Case 35-2005 — A 56-Year-Old Woman with Breast Cancer and Isolated Tumor Cells in a Sentinel Lymph Node
http://www.100md.com
《新英格兰医药杂志》
Presentation of Case
Dr. Barbara L. Smith (Surgical Oncology): A 56-year-old woman was referred to the multidisciplinary breast clinic, part of the cancer center of this hospital, for management of invasive breast cancer with a minimal tumor burden in a sentinel lymph node.
Four months earlier, screening mammography at another hospital revealed an ill-defined nodule, 0.8 cm in diameter, containing a few calcifications, in the upper outer quadrant of the right breast; the nodule had not been present two years previously. In a follow-up screening, magnification views of the nodule revealed a 1-cm mass in the outer quadrant of the right breast with pleomorphic calcifications suggestive of a neoplasm. The results of a complete blood count, electrocardiography, and chest radiography were normal. Core-biopsy specimens of the right breast obtained at that hospital one month later revealed infiltrating ductal carcinoma, grade 2 of 3, involving most of all five cores. The tumor cells expressed the estrogen-receptor protein. Two weeks later, the patient was referred to this hospital.
Seven years earlier, mammography had revealed microcalcifications in the right breast, and a breast biopsy had revealed benign fibrocystic changes. Menarche had occurred at 13 years of age; the patient (gravida 3, para 3) had her first pregnancy at 36 years of age and reached menopause at 51 years of age. She had taken oral contraceptives for 15 years in the past, but she had not received postmenopausal hormone-replacement therapy. She had no allergies to medications, no history of tobacco or illicit drug use, and consumed fewer than five alcoholic beverages per week. Her father had died in his 80s from leukemia and melanoma; her mother had smoked cigarettes and died in her 60s from lung cancer. There was no family history of breast or ovarian cancer. The patient was currently taking no medications.
On examination, the patient appeared well, and her vital signs were normal. There was a healed scar at the areolar border of the right breast and a palpable 1.5-cm mass at the 10-o'clock position in the anterior axillary line. There was no discharge or inversion of the nipples and no lymphadenopathy. The left breast was normal. The remainder of the examination was normal. The results of routine laboratory tests revealed no abnormalities.
One month later, a right partial mastectomy, intraoperative lymphangiography, and sentinel-lymph-node biopsy of the right axilla were performed after a subareolar injection of technetium-99m sulfur colloid. The tissue from the right breast contained an invasive ductal carcinoma 0.9 cm by 0.8 cm by 0.5 cm, which was classifed as grade 2 of 3, with invasion of lymphatic vessels but not of blood vessels. The distance of the invasive tumor from all margins was 0.2 cm or greater. Histopathological examination of the right axillary sentinel lymph node on sections stained with hematoxylin and eosin revealed several nests of metastatic ductal carcinoma in the subcapsular sinus, less than 0.02 cm in diameter, without extracapsular extension. Immunohistochemical staining for cytokeratin detected positive tumor cells on three slides with specimens obtained at deeper levels from the tissue block. The tumor was positive for estrogen-receptor protein and faintly positive for progesterone-receptor protein, as evaluated by immunohistochemistry. There was no overexpression of HER2/neu protein.
One month later, the patient returned to the multidisciplinary breast clinic for discussion of further management.
Radiological Discussion
Dr. Daniel B. Kopans: The mediolateral oblique mammogram shows a somewhat irregularly shaped mass, 0.8 cm in diameter, in the upper portion of the right breast (Figure 1A). A more detailed view (Figure 1B) reveals some calcifications within the lesion but none extending from it. On the craniocaudal image, the irregular mass is seen in the lateral portion of the breast. This mass is suspicious for cancer.
Figure 1. Mammogram of the Right Breast.
The mediolateral oblique mammogram demonstrates a somewhat irregularly shaped mass, 0.8 cm in diameter, in the upper portion of the right breast (Panel A). A more detailed view reveals some calcifications within the lesion but none extending from it (Panel B).
Pathological Discussion
Dr. Frederick C. Koerner: Sections of the mass reveal an intermediate-grade ductal carcinoma (Figure 2A) with invasion of lymphatic vessels. The right axillary sentinel lymph node (Figure 2B) contained two clusters of metastatic tumor cells, evident both in sections stained with hematoxylin and eosin and in sections stained for keratin with use of an immunohistochemical technique (Figure 2C). The largest nest spans less than 0.02 cm.
Figure 2. Breast and Axillary Sentinal Lymph-Node Biopsy Specimens.
The breast lumpectomy specimen (Panel A) contains nests of carcinoma cells penetrating the mammary fat. Two small clusters of carcinoma cells occupy the periphery of this sentinel lymph node (Panel B). Immunohistochemical staining for cytokeratin (Panel C) confirms that these are epithelial cells (Panels A and B, hematoxylin and eosin; Panel C, immunoperoxidase stain for cytokeratin).
Differences in staging systems proposed by the American Joint Committee on Cancer (AJCC) and the International Union against Cancer (UICC) have caused confusion regarding the staging of disease in patients with breast cancer who have small metastatic deposits in axillary lymph nodes. Both systems stratify patients according to the number of lymph nodes involved by carcinoma and according to the size of the metastatic foci (Table 1).1,2 However, while the UICC system uses "i" to denote "isolated tumor cells," the original AJCC system uses "i" to identify cases in which the tumor was detected on immunohistochemical staining for keratin but not on hematoxylin-and-eosin staining. The emphasis on the role of immunohistochemical staining reflects the belief that metastases detected only by immunohistochemical staining are small and, therefore, probably clinically insignificant. However, the presence of carcinoma cells in a section stained for keratin, but not in a section stained with hematoxylin and eosin, does not guarantee the small size of the metastasis — in this case, the foci of cancer were small, but they were detected on staining with hematoxylin and eosin. The AJCC has since revised the meaning of the "i" to coincide with the usage of the UICC (Table 1).3
Table 1. Comparison of Pathological Staging Classifications for Breast Cancer.
In summary, both current systems for assigning a disease stage on the basis of findings in the axillary lymph nodes rely on both the number of involved lymph nodes and the size of the metastatic foci. The method of detection of the tumor cells no longer plays a role in determining the stage. This patient's sentinel lymph node was staged as pN0 (i+).
Discussion of Management
The Axilla in a Patient with Minimal Disease in the Sentinel Lymph Node
Dr. Monica Morrow: This patient had a T1b breast carcinoma, as classified according to the AJCC staging system, in which T1b denotes a tumor size greater than 0.5 cm but not larger than 1.0 cm,1 with isolated tumor cells in a sentinel lymph node. In deciding whether further therapy to the axilla is indicated, clinicians needed to consider the likelihood that additional nodal metastases had already occurred, the risk of local recurrence if the axilla was untreated, the sequelae of treatment, and the potential impact of local therapy on survival.
Risk of Additional Nodal Metastases
This patient had tumor cells only in the subcapsular sinus of the lymph node. It has been suggested that epithelial cells in the breast may be transported to the subcapsular sinus during needle biopsies or surgical manipulation of the breast.4 However, such cells are usually accompanied by hemosiderin-laden macrophages and red cells in the subcapsular sinus, which were not described here. Thus, this patient was considered to have a true nodal metastasis.
In patients with T1b primary cancers with a positive sentinel lymph node, the reported risk of additional axillary-node metastases ranges from 12 percent to 34 percent (Table 2).5,6,7,8,9 The size of the metastases in the sentinel node influenced the risk of additional axillary disease in some studies,10 but not in others.8 In two studies, the risk of additional nodal metastases was greater among patients whose sentinel-lymph-node metastases were detected by staining with hematoxylin and eosin than among those whose metastases were detected by immunohistochemical staining,11,12 possibly indicating some correlation of the method of detection with the size of the metastasis.
