosis than negative nodes. In this study, the lymph node metastasis size and the number of involved lymph nodes were independent powerful predictors of DDFS and OS.
Key Words: Micrometastasis • Breast cancer • Neoadjuvant therapy • Lymph node metastasis • Tumor dormancy
|
INTRODUCTION
|
|---|
A pathologic response to neoadjuvant chemotherapy for locally advanced breast cancer is a well-established prognostic factor.1–4 Multiple studies have found that survival decreases with an increasing number of residual involved nodes after chemotherapy.4–7 Although in untreated patients there is a difference in prognosis between lymph node micrometastasis and macrometastasis, no study has evaluated the significance of residual lymphnode metastasis size or whether micrometastatic disease has a bearing on prognosis after neoadjuvant chemotherapy. Our objective was to evaluate the prognostic significance of lymph node metastasis size after treatment with neoadjuvant chemotherapy and to compare this with other known prognostic factors, including the number of positive nodes.
|
METHODS
|
|---|
Patients with histologically confirmed stage II or III breast cancer who received neoadjuvant chemotherapy at the University of North Carolina at Chapel Hill from 1991 to 2002 and included in an institutional review board – approved neoadjuvant chemotherapy database were eligible. Included patients had to have a standard completion level I and II axillary lymph node dissection after neoadjuvant chemotherapy and were excluded if they had a sentinel lymph node biopsy before neoadjuvant chemotherapy or if the largest metastasis size was not recorded and the slides were no longer available for review.
Most patients were treated on one of two neoadjuvant chemotherapy trials open during the study period. The first trial began with neoadjuvant doxorubicin followed by surgery followed by adjuvant cyclophosphamide, methotrexate, and fluorouracil and then radiation.1 The second trial began with neoadjuvant doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab followed by surgery and radiation.8 Patients with hormone receptor – positive tumors were recommended to receive adjuvant endocrine therapy; radiotherapy was administered at the discretion of the treating physician.
Pathology
Standard pathologic assessment of the axillary lymph node dissection was performed in each case with single-section hematoxylin and eosin (H&E) staining. All grossly identified lymph nodes were submitted in their entirety. Larger lymph nodes were sectioned into 2- to 3-mm slices before submission. H&E-stained slides from formalin-fixed, paraffin-embedded tissue were examined under light microscopy. The total lymph node count, number of positive lymph nodes, and size of the largest metastasis were reported for each case. The lymph node metastasis size and the number of positive nodes were determined from the pathology report.
The number of positive nodes was categorized according to the revised American Joint Committee on Cancer staging system:9 0, 1 to 3, 4 to 9, and >9. Micrometastasis was defined as any H&E-visible tumor no larger than 2 mm (Fig. 1
). Metastasis <.2 mm visible on H&E was categorized as micrometastasis. Cytokeratin immunohistochemistry was not used to detect micrometastasis. There were two categories of macrometastases, which were evaluated separately: those measuring >2 mm to 2 cm and those >2 cm. Node negative included only lymph nodes without any evidence of tumor by H&E.
View larger version (228K):
[in this window]
[in a new window]
|
FIG. 1. Lymph node micrometastasis after neoadjuvant chemotherapy. The subcapsular region of this lymph node contains a focus of metastatic adenocarcinoma characterized by multiple round nests of tumor cells with large hyperchromatic nuclei and eosinophilic cytoplasm. The aggregate dimension of these tumor cells is <2 mm—consistent with micrometastasis (stain, hematoxylin and eosin; original magnification, x200).
|
|
Statistical Analyses
The size of the largest lymph node metastasis and the number of positive lymph nodes were categorized by the previously mentioned criteria. Cox regression was used to examine the effect of the covariates of age, stage, estrogen receptor status, histological diagnosis (invasive ductal, invasive lobular, or not otherwise specified), pathologic primary tumor size, size of the largest lymph node metastasis, and number of positive nodes on both distant disease-free survival (DDFS) and overall survival (OS). Both univariate and multivariate models were examined. The size of the largest lymph node metastasis and the number of positive nodes excised were evaluated as both continuous and categorical variables. The Kaplan-Meier (or product-limit) method was used to estimate the DDFS and OS functions for the categorical size of the largest lymph node metastasis and the number of positive node variables. An order-restricted version of the log-rank test (a log-rank trend test) was used to test for ordered differences between estimated time-to event curves. Statistical analyses were performed with SAS statistical software, Version 9.1 (SAS Institute Inc., Cary, NC). This study was approved by the Committee for the Protection of Human Subjects at the University of North Carolina at Chapel Hill.
