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MSK Genomic Analysis Uncovers Features of Metastatic Cancer

NEW YORK – By profiling genomic and clinical features in tumors from tens of thousands of cancer patients, a team led by investigators at Memorial Sloan Kettering Cancer Center has uncovered features that may help predict a tumor's metastatic potential and organ sites it may affect.

"Our work shows that genomic alterations identified in tumor samples can inform our understanding of a tumor's potential to metastasize, at least in some cancer types," senior author Nikolaus Schultz, a researcher at MSKCC, said in an email.

"By publicly releasing clinical and genomic data from more than 25,000 patients," he added, "we hope that this will become a valuable resource for the community that will empower researchers and facilitate the study of metastatic disease."

As they reported in Cell on Thursday, the researchers analyzed targeted panel sequence data for 15,632 primary and 10,143 metastatic tumors from a total of 25,755 metastatic cancer patients in the MSK-MET cohort, including patients who had matched primary and metastatic tumor samples sequenced. With insights from more than 99,400 metastatic events identified in 21,546 metastatic cancer patients, they flagged genomic patterns corresponding to metastases from dozens of cancer types that affected 21 different organs, along with suspicious primary tumor changes in individuals with metastatic disease.

In contrast to prior studies that centered on either primary or metastatic tumors as a group, the team set out to characterize integrated genomic and clinical features of metastatic disease in the context of cancer type and anatomic site of metastasis.

"Even though most cancer deaths are due to metastatic disease, predicting whether or not an early-stage tumor will metastasize — as well as what organs will be eventually affected by metastases — remains a formidable challenge," Schultz explained. "We hypothesized that molecular profiling of tumors can provide useful information to investigate these questions."

Using electronic health record data, the researchers searched for patients with metastatic disease and information about the timing of metastasis. Together with molecular data across 341 to 468 cancer genes profiled with the MSK-IMPACT clinical sequencing assay, these insights made it possible to compare molecular features found in tumors from primary or metastatic sites in individuals with or without metastases.

"Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression," the authors wrote.

The team's results revealed alterations that were relatively common in certain cancer types or in metastatic tumors springing up at specific target sites. They also pointed to ties between enhanced chromosomal instability and metastatic burden, particularly in certain cancer types.

In particular, an increase in chromosomal instability turned up in metastatic forms of lung or prostate adenocarcinomas and in hormone receptor- and HER2-positive breast carcinomas originating in the duct, the researchers reported. On the other hand, they found that high-grade serous ovarian or colorectal cancers were more often marked by copy number changes linked to relatively early stages in the tumor development process. These cancers were also less likely to show metastases-associated chromosomal stability.

The researchers also found associations between primary cancer subtypes and the body sites that were later impacted by metastatic disease, including an overrepresentation in liver metastases among patients with metastatic forms of lung neuroendocrine cancer and an uptick in ovarian or peritoneum metastases in individuals with advanced lobular breast cancer.

MSK investigators are now gearing up to do related research focused on treatments that target metastatic tumor drivers through the newly-funded Marie-Josée and Henry R. Kravis Cancer Ecosystems Project. Clinical and genomic data generated for participants from the MSK-MET cohort so far is available online via the cBioPortal for Cancer Genomics database.

"We hope that [MSK-MET] will be a valuable resource for the community and will stimulate further research and applications in cancer care," the authors wrote, adding that "more integrated studies are needed to fully investigate the impact of tumor cell-extrinsic effects, such as cancer therapy, target-organ microenvironment, and systemic factors."

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