Table 2. Risk of Additional Axillary-Node Metastases in Women with T1b Carcinoma, from Several Studies.
Other variables may affect the risk of additional nodal disease. In 10 studies5,8,9,10,13,14,15,16,17,18 in which multivariate analysis was used to identify independent predictors of additional nodal disease, the number of involved sentinel nodes, the number of sentinel nodes removed, or the ratio between the two was predictive of additional nodal involvement in the majority of the studies that examined these factors.8,9,13,14,15 The tumor size was important in 5 of 10 reports and the presence of lymphatic or vascular invasion in 4, and no study found the tumor grade to be a significant predictor of additional axillary nodal disease.
A nomogram developed at the Memorial Sloan-Kettering Cancer Center in which multiple variables are used to predict the presence of additional nodal metastases9,19 predicted that the patient under discussion had a 19 percent risk of additional nodal disease (Table 3). This estimate is consistent with estimates made on the basis of tumor size alone (12 to 34 percent) or the size of metastases alone (14 to 24 percent). These calculations estimated only the risk of additional metastases detected by staining with hematoxylin and eosin. Chu et al.6 reported that in patients with sentinel-node metastases, 9 percent had tumor in nonsentinel nodes that was detected by immunohistochemical analysis alone. The prognostic significance of isolated tumor cells or very small metastatic deposits in axillary nodes detected only by immunohistochemical methods is uncertain. If the presence of such cells or deposits is considered to be biologically important, then the chance of this patient's having additional tumor in the axilla increases to approximately 30 percent.
Table 3. Memorial Sloan-Kettering Cancer Center Nomogram for Prediction of Additional Axillary-Node Disease in the Patient.
Risk of Axillary Recurrence
Local control is a major goal of the surgical treatment of breast carcinoma. Several retrospective and prospective studies suggest that the clinical rate of axillary recurrence is lower than the actual incidence of nodal metastases.20,21,22,23,24 Overall, the data suggest that the risk of axillary recurrence is approximately one third the risk of axillary metastases; this risk may be further decreased by radiation to tangential fields in the breast. In the patient under discussion, I would estimate the risk of axillary recurrence to be less than 5 percent with no further local therapy.
Effect of Axillary Treatment on Survival
Perhaps the most important consideration in assessing the need for additional local therapy in this patient was whether axillary treatment would have an impact on survival. Axillary dissection has been considered a staging procedure since the National Surgical Adjuvant Breast and Bowel Project B04 trial failed to show a survival benefit for clinically node-negative women treated with axillary dissection, as compared with observation and delayed dissection if metastases became clinically apparent.25 However, trials of radiotherapy after mastectomy have suggested that aggressive local therapy is associated with improved survival26,27 and that this benefit is most evident in patients with small primary tumors and limited nodal involvement, such as this patient. Although no single randomized trial examining the effect of axillary dissection on survival has shown a statistically significant benefit for the surgery,21,28,29,30,31,32 a meta-analysis of six trials33 found a 5.4 percent improvement in survival among patients who underwent axillary dissection. Unfortunately, a randomized trial designed to determine whether axillary dissection is beneficial in patients with a positive sentinel node that opened in 1999 was closed owing to poor accrual. In the absence of definitive data, a survival benefit for axillary dissection in the range of 5 percent cannot be ruled out or confirmed.
Sequelae of Axillary Dissection
The short-term and long-term morbidity associated with the procedure must be weighed against the potential benefits of axillary dissection. Recent randomized trials have provided clear evidence that several problems are significantly more common among patients undergoing axillary dissection than among those who undergo sentinel-node biopsy alone. These sequelae include pain (39 percent vs. 8 percent), numbness or paresthesia (68 percent vs. 1 percent), decreased mobility (31 percent vs. 0 percent), and lymphedema (75 percent vs. 7 percent).34,35
Axillary irradiation is an alternative to axillary dissection for maintaining local control in the axilla. It appears to be associated with a lower risk of lymphedema than axillary dissection in nonrandomized studies,36 but it may result in radiation pneumonitis or brachial plexopathy. In addition, it has the disadvantage of not providing information on the number of additional nodes involved with tumor, which may be useful when systemic treatment is considered. One randomized study comparing axillary dissection and irradiation reported a statistically significant higher rate of axillary recurrence after irradiation, although no survival difference was seen.28
The patient under discussion had an approximately 20 percent risk of additional axillary-lymph-node metastases; the risk of isolated axillary recurrence was low and by itself did not justify axillary dissection. However, knowing the number of involved nodes may assist in decision making about systemic therapy, and a small survival benefit for axillary dissection cannot be ruled out. Although the procedure is associated with substantial morbidity, which needed to be discussed with the patient, I believe the potential benefits outweighed the risks.
Systemic Therapy
Dr. Nancy E. Davidson: The use of adjuvant systemic therapy should be considered for a patient such as this one, as it is for virtually all women with invasive breast cancer. Whether to use it and what to recommend is determined by consideration of the risk of recurrence after local therapy alone, the efficacy of therapy, side effects of treatment, and the patient's preference. Several prognostic and predictive markers can help guide decision making in such a case. Prognostic markers predict the risk of recurrence in the absence of systemic therapy; these include axillary-lymph-node involvement, tumor size, histologic grade, expression of estrogen receptor , progesterone-receptor expression, and overexpression of the HER2 protein. Predictive markers are used to estimate the likelihood of benefit from a particular therapy. Expression of estrogen receptor and progesterone receptor predicts a response to endocrine therapy, and overexpression of HER2/neu predicts a response to trastuzumab, a monoclonal antibody directed against the HER2 protein.37 This patient's tumor expressed estrogen receptor and did not overexpress the HER2 protein.
Defining the Risk of Recurrence
The single most important prognostic factor for this patient was the extent of lymph-node involvement. Virtually all data on the risk of recurrence are derived from assessment of lymph nodes obtained through axillary-lymph-node dissection that have been stained with hematoxylin and eosin. Serial sectioning, immunohistochemical staining, or molecular analysis of sentinel nodes may identify the 30 percent of patients with lymph-node–negative breast cancer as defined by traditional staging who are destined to develop metastatic disease in the absence of systemic therapy, but these methods could also lead to identification of patients with minimal lymph-node involvement that will never be of clinical consequence. In the past, it is possible that this patient would have been thought to have node-negative breast cancer and treated accordingly.
Since there is an 80 percent chance that further axillary dissection would not identify other positive axillary lymph nodes in this patient, a rational first approach is to consider the risk of recurrence of this small breast cancer if it were node-negative, in the absence of systemic therapy. Data from both retrospective series38,39 and randomized trials40 suggest that local therapy alone may be sufficient for women with small tumors and low lymph-node burden. In a recent study, patients such as this one who had sentinel-lymph-node metastases up to 0.02 cm in diameter had the same disease-free and overall survival as those whose sentinel lymph nodes were negative.41
A model that uses multiple clinical and pathological variables to predict mortality rates associated with breast cancer42 predicts a 15-year risk of breast-cancer–specific mortality of 53 percent for this patient without systemic therapy. However, this model is based on a small number of patients and has not been validated in an independent population. Finally, the Oncotype Dx 21 multigene assay (Genomic Health), which identifies node-negative patients with a low recurrence score who are likely to have an excellent outcome with tamoxifen alone, could theoretically be used.43,44 In the pivotal studies of this assay, only 16 percent of participants had T1a or T1b tumors, as this patient did; 63 percent of those had a low recurrence score.
