Tumor Side as Model of Integrative Molecular Classification of Colorectal Cancer

In this issue of Clinical Cancer Research, Loree and colleagues investigated whether a precise definition of primary tumor location rather than a simplified right-versus-left division provides further information about the tumor's biology and clinical course (1). Conventionally, tumors proximal to the splenic flexure are defined as right-sided tumors because the proximal two thirds of the transverse colon arises embryologically from the midgut, and only the distal portion arises from the hindgut. Tumor side is an independent prognostic factor in patients with metastatic colorectal cancer: Those with left-sided primaries, located at or distal to splenic flexure, have improved outcomes (2). In addition, it is also a powerful predictor of benefit with anti-EGFR therapies in patients with RAS wild-type metastatic colorectal cancer: Those with right-sided tumors derive, if at all, very limited survival benefit with the addition of cetuximab or panitumumab to chemotherapy irrespective of treatment line (2).

Overall, right-sided colon cancers are more likely to have genome-wide hypermethylation via the CpG island methylator phenotype (CIMP), hypermutated state through microsatellite instability (MSI), BRAF^V600E mutations, and lower expression levels of receptor tyrosine kinase (RTK) ligands such as EREG and AREG (3). Notably, Loree and colleagues describe a continuum of molecular changes from cecum to rectum not only in terms of RAS/BRAF^V600E mutations, MSI and CIMP status, but also in transcriptomic signatures like consensus molecular subtype (CMS) groups, which have been linked to survival and anti-EGFR benefit (1). More specifically, the prevalence of these molecular markers varies dramatically within tumors of the same colon side but at different locations (Fig. 1). From a biological perspective, transverse colon tumors were more similar to left- than right-sided colorectal cancer. In fact, right division preceding the transverse colon maximized prognostic differences by side, and patients with transverse colon tumors appeared to derive benefit from anti-EGFR agents in the chemotherapy-refractory setting. The findings by Loree and colleagues open the door for more in-depth research on this topic and site-specific correlative analyses with patient outcome under standard-of-care therapies.

Although it is always interesting to slice and dice further, the global understanding of molecular drivers in primary tumors originating in the right and left sides of the colon has been very insightful. In summary, mutational activation of MAPK and/or PI3K pathway genes is found in nearly all right-sided tumors, potentially related to selective pressure for more mutations and, therefore, less dependency on RTK signaling. On the other hand, the prevalence of driver oncogenic mutations is significantly lower in left-sided tumors, where transcriptional activation of ligands that activate EGFR likely plays a critical pathogenic role. The diverse tumorigenesis pathways in right- and left-sided colorectal cancer may be related to differential gene expression and methylation levels in normal mucosa, distinct microbiota, and luminal content. These differences are evident from early stages of carcinogenesis and remain significant in metastatic lesions. Dysplastic sessile serrated adenomas, for example, are more prevalent in the right side of the colon, as are interval cancers developed after colonoscopies for colorectal cancer screening (4). Studies also suggest that the effectiveness of colonoscopies and polypectomies in reducing colorectal cancer death risk is substantially higher in left-sided premalignant lesions as compared to those arising in the right side (5). These observations can in part be related to a more aggressive biology of colorectal cancer arising in the right side of the colon.

From a clinical perspective, we need to acknowledge some limitations of existing literature on the predictive value of tumor sidedness in the metastatic setting. First, they represent a post hoc unplanned analysis of clinical studies, and in many cases, primary tumor location was not prospectively collected, as the data are not routinely recorded during colonic resection. As Loree and colleagues recognize, an accurate definition of location is not easy and sometimes relies on a combined endoscopic, pathologic, imaging, and clinical assessment (1). Second, some studies excluded the transverse colon from correlative analyses dichotomizing right and left colorectal cancer. Third, the sample size of many retrospective clinical trial cohorts is relatively small, especially the RAS wild-type right-sided subpopulation eligible for anti-EGFR therapies, which usually represents only 20% of the overall RAS wild-type population. Finally, some studies lack stratification by BRAF^V600E mutation status, an important prognostic and predictive marker in metastatic colorectal cancer (2).

Nevertheless, survival models adjusting for both genomic and transcriptomic markers may still reveal significant interactions between tumor location and benefit with EGFR-targeted agents. This could be related to the fact that transcriptomic markers linked to anti-EGFR resistance, such as reduced EGFR ligands expression, MSI-like phenotype, and mesenchymal activation, are threshold dependent and not mutually exclusive. Alternatively, genomics and transcriptomics are not explaining critical components of colorectal cancer biology, such as tumor microenvironment features, which are still captured by tumor location. Indeed, the aggregated knowledge supports a model whereby tumor location represents a surrogate of major biological differences that go beyond genomics and transcriptomics, and highlights the importance of an integrative multimolecular characterization of the disease to advance precision medicine, including cancer cell interactions with immune and stromal cells and the microbiome. These “smaller pieces of the pie” are becoming increasingly important as we embrace the advent of molecularly guided therapies and combinations with immunostimulatory drugs.

Despite being overly simplistic, dichotomizing the colon into right and left sides provides an important categorization with immediate clinical implications. As advocated by others, sidedness should be a stratification factor in future clinical trials in metastatic colorectal cancer (2). In addition, given the continuum of genotypic and phenotypic alterations moving from cecum to rectum, we now have robust evidence that primary tumor location should be considered part of the translational workup of all clinical studies irrespective of chemotherapy backbone, targeted agent, or immunotherapeutic drug under investigation.

R. Dienstmann reports receiving speakers bureau honoraria from Roche and is a consultant/advisory board member for Novartis, Roche, and Symphogen.

R. Dienstmann has received financial support from “la Caixa” Foundation, European Union's Horizon 2020 Research and Innovation Program 2014 2020 under grant agreement no. 634143, and Grant for Oncology Innovation under the project “Next generation of clinical trials with matched targeted therapies in colorectal cancer.”