Modern Staging in Primary Breast Cancer-aspects of micrometastatic disease in bone marrow and molecular profiles in lymph node metastases

Abstract: Breast cancer is a heterogeneous disease with variations in the biological profile and subsequent clinical prognosis. Molecular mechanisms for tumour progression are currently being explored in scientific settings, suggesting parallel evolution of tumour cells at primary and metastatic locations. The molecular profiles could be altered affecting individual patient’s treatment and prognosis. In the work presented in this thesis the main focus was on evaluating tumour tissue and disseminated cells from different metastatic locations, to analyse the distribution of biomarkers and relate them to the prognosis for individual patients. A relationship has been recognised between the presence of disseminated tumour cells (DTCs) in bone marrow and poor prognosis in several studies, but the method of DTC detection has yet to be validated. It is at present not known whether DTCs will grow into overt metastases or which biologic events are involved in the metastatic process. In paper I, Bone marrow biopsies were performed at the time of primary surgery and the presence of DTCs analysed. After 5 years of follow-up, all reports of events were abstracted from the patient’s records and a database was constructed for all the patients included in the study. The presence of DTCs in the bone marrow was found not to have any prognostic influence and it was concluded that it is too early for clinical implementation due to discrepancies in methods between studies, and the invasive nature of bone marrow biopsies. Oestrogen receptors (ER), progesterone receptors (PR), Ki67 and human epidermal growth factor receptor 2 (HER2) were compared in primary breast cancer tumours and the synchronous lymph node metastases (Papers II and IV) and primary tumours and relapses (Paper IV). High concordance was found between primary tumours and lymph node metastases regarding separate biomarker expression in both papers, but a significant skewness was observed when biomarkers in primary tumours were compared to those in relapses. Classification into molecular subtype according to the St Gallen guidelines (Papers III and IV) identified a shift in molecular subtype in individual patients that affected prognosis, suggesting that the molecular subtype of the lymph node metastasis has a prognostic influence. Prognostic information for the individual patient can thus be obtained by analysing biomarker expression in synchronous metastatic lymph nodes. The findings presented in Paper IV support the recommendation that biomarker analysis is performed in loco-regional and distant relapses.