Efficacy and Toxicity of Adjuvant Systemic Therapy
A second consideration for this patient was the balance of the efficacy and side effects of therapy. Several expert panels provide guidance that is based on a combination of evidence and the opinions of specialists. The 2005 St. Gallen Consensus Panel classifies a patient such as the one under discussion as at moderate risk for recurrence if fewer than four axillary lymph nodes are involved and recommends endocrine therapy, with consideration of chemotherapy.45 The guidelines of the National Comprehensive Cancer Network (available at www.nccn.org) also support the use of adjuvant hormonal therapy, with or without chemotherapy.
Because of the patient's positive estrogen-receptor test, endocrine therapy was the key element of systemic therapy for this patient, regardless of her lymph-node status. Long-term results from the Early Breast Cancer Trialists' Collaborative Group have demonstrated a clear benefit associated with five years of tamoxifen treatment in estrogen-receptor–positive patients of any nodal status,46 with a higher absolute benefit for women with node-positive breast cancer who have a higher risk of recurrence. Two recent trials have suggested that aromatase inhibitors are superior to tamoxifen in terms of disease-free survival after approximately three years of follow-up, but without an overall survival benefit.47,48 Both tamoxifen and aromatase inhibitors cause menopausal symptoms. Tamoxifen has rare but serious side effects consisting of venous thromboembolic events and uterine cancer, because of its partial estrogen-agonist properties, whereas aromatase inhibitors are linked to osteoporosis and fractures, because of their estrogen-deprivation effects. The 2004 American Society of Clinical Oncology technology assessment states that optimal endocrine therapy for postmenopausal women with early-stage steroid-receptor–positive breast cancer includes an aromatase inhibitor alone or after the use of tamoxifen.49
The most difficult question for us in relation to this patient was how to judge the value of adjuvant chemotherapy in addition to endocrine therapy, because the studies with results available to us used older regimens, did not use aromatase inhibitors, and may have classified a patient such as this one as node-negative. A recent study from Italy of patterns of care suggested that clinicians are increasingly considering any evidence of lymph-node involvement as suggestive of a worse prognosis than in cases that have no lymph-node involvement.50
The ADJUVANT! online Web-based model51 to predict 10-year outcomes with or without therapy provides a useful tool for patient counseling and has recently been validated with use of population-derived outcomes of patients with early-stage breast cancer who have been treated in British Columbia, Canada.52 It takes into account the patient's age and any coexisting illnesses, lymph-node status, tumor size, histologic grade, and estrogen-receptor status to provide an estimate of 10-year disease-free and overall survival with various combinations of endocrine therapy and chemotherapy. If we assume that this patient had perfect health and was indeed node-negative, then the use of an aromatase inhibitor would be predicted to improve her chances of 10-year disease-free survival by approximately 9 percent, and the addition of dose-dense chemotherapy with anthracycline and taxane would add another 4 percent improvement; however, these interventions improve 10-year overall survival by only 1.9 percent. Increasing lymph-node involvement is associated with increases in absolute benefit for both treatment with aromatase inhibitors and chemotherapy. The potential benefits must be balanced against the side effects of chemotherapy, which include a 1 to 2 percent risk of substantial toxic effects (including treatment-related death, anthracycline-induced cardiomyopathy, and secondary leukemia).53
Adjuvant endocrine therapy is appropriate for a postmenopausal patient with T1b estrogen-receptor–positive breast cancer no matter what the lymph-node burden, and I would recommend an aromatase inhibitor in a case such as this one. The value of adjuvant chemotherapy is uncertain for a patient with isolated tumor cells in the sentinel node, and the risks of chemotherapy might approximate the benefits. I would recommend axillary-lymph-node dissection to complete staging and refine the risk assessment, since the demonstration of additional lymph-node involvement would strengthen recommendations for chemotherapy. The patient's preference regarding the use of chemotherapy would be a key consideration. If she declined chemotherapy or wished to have chemotherapy no matter what, then axillary lymph-node dissection could be omitted.
Dr. Ann H. Partridge (Medical Oncology at Dana–Farber Cancer Institute): How does vascular invasion play into the decision about axillary-lymph-node dissection and systemic treatment?
Dr. Morrow: In the 10 studies that I reviewed, only 4 identified lymphovascular invasion as an independent predictor of axillary nodal metastases. So I would not take that into consideration in making my decision about axillary-node dissection.
Dr. Davidson: The importance of vascular invasion as a poor prognostic factor is controversial.45 It is included in the Memorial Sloan-Kettering nomogram but not in the ADJUVANT! online model. It did not weigh heavily in my consideration in this case.
A Physician: Could the discrepancy between the number of positive lymph nodes found at axillary dissection and the axillary-failure rates in the absence of dissection be accounted for by the fact that these are only counted when the axilla is the first site of failure?
Dr. Morrow: That is a factor. In addition, in women who are receiving breast irradiation to tangential fields, a substantial part of the axilla is included in the field, and this may reduce the axillary-failure rates. Finally, when we do a sentinel-node biopsy, we manually inspect the axilla, so that we do not leave behind gross nodal disease that could present as early first failure.
Dr. Nancy Lee Harris (Pathology): Dr. Smith, can you tell us what was done for this patient?
Dr. Smith: This patient was very well informed and had read many of the articles discussed today. She wanted systemic chemotherapy regardless of what additional nodal disease might be present, and she was concerned about the possible effects on her arm of axillary dissection. She elected not to have additional axillary surgery, and she received four cycles of doxorubicin–cyclophosphamide every three weeks. She elected to receive irradiation to her axilla according to a protocol that we have at our institution. Tamoxifen was begun at the same time as radiation treatment, with a plan to switch in about two years to treatment with an aromatase inhibitor.
Anatomical Diagnosis
Invasive ductal carcinoma of the breast with isolated tumor cells in a sentinel lymph node (T1b pN0 (i+)).
Dr. Davidson reports having received consulting fees from Lilly for serving on the data safety and management board for the Raloxifene Use in the Heart (RUTH) trial, and lecture fees from AstraZeneca. Dr. Morrow reports having received grant support from Avon Products Foundation.
Source Information
From the Johns Hopkins University School of Medicine, Baltimore (N.E.D.).; the Fox Chase Cancer Center, Philadelphia (M.M.); and the Departments of Radiology (D.B.K.) and Pathology (F.C.K.), Massachusetts General Hospital and Harvard Medical School — both in Boston.
References
Greene FL, Page DL, Fleming ID, et al., eds. AJCC cancer staging manual. 6th ed. New York: Springer-Verlag, 2002.
Sobin LH, Wittekind C, eds. TNM: classification of malignant tumours. 6th ed. New York: Wiley-Liss, 2002.
Singletary SE, Greene FL, Sobin LH. Classification of isolated tumor cells: clarification of the 6th edition of the American Joint Committee on Cancer Staging Manual. Cancer 2003;98:2740-2741.
Carter BA, Jensen RA, Simpson JF, Page DL. Benign transport of breast epithelium into axillary lymph nodes after biopsy. Am J Clin Pathol 2000;113:259-265.
Wong SL, Edwards MJ, Chao C, et al. Predicting the status of the nonsentinel axillary nodes: a multicenter study. Arch Surg 2001;136:563-568.
Chu KU, Turner RR, Hansen NM, Brennan MB, Giuliano AE. Sentinel node metastasis in patients with breast carcinoma accurately predicts immunohistochemically detectable nonsentinel node metastasis. Ann Surg Oncol 1999;6:756-761.
Nos C, Harding-MacKean C, Freneaux P, et al. Prediction of tumour involvement in remaining axillary lymph nodes when the sentinel node in a woman with breast cancer contains metastases. Br J Surg 2003;90:1354-1360.
Viale G, Maiorano E, Pruneri G, et al. Predicting the risk for additional axillary metastases in patients with breast carcinoma and positive sentinel lymph node biopsy. Ann Surg 2005;241:319-325.
