Side Matters in Colorectal Cancer

CUTTING-EDGE CANCER RESEARCH is often focused with pinpoint precision on tiny variations in the genetic code. It’s akin to working with typos in a phonebook. So last summer, when researchers revealed that there may be a significant difference between colorectal cancer that emerges on the right side of the body versus that arising on the left side, oncologists got very curious about this apparently much more simple discovery.

It has been observed for years that patients with rightsided colorectal cancer had worse outcomes than those with left-sided disease. Nobody knew why, and while there was some evidence of molecular differences based on where a colorectal cancer emerged, the consensus assumption seemed reasonable: Right-sided patients fared worse because their disease was less likely to be caught at an early stage.

Stool is more liquid on the right side, and the bowel is larger. “We assumed that you would need a more advanced cancer on the right side to manifest symptoms,” explains Alan Venook, M.D., a gastrointestinal (GI) oncologist at the UCSF Helen Diller Family Comprehensive Cancer Center, in California. Patients with a right-sided tumor were thus more likely to be diagnosed with later-stage disease. It was serendipity that made Venook rethink left versus right. He was invited to give a memorial lecture at Cornell Medical School in April 2016 in honor of Scott Wadler, a specialist in GI cancers who had died in 2007. While researching his talk, Venook found a 2001 paper that showed a five-month difference in survival between left- and right-handed colorectal cancers. “Now, that blew my mind,” says Venook. Because the therapy regimen in the paper was obsolete, the research never got the attention it deserved.

Venook was motivated to re-examine data he’d helped generate as the lead investigator on Cancer and Leukemia Group B/Southwest Oncology Group 80405, a trial that had studied some combination therapies for metastatic colorectal cancer. As its ponderous name and number suggests, it was one of the thousands of generally anonymous studies that, bit by bit, advance cancer treatment.

Study 80405 had largely wrapped up by 2014, but it had never looked at where the cancer had arisen. “It hadn’t occurred to us that that was relevant,” says Venook. “In almost no study in that era did we capture that information.” For six weeks, a small team combed through more than a thousand patient files, pulling out the primary disease location in the colon.

When they ran the numbers, the differences leapt off the page. To double-check, he scoured other studies. “It just blew my mind. I had no clue that it was this big a difference,” says Venook.

Colleagues were similarly intrigued when Venook presented his analysis in 2016 (it hasn’t been published yet). For patients with metastatic colorectal cancer, he found, the sidedness of the primary tumor within the colon appears to affect both survival and the effectiveness of commonly used biological agents Avastin (bevacizumab) and Erbitux (cetuximab), which are designed to interfere with the formation of blood vessels that feed a tumor, and with growth factor receptor signaling. Patients with left-sided disease enjoyed a median overall survival of 33 months compared with 19.4 months in right-sided disease. And a comparison of Avastin and Erbitux showed that Erbitux might actually be harmful to patients with right-sided tumors.

Because the study was not originally designed to scrutinize sidedness, scientists believe more research is needed for confirmation. But the issue has the attention of GI oncologists. “Most of us believe this finding could be practice-changing,” says Mohamed Salem, M.D., of the Lombardi Comprehensive Cancer Center at Georgetown University, in Washington, D.C.

UNDERSTANDING COLORECTAL CANCER

Anatomically, the colon, or large intestine, seems like a single organ, a unified piece of human plumbing. For years, the primary tool of colorectal cancer screening was a sigmoidoscope, which only views the left side of the colon. The premise: no polyps — potentially precancerous growths — on the left side meant that the right colon would be fine, since more cancers do, in fact, arise in the rectum, or left side of the colon. That was eventually disproven, one reason why colonoscopy, which can examine the entire colon, is now favored by many providers. Flexible sigmoidoscopy is still used for screening, but performed every five years compared to every decade for colonoscopy.

In fact, the two sides of the colon emerge from different parts of embryo. Every cell in the body descends from that first fusion between the egg and the sperm, but as the embryo grows, these cells begin to develop in different directions. Some cells become skin, while other cells become neurons in the brain. Some cells become the right colon, while others become the left colon. The right colon comes from the mid gut while the left colon comes from the hind gut, and they have different blood supplies. The cells on the left and rights sides function slightly differently, and therefore, while they possess the same genes, they may not all be turned on to express the same set of proteins. “That doesn’t mean their gene expression patterns are necessarily different, but it certainly would be believable that they are,” says Venook.

