The evolution of the sentinel node procedure in the treatment of breast cancer.

This thesis is based on 10 original articles, of which 3 were previously included in the PhD thesis "Staging of women with breast cancer after introduction of sentinel node guided axillary dissection". In the PhD thesis is was shown that the introduction of sentinel lymph node dissection (SLND) in the treatment of breast cancer in Denmark has resulted in an increased identification of patients with micrometastases or isolated tumor cells (ITC) in the lymph nodes. Not all these small metastases are likely to disseminate to non-sentinel nodes. This thesis provides evidence that a previous surgical excision of a breast tumor is likely to lead to iatrogenic displacement of tumor cells resulting in a nearly four-fold increased risk of ITC in the sentinel node. These tumor cells are not associated with non-sentinel node metastases. Especially ITC, but also micrometastases and some macrometastases, are not identified on perioperative frozen sections, but found postoperatively at the conventional histopathological examination. These patients are offered an axillary lymph node dissection (ALND) as a second procedure. It has been suggested that this two-stage procedure reduces the number of lymph nodes removed, because of fibroses from previous surgery. In this thesis it was shown that a two-stage procedure does not result in a clinically relevant impairment of the number of lymph nodes removed by ALND. Based on patient, tumor, and sentinel node characteristics from the Danish Breast Cancer Group database, two predictive models for non-sentinel node metastases, when only micrometastases or ITC are found in the sentinel node, were developed, as a part of the PhD thesis. These two models have now been internally validated, and a cross-validation in a Finnish patient material has been performed in cooperation with researchers from Helsinki. The model for patients with micrometastases proved to be robust under internal as well as external validation and could be used to identify patients with micrometastases that might still benefit from an ALND. Efforts should continue to improve the model. As a part of the PhD thesis, new molecular markers were tested for prediction of non-sentinel node metastases. In addition, method of detection of the breast cancer could be a possible predictor of non-sentinel node metastases. It has been hypothesized that breast cancers detected by screening represent a clinical indolent group of cancers with lower risk of non-sentinel node metastases compared to symptomatic cancers. This hypothesis was tested in this thesis in a large Danish dataset. No significant difference in the risk of non-sentinel node metastases was found between patients with screen-detected and symptomatic breast cancers, and a less aggressive treatment of the axilla in patients with screen-detected breast cancers cannot be supported. Likewise, the method of detection is not expected to be able to improve the predictive models. Until 2012, the standard treatment of Danish patients with micrometastases or ITC in the sentinel node was ALND. Still, in selected patients ALND was not performed. This thesis includes a comparison of the risk of axillary recurrence and survival between patients with and without ALND. The overall axillary recurrence rate was only 1.6% after 6 years of follow-up, despite between 9 - 18 % of these patients are expected to have non-sentinel node metastases. No significant difference was seen in axillary recurrence and overall survival between patients with and without ALND. These results support the safety of omitting ALND in patients with only micrometastases or ITC in the sentinel node and since 2012 Danish breast cancer patients with ITC or up to two micrometastatic sentinel nodes are no longer offered an ALND. In Denmark the standard surgical treatment of the axilla in locally recurrent breast cancer is no further treatment of the axilla in case of previous ALND, and ALND in case of previous SLND.  To investigate whether SLND can be extended to this patient group, a Danish multicenter study was performed. Despite a reduced detection rate, especially after previous ALND, SLND seemed to be a feasible procedure in locally recurrent breast cancer. The procedure can spare a clinically significant number of patients an unnecessary ALND and improve staging and local control after previous ALND. The increased number of patients with aberrant drainage underlines the importance of preoperative lymphoscintigraphy at local recurrence.