Van Zee KJ, Manasseh DM, Bevilacqua JL, et al. A nomogram for predicting the likelihood of additional nodal metastases in breast cancer patients with a positive sentinel node biopsy. Ann Surg Oncol 2003;10:1140-1151.
Leidenius MH, Vironen JH, Riihela MS, et al. The prevalence of non-sentinel node metastases in breast cancer patients with sentinel node micrometastases. Eur J Surg Oncol 2005;31:13-18.
Mignotte H, Treilleux I, Faure C, Nessah K, Bremond A. Axillary lymph-node dissection for positive sentinel nodes in breast cancer patients. Eur J Surg Oncol 2002;28:623-626.
Kamath VJ, Giuliano R, Dauway EL, et al. Characteristics of the sentinel lymph node in breast cancer predict further involvement of higher-echelon nodes in the axilla: a study to evaluate the need for complete axillary lymph node dissection. Arch Surg 2001;136:688-692.
Hwang RF, Krishnamurthy S, Hunt KK, et al. Clinicopathologic factors predicting involvement of nonsentinel axillary nodes in women with breast cancer. Ann Surg Oncol 2003;10:248-254.
Menes TS, Tartter PI, Mizrachi H, Constantino J, Estabrook A, Smith SR. Breast cancer patients with pN0(i+) and pN1(mi) sentinel nodes have high rate of nonsentinel node metastases. J Am Coll Surg 2005;200:323-327.
Goyal A, Douglas-Jones A, Newcombe RG, Mansel RE. Predictors of non-sentinel lymph node metastasis in breast cancer patients. Eur J Cancer 2004;40:1731-1737.
Travagli JP, Atallah D, Mathieu MC, et al. Sentinel lymphadenectomy without systematic axillary dissection in breast cancer patients: predictors of non-sentinel lymph node metastasis. Eur J Surg Oncol 2003;29:403-406.
Fournier K, Schiller A, Perry RR, Laronga C. Micrometastasis in the sentinel lymph node of breast cancer does not mandate completion axillary dissection. Ann Surg 2004;239:859-863.
Sachdev U, Murphy K, Derzie A, Jaffer S, Bleiweiss IJ, Brower S. Predictors of nonsentinel lymph node metastasis in breast cancer patients. Am J Surg 2002;183:213-217.
Lambert L, Hunt KK, Hwang RF. Validation of a breast cancer nomogram for predicting additional nodal metastases after positive sentinel node biopsy. Ann Surg Oncol 2005;12:Suppl 1:S17-S17. abstract.
Langer I, Marti WR, Guller U, et al. Axillary recurrence rate in breast cancer patients with negative sentinel lymph node (SLN) or SLN micrometastases: prospective analysis of 150 patients after SLN biopsy. Ann Surg 2005;241:152-158.
Fant JS, Grant MD, Knox SM, et al. Preliminary outcome analysis in patients with breast cancer and a positive sentinel lymph node who declined axillary dissection. Ann Surg Oncol 2003;10:126-130.
Guenther JM, Hansen NM, DiFronzo LA, et al. Axillary dissection is not required for all patients with breast cancer and positive sentinel nodes. Arch Surg 2003;138:52-56.
Greco M, Agresti R, Cascinelli N, et al. Breast cancer patients treated without axillary surgery: clinical implications and biologic analysis. Ann Surg 2000;232:1-7.
Holmberg SB, Crivellari D, Zahrieh J, et al. A randomized trial comparing axillary clearance versus no axillary clearance in patients older than 60 years with breast cancer: first results of International Breast Cancer Study Group Trial 10-93. J Clin Oncol 2004;22:Suppl:4S-4S. abstract.
Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-1241.
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.
Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999;353:1641-1648.
Louis-Sylvestre C, Clough K, Asselain B, et al. Axillary treatment in conservative management of operable breast cancer: dissection or radiotherapy? Results of a randomized study with 15 years of follow-up. J Clin Oncol 2004;22:97-101.
Kaae S, Johansen H. Does simple mastectomy followed by irradiation offer survival comparable to radical procedures? Int J Radiat Oncol Biol Phys 1977;2:1163-1166.
Langlands AO, Prescott RJ, Hamilton T. A clinical trial in the management of operable cancer of the breast. Br J Surg 1980;67:170-174.
Atkins H, Hayward JL, Klugman DJ, Wayte AB. Treatment of early breast cancer: a report after ten years of a clinical trial. BMJ 1972;2:423-429.
Hayward JL. The Guy's trial of treatments of "early" breast cancer. World J Surg 1977;1:314-316.
Orr RK. The impact of prophylactic axillary node dissection on breast cancer survival -- a Bayesian meta-analysis. Ann Surg Oncol 1999;6:109-116.
Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003;349:546-553.
Mansel RE, Goyal A, Newcombe RG. Objective assessment of lymphedema, shoulder function and sensory deficit after sentinel node biopsy for invasive cancer: ALMANAC trial. Breast Cancer Res Treat 2004;88:Suppl 1:S12-S12. abstract.
Galper S, Recht A, Silver B, et al. Factors associated with regional nodal failure in patients with early stage breast cancer with 0-3 positive axillary nodes following tangential irradiation alone. Int J Radiat Oncol Biol Phys 1999;45:1157-1166.
Hayes DF. Markers of increased risk for failure of adjuvant therapies. Breast 2003;12:543-549.
Quiet CA, Ferguson DJ, Weichselbaum RR, Hellman S. Natural history of node-negative breast cancer: a study of 826 patients with long-term follow-up. J Clin Oncol 1995;13:1144-1151.
Quiet CA, Ferguson DJ, Weichselbaum RR, Hellman S. Natural history of node-positive breast cancer: the curability of small cancers with a limited number of positive nodes. J Clin Oncol 1996;14:3105-3111.
Fisher B, Bryant J, Dignam J, et al. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol 2002;20:4141-4149.
Hansen NM, Grube BJ, Te W, Brennan ML, Turner R, Guiliano AE. Clinical significance of axillary micrometastases in breast cancer: how small is too small? Proc Am Soc Clin Oncol 2001;20:24a. abstract.
Kattan MW, Giri D, Panageas KS, et al. A tool for predicting breast carcinoma mortality in women who do not receive adjuvant therapy. Cancer 2004;101:2509-2515.
Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004;351:2817-2826.
Paik S, Shak S, Tang G, et al. Expression of the 21 genes in the Recurrence Score assay and prediction of clinical benefit from tamoxifen in NSABP study B-14 and chemotherapy in NSABP study B-20. In: Proceedings of the 27th Annual San Antonio Breast Cancer Symposium, San Antonio, Tex., December 8–11, 2004. abstract.
Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thurlimann B, Senn H-J. Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 2005;16:1569-1583.
Early Breast Cancer Trialists' Collaborative Goup (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet 2005;365:1687-1717.
Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005;365:60-62.
Thurlimann BJ, Keshaviah A, Mouridsen J, et al. BIG 1-98: randomized double phase III study to evaluate letrozole (L) vs tamoxifen (T) as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. J Clin Oncol 2005;23:65-65. abstract.
Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005;23:619-629.
Colleoni M, Rotmensz G, Peruzzotti G, et al. Size of breast cancer metastases in axillary lymph nodes: clinical relevance of minimal lymph node involvement. J Clin Oncol 2005;23:1379-1389.
Ravdin PM, Siminoff LA, Davis GJ, et al. Computer program to assist in making decision about adjuvant therapy for women with early breast cancer. J Clin Oncol 2001;19:980-991.
Olivotto IA, Bajdik CD, Ravdin PM, et al. Population-based validation of the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol 2005;23:2716-2725.
Shapiro CL, Recht A. Side effects of adjuvant treatment of breast cancer. N Engl J Med 2001;344:1997-2008.(Nancy E. Davidson, M.D., )
Dr. Barbara L. Smith (Surgical Oncology): A 56-year-old woman was referred to the multidisciplinary breast clinic, part of the cancer center of this hospital, for management of invasive breast cancer with a minimal tumor burden in a sentinel lymph node.
Four months earlier, screening mammography at another hospital revealed an ill-defined nodule, 0.8 cm in diameter, containing a few calcifications, in the upper outer quadrant of the right breast; the nodule had not been present two years previously. In a follow-up screening, magnification views of the nodule revealed a 1-cm mass in the outer quadrant of the right breast with pleomorphic calcifications suggestive of a neoplasm. The results of a complete blood count, electrocardiography, and chest radiography were normal. Core-biopsy specimens of the right breast obtained at that hospital one month later revealed infiltrating ductal carcinoma, grade 2 of 3, involving most of all five cores. The tumor cells expressed the estrogen-receptor protein. Two weeks later, the patient was referred to this hospital.
Seven years earlier, mammography had revealed microcalcifications in the right breast, and a breast biopsy had revealed benign fibrocystic changes. Menarche had occurred at 13 years of age; the patient (gravida 3, para 3) had her first pregnancy at 36 years of age and reached menopause at 51 years of age. She had taken oral contraceptives for 15 years in the past, but she had not received postmenopausal hormone-replacement therapy. She had no allergies to medications, no history of tobacco or illicit drug use, and consumed fewer than five alcoholic beverages per week. Her father had died in his 80s from leukemia and melanoma; her mother had smoked cigarettes and died in her 60s from lung cancer. There was no family history of breast or ovarian cancer. The patient was currently taking no medications.
On examination, the patient appeared well, and her vital signs were normal. There was a healed scar at the areolar border of the right breast and a palpable 1.5-cm mass at the 10-o'clock position in the anterior axillary line. There was no discharge or inversion of the nipples and no lymphadenopathy. The left breast was normal. The remainder of the examination was normal. The results of routine laboratory tests revealed no abnormalities.
One month later, a right partial mastectomy, intraoperative lymphangiography, and sentinel-lymph-node biopsy of the right axilla were performed after a subareolar injection of technetium-99m sulfur colloid. The tissue from the right breast contained an invasive ductal carcinoma 0.9 cm by 0.8 cm by 0.5 cm, which was classifed as grade 2 of 3, with invasion of lymphatic vessels but not of blood vessels. The distance of the invasive tumor from all margins was 0.2 cm or greater. Histopathological examination of the right axillary sentinel lymph node on sections stained with hematoxylin and eosin revealed several nests of metastatic ductal carcinoma in the subcapsular sinus, less than 0.02 cm in diameter, without extracapsular extension. Immunohistochemical staining for cytokeratin detected positive tumor cells on three slides with specimens obtained at deeper levels from the tissue block. The tumor was positive for estrogen-receptor protein and faintly positive for progesterone-receptor protein, as evaluated by immunohistochemistry. There was no overexpression of HER2/neu protein.
One month later, the patient returned to the multidisciplinary breast clinic for discussion of further management.
Radiological Discussion
Dr. Daniel B. Kopans: The mediolateral oblique mammogram shows a somewhat irregularly shaped mass, 0.8 cm in diameter, in the upper portion of the right breast (Figure 1A). A more detailed view (Figure 1B) reveals some calcifications within the lesion but none extending from it. On the craniocaudal image, the irregular mass is seen in the lateral portion of the breast. This mass is suspicious for cancer.
Figure 1. Mammogram of the Right Breast.
The mediolateral oblique mammogram demonstrates a somewhat irregularly shaped mass, 0.8 cm in diameter, in the upper portion of the right breast (Panel A). A more detailed view reveals some calcifications within the lesion but none extending from it (Panel B).
Pathological Discussion
Dr. Frederick C. Koerner: Sections of the mass reveal an intermediate-grade ductal carcinoma (Figure 2A) with invasion of lymphatic vessels. The right axillary sentinel lymph node (Figure 2B) contained two clusters of metastatic tumor cells, evident both in sections stained with hematoxylin and eosin and in sections stained for keratin with use of an immunohistochemical technique (Figure 2C). The largest nest spans less than 0.02 cm.
Figure 2. Breast and Axillary Sentinal Lymph-Node Biopsy Specimens.
The breast lumpectomy specimen (Panel A) contains nests of carcinoma cells penetrating the mammary fat. Two small clusters of carcinoma cells occupy the periphery of this sentinel lymph node (Panel B). Immunohistochemical staining for cytokeratin (Panel C) confirms that these are epithelial cells (Panels A and B, hematoxylin and eosin; Panel C, immunoperoxidase stain for cytokeratin).
Differences in staging systems proposed by the American Joint Committee on Cancer (AJCC) and the International Union against Cancer (UICC) have caused confusion regarding the staging of disease in patients with breast cancer who have small metastatic deposits in axillary lymph nodes. Both systems stratify patients according to the number of lymph nodes involved by carcinoma and according to the size of the metastatic foci (Table 1).1,2 However, while the UICC system uses "i" to denote "isolated tumor cells," the original AJCC system uses "i" to identify cases in which the tumor was detected on immunohistochemical staining for keratin but not on hematoxylin-and-eosin staining. The emphasis on the role of immunohistochemical staining reflects the belief that metastases detected only by immunohistochemical staining are small and, therefore, probably clinically insignificant. However, the presence of carcinoma cells in a section stained for keratin, but not in a section stained with hematoxylin and eosin, does not guarantee the small size of the metastasis — in this case, the foci of cancer were small, but they were detected on staining with hematoxylin and eosin. The AJCC has since revised the meaning of the "i" to coincide with the usage of the UICC (Table 1).3
Table 1. Comparison of Pathological Staging Classifications for Breast Cancer.
In summary, both current systems for assigning a disease stage on the basis of findings in the axillary lymph nodes rely on both the number of involved lymph nodes and the size of the metastatic foci. The method of detection of the tumor cells no longer plays a role in determining the stage. This patient's sentinel lymph node was staged as pN0 (i+).
Discussion of Management
The Axilla in a Patient with Minimal Disease in the Sentinel Lymph Node
Dr. Monica Morrow: This patient had a T1b breast carcinoma, as classified according to the AJCC staging system, in which T1b denotes a tumor size greater than 0.5 cm but not larger than 1.0 cm,1 with isolated tumor cells in a sentinel lymph node. In deciding whether further therapy to the axilla is indicated, clinicians needed to consider the likelihood that additional nodal metastases had already occurred, the risk of local recurrence if the axilla was untreated, the sequelae of treatment, and the potential impact of local therapy on survival.
Risk of Additional Nodal Metastases
This patient had tumor cells only in the subcapsular sinus of the lymph node. It has been suggested that epithelial cells in the breast may be transported to the subcapsular sinus during needle biopsies or surgical manipulation of the breast.4 However, such cells are usually accompanied by hemosiderin-laden macrophages and red cells in the subcapsular sinus, which were not described here. Thus, this patient was considered to have a true nodal metastasis.
In patients with T1b primary cancers with a positive sentinel lymph node, the reported risk of additional axillary-node metastases ranges from 12 percent to 34 percent (Table 2).5,6,7,8,9 The size of the metastases in the sentinel node influenced the risk of additional axillary disease in some studies,10 but not in others.8 In two studies, the risk of additional nodal metastases was greater among patients whose sentinel-lymph-node metastases were detected by staining with hematoxylin and eosin than among those whose metastases were detected by immunohistochemical staining,11,12 possibly indicating some correlation of the method of detection with the size of the metastasis.
