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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Intratumour heterogeneity, clonal selection and metastatic propensity in breast cancer

Tildelt: kr 3,8 mill.

Prosjektets hovedmålsetning er å studere sammenheng mellom intratumor klonal heterogenitet og grad av lymfeknutespredning til axillen, som er den viktigste prognostiske faktor med tanke på tilbakefall og spredning ved brystkreft. Vi har tatt ut DNA fra et utvalg av primære brystkreftsvulster med stor variasjon i lymfeknutespredning samt de tilhørende lymfeknutene. Prøvene skal gjennomgå hel-exom sekvensering, men vi har hatt forsinkelser av logistiske grunner grunnet corona-epidemien. Analysene vil imidlertid bli gjennomført i løpet av kort tid, deretter undergå bioinformatisk bearbeiding. De genom-analysene som framkommer forventes å gi viktig ny informasjon om hvilke faktorer som bestemmer lymfeknutespredning, den viktigste prognostiske indikator for senere fjernspredning ved brystkreft, og hvorfor lymfeknutespredningen predikerer for fjernmetastaser. Vår hovedhypotese her er at lymfeknutespredningen reflekterer intratumor klonal heterogenitet, og at dette er den underliggende årsaken til økt spredningsrisiko.

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

Budsjettformål:

BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering