Mohn Cancer Research Laboratory

Cancer treatment

Overview of our most important scientific findings associated with cancer treatment.

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Epirubicin and docetaxel affect tumour composition in primary breast cancer

It is well known that most tumours are heterogeneous, e.g. they consist of different subclones ("colonies") of cancer cells carrying different sets of mutations. 

In previous studies, we have shown that we can track the evolution of subclones from tumorigenesis to diagnosis, by analysing samples taken from patients at the time of diagnosis. In this study, we have analysed subclones and how these evolve during chemotherapy in primary breast cancer. We found that both of the drugs epirubicin and docetaxel caused massive alterations in the composition of subclones in most patients, regardless of therapy response.

Research articles associated with these findings (link to article in image):

Early treatment with PARP inhibitors results in high response rate in triple-negative breast cancer 

Triple-negative breast cancer (TNBC) is a breast cancer subtype often affecting younger women and is the breast cancer type associated with the most serious prognosis. Contrasting hormone receptor positive and HER2+ breast cancers, for which targeted therapy (antihormone or HER2 antibodies) are available, TNBC up to recently has been treated with chemotherapy only. 

TNBC however often harbor gene mutations causing defects in particular cellular functions, including DNA repair. This has led to development of compounds targeting such defects in particular, so-called PARP inhibitors. PARP (poly-ADP ribose polymerase) are special enzymes regulating DNA repair, and inhibiting these prevents the repair of damaged DNA in the cancer cells, ultimately leading to cancer cell death. However, subsequent studies revealed such PARP inhibitors to have anti-tumour effects in a limited number of TNBCs associated with breast cancer type-1 and type-2 gene (BRCA1/2) germline mutations only

In the PETREMAC-trial, we showed that PARP inhibition (with olaparib) may cause anti-tumour effects across a wider panel of TNBCs, provided the drug is administered in an early treatment setting. Moreover, we were able to identify mutations across distinct genes predicting for such response. Most importantly, apart from gene mutations, so-called epimutations, affecting the BRCA1 gene, was associated with PARP inhibitor response. Most genes are regulated through so-called promoters, best characterized as on-and-off switches of gene function, and epimutations in general means abnormal switching off of genes that are normally active.

BRCA1 epimutations are found in 25-30% of all TNBC and our findings indicate a wider benefit of PARP inhibition in TNBC that may have significant implications to future treatment regimens.

Research articles associated with these findings (link to article in image):

Genomic evolution in advanced melanoma

Cancer is not a static but a dynamic process, with new mutations and subclones continuously arising.

Here, we showed that in malignant melanomas most mutations arise as early events.

Moreover, we showed that in some cases not only the primary tumour, but also metastatic deposits, may seed metastatic cells to other organs. In such cases, the cells may carry signatures of the therapy they have escaped from, like radiation treatment.

Research articles associated with these findings (link to article in image):

Heterogeneity in liver metastases is linked to shorter survival rate in colorectal cancer 

Colon cancers typically metastasize first to the liver and many patients have multiple metastatic lesions in their livers.

In this study, we examined if different liver metastases in the same patient were similar (homogenous) or different (heterogenous) from a genomic perspective. We found a large variation in the degree of heterogeneity between patients, as measured by copy number analyses of the genomes in the metastatic lesions. Further, we found that high heterogeneity was associated with a poor clinical outcome, with shorter survival.

Research articles associated with these findings (link to article in picture):