DISTANT METASTASES FROM PRIMARY TUMOR IN COLORECTAL CANCER

The long-standing assumption that distant metastases arise from lymph node metastases is being challenged by new research suggesting that distant metastases may come directly from the primary tumor itself, at least in colorectal cancer (CRC), researchers report.

"There are two different models to explain how distant metastases can evolve," lead author, Kamila Naxerova, PhD, research fellow, Edwin L. Steele Laboratories for Tumor Biology, Massachusetts General Hospital and Harvard Medical School in Boston, explained to Medscape Medical News.

"The first is that cells from the primary tumor travel to the lymph nodes, where they expand and continue to colonize other organs," Dr Naxerova noted.

"The other model is that lymph node metastases and distant metastases can have independent origins within the primary tumor and that one part of the primary tumor may give rise to liver, brain, or lung metastases, whereas another part may give rise to lymph node metastases," she added.

"And in the majority of colorectal cancer cases we examined, we did not find that the lymph nodes were responsible for the seeding of distant metastases, but rather it was the primary tumor itself that bore the responsibility," Dr Naxerova observed.

Senior author on the paper, Rakesh K. Jain, PhD, director of the Edwin L. Steele Laboratories and Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School, commented in a statement:  "Lymph nodes are usually considered as contributors to distant metastases. Yet multiple retrospective and prospective studies have shown that complete dissection of lymph nodes does not confer survival advantage in a number of malignancies. Our study provides the first direct genetic evidence towards resolving this enigma."

The study was published online July 7 in Science.

Researchers collected samples from multiple tumor regions for each of the 19 patients involved in study to arrive at a total of 239 evaluable archival biopsy samples.

"Of the 19 patients, 17 had liver metastases," they report.

On the basis of analyses of small, mutation-prone segments of the genome referred to as polyguanine repeats, researchers traced relationships between primary and metastatic tumors and identified specific areas within the primary tumor that had been the source of metastases based on their genetic profile.

"We first investigated the genetic distances among lymph node metastases, primary tumor biopsies, and distant metastases," the study authors explain.

In 73% of lymph node metastases, they observed that the distance to the primary tumor was shorter than the distance to distant metastases.

Conversely, 69% of distant metastases had a shorter genetic distance to the primary tumor than to any lymph node metastasis.

"This indicates that both types of metastatic lesions likely originated from distinct subclones in the primary tumor in most cases," they observed.

They then explored the idea that if a patient's phylogenetic tree contained a clade that had at least one lymph node and at least one distant metastasis but no primary tumor sample, that lymph node and distant metastases must have a common origin, as this would indicate that both types of metastases were seeded from the same subclone or that lymph node metastases gave rise to distant metastases.

Conversely, "a patient was classified as having distinct origins of lymphatic and distant metastases if no such clade existed," they added. A clade is a grouping that includes a common ancestor and all the descendants of that ancestor. 

Thirty-five percent of the 17 tumors thus analyzed had a common origin for both lymphatic and distant metastases, they report.

However, this meant that 65% of the tumors analyzed fell into the distinct-origins group, a sign that the tumors contained multiple, genetically distinct metastatic ancestors, as investigators point out.

They also explored the possibility that the two classifications of tumor origin might have been influenced by clinicopathologic variables and found that none of the factors examined correlated with tumor origin.

"Most importantly, we found no association between origin and treatment history," the researchers write.

Dr Naxerova feel's that it is soon for their research to change how oncologists might approach the management of patients with CRC.

However, "what we hope will happen is that people will start thinking about the lymph nodes in a new way and not just assume that lymph nodes give rise to distant metastases and therefore they need to be removed," she said.

She also noted that while the sample size analyzed in the current study was too small to permit them to report on any differences in clinical outcomes, they did observe that patients with distinct origin metastases died considerably faster than patients with common origin metastases.

This suggests that multiple metastasis origins may well be a sign that the primary tumor is very aggressive, Dr Naxerova suggested.  

The research team is now following up with a larger cohort of up to 100 patients to confirm whether survival differences exist between patients with common vs distinct origins.   

Dr Naxerova and Dr Jain have disclosed no relevant financial relationships.

Science. Published online July 6, 2017.