|
RESULTS
|
|---|
Patient and Tumor Characteristics
One hundred twenty-two patients were included in this study. Table 1 lists the patient and tumor characteristics. Included patients primarily (72%) had stage III disease, although a minority of stage II cases were included. One hundred five patients (86%) had ductal histological characteristics, and 11 (9%) had lobular histological characteristics. The neoadjuvant regimens included anthracycline-based regimens (n = 67; 55%), anthracycline- and taxane-based regimens with or without trastuzumab (n = 42; 34%), and non – anthracycline-based regimens (n = 13; 11%). After neoadjuvant chemotherapy, 58 (48%) patients were node negative, and 64 (52%) were node positive. For patients with metastasis, the median largest metastasis size was 7 mm (range, .1 mm to 6.5 cm), and the median number of lymph nodes involved was 4 (range, 1–40).
Survival
The median follow-up time for survivors was 5.4 years (range, 1.2–12.6 years). As expected, patients with negative nodes did well, and patients with an increasing number of positive nodes had progressively significantly worse DDFS (Fig. 2A) and OS (Fig. 3A) (P < .0001 for both). Additionally, patients with an increasing size of the largest lymph node metastasis had progressively significantly worse DDFS (Fig. 2B) and OS (Fig. 3B) (P < .0001 for both). There was also a significant difference in outcome between node-negative disease and metastasis <2 mm. Although the number of patients with micrometastasis was small (n = 11), their relapse pattern seemed similar to that in patients with metastasis of 2 mm to 2 cm and was significantly worse than that in patients who had node-negative disease. The 5-year DDFS for patients with residual micrometastasis was 42% (95% confidence interval [CI], 11%–72%), which was significantly worse than that of node-negative patients (85%; 95% CI, 73%–92%; P = .02). Similarly, OS was significantly worse among micrometastatic disease (43%; 95% CI, 7%–76%) compared with node-negative disease (94%; 95% CI, 83%–98%; adjusted P = .005). Patients with residual lymph node metastasis >2 cm did extremely poorly, with a 5-year DDFS of only 14%.
View larger version (38K):
[in this window]
[in a new window]
|
FIG. 2. Kaplan-Meier curves for distant disease-free survival (DDFS) for (A) the number of positive lymph node groupings and (B) the size of largest lymph node metastasis groupings. The log-rank trend tests for DDFS for both the number of positive lymph node groupings and the size of the largest lymph node metastasis groupings were highly significant (P < .0001).
|
|
View larger version (36K):
[in this window]
[in a new window]
|
FIG. 3. Kaplan-Meier curves for overall survival (OS) for (A) the number of positive lymph node groupings and (B) the size of largest lymph node metastasis groupings. The log-rank trend tests for OS for both the number of positive lymph node groupings and the size of the largest lymph node metastasis groupings were highly significant (P < .0001).
|
|
The relationships of prognostic factors to DDFS and OS are shown in Tables 2 and 3. Univariable Cox modeling of DDFS demonstrated that the size of the largest lymph node metastasis, as either a continuous or categorical variable, was highly prognostic (P < .0001 for both). The number of positive lymph nodes, as either a continuous or categorical variable, was highly prognostic (P = .0003 and P < .0001, respectively). The pathologic primary tumor size (P = .002) and the clinical stage at the time of diagnosis (P = .03) were also significantly prognostic (Table 2). For OS, univariable Cox modeling yielded results comparable to DDFS modeling (Table 3). Multivariable Cox modeling demonstrated that the categorical variable for the size of the largest lymph node metastasis alone worked best for predicting both DDFS and OS.
|
DISCUSSION
|
|---|
Although multiple neoadjuvant chemotherapy studies have demonstrated that the number of involved nodes is a negative prognostic factor,4–7 no study has evaluated the prognostic significance of lymph node metastasis size. We found that the size of the largest remaining metastasis was also an important prognostic factor and that even residual micrometastatic disease after neoadjuvant chemotherapy was predictive of a poorer prognosis than negative nodes. It is interesting to note that our definition of micrometastasis included metastasis <.2 mm, which would be categorized as node negative in the revised American Joint Committee on Cancer staging system. Our data suggest that any residual disease in the axilla, no matter how small, is associated with a worse survival than truly node-negative disease. Patients with residual lymph node metastasis >2 cm fared extremely poorly, with a 5-year DDFS of only 14%.
