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Whole-Genome Sequencing of Biopsies Provides Treatment Clues for Dutch Metastatic Cancer Patients

ROTTERDAM (GenomeWeb) – Whole-genome sequencing of tumor biopsies has helped more than 200 advanced cancer patients in the Netherlands obtain off-label treatment with an anti-cancer drug so far, providing a clinical benefit for about a third of them, according to a presentation at the Association for Molecular Pathology's AMP Europe 2018 meeting here yesterday.
Paul Roepman, a clinical molecular biologist at the Hartwig Medical Foundation in Amsterdam, presented the results as part of an update on a Dutch national initiative, under which the foundation provides whole-genome sequencing of tumor biopsies from metastatic cancer patients for two clinical trials — the Drug Rediscovery Protocol (DRUP) trial, which matches advanced cancer patients with drugs based on their tumor's molecular profile, and the Center for Personalized Cancer Treatment (CPCT-02) study, which examines the link between tumor DNA profiles and response to therapy. 
At present, he said, more than 40 out of 80 hospitals in the Netherlands participate in the initiative, and the HMF sequences about 7.5 percent of all metastatic cancer patient biopsies in the country, processing 250 to 300 samples per month with a turnaround time of about three weeks from biopsy to report.
Hospitals collect fresh-frozen metastatic tumor biopsies along with a blood sample, the serum part of which is frozen for future analysis of circulating tumor DNA. Whole-genome sequencing of the matched tumor/normal samples is then performed on an Illumina X Ten, followed by somatic variant calling. Germline variants from the blood sample are not called automatically but only upon request. 
Roepman noted that the researchers plan to start sequencing RNA from the tumors soon for gene fusion and gene expression analysis.
They also bioinformatically assess tumor cell purity, he said, which is based on the allelic imbalance that is present in many but not all tumor types. This assessment can be used to determine local ploidy of variants, loss of heterozygosity, and clonality, which can help identify potential driver mutations.
The sequencing results are entered into a database that has so far amassed data from about 2,800 metastatic cancer patients, with breast and colorectal cancer being the two most frequent cancers. Researchers worldwide can request access to the data for their studies. The hope is to increase the number of patients to 6,000 by the end of this year, according to Rene Bernards from the Netherlands Cancer Institute in Amsterdam.
In addition to providing research data, the HMF issues patient reports, which Roepman said have been of increasing interest to clinicians and have been used by tumor boards to decide whether a patient is eligible for a specific treatment. The report includes many types of tumor aberrations, including single-nucleotide variants, indels, copy number variants, gene fusions, and structural variants. In addition, it contains data on microsatellite instability (MSI) and on mutational load across the exome, which can be used to determine eligibility for immunotherapy.
An analysis of MSI and mutational load for different types of cancers has shown that their levels appear to be tumor-specific, he said, and a combination of the two markers may be used in the future to stratify patients for immunotherapy.
As part of the DRUP trial, in which more than 500 patients are currently enrolled, over 200 patients who had run out of treatment options have received access to off-label drugs, he reported, which has shown a clinical benefit in about 30 to 35 percent of them. 
Specifically, he mentioned the case of a prostate cancer patient who had a biopsy taken before his seventh line of treatment. Sequencing of the biopsy found that his mutational load was extremely high, and he was included in an immunotherapy study as a consequence, to which he responded very well.
Asked why the HMF decided to do whole-genome sequencing despite its high cost and the necessity to obtain fresh-frozen material, Roepman said an advantage is that it covers all types of genetic variants. He cited the example of a patient with a structural variant in one of the BRCA genes that would have been missed by a targeted sequencing panel. However, he said that with the development of ever larger panels, the advantage of whole-genome sequencing is getting smaller.