Evolution of Predictive Biomarkers for Metastatic CRC - Episode 3

Importance of Tumor Sidedness in mCRC


Scott Kopetz, MD, PhD: The molecular features of the tumor can be integrated with tumor location, which we’ve increasingly recognized as an important biomarker that captures other aspects of the tumor biology that are not included in the standard gene mutation profiling efforts. The sidedness of the tumor has been shown to influence the sensitivity of the tumor to EGFR inhibitor treatment, especially in first-line administration.

Richard Kim, MD: There are differences between the right-sided tumor and the left-sided tumor. We know that based on even the embryonic origin, they are totally different. Typically, the transverse colon in the middle is lumped to the right-sided tumor. We know that sidedness of the tumor is prognostic. Patients who have right-sided tumors tend to have poor prognoses compared to patient with left-sided tumors independent of the profiling, independent of the treatment. If you look at the phenotype, if you look at the molecular profiling of left versus right, it is also different as well. If you look at the right-sided tumor, it tends to be more mucinous, it tends to be more poorly differentiated, it tends to include more MSI [microsatellite instability]-high patients, and it tends to include more BRAF-mutant patients. So this tells you right now it’s a little bit more of a poor prognosis.

And the left-sided tumor tends to have more HER2 amplification, especially in the rectal area. It tends to have a higher rate of HER2 amplification. There is a higher chance of being a RAS wild type. And there’s also higher expression of epiregulin, which is a ligand that binds to EGFR. And we know that’s one of the possible predictive markers of EGFR. So, if you look at the profiling of a left-sided tumor, phenotypically, it looks like it responds better to EGFR inhibitors. So those are the subtle differences between the left- versus the right-sided tumor.

Scott Kopetz, MD, PhD: When we integrate the molecular features of the tumor, and tumor sidedness, this helps us to improve our treatment options and selection for first-line therapy. The data suggest that in patients with RAS- or BRAF-mutated tumors, or right-sided tumors, that these are tumors that do not respond well to anti-EGFR inhibition in combination with chemotherapy in first-line setting. There are some data developing suggesting the same for HER2 amplifications, that patients don’t respond as well to anti-EGFR therapy, although that still requires a few additional studies to really confirm that before it will be included into treatment guidelines.

The sidedness information is increasingly important, and I think this has impact not only for first-line chemotherapy combination use, which is where most data are, but also thinking about what the role for anti-EGFR therapies are in second- or later-line treatments. In my practice, we’ll commonly utilize an anti-EGFR therapy in the first line in RAS/RAF wild-type patients who are not HER2 amplified and have left-sided tumors. And then we have long conversations about the wild-type tumors from right-sided primaries, where we may utilize EGFR therapy, but if we do it’s later in the disease course—third line, fourth line, or beyond.

Transcript Edited for Clarity