Breast Cancer Axillary Staging: Much Ado About Micrometastatic Disease

The primary goals of diagnostic cancer staging are to provide prognostic information and to inform treatment recommendations. The use of uniform staging definitions also allows clinicians and researchers to communicate in a common language and to place cancer outcomes, whether in the context of clinical trials, observational studies, or population-based cohorts, into their proper context. The most commonly used staging system in breast cancer relies almost exclusively on anatomic features and is defined as “tumor node metastasis” (TNM). The American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) developed TNM staging in 1978 and have periodically refined it since that time, with the most recent seventh edition completed in 2010. At least two features of AJCC staging are worth noting: first, the definition (in 2010) of T1N1mi disease as stage IB, and second, the absence of consideration of tumor biologic subtype despite a growing awareness of the seminal importance of subtype on breast cancer outcomes. In patients with breast cancer, staging of the regional lymph nodes has traditionally been an integral part of management, and nodal status is considered a significant factor in prognostication and selection of multimodality therapy. After years of surgically clearing the axilla of nodal tissue, contemporary surgical management favors sentinel lymph node dissection (SLND). This procedure continues to provide the necessary diagnostic and prognostic information, while limiting morbidity and improving quality of life. As SLND has gained acceptance, efforts have been made to evaluate and report extent of disease within the axilla with greater precision. Extensive pathologic analysis has resulted in a complex system of nodal classification, including isolated tumor cells and micrometastases, which has generated significant debate as to the clinical relevance of small tumor deposits that likely would not have been identified in many cases in the era of routine axillary dissection. Put simply, the debate has centered on whether the detection of small-volume axillary disease identifies patients at higher risk of recurrence and whether these individuals warrant additional measures to reduce that risk. In this issue of the Journal of Clinical Oncology, Mittendorf et al present an analysis that challenges the relevance of the current stage I classification. The authors analyzed more than 8,000 patients with breast cancer from two prospective cohorts containing approximately 5,580 patients with stage I disease (5,000 stage IA [T1N0] and 580 stage IB [T0-1N1mi]), with 6.5 to 9 years median follow-up. One cohort was derived from a series at MD Anderson Cancer Center (MDACC) of clinically node-negative patients undergoing SLND; the other came from the American College of Surgeons Oncology Group ACOSOGZ0010 trial (Prognostic Study of Sentinel Lymph Node and Bone Marrow Metastases in Women With Stage I or Stage IIA Breast Cancer) and included patients with T1-2N0 disease. In both studies, the SLN was evaluated by hematoxylin and eosin (HE) staining; at MDACC, all nodes were also analyzed by immunohistochemistry (IHC), and providers were aware of results. In the ACOSOG-Z0010 trial, however, IHC was used only if the HE analysis was negative, with providers blinded to IHC results. Adjuvant trastuzumab was not administered as part of therapy at the time of the studies. Analysis of each cohort demonstrated no significant difference in survival end points, including recurrence-free and overall survival, between stage IA and IB disease. Their data align with other recent analyses from ACOSOG-Z0010 and National Surgical Adjuvant Breast and Bowel Project NSABP B-32 (Surgery to Remove Sentinel Lymph Nodes With or Without Removing Lymph Nodes in the Armpit in Treating Women With Breast Cancer) regarding the minimal prognostic utility of identifying occult small-volume SLN disease. As expected, generally inferior survival was observed in the comparison of stage IIA with the stage I categories. In a secondary analysis, biologic features, including estrogen receptor status and locally determined grade, were able to stratify survival outcomes in stage I patients. Therefore, on the basis of these findings, Mittendorf et al raise the question: if cancer staging is designed to stratify patients by prognosis, how can we support a category which does not refine our ability to present risk to patients? In addition, although traditional staging is defined by anatomy, is it possible to incorporate aspects of tumor biology? Multiple recent observations have recognized the importance of biologic factors in prognostication for small, node-negative tumors. In general, it is acknowledged that patients presenting with stage I breast cancer generally carry an excellent prognosis, although survival outcomes may vary by biologic subtype. Several observational studies have confirmed increased risks for small human epidermal growth factor receptor 2 (HER2) –positive cancers compared with same stage hormone receptor–positive and/or HER2-negative tumors. Given the recognition of increased risk, successful application of HER2-directed therapy for small HER2-positive cancers has translated into highly favorable outcomes and has become a standard of care for many stage 1 patients. Likely related to the recognition JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 10 APRIL 1 2015