Prognostic factors in colorectal cancer

Abstract

Prognosis in colorectal cancer (CRC) is largely stage dependent. Classification of disease stage is done according to the tumor, node, and metastasis-staging system (TNM). Disease stage often dictates treatment options and follow-up strategies but is not the only influencing factor in prognostic predictions. Patient factors like age, co-morbidity, education level, lifestyle et cetera have a pronounced impact on prognosis. The rapidly evolving understanding of molecular mechanisms is adding more information to the picture. These are factors that will help clinicians tailor more precise and personalized treatment protocols. Comprehensive scientific endeavors like the Cancer Genome Atlas project and the International Genomic Consortium have facilitated the understanding of the molecular basis of cancer regarding oncogenesis, progression, and resistance. The understanding of the molecular background mechanisms of cancer initiation and development provides us with information when designing new and more precise treatments. The evolving information surplus advocates for new technological systems that can help us handle vast amounts of data.

Despite the foreseen progress in cancer treatment the need for more reliable prognostic markers is evident. Prognostic factors and prognostic markers will probably be of even greater importance in the future due to the increasing number of patients. Better prognostic tools will help clinicians allocate care and resources more efficiently. This will guide the design of treatment and follow-up and is especially true for CRC stage II patients, in which prognosis can be difficult to predict. This led us to the pursuit and evaluation of prognostic factors and markers, especially in CRC stage II patients.

In Paper I, we wanted to evaluate the prognostic significance of microsatellite instability (MSI). MSI is a genetic feature seen in about 15% of patients with sporadic colorectal cancer. This marker is basically part of routine diagnostic workup today. Its clinical and prognostic significance, however, has been long debated. To investigate the independent prognostic significance of MSI a cohort of 463 Swedish CRC patients was evaluated. Patients with MSI tumors were compared to patients with microsatellite stable (MSS) tumors. Patients subject to curative surgery during 2002-2006 in the Swedish Low-risk Colorectal Cancer Study Group cohort were included. Follow-up and treatment data were retrieved from patient records. Statistical analyses to assess MSI status and prognosis were done using logistic regression and survival analyses by the Kaplan-Meier method. Cox regression hazards model adjusted for age, sex, stage, comorbidity, and tumor location. MSI tumors were present in 66 patients (14%). Within 6 years, distant recurrences were present in 9.1% and 20.2% (P=0.049) of MSI and MSS patients, respectively. Death occurred in 25.8% and 31.5% of MSI and MSS patients, respectively. There was no statistically significant difference in overall mortality (HR 0.80, 95%CI 0.46-1.38), relapse-free survival (HR 0.82, 95%CI 0.50-1.36), or cancer-specific mortality (HR 1.60, 95%CI 0.73-3.51). Despite distant metastases being less common in patients with MSI, there was no association between MSI and overall, relapse-free or cancer-specific survival.

In Paper II the aim was to investigate the impact of lifestyle factors on survival in CRC stage I-III patients. Modifiable lifestyle factors are associated with CRC risk but the impact on survival is less known. A study of 1098 CRC patients from the Swedish Low-risk Colorectal Cancer Study Group cohort was conducted to investigate the combined effects of a healthy lifestyle and body mass index (BMI) on prognosis following CRC diagnosis. Self-reported data on lifestyle habits, adherence to a Mediterranean diet pattern, and BMI five years before CRC diagnosis were used to construct a healthy lifestyle score (HL). Based on the HL score the patients were grouped from the least to most healthy and divided into four categories. Using the Kaplan–Meier method survival analyses were performed to assess recurrence-free survival and overall survival across categories of exposure, and Cox proportional hazards models adjusted for age, sex, and educational level. Among 1098 participants, 233 (21.2%) had an HL score of 0–1 (least healthy), 354 (32.2%) HL score of 2, 357 (32.5%) HL score of 3 and 154 (14.0%) HL score 4 (most healthy). Patients with the healthiest lifestyle (HL score 4) compared to the least healthy (HL score 0–1) had an improved recurrence-free survival (HL 4 vs HL 0–1, HRadj 0.51 (95% CI 0.31–0.83) and overall survival (HL 4 vs HL 0–1, HRadj 0.52 (95% CI 0.38–0.70). In conclusion, adherence to a healthy lifestyle may increase the recurrence-free and overall survival of patients with stage I–III CRC.

In Paper III, a genome-wide association study (GWAS) was performed in order to find prognostic markers in stage II CRC. There is a strong need for additional markers due to the prognostic heterogeneity in stage II patients. Subsets of patients in stage II have a very good prognosis equal to stage I while others seem to join stage III patients in their elevated risk of suffering recurrence and disease progression. Therefore, more reliable prognostic tools are warranted to predict patients at high risk for metastasis. Stage II colorectal cancer patients from a homogenous Swedish cohort were selected in pursuit of germline mutations associated with recurrence. 62 patients who developed metastasis during follow-up were compared with 291 patients without metastasizing disease. A haplotype GWAS was performed to establish associations with metastasis and risk loci. 145 haplotypes were suggested with the lowest P-value (p<5 x 10-6). Among those were 27 unique haplotypes suggested to contain at least one genetic variant associated with prognosis. Estimated haplotype frequencies were from 2.5 to 16.6%, with odds ratios ranging from 2.98 to 27.7. This study of 353 stage II colorectal cancer patients from a homogenous Swedish population suggests 27 candidate regions to harbor genetic variants influencing prognosis. Further studies to validate the haplotypes and define the risk markers are warranted.