Several retrospective studies have shown that in patients treated with a definitive breast cancer operation including axillary lymph node dissection but without neoadjuvant chemotherapy, lymph node micrometastases have a small survival disadvantage when compared with node-negative disease.10,11 Examining neoadjuvantly treated patients, we have found that there is also a significant difference in 5-year OS between patients with residual micrometastatic disease in the lymph nodes and those with negative nodes after chemotherapy.
Recent studies have evaluated histopathologic indices of the response in lymph nodes to induction chemotherapy. Newman et al.12 correlated tumor regression within the axillary lymph nodes (as defined by nodal fibrosis, mucin pools, or foamy histiocytes) with outcome and found that detection of a treatment effect identified a subset of patients with an outcome intermediate between that of completely node-negative and node-positive cases. Singh et al.13 correlated proliferation and angiogenesis in the primary tumor and in the lymph nodes before and after neoadjuvant chemotherapy and found that all patients who showed an excellent clinical response expressed either a decrease in the proliferation index or an absence of a high level of vascular endothelial growth factor expression in their tissues after chemotherapy. It is interesting to note that in untreated cancers, we previously showed that lymph node micrometastasis had significantly lower proliferation rates than macrometastasis (12% vs. 35%; P = .003), lower microvessel density (1 vs. 17; P < .0001), and no difference in apoptosis.14 The size of the largest metastasis may be related to specific histopathologic indices of response, although this has not yet been studied.
For clinically node-negative patients, our present institutional paradigm is to perform sentinel lymph node biopsy before neoadjuvant chemotherapy and to complete the axillary lymph node dissection after chemotherapy.15 During the time period of this study (1990–2002), 15 patients were treated with a sentinel lymph node biopsy before chemotherapy and were excluded from our analyses. Therefore, the significance of lymph node size in patients who had a sentinel lymph node biopsy before starting chemotherapy is unknown. Additionally, we did not perform immunohistochemistry with antibodies to cytokeratin on the axillary lymph nodes, and therefore the significance of cytokeratin-detected metastases is also unknown.
In conclusion, we found that any residual tumor in the axillary lymph nodes after neoadjuvant chemotherapy is a poor prognostic factor, with worsened survival at 5 years regardless of the metastasis size. Lymph node metastasis size was a powerful predictor of DDFS and OS, as was the number of positive lymph nodes. If confirmed, this suggests that lymph node metastasis size may be a valuable additional prognostic factor for outcome after neoadjuvant chemotherapy.
|
ACKNOWLEDGMENTS
|
|---|
Supported by the University of North Carolina Breast Cancer SPORE award from the National Cancer Institute (P50-CA 58223), the National Institutes of Health (M01RR00046 [L.A.C.] and 1 K08 CA098034-01A2 [N.K.-D.]), and the Breast Cancer Research Foundation. Dr. Klauber-DeMore is the recipient of the American Society of Surgical Oncology/Breast Cancer Research Foundation Career Development Award and the Sidney Kimmel Translational Research Award.
Received for publication March 3, 2005.
