Genetic alterations governing response to breast cancer therapy

Chemotherapy is the backbone in medical breast cancer treatment and tumours that become resistant to chemotherapy is the main cause of therapy failure and death among patients. In the present project, we have used state of the art genetic and molecular analyses in a unique set of in-house biobanks. These biobanks include tissue samples from cancer patients, taken before, during and after chemotherapy. Importantly the patients have been treated with monotherapy, meaning that they have only received one single drug at a time. Also, the drugs have been given in the timespan between diagnosis and surgery, enabling direct physical measurement of how much the tumour has grown or shrunk during the treatment. This is an ideal study design since any molecular feature or genetic error identified in the tumour samples before treatment can be linked directly to each patient's response to a single drug. Also, by comparing the genetic variations present in the tumour samples before versus after treatment, we can identify what subtypes/clones of cancer cells that are killed and what subtypes/clones of cancer cells that survive and grow, during the course of the treatment. Data from the project has shown that we are now able to identify subclones of cancer cells that are sensitive or resistant to the treatment each patient has received. We detect specific subclones that are eradicated by the therapy while we also detect other subclones / cell types that are resistant and grow, and subsequently dominate in the tumour.The project has also led to identification of specific molecular mechanisms causing resistance to commonly used chemotherapeutics and these findings will persued in future work. The aim and impact of the project is to decipher the molecular mechanisms of chemoresistance and thereby open new possibilities in the search for biological markers and tests that can be used to predict efficacy of a given treatment in each patient. This will also contribute to identification of new strategies circumvent drug failure in the future.

Prosjektet har leia til to hovedtypar av resultat: 1. Vi har identifisert konkrete molekylære mekanismar som forsårsaker resistens mot vanlige typar cellegift hos brystkreftpasientar, ved samanlikning av somatiske gendefekter i svulstar fpr pasientar med god versus pasientar med dårlig effekt av behandling. 2. Vi har identifisert molekylære karakeristika i subklonar av kreftceller som vert utrydda versus kreftceller som overlever cellegiftbehandling ved å samanlikne subklonar sammansetting av svulstar før og etter behandling i samme pasient. Begge desse typane funn har store implikasjonar for korleis vi (og andre) vil designe neste generasjon av kliniske studier for brystkreft. Kunnskapen som er nådd i prosjektet vil bli brukt i studier der gentesting av svulst vil bli gjort før behandlingsstart, og behandling vil bli valgt basert på resultat av gentest. Dette vil medføre betra persontilpassa behandling: Pasientar vil tidlig bli behandla med medikament som er predikert å virke best for deira svulst, medan dei vert spart for bivirkningar av medikament som kan predikerast å ikkje virke.

Chemotherapy is the backbone in medical breast cancer treatment and resistance to chemotherapy is the main cause of therapy failure and death among patients. Defects in signalling pathways triggering apoptosis, cell cycle arrest and senescence, as well as pathways governing DNA repair have been linked to resistance / sensitivity to DNA damaging chemotherapy. While these contemporary data are fragmented, and our understanding of chemoresistance remains poor, they have provided exiting clues for future research that may lead to a more comprehensive understanding and pave the way for novel and optimal use of chemotherapeutic drugs. We hypothesise that the molecular mechanisms causing resistance or sensitivity to DNA damaging chemotherapy in vivo, is a synergy determined by the integrity of signalling pathways triggering apoptosis, cell cycle arrest or senescence and pathways of DNA repair. More specifically, we hypothesise that the combined status of p53-/pRb-pathway integrity and integrity of DNA repair mechanisms decide whether a cancer cell respond to DNA damaging drug or not. In the present program, we will test this hypothesis by state of the art genetic and molecular analyses in a highly unique set of in-house biobanks. These biobanks include pre- and post-treatment samples from clinical studies where breast cancer patients have been treated with monotherapy in the timespan between diagnosis and surgery, with detailed recording of therapy response. This is an ideal study design since any molecular feature identified in the tumour samples can be linked directly to each patient’s response to a single drug. Subsequently, we will validate the potential findings by in vitro models. The aim and impact of the proposal is to decipher the molecular mechanisms of chemoresistance and thereby open new possibilities in the search for biomarkers with improved predictive value, and further to fuel future research on strategies to circumvent drug failure.