Staging of women with breast cancer after introduction of sentinel node guided axillary dissection.

Today, sentinel lymph node dissection (SLND) has replaced axillary lymph node dissection (ALND) as standard procedure for staging of the axilla in the treatment of breast cancer. SLND can accurately stage the axilla by removing on average only two lymph nodes. Only in case of metastatic spread to sentinel nodes an ALND is offered. Removing fewer nodes has made more extensive histopathological examinations of the lymph nodes possible and as a consequence more metastases are found. This has resulted in stage migration. Based on data from the nationwide Danish Breast Cancer Cooperative Group (DBCG) database we have estimated the magnitude and therapeutic consequences of this stage migration in Denmark by comparing the distribution of lymph node metastases in breast cancer patients operated in 1993-1996 and 2005-2008; before and after introducing SLND. The proportion of patients having macrometastases was not significantly different in the two periods, whereas the proportion of patients with micrometastases increased significantly from 5.1% to 9.0%. However, the proportion of patients offered adjuvant systemic treatment due to positive nodal status as the only high-risk criterion did only increase from 7.8% to 8.8%, when estimated using today´s criteria for risk-allocation, because nodal status is now less important in risk-allocation. In general, only 15-20% of patients with micrometastases and 10-15% of patients with isolated tumor cells (ITC) in sentinel node have further metastatic spread to non-sentinel nodes (NSN). Thus, the majority of these patients does not benefit from additional ALND but still run the risk of arm morbidity. Based on data from the DBCG database, we have developed two models to predict NSN metastases in breast cancer patients with micrometastases or ITC in the sentinel node. A total number of 304 breast cancer patients with ITC and 1577 patients with micrometastases in sentinel node operated in 2001-2008 with SLND and subsequent ALND were identified in the database. In patients with ITC in sentinel node the risk of NSN metastases was significantly associated with younger age at diagnosis, increasing tumor size and increasing proportion of positive sentinel nodes in a multivariate analysis. If patients were ≥ 40 years at diagnosis with tumor size ≤ 2 cm as well as one or more negative sentinel nodes, NSN metastases were found in only 2%. Omission of ALND in this group would spare 1/3 of patients with ITC in sentinel node for an ALND. In patients with micrometastases in sentinel node the risk of NSN metastases was significantly associated with increasing tumor size, lymphovascular invasion, negative hormone receptor status, location of tumor in the upper lateral quadrant of the breast and increasing proportion of positive sentinel nodes in a multivariate analysis. However, a model based on these traditional prognostic markers could not identify a subgroup of patients with a risk of NSN metastases less than 10%. We then investigated whether the biochemical prognostic markers TIMP-1, Ki67 and HER2 could support the model. In a matched case-control study 25 cases with micrometastases in sentinel node and additional metastatic spread to NSN were compared to 50 matched controls with micrometastases in sentinel node but without NSN metastases. Despite being prognostic markers in breast cancer, we found no significant differences in the expression of these three biochemical markers between patients with and without NSN metastases. Not all NSN metastases will become clinically relevant, making ALND redundant in many breast cancer patients. Accordingly, there is a trend towards omission of ALND in breast cancer patients with minimal metastatic disease in sentinel node. As a result, a tool is needed to identify a group of patients with high risk of recurrence, where ALND should still be offered. In our model a small group of patients with micrometastases had a high risk of NSN metastases on nearly 40%, comparable to patients with macrometastases, indicating that ALND may still be recommended in this subgroup in the future.