Prediction of overall survival in stage II and III colon cancer beyond TNM system: a retrospective, pooled biomarker study

Abstract

BackgroundTNM staging alone does not accurately predict outcome in colon cancer (CC) patients who may be eligible for adjuvant chemotherapy. It is unknown to what extent the molecular markers microsatellite instability (MSI) and mutations in BRAF or KRAS improve prognostic estimation in multivariable models that include detailed clinicopathological annotation.Patients and methodsAfter imputation of missing at random data, a subset of patients accrued in phase 3 trials with adjuvant chemotherapy (n = 3016)—N0147 (NCT00079274) and PETACC3 (NCT00026273)—was aggregated to construct multivariable Cox models for 5-year overall survival that were subsequently validated internally in the remaining clinical trial samples (n = 1499), and also externally in different population cohorts of chemotherapy-treated (n = 949) or -untreated (n = 1080) CC patients, and an additional series without treatment annotation (n = 782).ResultsTNM staging, MSI and BRAFV600E mutation status remained independent prognostic factors in multivariable models across clinical trials cohorts and observational studies. Concordance indices increased from 0.61–0.68 in the TNM alone model to 0.63–0.71 in models with added molecular markers, 0.65–0.73 with clinicopathological features and 0.66–0.74 with all covariates. In validation cohorts with complete annotation, the integrated time-dependent AUC rose from 0.64 for the TNM alone model to 0.67 for models that included clinicopathological features, with or without molecular markers. In patient cohorts that received adjuvant chemotherapy, the relative proportion of variance explained (R2) by TNM, clinicopathological features and molecular markers was on an average 65%, 25% and 10%, respectively.ConclusionsIncorporation of MSI, BRAFV600E and KRAS mutation status to overall survival models with TNM staging improves the ability to precisely prognosticate in stage II and III CC patients, but only modestly increases prediction accuracy in multivariable models that include clinicopathological features, particularly in chemotherapy-treated patients.

An immune infiltration signature to predict the overall survival of patients with colon cancer

“…At present, TNM staging remains the gold standard for evaluation of the prognosis in colon cancer. However, clinical outcomes are quite different in colon cancer patients, even in those with identical TNM stage and similar therapeutic strategy, implying that the conventional clinicopathologic staging offers insufficient clinical information. Thus, it is imperative to explore novel approaches, in particular, molecular biomarkers, to discriminate the patients with colon cancer who exhibit different prognosis.…”

Molecular subtyping improves prognostication of Stage 2 colorectal cancer

“…A potential limitation of the study is the relatively low numbers of CMS4 tumours, as discussed above, and that almost half of the tumours in our cohort are CMS2, and this imbalance may affect the power of our study to detect effects specific to CMS1, 3 and 4. [34] have been investigated with regard to their prognostic potential in this tumour group, but have not widely adopted to direct clinical management.…”

“…Various factors including acute presentation with obstruction and perforation, histological factors such as perineural and perivascular invasion, as well as high grade, have been used as markers of poor prognosis, and as such indicators for adjunctive postoperative chemotherapy. Further stratification using molecular markers, such as BRAF and KRAS mutations, and MSI status[34] have been investigated with regard to their prognostic potential in this tumour group, but have not widely adopted to direct clinical management.Molecular subtyping is a cornerstone of precision medicine in cancer treatment, and the mutation status of genes in the EGFR pathways, including RAS genes, PIK3CA, PTEN and BRAF have been shown to predict response to EGFR blockade therapy in CRC [37]. MSI status and the effect of the tumour microenvironment, in particular the amount and type of tumour infiltrating lymphocytes, have more recently been proposed as predictors of response to immunotherapy [38].…”

Identification of several plasma proteins whose levels in colorectal cancer patients differ depending on outcome

“…Stage at diagnosis is the most important prognostic factor for CRC . The anatomically based TNM staging system, although widely used, struggles to clearly distinguish groups of patients with different prognosis among stage II and III CRC patients, particularly in those who receive adjuvant chemotherapy . For stage III CRC patients, an overall survival benefit has been established for fluorouracil‐based chemotherapy, although for patients with stage II CRC, the use of adjuvant chemotherapy is controversial.…”

“…5 The anatomically based TNM staging system, although widely used, struggles to clearly distinguish groups of patients with different prognosis among stage II and III CRC patients, particularly in those who receive adjuvant chemotherapy. 6 For stage III CRC patients, an overall survival benefit has been established for fluorouracil-based chemotherapy, although for patients with stage II CRC, the use of adjuvant chemotherapy is controversial. Studies have failed to demonstrate a significant overall survival benefit in stage II CRC patients who receive adjuvant therapy, and current guidelines do not support its routine use.…”