Accepted for publication November 9, 2005.
|
REFERENCES
|
|---|
- Cance WG, Carey LA, Calvo BF, et al. Long-term outcome of neoadjuvant therapy for locally advanced breast carcinoma: effective clinical downstaging allows breast preservation and predicts outstanding local control and survival. Ann Surg 2002; 236:295–302.[CrossRef][Medline]
- Carey LA, Metzger R, Dees EC, et al. American Joint Committee on Cancer tumor-node-metastasis stage after neoadjuvant chemotherapy and breast cancer outcome. J Natl Cancer Inst 2005; 97:1137–42.[Abstract/Free Full Text]
- Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998; 16:2672–85.[Abstract]
- Kuerer HM, Newman LA, Buzdar AU, et al. Residual metastatic axillary lymph nodes following neoadjuvant chemotherapy predict disease-free survival in patients with locally advanced breast cancer. Am J Surg 1998; 176:502–9.[CrossRef][Medline]
- Botti C, Vici P, Lopez M, Scinto AF, Cognetti F, Cavaliere R. Prognostic value of lymph node metastases after neoadjuvant chemotherapy for large-sized operable carcinoma of the breast. J Am Coll Surg 1995; 181:202–8.[Medline]
- Gajdos C, Tartter PI, Estabrook A, Gistrak MA, Jaffer S, Bleiweiss IJ. Relationship of clinical and pathologic response to neoadjuvant chemotherapy and outcome of locally advanced breast cancer. J Surg Oncol 2002; 80:4–11.[CrossRef][Medline]
- McCready DR, Hortobagyi GN, Kau SW, Smith TL, Buzdar AU, Balch CM. The prognostic significance of lymph node metastases after preoperative chemotherapy for locally advanced breast cancer. Arch Surg 1989; 124:21–5.[Abstract]
- Carey CA, Dees EC, Dressler L, et al. Response to trastuzumab (Herceptin) given with paclitaxel (Taxol) immediately following 4 AC as initial therapy for breast cancer. Breast Cancer Res Treat 2002; 76(Suppl 1):4292.
- Singletary SE, Allred C, Ashley P, et al. Staging system for breast cancer: revisions for the 6th edition of the AJCC Cancer Staging Manual. Surg Clin North Am 2003; 83:803–19.[CrossRef][Medline]
- Prognostic importance of occult axillary lymph node micrometastases from breast cancers. International (Ludwig) Breast Cancer Study Group. Lancet 1990; 335:1565–8.[CrossRef][Medline]
- Dowlatshahi K, Fan M, Bloom KJ, et al. Occult metastases in the sentinel lymph nodes of patients with early stage breast carcinoma: a preliminary study. Cancer 1999; 86:990–6.[CrossRef][Medline]
- Newman LA, Pernick NL, Adsay V, et al. Histopathologic evidence of tumor regression in the axillary lymph nodes of patients treated with preoperative chemotherapy correlates with breast cancer outcome. Ann Surg Oncol 2003; 10:734–9.[Abstract/Free Full Text]
- Singh M, Capocelli KE, Marks JL, et al. Expression of vascular endothelial growth factor and proliferation marker MIB1 are influenced by neoadjuvant chemotherapy in locally advanced breast cancer. Appl Immunohistochem Mol Morphol 2005; 13:147–56.[CrossRef][Medline]
- Klauber-Demore N, Van Zee KJ, Linkov I, Borgen PI, Gerald WL. Biological behavior of human breast cancer micrometastases. Clin Cancer Res 2001; 7:2434–9.[Abstract/Free Full Text]
- Ollila DW, Neuman HB, Sartor C, Carey LA, Klauber-Demore N. Lymphatic mapping and sentinel lymphadenectomy prior to neoadjuvant chemotherapy in patients with large breast cancers. Am J Surg 2005; 190:371–5.[Medline]
This article has been cited by other articles:
|
|
|
|
 
J. S. Jeruss, E. A. Mittendorf, S. L. Tucker, A. M. Gonzalez-Angulo, T. A. Buchholz, A. A. Sahin, J. N. Cormier, A. U. Buzdar, G. N. Hortobagyi, and K. K. Hunt
Combined Use of Clinical and Pathologic Staging Variables to Define Outcomes for Breast Cancer Patients Treated With Neoadjuvant Therapy
J. Clin. Oncol.,
January 10, 2008;
26(2):
246 - 252.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Kaufmann, G. von Minckwitz, H. D. Bear, A. Buzdar, P. McGale, H. Bonnefoi, M. Colleoni, C. Denkert, W. Eiermann, R. Jackesz, et al.
Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006
Ann. Onc.,
December 1, 2007;
18(12):
1927 - 1934.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
INTRODUCTION
