Are Axillary Lymph Nodes Still Relevant in Breast Cancer

The importance of axillary nodal metastases in breast cancer has been recognized at least since the time of Wilhelm Fabry (1560–1634), who described axillary nodal excision in conjunction with primary tumor surgery. Understanding precisely what axillary metastases mean has been a work in progress for centuries. By the 18th century breast cancer progression was envisioned as an orderly process beginning in the breast, spreading to nodal basins, and then disseminating to distant sites. In the late 19th century William Halstead popularized the notion that radical nodal surgery could interrupt this progression and save lives. This view was challenged by Devitt in 1962 based on retrospective data that failed to show a survival advantage for radical nodal surgery. He astutely recognized that ‘‘...breast cancer patients do not do poorly because they have regional lymph node metastases, rather they have these metastases when they do poorly’’. The randomized prospective NSABP B-04 trial, which was first reported in 1977, confirmed that the addition of axillary dissection to mastectomy does not improve distant diseasefree or overall survival. In a 1980 review Bernard Fisher asserted that ‘‘...breast cancer is a systemic disease, likely at its inception,’’ and ‘‘The positive lymph node is the reflection of an interrelationship that permits the development of metastases rather than the instigator of distant disease’’. Identifying a lymph node metastasis is only the crudest possible indicator that a primary tumor possesses the machinery to thrive outside of the breast in a host who lacks the capacity to prevent it. Though there is considerable overlap between the tumor skill set required to generate a lymph node metastasis and the skill set required to proliferate in a distant organ, the study by Gangi et al. in this issue of the Annals reminds us that lymph node metastases are neither necessary nor sufficient for the generation of lethal distant metastatic disease. The specific observation was that tumor subtype, approximated by immunohistochemical staining for estrogen receptor, progesterone receptor, and HER2/neu, did not independently predict lymph node positivity, though young age, larger tumors, higher grade, and lymphovascular invasion did. Breast cancer intrinsic subtype, ascertained by gene expression profiling, is known to predict breast cancer outcome. Immunohistochemistry provides only an inexact approximation of these intrinsic subtypes, and the 3-marker panel used by these investigators is inferior to larger panels that include EGFR, cytokeratins, and Ki67. The authors focus on triple negative breast cancer, which is a reasonable immunohistochemistry classification, but it must be recognized that this defines a fairly heterogeneous group of tumors and additional markers are required to more closely approximate the truly poor prognosis basal phenotype. Nevertheless, the conclusion that triple negative breast cancer, though associated with a poor prognosis, is not associated with a higher rate of lymph node metastases is consistent with prior studies suggesting that basal phenotype breast is actually associated with a lower rate of lymph node metastases than hormone-sensitive subtypes. These tumors clearly possess the machinery to disseminate and grow in distant organs, but some feature of the tumor-host interaction frequently precludes establishment of nodal metastases. Whether this reflects a deficiency in the tumors or an efficiency in the nodes is not known. Axillary nodal status has long been recognized as one of the strongest predictors of breast cancer recurrence and mortality. In the wake of rapid advances in molecular profiling, this role is appropriately being challenged, but much work is still required if we are to obtain the same information about tumor-host interactions through other Society of Surgical Oncology 2014