Genomic analysis of different brain metastases reveals common mutations that could promise viable therapeutic targets

The Vall d’Hebron University Hospital and the Vall d’Hebron Institute of Oncology (VHIO) have participated in an international study that has sequenced the entire exome (the part of the genome containing information that will give rise to proteins) of 86 brain metastases, primary tumors and normal tissue. Metastases mainly arose from lung cancers (38 cases), breast cancers (21 cases) and renal cell carcinomas (10 cases).

The study evidences that many brain metastases evolve independently and can develop shared genetic alterations that remain undetected in primary tumor biopsies: this occurred in 53% of the cases analyzed.The study also indicates that many of these mutations are associated with sensitivity to certain proteins (PI3K, AKT, mTOR, CDK) as well as inhibitors of HER2 and EGFR. The very fact that the starting block for the design of therapies against cerebral metastases are primary tumor samples, demonstrates both the importance and promise of these data. This present research not only unmasks genetic mutations that have not been previously described, but also shows them to be common to the majority of metastases; these mutations are associated with different groups of proteins that could become viable therapeutic targets for novel, more precise anti-cancer therapies.

Josep Tabernero, Head of the Medical Oncology Department of Vall d’Hebron University Hospital, Director of VHIO, and co-author of the study, explains that “findings from this study are important since they open new avenues towards designing more precise therapies for patients with brain metastases – tumors with a very poor prognosis and for which we don’t currently have very effective anti-cancer weaponry. Now however, thanks to this study, we have seen that there are genetic characteristics common to different mutations, which are shared by many of the brain metastases analyzed. We will now need to expand our research aimed at establishing whether they can effectively become therapeutic targets suitable for treatment of these patients”

A mosaic of genetic mutation and potential for drug development

In 53% of cases analyzed in the study, at least one genetic alteration was observed that was not detected in the tumor biopsy. In the majority of these cases, the alterations are associated with a greater sensitivity to various groups of proteins, which could promise avenues for the design of individualized, tailored therapies based on inhibitors of these proteins.

“The discovery that genetic mutations in cerebral metastases could differ from those in the primary tumor from which the metastases derive, brings another layer of complexity in our understanding of the molecular characteristics of the disease and in determining the optimum treatment for each patient. If we only have data about the primary tumor, we cannot establish the particularities of brain metastasis nor how best to treat it. We must therefore not only study and characterize the primary tumor in depth but also the arising brain metastases in order to render therapy more effective,” comments Joan Seoane, ICREA Professor, Director of Translational Research at VHIO, and co-author of the study.

The study established that the alterations affecting the CDK family of proteins were shared across the whole series of cases, with 71 alterations in 48 cases occurring in ten of the eleven genes assessed. Of the 71 alterations, 44 were shared, 7 were present only in the primary sample, and 20 only in the metastasis tissue sample. Regarding the mutations affecting the PI3K, AKT and mTOR group of proteins, these were also frequent, with 43 alterations in 37 cases occurring in ten out of the fifteen genes assessed. Of the 43 alterations, 24 were shared, 5 were only detected in the primary sample, and 14 only in the metastasis tissue sample.

The study also revealed mutations that predict sensitivity to inhibitors of EGFR and of HER2 (e.g. trastuzumab, gefitinib, cetuximab, erlotinib, lapatinib) in 26 cases, in two of the four genes assessed.

A cancer with few therapeutic options

Brain metastases, especially those arising from melanomas, lung, and breast cancers, are the most frequent type of brain tumor. Some 200,000 cases are diagnosed each year in the United States alone, and average survival varies from 3 to 27 months after metastatic dissemination to the brain. Unfortunately current treatment options are limited, and the majority of current clinical trials in the United States exclude patients with brain metastases.

Brain metastases are an unmet need in current cancer treatment and care. Approximately 8–10% of cancer patients will develop brain metastases, and more than half of these patients will die within a few months of diagnosis. For this reason, the study published in Cancer Discovery is an important advance for a disease that is still poorly understood and without effective treatment.
*Reference to the article: “Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets”. Cancer Discovery