Expert Discusses Differences Between Early-Onset and Traditional CRC

Manish Shah, MD

Based on the differences in clinical presentation and location of the tumors, researchers believe there are important molecular differences between early-onset and traditional colorectal cancer (CRC). Further follow-up is required to determine the reasons for these differences in tumor genesis and mutational characteristics, says Manish Shah, MD.

OncLive: Please discuss how early-onset CRC is distinct from traditional CRC.

In an interview with OncLive at the 2017 AACR annual meeting, Shah, director of gastrointestinal oncology, Weill Cornell Medicine and New York-Presbyterian Hospital, discussed ongoing efforts to understand the distinction between early-onset CRC and traditional CRC.Shah: Early-onset CRC seems to be rising in incidence. We have known this for some time, but it's been confirmed on the most recent analysis, creating a main question of why that is the case, which was addressed in this study.

SEER data, risk factor analysis data, and available genomic data from The Cancer Genome Atlas (TCGA) were used to determine if these early-onset CRCs are similar to traditional CRC, or if they seem to be different and distinct in some way.

What we found is that they are indeed somewhat distinct. Early-onset CRC has typically been defined as development of CRC before the age of 40 and is more prevalent in the left side of the colon. What we found is that if you look from the rectum to the descending colon in an almost linear fashion, you can see the relevant incidence of early-onset colon cancer decreasing from left to right. This suggests that it's not a random event. There's something specific about the biology of the left side of the colon that is causing early-onset CRCs to increase.

We also looked at risk factors, such as tobacco use, alcohol use, diabetes, and obesity. These risk factors, except for alcohol use, are associated with traditional CRC within the older population across the United States; however, in younger populations, they weren’t associated with CRC. That was the second clue that suggests that early-onset tumors may have a different biology, because they’re not associated with the typical risk factors for traditional CRC.

How long has early-onset CRC been increasing in prevalence?

We are expanding this research and have identified an additional 40 cases at NewYork-Presbyterian/Weill Cornell Medical Center, where they have almost completed the sequencing. In my opinion, our next step in terms of research is to figure out how these early-onset CRCs are distinct from traditional CRC. For the last 2 decades, we’ve seen this phenomenon. The numbers are subtle. The incidence of traditional CRC has gone down about 1% to 1.5% per year. That is largely attributed to the screening programs that were developed in the early 1990s.

Are right-sided and left-sided CRC treated differently?

Ten to 15 years later, we’ve begun to see that the incidence of CRC in people over the age of 50 has decreased. However, since about 2001, the early-onset CRCs have risen by about 3% per year, making a difference of 4.5%. One might think that this makes an argument to screen earlier, but based on our own analysis, I am not sure that’s correct because the biology is different. It’s not clear that early-onset disease screening will have the same benefit.They are treated differently simply because the prevalence of markers on the left- and right-side are different. Left-sided tumors tend to be KRAS wild-type and seem to be driven by EGFR making them more sensitive to EGFR antibody inhibitors like cetuximab (Erbitux) or panitumumab (Vecitbix). The right-sided tumors are more BRAF driven, meaning those tumors are going to be less sensitive to EGFR antibody inhibitors.

Can you expand on the next steps with the research?

Do you want to highlight anything else about this area?

They are treated differently but the real question is, do we need a molecular marker to help decide our treatment, or can we just know if it is left- or right-sided? In my opinion, the molecular marker is going to be more important. Although we often think of the colon as one organ, we are learning that it is very different from left to right.It's clear that early-onset CRC is increasing in frequency and we believe that’s related to being on the left-side of the colon. We want to understand the biology around why these tumors are increasing in frequency and our research is focused on comparing early-onset tumors to traditional tumors to determine the genetic differences. Our future research will look at the microenvironment within these tumors, as well as the microbiology and microbiome, which is another active area of research at Weill Cornell. CRC in the United States is one of the most important GI malignancies. It effects 150,000 patients a year. To realize that early-onset CRC is increasing in frequency is an important issue. Of all patients diagnosed with CRC 20 years ago, only 5% of them were early-onset, but now, 15% are in the early-onset group. This research is just the beginning of a longer process to understand the unique biology of these diseases, and, ultimately, how we can leverage that for better treatments.

Betel D, Yeo H, Yantiss R, et al. Early-onset colorectal cancer is distinct from traditional colorectal cancer. Presented at the 2017 AACR Annual Meeting; April 2-5, Washington, DC. Abstract 274.

The final clue was the genomic analysis from TCGA. We looked at the data set that was available to us, which was over 215 colon cancers, and only 15 of them were early-onset, making it a small sample set. In that small sample set, we identified several gene candidates that seemed to make early-onset CRC more prevalent. These were genes in the arachidonic acid/COX pathways.