It’s also assumed that the microbiome, which affects the way the body operates, plays a role. The microbiome is composed of all the genes within the collection of microbes (mostly bacteria) that live in and on humans. The vast majority of the GI microbiome resides in the colon, where it interacts constantly with the immune system through the lining of the intestine. It can affect the chemical composition of the colon contents, including what is absorbed into the body, But the microbiome is a moving target: different in different parts of the colon, different in every person and different over time. “The microbiome is very hard to understand in colon cancer,” Venook says. It’s also disrupted by the procedures used to diagnose and treat colorectal cancer. “This is a black box. Undoubtedly this is important, but we just don’t know how.”

While colon cancer is typically a disease of older people, Salem reports “an alarming finding:” over the last 10 to 15 years, an increase in colorectal cancer for patients between the ages of 20 and 49. And while there has been a slight overall decline in colorectal cancer, the frequency of rightsided colon cancer appears to be increasing. But the right/ left divide is more complex than just patients with left-sided disease doing a little better. There is slightly more left-sided disease than right. Patients with right-sided disease also tend to be older and are more likely to be female.

Right-sided disease is also subtly different: more advanced, with larger tumors that look different and have different chemical signatures.

The information about sidedness also comes on the heels of a major upgrade in our understanding of colorectal cancer. As our ability to decode the genetics and molecular biology of tumors has gotten both cheaper and more powerful, colorectal cancer is now recognized as more than one disease. Gene mutations like HER2 and BRAF, which can be targeted with drugs, are just part of the picture, as experts are learning that the overall biology of the tumor is also important when it comes to designing treatment. In 2015, scientists divided the disease into what they call “consensus molecular subtypes:” CM1, CM2, CM3 and CM4.

Between this new classification system and left/right awareness, future clinical trials hold greater promise than ever. Among the first tasks is finding out what the sidedness means. “It’s our job to figure out what it’s a surrogate for,” says Venook. “Is it an independent prognosticator, or some kind of voodoo we don’t understand?”

“Any future clinical trials will stratify patients according to the side,” adds Salem.

APPLYING NEW IDEAS

But can this information be used now? First of all, it’s important to understand that right-sided disease is not a death sentence. “I’ve had patients say ‘Oh, I’ve got right-sided cancer. I’m toast,’” says Venook. “These are generalities, these are averages. There are patients within the group who do fine.” Indeed, if caught early enough, surgery to excise rightsided disease is typically less complicated than that undertaken for left-sided colorectal cancer.

Alternatively, the intel can be comforting to some with left-sided disease. While C. Damon Hecker, a Virginia-based executive, was in the midst of chemo for his stage 3 colorectal cancer, his wife, Karen, did most of the family education, reading journal articles and connecting with Colon Town and other patient communities. When she learned about the right/left difference, she happily conveyed the news to her husband — it was, after all, among the more encouraging statistics in the face of the loss of nearly a foot of his left colon.

“I didn’t give a s***, to be honest,” he confesses — the chemo was hitting him hard. “I was pretty focused on other things, but it helped her.” She agrees: “You’re always looking for an edge.”

Once the disease is metastatic, treatment options change. Salem and Venook now use sidedness as one variable of many, on a case-by-case basis.

First of all, learning that Erbitux is riskier for right-sided patients bodes well in the long term. “As a physician, the first directive is to not harm your patient,” says Salem. The patient’s ideas about quality of life and ambition of treatment are also very important. Often enough — and in the absence of confirmed guidelines suggesting that Erbitux not be used in right-sided colorectal cancers — treatment choice is governed by side effects, like the desire to avoid a rash, or pre-existing medical conditions such as hypertension. Also, Erbitux is not used in colon cancers bearing KRAS mutations.

“We cannot cure most colon cancer patients,” admits Salem. “Yet the median overall survival has increased from six months 20 years ago to almost three years. The main change is that we have more drugs. It is important to receive all lines of therapy. The more options available, the better you do.”

Right-sided disease might also mean choosing clinical trials. “We may treat you more aggressively,” says Venook. The breast cancer drug Herceptin, which targets an overexpression of the protein HER2, is in trial for colorectal cancer now, and immune therapy options are blossoming. And it should not take long for the research community to incorporate left/right dynamics and the new molecular subtypes into a whole raft of new trials.

“This is a reason to make sure that you are in contact with, or actually see, a doctor at a major center,” says Venook. “This is an evolution, and they are the people that know about it.”

Salem agrees: “Clinical trials give you an opportunity for 2018 therapy.”