Table 2. Risk of Additional Axillary-Node Metastases in Women with T1b Carcinoma, from Several Studies.
Other variables may affect the risk of additional nodal disease. In 10 studies5,8,9,10,13,14,15,16,17,18 in which multivariate analysis was used to identify independent predictors of additional nodal disease, the number of involved sentinel nodes, the number of sentinel nodes removed, or the ratio between the two was predictive of additional nodal involvement in the majority of the studies that examined these factors.8,9,13,14,15 The tumor size was important in 5 of 10 reports and the presence of lymphatic or vascular invasion in 4, and no study found the tumor grade to be a significant predictor of additional axillary nodal disease.
A nomogram developed at the Memorial Sloan-Kettering Cancer Center in which multiple variables are used to predict the presence of additional nodal metastases9,19 predicted that the patient under discussion had a 19 percent risk of additional nodal disease (Table 3). This estimate is consistent with estimates made on the basis of tumor size alone (12 to 34 percent) or the size of metastases alone (14 to 24 percent). These calculations estimated only the risk of additional metastases detected by staining with hematoxylin and eosin. Chu et al.6 reported that in patients with sentinel-node metastases, 9 percent had tumor in nonsentinel nodes that was detected by immunohistochemical analysis alone. The prognostic significance of isolated tumor cells or very small metastatic deposits in axillary nodes detected only by immunohistochemical methods is uncertain. If the presence of such cells or deposits is considered to be biologically important, then the chance of this patient's having additional tumor in the axilla increases to approximately 30 percent.
Table 3. Memorial Sloan-Kettering Cancer Center Nomogram for Prediction of Additional Axillary-Node Disease in the Patient.
Risk of Axillary Recurrence
Local control is a major goal of the surgical treatment of breast carcinoma. Several retrospective and prospective studies suggest that the clinical rate of axillary recurrence is lower than the actual incidence of nodal metastases.20,21,22,23,24 Overall, the data suggest that the risk of axillary recurrence is approximately one third the risk of axillary metastases; this risk may be further decreased by radiation to tangential fields in the breast. In the patient under discussion, I would estimate the risk of axillary recurrence to be less than 5 percent with no further local therapy.
Effect of Axillary Treatment on Survival
Perhaps the most important consideration in assessing the need for additional local therapy in this patient was whether axillary treatment would have an impact on survival. Axillary dissection has been considered a staging procedure since the National Surgical Adjuvant Breast and Bowel Project B04 trial failed to show a survival benefit for clinically node-negative women treated with axillary dissection, as compared with observation and delayed dissection if metastases became clinically apparent.25 However, trials of radiotherapy after mastectomy have suggested that aggressive local therapy is associated with improved survival26,27 and that this benefit is most evident in patients with small primary tumors and limited nodal involvement, such as this patient. Although no single randomized trial examining the effect of axillary dissection on survival has shown a statistically significant benefit for the surgery,21,28,29,30,31,32 a meta-analysis of six trials33 found a 5.4 percent improvement in survival among patients who underwent axillary dissection. Unfortunately, a randomized trial designed to determine whether axillary dissection is beneficial in patients with a positive sentinel node that opened in 1999 was closed owing to poor accrual. In the absence of definitive data, a survival benefit for axillary dissection in the range of 5 percent cannot be ruled out or confirmed.
Sequelae of Axillary Dissection
The short-term and long-term morbidity associated with the procedure must be weighed against the potential benefits of axillary dissection. Recent randomized trials have provided clear evidence that several problems are significantly more common among patients undergoing axillary dissection than among those who undergo sentinel-node biopsy alone. These sequelae include pain (39 percent vs. 8 percent), numbness or paresthesia (68 percent vs. 1 percent), decreased mobility (31 percent vs. 0 percent), and lymphedema (75 percent vs. 7 percent).34,35
Axillary irradiation is an alternative to axillary dissection for maintaining local control in the axilla. It appears to be associated with a lower risk of lymphedema than axillary dissection in nonrandomized studies,36 but it may result in radiation pneumonitis or brachial plexopathy. In addition, it has the disadvantage of not providing information on the number of additional nodes involved with tumor, which may be useful when systemic treatment is considered. One randomized study comparing axillary dissection and irradiation reported a statistically significant higher rate of axillary recurrence after irradiation, although no survival difference was seen.28
The patient under discussion had an approximately 20 percent risk of additional axillary-lymph-node metastases; the risk of isolated axillary recurrence was low and by itself did not justify axillary dissection. However, knowing the number of involved nodes may assist in decision making about systemic therapy, and a small survival benefit for axillary dissection cannot be ruled out. Although the procedure is associated with substantial morbidity, which needed to be discussed with the patient, I believe the potential benefits outweighed the risks.
Systemic Therapy
Dr. Nancy E. Davidson: The use of adjuvant systemic therapy should be considered for a patient such as this one, as it is for virtually all women with invasive breast cancer. Whether to use it and what to recommend is determined by consideration of the risk of recurrence after local therapy alone, the efficacy of therapy, side effects of treatment, and the patient's preference. Several prognostic and predictive markers can help guide decision making in such a case. Prognostic markers predict the risk of recurrence in the absence of systemic therapy; these include axillary-lymph-node involvement, tumor size, histologic grade, expression of estrogen receptor , progesterone-receptor expression, and overexpression of the HER2 protein. Predictive markers are used to estimate the likelihood of benefit from a particular therapy. Expression of estrogen receptor and progesterone receptor predicts a response to endocrine therapy, and overexpression of HER2/neu predicts a response to trastuzumab, a monoclonal antibody directed against the HER2 protein.37 This patient's tumor expressed estrogen receptor and did not overexpress the HER2 protein.
Defining the Risk of Recurrence
The single most important prognostic factor for this patient was the extent of lymph-node involvement. Virtually all data on the risk of recurrence are derived from assessment of lymph nodes obtained through axillary-lymph-node dissection that have been stained with hematoxylin and eosin. Serial sectioning, immunohistochemical staining, or molecular analysis of sentinel nodes may identify the 30 percent of patients with lymph-node–negative breast cancer as defined by traditional staging who are destined to develop metastatic disease in the absence of systemic therapy, but these methods could also lead to identification of patients with minimal lymph-node involvement that will never be of clinical consequence. In the past, it is possible that this patient would have been thought to have node-negative breast cancer and treated accordingly.
Since there is an 80 percent chance that further axillary dissection would not identify other positive axillary lymph nodes in this patient, a rational first approach is to consider the risk of recurrence of this small breast cancer if it were node-negative, in the absence of systemic therapy. Data from both retrospective series38,39 and randomized trials40 suggest that local therapy alone may be sufficient for women with small tumors and low lymph-node burden. In a recent study, patients such as this one who had sentinel-lymph-node metastases up to 0.02 cm in diameter had the same disease-free and overall survival as those whose sentinel lymph nodes were negative.41
A model that uses multiple clinical and pathological variables to predict mortality rates associated with breast cancer42 predicts a 15-year risk of breast-cancer–specific mortality of 53 percent for this patient without systemic therapy. However, this model is based on a small number of patients and has not been validated in an independent population. Finally, the Oncotype Dx 21 multigene assay (Genomic Health), which identifies node-negative patients with a low recurrence score who are likely to have an excellent outcome with tamoxifen alone, could theoretically be used.43,44 In the pivotal studies of this assay, only 16 percent of participants had T1a or T1b tumors, as this patient did; 63 percent of those had a low recurrence score.
Efficacy and Toxicity of Adjuvant Systemic Therapy
A second consideration for this patient was the balance of the efficacy and side effects of therapy. Several expert panels provide guidance that is based on a combination of evidence and the opinions of specialists. The 2005 St. Gallen Consensus Panel classifies a patient such as the one under discussion as at moderate risk for recurrence if fewer than four axillary lymph nodes are involved and recommends endocrine therapy, with consideration of chemotherapy.45 The guidelines of the National Comprehensive Cancer Network (available at www.nccn.org) also support the use of adjuvant hormonal therapy, with or without chemotherapy.
Because of the patient's positive estrogen-receptor test, endocrine therapy was the key element of systemic therapy for this patient, regardless of her lymph-node status. Long-term results from the Early Breast Cancer Trialists' Collaborative Group have demonstrated a clear benefit associated with five years of tamoxifen treatment in estrogen-receptor–positive patients of any nodal status,46 with a higher absolute benefit for women with node-positive breast cancer who have a higher risk of recurrence. Two recent trials have suggested that aromatase inhibitors are superior to tamoxifen in terms of disease-free survival after approximately three years of follow-up, but without an overall survival benefit.47,48 Both tamoxifen and aromatase inhibitors cause menopausal symptoms. Tamoxifen has rare but serious side effects consisting of venous thromboembolic events and uterine cancer, because of its partial estrogen-agonist properties, whereas aromatase inhibitors are linked to osteoporosis and fractures, because of their estrogen-deprivation effects. The 2004 American Society of Clinical Oncology technology assessment states that optimal endocrine therapy for postmenopausal women with early-stage steroid-receptor–positive breast cancer includes an aromatase inhibitor alone or after the use of tamoxifen.49
The most difficult question for us in relation to this patient was how to judge the value of adjuvant chemotherapy in addition to endocrine therapy, because the studies with results available to us used older regimens, did not use aromatase inhibitors, and may have classified a patient such as this one as node-negative. A recent study from Italy of patterns of care suggested that clinicians are increasingly considering any evidence of lymph-node involvement as suggestive of a worse prognosis than in cases that have no lymph-node involvement.50
The ADJUVANT! online Web-based model51 to predict 10-year outcomes with or without therapy provides a useful tool for patient counseling and has recently been validated with use of population-derived outcomes of patients with early-stage breast cancer who have been treated in British Columbia, Canada.52 It takes into account the patient's age and any coexisting illnesses, lymph-node status, tumor size, histologic grade, and estrogen-receptor status to provide an estimate of 10-year disease-free and overall survival with various combinations of endocrine therapy and chemotherapy. If we assume that this patient had perfect health and was indeed node-negative, then the use of an aromatase inhibitor would be predicted to improve her chances of 10-year disease-free survival by approximately 9 percent, and the addition of dose-dense chemotherapy with anthracycline and taxane would add another 4 percent improvement; however, these interventions improve 10-year overall survival by only 1.9 percent. Increasing lymph-node involvement is associated with increases in absolute benefit for both treatment with aromatase inhibitors and chemotherapy. The potential benefits must be balanced against the side effects of chemotherapy, which include a 1 to 2 percent risk of substantial toxic effects (including treatment-related death, anthracycline-induced cardiomyopathy, and secondary leukemia).53
Adjuvant endocrine therapy is appropriate for a postmenopausal patient with T1b estrogen-receptor–positive breast cancer no matter what the lymph-node burden, and I would recommend an aromatase inhibitor in a case such as this one. The value of adjuvant chemotherapy is uncertain for a patient with isolated tumor cells in the sentinel node, and the risks of chemotherapy might approximate the benefits. I would recommend axillary-lymph-node dissection to complete staging and refine the risk assessment, since the demonstration of additional lymph-node involvement would strengthen recommendations for chemotherapy. The patient's preference regarding the use of chemotherapy would be a key consideration. If she declined chemotherapy or wished to have chemotherapy no matter what, then axillary lymph-node dissection could be omitted.
Dr. Ann H. Partridge (Medical Oncology at Dana–Farber Cancer Institute): How does vascular invasion play into the decision about axillary-lymph-node dissection and systemic treatment?
Dr. Morrow: In the 10 studies that I reviewed, only 4 identified lymphovascular invasion as an independent predictor of axillary nodal metastases. So I would not take that into consideration in making my decision about axillary-node dissection.
Dr. Davidson: The importance of vascular invasion as a poor prognostic factor is controversial.45 It is included in the Memorial Sloan-Kettering nomogram but not in the ADJUVANT! online model. It did not weigh heavily in my consideration in this case.
A Physician: Could the discrepancy between the number of positive lymph nodes found at axillary dissection and the axillary-failure rates in the absence of dissection be accounted for by the fact that these are only counted when the axilla is the first site of failure?
Dr. Morrow: That is a factor. In addition, in women who are receiving breast irradiation to tangential fields, a substantial part of the axilla is included in the field, and this may reduce the axillary-failure rates. Finally, when we do a sentinel-node biopsy, we manually inspect the axilla, so that we do not leave behind gross nodal disease that could present as early first failure.
Dr. Nancy Lee Harris (Pathology): Dr. Smith, can you tell us what was done for this patient?
Dr. Smith: This patient was very well informed and had read many of the articles discussed today. She wanted systemic chemotherapy regardless of what additional nodal disease might be present, and she was concerned about the possible effects on her arm of axillary dissection. She elected not to have additional axillary surgery, and she received four cycles of doxorubicin–cyclophosphamide every three weeks. She elected to receive irradiation to her axilla according to a protocol that we have at our institution. Tamoxifen was begun at the same time as radiation treatment, with a plan to switch in about two years to treatment with an aromatase inhibitor.
Anatomical Diagnosis
Invasive ductal carcinoma of the breast with isolated tumor cells in a sentinel lymph node (T1b pN0 (i+)).
Dr. Davidson reports having received consulting fees from Lilly for serving on the data safety and management board for the Raloxifene Use in the Heart (RUTH) trial, and lecture fees from AstraZeneca. Dr. Morrow reports having received grant support from Avon Products Foundation.
Source Information
From the Johns Hopkins University School of Medicine, Baltimore (N.E.D.).; the Fox Chase Cancer Center, Philadelphia (M.M.); and the Departments of Radiology (D.B.K.) and Pathology (F.C.K.), Massachusetts General Hospital and Harvard Medical School — both in Boston.
References
Greene FL, Page DL, Fleming ID, et al., eds. AJCC cancer staging manual. 6th ed. New York: Springer-Verlag, 2002.
Sobin LH, Wittekind C, eds. TNM: classification of malignant tumours. 6th ed. New York: Wiley-Liss, 2002.
Singletary SE, Greene FL, Sobin LH. Classification of isolated tumor cells: clarification of the 6th edition of the American Joint Committee on Cancer Staging Manual. Cancer 2003;98:2740-2741.
Carter BA, Jensen RA, Simpson JF, Page DL. Benign transport of breast epithelium into axillary lymph nodes after biopsy. Am J Clin Pathol 2000;113:259-265.
Wong SL, Edwards MJ, Chao C, et al. Predicting the status of the nonsentinel axillary nodes: a multicenter study. Arch Surg 2001;136:563-568.
Chu KU, Turner RR, Hansen NM, Brennan MB, Giuliano AE. Sentinel node metastasis in patients with breast carcinoma accurately predicts immunohistochemically detectable nonsentinel node metastasis. Ann Surg Oncol 1999;6:756-761.
Nos C, Harding-MacKean C, Freneaux P, et al. Prediction of tumour involvement in remaining axillary lymph nodes when the sentinel node in a woman with breast cancer contains metastases. Br J Surg 2003;90:1354-1360.
Viale G, Maiorano E, Pruneri G, et al. Predicting the risk for additional axillary metastases in patients with breast carcinoma and positive sentinel lymph node biopsy. Ann Surg 2005;241:319-325.
