title: Negative lymph node count is associated with survival of colorectal cancer patients, independent of tumoral molecular alterations and lymphocytic reaction.
abstract: OBJECTIVE
  The number of recovered lymph nodes is associated with good prognosis among colon cancer patients undergoing surgical resection. However, little has been known on prognostic significance of lymph node count after adjusting for host immune response to tumor and tumoral molecular alterations, both of which are associated with the lymph node count and patient survival.
  
  
  METHODS
  Among 716 colorectal cancers (stages 1-4) in two independent prospective cohorts, we examined patient survival in relation to the negative lymph node count and lymph node ratio (LNR; positive to total lymph node counts). Cox proportional hazard models were used to compute hazard ratio of deaths, adjusted for patient, specimen, and tumoral characteristics, including lymphocytic reactions, KRAS and BRAF mutations, p53 expression, microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), and LINE-1 methylation.
  
  
  RESULTS
  Compared with patients with 0-3 negative lymph nodes, patients with 7-12 and > or =13 negative nodes experienced a significant reduction in cancer-specific and overall mortality in Kaplan-Meier analysis (log-rank P<0.0001), univariate Cox regression (P(trend)<0.0001), and multivariate analysis (P(trend)<0.0003), independent of potential confounders examined. The benefit associated with the negative node count was apparent across all stages, although the effect was significantly greater in stages 1-2 than stages 3-4 (P(interaction)=0.002). In both stage 3 and stage 4, smaller LNR was associated with improved survival (log-rank P<0.0001).
  
  
  CONCLUSIONS
  The negative lymph node count is associated with improved survival of colorectal cancer patients, independent of lymphocytic reactions to tumor and tumoral molecular features including MSI, CIMP, LINE-1 hypomethylation and BRAF mutation.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA. shuji_ogino@dfci.harvard.edu
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.forename: Natsumi
authors.initials: N
authors.lastname: Irahara
authors.forename: Kaori
authors.initials: K
authors.lastname: Shima
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kirkner
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Meyerhardt
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
mesh_terms: D000368:Aged; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000209:etiology / Q000401:mortality* / Q000473:pathology*; D018899:CpG Islands / Q000235:genetics; D005260:Female; D006801:Humans; D008197:Lymph Node Excision; D008213:Lymphocyte Activation / Q000502:physiology; D016246:Lymphocytes, Tumor-Infiltrating / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016019:Survival Analysis; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins