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Metastatic Tumor Profiles Lead to Potential Treatment Targets

NEW YORK – A research team from the Netherlands has profiled metastatic tumor samples from several thousand individuals with a wide range of cancer types, uncovering some alterations that lined up with those in primary tumors and others that were distinct.

The work "demonstrates the importance of comprehensive genomic tumor profiling for precision medicine in cancer," the researchers wrote in their study, published online today in Nature. The work was led by senior and corresponding author Edwin Cuppen, a researcher affiliated with the Hartwig Medical Foundation in the Netherlands, the Center for Personalized Cancer Treatment, and the University Medical Center Utrecht.

"The cohort is still expanding," they noted, "with data from 4,000 patients already available, and includes data that go beyond the basic clinical and genomic data analyzed in this paper such as post-biopsy treatments and responses, and previous treatment information."

For their published study, the researchers sequenced the genomes of 2,520 tumor samples and matched normal tissue from 2,399 individuals with metastatic cancer. By sifting through more than 70 million somatic changes in the tumors — including point mutations, small insertions and deletions, copy number shifts, and other features — they distinguished between mutations present at earlier stages of disease and those that cropped up during treatment.

The sequences uncovered somatic mutation differences from one cancer type to the next, for example, including large numbers of point mutations in tumors stemming from lung cancer or melanoma. They also highlighted driver gene changes and recurrently mutated genes that seem to be important in the metastatic cancer setting.

"Our results demonstrate that [whole-genome sequencing] analyses of metastatic cancer can provide novel and relevant insights, and are instrumental in addressing some of the key challenges in precision medicine in cancer," the authors wrote, adding that the sample set profiled for the current study "provides a valuable complementary resource to whole-genome sequence-based data of primary tumors … in advancing fundamental and translational research."

In more than half of metastases, for example, the team unearthed whole-genome duplication events, with as many as 80 percent of esophageal tumors showing these duplications. Meanwhile, some 62 percent of patients had alterations that were flagged as clinically actionable, either using approved treatments or experimental drugs.

The alterations identified in 18 percent of the patients led to on-label treatment strategies, the researchers reported, while roughly 13 percent had mutations that might be amenable to off-label treatment. Another 31 percent of the cases involved tumor alterations that coincided with eligibility for specific clinical trials.

"The number of potentially relevant diagnostic molecular tests is increasing rapidly as more targeted medications are becoming available for cancer patients," Cuppen said in a statement. "Although some of these indications are relatively rare … detecting such variants is relevant for a broad range of cancer indications." 

An approach similar to that used in the study is being applied as a clinical-grade, sequencing-based cancer diagnostic test in the Netherlands, according to a release from the Hartwig Medical Foundation. Through that program, DNA from fresh frozen tumor samples and blood samples collected in hospitals are sequenced and analyzed at the Hartwig Medical Foundation to average depths of 100-fold and 35-fold, respectively.

The organization noted that a prospective study has been established to directly compare whole-genome sequencing to more conventional, standard of care cancer diagnostic testing, which may inform how genome-based testing is applied in the clinic down the road.