Van Zee KJ, Manasseh DM, Bevilacqua JL, et al. A nomogram for predicting the likelihood of additional nodal metastases in breast cancer patients with a positive sentinel node biopsy. Ann Surg Oncol 2003;10:1140-1151.
Leidenius MH, Vironen JH, Riihela MS, et al. The prevalence of non-sentinel node metastases in breast cancer patients with sentinel node micrometastases. Eur J Surg Oncol 2005;31:13-18.
Mignotte H, Treilleux I, Faure C, Nessah K, Bremond A. Axillary lymph-node dissection for positive sentinel nodes in breast cancer patients. Eur J Surg Oncol 2002;28:623-626.
Kamath VJ, Giuliano R, Dauway EL, et al. Characteristics of the sentinel lymph node in breast cancer predict further involvement of higher-echelon nodes in the axilla: a study to evaluate the need for complete axillary lymph node dissection. Arch Surg 2001;136:688-692.
Hwang RF, Krishnamurthy S, Hunt KK, et al. Clinicopathologic factors predicting involvement of nonsentinel axillary nodes in women with breast cancer. Ann Surg Oncol 2003;10:248-254.
Menes TS, Tartter PI, Mizrachi H, Constantino J, Estabrook A, Smith SR. Breast cancer patients with pN0(i+) and pN1(mi) sentinel nodes have high rate of nonsentinel node metastases. J Am Coll Surg 2005;200:323-327.
Goyal A, Douglas-Jones A, Newcombe RG, Mansel RE. Predictors of non-sentinel lymph node metastasis in breast cancer patients. Eur J Cancer 2004;40:1731-1737.
Travagli JP, Atallah D, Mathieu MC, et al. Sentinel lymphadenectomy without systematic axillary dissection in breast cancer patients: predictors of non-sentinel lymph node metastasis. Eur J Surg Oncol 2003;29:403-406.
Fournier K, Schiller A, Perry RR, Laronga C. Micrometastasis in the sentinel lymph node of breast cancer does not mandate completion axillary dissection. Ann Surg 2004;239:859-863.
Sachdev U, Murphy K, Derzie A, Jaffer S, Bleiweiss IJ, Brower S. Predictors of nonsentinel lymph node metastasis in breast cancer patients. Am J Surg 2002;183:213-217.
Lambert L, Hunt KK, Hwang RF. Validation of a breast cancer nomogram for predicting additional nodal metastases after positive sentinel node biopsy. Ann Surg Oncol 2005;12:Suppl 1:S17-S17. abstract.
Langer I, Marti WR, Guller U, et al. Axillary recurrence rate in breast cancer patients with negative sentinel lymph node (SLN) or SLN micrometastases: prospective analysis of 150 patients after SLN biopsy. Ann Surg 2005;241:152-158.
Fant JS, Grant MD, Knox SM, et al. Preliminary outcome analysis in patients with breast cancer and a positive sentinel lymph node who declined axillary dissection. Ann Surg Oncol 2003;10:126-130.
Guenther JM, Hansen NM, DiFronzo LA, et al. Axillary dissection is not required for all patients with breast cancer and positive sentinel nodes. Arch Surg 2003;138:52-56.
Greco M, Agresti R, Cascinelli N, et al. Breast cancer patients treated without axillary surgery: clinical implications and biologic analysis. Ann Surg 2000;232:1-7.
Holmberg SB, Crivellari D, Zahrieh J, et al. A randomized trial comparing axillary clearance versus no axillary clearance in patients older than 60 years with breast cancer: first results of International Breast Cancer Study Group Trial 10-93. J Clin Oncol 2004;22:Suppl:4S-4S. abstract.
Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-1241.
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.
Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999;353:1641-1648.
Louis-Sylvestre C, Clough K, Asselain B, et al. Axillary treatment in conservative management of operable breast cancer: dissection or radiotherapy? Results of a randomized study with 15 years of follow-up. J Clin Oncol 2004;22:97-101.
Kaae S, Johansen H. Does simple mastectomy followed by irradiation offer survival comparable to radical procedures? Int J Radiat Oncol Biol Phys 1977;2:1163-1166.
Langlands AO, Prescott RJ, Hamilton T. A clinical trial in the management of operable cancer of the breast. Br J Surg 1980;67:170-174.
Atkins H, Hayward JL, Klugman DJ, Wayte AB. Treatment of early breast cancer: a report after ten years of a clinical trial. BMJ 1972;2:423-429.
Hayward JL. The Guy's trial of treatments of "early" breast cancer. World J Surg 1977;1:314-316.
Orr RK. The impact of prophylactic axillary node dissection on breast cancer survival -- a Bayesian meta-analysis. Ann Surg Oncol 1999;6:109-116.
Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003;349:546-553.
Mansel RE, Goyal A, Newcombe RG. Objective assessment of lymphedema, shoulder function and sensory deficit after sentinel node biopsy for invasive cancer: ALMANAC trial. Breast Cancer Res Treat 2004;88:Suppl 1:S12-S12. abstract.
Galper S, Recht A, Silver B, et al. Factors associated with regional nodal failure in patients with early stage breast cancer with 0-3 positive axillary nodes following tangential irradiation alone. Int J Radiat Oncol Biol Phys 1999;45:1157-1166.
Hayes DF. Markers of increased risk for failure of adjuvant therapies. Breast 2003;12:543-549.
Quiet CA, Ferguson DJ, Weichselbaum RR, Hellman S. Natural history of node-negative breast cancer: a study of 826 patients with long-term follow-up. J Clin Oncol 1995;13:1144-1151.
Quiet CA, Ferguson DJ, Weichselbaum RR, Hellman S. Natural history of node-positive breast cancer: the curability of small cancers with a limited number of positive nodes. J Clin Oncol 1996;14:3105-3111.
Fisher B, Bryant J, Dignam J, et al. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol 2002;20:4141-4149.
Hansen NM, Grube BJ, Te W, Brennan ML, Turner R, Guiliano AE. Clinical significance of axillary micrometastases in breast cancer: how small is too small? Proc Am Soc Clin Oncol 2001;20:24a. abstract.
Kattan MW, Giri D, Panageas KS, et al. A tool for predicting breast carcinoma mortality in women who do not receive adjuvant therapy. Cancer 2004;101:2509-2515.
Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004;351:2817-2826.
Paik S, Shak S, Tang G, et al. Expression of the 21 genes in the Recurrence Score assay and prediction of clinical benefit from tamoxifen in NSABP study B-14 and chemotherapy in NSABP study B-20. In: Proceedings of the 27th Annual San Antonio Breast Cancer Symposium, San Antonio, Tex., December 8–11, 2004. abstract.
Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thurlimann B, Senn H-J. Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 2005;16:1569-1583.
Early Breast Cancer Trialists' Collaborative Goup (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet 2005;365:1687-1717.
Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005;365:60-62.
Thurlimann BJ, Keshaviah A, Mouridsen J, et al. BIG 1-98: randomized double phase III study to evaluate letrozole (L) vs tamoxifen (T) as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. J Clin Oncol 2005;23:65-65. abstract.
Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005;23:619-629.
Colleoni M, Rotmensz G, Peruzzotti G, et al. Size of breast cancer metastases in axillary lymph nodes: clinical relevance of minimal lymph node involvement. J Clin Oncol 2005;23:1379-1389.
Ravdin PM, Siminoff LA, Davis GJ, et al. Computer program to assist in making decision about adjuvant therapy for women with early breast cancer. J Clin Oncol 2001;19:980-991.
Olivotto IA, Bajdik CD, Ravdin PM, et al. Population-based validation of the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol 2005;23:2716-2725.
Shapiro CL, Recht A. Side effects of adjuvant treatment of breast cancer. N Engl J Med 2001;344:1997-2008.(Nancy E. Davidson, M.D., )