Primary tumor location as a prognostic factor in metastatic colorectal cancer.

Tumors arising from the colorectal tract are a heterogeneous complex of diseases that result from the accumulation of distinctive genetic and epigenetic alterations (1,2). Despite increased understanding into the molecular pathways underlying colorectal cancer (CRC), relatively few biomarkers are prognostic for survival (1–3). Germline mutations in DNA mismatch repair genes, definitive of Lynch syndrome, in stage II/III disease and BRAF V600E mutations in stage IV disease are notable exceptions (4–6). Biological and clinical evidence supports that proximal (right-sided) and distal (left-sided) CRCs follow different molecular pathways of carcinogenesis. Right-sided tumors are more likely to be diploid and to be characterized by mucinous histology, high microsatellite instability, CpG island methylation, and BRAF mutations (6–10). In contrast, left-sided tumors are frequently infiltrating, constricting lesions, with a phenotype that involves chromosomal instability and aneuploidy (7–9). Microarray studies of sporadic CRC biopsies demonstrate unique gene expression profiles for right- and left-sided cancers, potentially related to distinct embryonic origins and postnatal regulation (11,12). Extensive sequencing analyses described a characteristic branching pattern of cancer evolution supporting that tumor biology is characterized simultaneously by intratumor heterogeneity and the preservation of ancestral aberrations within the primary tumor and corresponding metastatic sites (13,14). Previous attempts to evaluate the effect of primary tumor location on outcome in metastatic CRC (mCRC) have been complicated by sample size, a high degree of heterogeneity in received treatments, and limited information on molecular and pathologic features (15−17). The objectives of the present analysis were first to assess primarily the prognostic impact and secondly the predictive effect of primary tumor location for an antiangiogenic treatment by interrogating three large independent patient cohorts. Because of the prognostic significance of BRAF mutations and mucinous histology (5,6,18) and the association of these characteristics with right-sided mCRC, a multivariable model and a subgroup analysis in nonmucinous and BRAF wild-type cancers were used to separately assess outcomes in the PROVETTA study (chosen as an exploratory set based on availability of clinical and molecular features). The prognostic effect of primary tumor location was subsequently verified and validated using data from two large phase III trials.