Study Shows Colorectal Cancer Tumors May Metastasize Earlier Than Expected

Metastatic colorectal cancers may spread throughout the body earlier than previously thought, even before the original tumor is clinically detectable, according to a new study published in Nature Genetics.

Colorectal cancer, which is the second-leading cause of cancer death in the United States, often metastasizes to the liver and more rarely to the brain. Previously, it was assumed that cancer metastasis most often occurs in advanced primary tumors over time. However, new evidence suggests that metastasis can occur much earlier at the start of the cancer’s development.

For the study, the researchers looked to reconstruct when metastasis occurred on a patient-by-patient basis and to identify the main drivers. According to the researchers, a better understanding of the timing and molecular determinants of metastasis can help better inform treatment and prevention efforts.

By analyzing tumor-genome data, the researchers compared patterns of genetic mutations in the primary tumors of 118 biopsies from 23 patients with patterns in their liver or brain metastases. According to the data, genomic divergence between the primary tumor and metastasis is low. In 17 of 21 patients included in the analysis, the metastatic tumors originated from just 1 cell early in the primary tumor’s development while the carcinoma is still clinically undetectable.

Then, using a computer program and statistical method, the researchers measured the time of metastatic spread relative to the size of the primary tumor in an individual patient. The findings represent the first quantitative evidence for early metastatic spread in human colon cancer, according to the study authors.

Additionally, the researchers analyzed 938 individuals with metastatic colon cancer and 1813 with non-metastatic colon cancer whose medical histories were unknown and whose primary tumors had been profiled to identify genetic changes in known cancer-associated genes.

The results indicated that a specific combination of mutations, such as mutations in a gene called PTPRT, were highly predictive of metastatic cancer, the researchers noted. Previous research has suggested that the loss of PTPRT function increases the activity of STAT3, a protein that enhances cellular survival.

“The findings were quite surprising,” Christina Curtis, PhD, assistant professor of medicine and of genetics at Stanford University School of Medicine, said in a press release. “In the majority of metastatic colorectal cancer patients analyzed in this study, the cancer cells had already spread and begun to grow long before the primary tumor was clinically detectable. This indicates that metastatic competence was attained very early after the birth of the cancer. This runs counter to the prevailing assumption that metastasis occurs late in advanced primary tumors and has implications for patient stratification, therapeutic targeting, and earlier detection.”

Identifying patients with early-stage colorectal cancer tumors that are more likely to metastasize could help guide treatment decisions, the researchers concluded.

References

Hu Z, Ding J, Zhicheng M, et al. Quantitative evidence for early metastatic seeding in colorectal cancer. Nature Genetics. 2019. https://www.nature.com/articles/s41588-019-0423-x

Most metastatic colorectal cancers have spread before diagnosis [news release]. Stanford Medicine. http://med.stanford.edu/news/all-news/2019/06/most-metastatic-colorectal-cancers-have-spread-before-diagnosis.html. Accessed June 17, 2019.