Intratumour heterogeneity, clonal selection and metastatic propensity in breast cancer

The main goal of this project is to study correlations between clonal heterogeneity and the extent of lymph node metastases, the most important factor predicting risk of relapse and distant metastases, in breast cancer. We have extracted DNA from a set of primary breast cancers revealing substantial spread in their extent of lymph node metastases. Now, we are in the process of performing whole genome sequencing of primary tumour and lymph node metastases to address this topic. However, due to the corona epidemics with laboratory close-down including contemporary delays in the delivery of reagents and equipment (like pipette tips), we have suffered unexpected delays, and the laboratory work estimated for early autumn is now planned for the end of the year, subsequently to be followed by our bioinformatics analyses. The data are expected to give important new information regarding which factors direct lymph node metastatis and, thus, regulate the metastatic process in general. Our main hypothesis is that these processes relates to intratumour clonal heterogeneity; thus, metastatic propensity is directed by clonal heterogeneity, with lymph node spread acting as a surrogate parameter.

Disse resultatene vil komme i løpet av 2021

Intra-tumour heterogeneity constitutes a major problem with respect to molecularly targeted therapies. Whilst the evaluation of genetic markers that underlie these treatment strategies rely on representative biopsies, contemporary data has revealed that primary breast cancers (BC) may harbour different subclones. As a result, diagnostic samples may overlook important molecular changes of prognostic importance as well as alterations for which targeted therapies could have been offered. Thus, in the era of personalized medicine, misclassification of tumours could mean loss of therapy options likely to benefit individual patients. Axillary lymph node (ALN) metastases play a central role in the management of BC as they have been shown to be the most important factor predicting distant relapse. One may envision that rare subclones in the primary tumour, capable of metastasizing, are disseminated to the axilla where they expand. However, little is known of the genetic alterations that characterize ALNs. We hypothesize that ALN metastases are a surrogate of intra-tumor heterogeneity at the primary site. Consequently, ALN can allow us to obtain a more representative picture of the alterations characterizing heterogeneous primary BC. The aims of the present program are: 1. Characterizing the genetic alterations and heterogeneity of anatomically annotated ALN metastases and comparison with defined regions of the matched primary tumour. 2. Evaluating the significance of the genetic alterations private to ALN metastases by comparison with the profile of circulating tumour cells. 3. Identifying potentially ?druggable? genomic aberrations that are responsible for lymphatic and hematogeneous dissemination. We will employ state of the art next generation sequencing techniques and well characterized cohorts of patients to achieve these aims with the hope that it will translate into a broader knowledge of the relevance of intra-tumor heterogeneity and better management of BC patients