New Science Paper Questions Sequential Role of Lymph Nodes in CRC Metastases

A new study, published by researchers at Massachusetts General Hospital, has questioned the traditional model of cancer metastases that implicates lymph nodes in helping seed cancer cells at distant sites. The recognition of distinct subclones from the primary tumor at distant metastatic sites and in lymph nodes led the authors to their conclusion.

The current study is a follow-up on a 2014 report, published by the authors in PNAS, wherein they tried to create a “family tree” of metastases. The assay that resulted from the study helped reveal how intratumor genetic heterogeneity dictates cancer evolution and, ultimately, patient outcomes. The PCR-based genotyping assay developed by the authors allows for an assessment of the mitotic history and clonal architecture of cancer. Their analysis, which used colon cancer samples in 22 patients, found a distinct association between the primary and the metastatic tumor in each patient. Additionally, the authors found that in some instances, genetic profiles of metastases were similar to those of only some cells in the primary tumor.

Historically, the TNM—tumor (T), nodal (N), and distant metastasis (M)—staging scheme is used for prognosis, and patients with lymph node metastases are predicted to have a higher likelihood of developing distant metastases. However, studies have shown that removal of metastatic lymph nodes did not always improve survival.

In the current study, published in the journal Science, the authors examined the evolutionary relationship between the primary tumor, lymph node, and distant metastases in human colorectal cancer (CRC) using 213 archived samples from 17 patients. Using their genotyping assay on these tumor samples, the authors found that both the lymph node and distant metastases in 35% of patients had developed from the same cells in the primary tumor (shared clonality). However, in the remaining 65% of patients, cell types in the lymph node and distant metastases were different and matched different cell types within the primary tumor, indicating distinct subclonal origins.

This indicates that “two different lineage relationships between lymphatic and distant metastases exist in colorectal cancer,” the authors concluded.

“We now suspect that lymph node metastases simply indicate the presence of an aggressive primary tumor, rather than being directly responsible for the formation of distant metastases,” said Kamila Naxerova, PhD, first author on the study. Naxerova was also the corresponding author on the group’s PNAS study. Future studies, she said, should investigate whether clinical outcomes are different in these 2 distinct patient populations. If so, then the PCR-based assay developed by their laboratory could be a good prognostic tool, she added.

Senior author Rakesh K. Jain, PhD, director of the Steele Labs, Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School, said, “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.”