Influence of Microsatellite Instability and KRAS and BRAF Mutations on Lymph Node Harvest in Stage I–III Colon Cancers

Abstract

Lymph node (LN) harvest is influenced by several factors, including tumor genetics. Microsatellite instability (MSI) is associated with improved node harvest, but the association to other genetic factors is largely unknown. Research methods included a prospective series of stage I-III colon cancer patients undergoing ex vivo sentinel-node sampling. The presence of MSI, KRAS mutations in codons 12 and 13, and BRAF V600E mutations was analyzed. Uni-and multivariate regression models for node sampling were adjusted for clinical, pathological and molecular features. Of 204 patients, 67% had an adequate harvest (≥12 nodes). Adequate harvest was highest in patients whose tumors exhibited MSI (79%; odds ratio [OR] 2.5, 95% confidence interval [CI] 1.2-4.9; P = 0.007) or were located in the proximal colon (73%; 2.8, 1.5-5.3; P = 0.002). In multiple linear regression, MSI was a significant predictor of the total LN count (P = 0.02). Total node count was highest for cancers with MSI and no KRAS/BRAF mutations. The independent association between MSI and a high LN count persisted for stage I and II cancers (P = 0.04). Tumor location in the proximal colon was the only significant predictor of an adequate LN harvest (adjusted OR 2.4, 95% CI 1.2-4.9; P = 0.01). An increase in the total number of nodes harvested was not associated with an increase in nodal metastasis. In conclusion, number of nodes harvested is highest for cancers of the proximal colon and with MSI. The nodal harvest associated with MSI is influenced by BRAF and KRAS genotypes, even for cancers of proximal location. Mechanisms behind the molecular diversity and node yield should be further explored.

How does lymph node yield affect survival outcomes of stage I and II colon cancer?

“…The association between microsatellite instability and lymph node yield has also been explored. Adequate lymph node harvest was more likely seen in tumours with microsatellite instability, with an odds ratio of 2.3 to 2.5 [28,29]. While tumours with microsatellite instability were known to be associated with a good prognosis, whether this is the answer as to why patients with a greater lymph node yield had better survival remains to be elucidated [30][31][32][33].…”

High Variability in Lymph Node Counts Among an International Cohort of Pathologists: Questioning the Scientific Validity of Node Counts

“…Multiple studies have attempted to assess LNC variability and have demonstrated a variety of factors, including the patient's anatomy, tumor biology, experience of the gross examiner, and use of fat-clearing solutions. 6,[8][9][10][11][12] Although many of these studies also identify the pathologist as a significant source of variation, this has not been uniformly true. 13 By far, the least investigated aspect of LNC is the actual enumeration process of the pathologist during microscopic review; however, this is the time at which the LNC is determined.…”

KRAS mutation in patients undergoing hepatic resection for colorectal liver metastasis: A biomarker of cancer biology or a byproduct of patient selection?

“…KRAS is known as an early mutated event in CRC and is found in approximately 15% of patients with advanced adenomas and in 35% to 45% of patients with primary CRC (TNM stages I-III). 8,9 The frequency of KRAS mutations in patients with a CRLM corresponds well, but not perfectly, with the status of the primary tumor. Studies have reported the variably of KRAS testing in the primary tumor, metastasis, or both, with some mutations noted on formalin-fixed and others on fresh frozen tissue.…”

“…It is interesting to note that patients with KRAS wild‐type status respond best to anti‐EGFR treatment. KRAS is known as an early mutated event in CRC and is found in approximately 15% of patients with advanced adenomas and in 35% to 45% of patients with primary CRC (TNM stages I‐III) . The frequency of KRAS mutations in patients with a CRLM corresponds well, but not perfectly, with the status of the primary tumor.…”

“…KRAS is known as an early mutated event in CRC and is found in approximately 15% of patients with advanced adenomas and in 35% to 45% of patients with primary CRC (TNM stages I-III). 8,9 The frequency of KRAS mutations in patients with a CRLM…”