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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Genome-directed breast cancer therapy

Alternative title: Genomikk-styrt brystkreftbehandling

Awarded: NOK 14.9 mill.

The first results from the study on primary breast cancer has been published (Eikesdal et al; Annals of Oncology 2021). Here, we showed PARP inhibitors may have a broader use in for trippel-negative breast cancer (TNBC) than previously considered. TNBC is the breast cancer subtype associated with the gravest prognosis, often affects younger women, and is the breast cancer subtype associated with germline mutations in the breast cancer type-1 gene (BRCA1). Apart from BRCA1, TNBC often harbor gene mutations affecting other genes involved in the same functional pathways as BRCA1, disturbing DNA repair in response to damage. PARP inhibitors is a group of drugs selectively targeting breast and ovarian cancer harbouring such gene defects. However, up to recently clinical responses to PARP inhibitors in TNBC was limited to tumours arising in individuals harbouring germline mutations in either BRCA1 or the breast cancer type-2 gene (BRCA2). ermline mutations in these two genes accounts for a limited number of TNBCs only. Thus, for the majority of TNBCs, PARP inhibition was reported to not have anti-tumour effects in advanced disease. Treating TNBCs in the neoadjuvant setting with the PARP inhibitor Olaparib, we recorded clinical responses in more than 50% of unselected tumours. Moreover, we were able to identify mutations in genes other than BRCA1/2 predicting therapy response. Of particular interest was the finding that so-called epimutations in the BRCA1 gene predicted therapy benefit. Most genes contain so-called promoter areas, DNA segments located close upstream to the gene that actually function as on-and-off switcher, thus regulating gene activity. Epimutations are processes causing aberrant promoter regulation; in the case of BRCA1, they switch of the activity of a normally active gene. Contrasting BRCA1/2 gene mutations occurring in a small number of TNBC only, BRCA1 epimutations are found in 25-30% of TNBCs. In another project funded by the Norwegian Research Council (288260), we found that BRCA1 epimutations detected in normal tissue (white blood cells) from healthy individuals predicting risk of TNBC. Thus, BRCA1 epimutations in normal cells may be a cancer-triggering event in a substantial percentage of TNBC. Taken together, the findings from the two projects links carcinogenesis and therapy response in a manner of potential great importance. Our data indicates these epimutations may arise at the embryonic stage, and we are currently studying this phenomenon further. In addition to these findings, our therapy study in primary breast cancer revealed that many patients with hormone receptor (estrogen receptor) positive tumours might avoid chemotherapy, as the same outcome may be achieved by optimal application of endocrine therapy. Our work here centers on identification of better predictive marker, advocating optimal selection of patients for individualized therapy upfront. All tumours have been screened by our in-house 360 gene panel, and we are in the process of completing full genome sequencing (WGS) of all samples on our in-house Novaseq high- throughput sequencer. Complementary to that, we apply RNA sequencing of the full transcriptome. Further, as for the HER2+ tumours in this study, treated with optimal anti-HER2 treatment in concert with chemotherapy, these tumours are undergoing the same genome (WGS and RNA sequencing) procedures as the TNBC and hormone receptor positive tumours to identify improved predictive markers to outcome. Regarding the second study, the so-called «TP53 study» in which patients with either metastatic or early breast cancer is treated with cyclophosphmide high-dose therapy, we are currently recruiting well following a nearly two year delay due to erroneous handling of the study by the Norwegian Drug Authorities (SLV). All together, we now have recruited about 50 patients in total, observing a high response rate among patients with primary disease. As for the first study, we are currently implementing WGS as well as RNA sequencing to characterize potential predictive markers. At this stage, we are close to completing the wet-lab program on these tumour sets. By doing so, we generate what we coin a “virtual biobank”, storing full-scale data from WGS and RNA seq analysis for later bioinformatics assessment. The benefit of such an approach relates to not only project logistics but result generation in particular. Thus, bioinformatics tools are in continuous development, meaning that such analysis, and the potential results generated, may be significantly improved over the years to come. It also means that future PhD and postdoc candidates may have data ready for analysis.

Resultatene så langt, spes mhp trippel-negativ brystkreft og effekten av PARP-hemning, legger grunnlag for nye behandlingsformer. Resultatene må verifiseres i uavhengige studier, men forventes å ha betydlig impact på behandling av denne pasientgruppe, i det funnene viser at en langt større gruppe pasienter enn tidligere antatt vil kunne ha nytte av slik behandling. Hva gjelder TP53 studien, vil hoved- resultatene herifra, om bekreftet, kunne få store kliniske implikasjoner for behandlingen av sub-grupper av pasienter.

Breast cancer is the most frequent cancer form among Norwegian women, mounting to > 3,300 new cases on an annual basis. While therapy has improved significantly over the recent decades, about 20% of all patients develop systemic disease, for which treatment remains palliative. Patients with cancers harbouring mutations in cell cycle regulators like the TP53 gene (?guardian of the genome?) or genes involved in DNA repair like BRCA1 have a particular high risk of relapse. Although defects in these genes are associated with resistance to certain chemotherapeutics, merging evidence indicates that such defects may also sensitize cancer cells to treatment with other drugs. The aim of the present proposal is to develop more effective targeted therapy regimens against breast cancers harbouring such molecular defects. Moreover, by establishing predictive markers correctly identifying tumours benefitting from such therapies, we aim at improving outcome for patients harbouring such poor prognostic tumours. To do so, we aim at establishing a program integrating two clinical trials focusing on high risk breast cancers; one trial for locally advanced and one trial for metastatic breast cancers. In both trials, treatment will be directed by genomic defects identified in the individual tumours. In particular, we will exploit defects in TP53 and BRCA1/2 for therapeutic benefit in affected patients. Through the proposed program, comprehensive genomic analysis will be used to individualize cancer therapy to patients with breast cancer, in order to improve response to therapy, while avoiding side effects of ineffective treatment regimens.

Funding scheme:

BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering