The State of Colorectal Cancer Research and Care: Q+A with Drs. Debbie Bakes and Rachael Safyan

Colorectal cancer is the third most common cancer in men and women. While colorectal cancer is commonly referred to as one type of cancer, it comprises both colon and rectal cancer. In the U.S., 104,000 new cases of colon cancer are estimated this year and 45,000 new cases of rectal cancer.

Debbie Bakes, MD, and Rachael Safyan, MD, members of the Herbert Irving Comprehensive Cancer Center, discuss prevention, screening, and what’s ahead in colorectal cancer treatment and research. Dr. Bakes is assistant professor of surgery at Columbia University Vagelos College of Physicians & Surgeons (VP&S) and a colorectal surgeon affiliated with NewYork-Presbyterian Hudson Valley and NewYork-Presbyterian/Columbia, and Dr. Safyan is assistant professor of medicine at VP&S specializing in the treatment of colorectal cancers and pancreatic cancer at NewYork-Presbyterian/Columbia.

What are the common risk factors of colorectal cancer?

DB: There are multiple risk factors of developing colorectal cancer, with age being the biggest risk factor. As we age, the risks for colorectal cancer increases, particularly for people age 45 and older. Having a family history of colon cancer also increases one’s risk, as well as a family history of inflammatory bowel disease, such as Crohn's disease or ulcerative colitis, or ovarian, endometrial, and breast cancer. Another major risk factor is obesity and having a high-fat diet.

How can colorectal cancer be prevented?

DB: Following a low-fat, high-fiber diet and exercising regularly reduces your risk for colorectal cancer. Colorectal cancer starts out as a benign polyp, or a growth, found on the lining of the colon or the rectum. Most polyps often produce no symptoms. If these polyps are detected and removed before disease progression, then colorectal cancer can be prevented—that’s where screening plays a huge role.

The American Cancer Society and the American Society of Colorectal Surgery recommend that people with average risk and no family history should begin screening at age 45, and this is a recent change. That age used to be 50, but with colon cancer affecting the younger population, the recommendation was lowered.

What’s driving the shift in screening guidelines?

DB: One in 10 colon cancer patients are being diagnosed before the age of 50, and the incidence rate has been increasing for people younger than 50 while decreasing in older individuals. There is a notion that the rate is decreasing in older patients because there is a better adherence to screening colonoscopies at that age. And unfortunately, patients that are being diagnosed at an earlier age also have more advanced disease. It remains unclear if the common modifiable risk factors—diet, obesity, inactivity, and patient family history—are all playing a role in the earlier onset but there's definitely some correlation.

What are some existing challenges in colorectal cancer?

DB: People are still reluctant to get their colonoscopy screenings, which is so important for early prevention, early detection, and overall survival outcomes. Another challenge we’re all facing is increasing the overall public awareness about the young onset of colorectal cancer, as well as the differences in incidence and mortality rates among different racial and ethnic groups. Colorectal cancer affects men and women of all races and ethnicity but when you look at the raw data, African Americans and Hispanics are more likely to be diagnosed with colorectal cancer in advanced stages. Unfortunately, the incidence rates in these groups are also on the rise. We need to push for more public awareness so that we can continue to catch colorectal cancer early in all patient populations.

RS: At the time of their diagnosis, about 20% of patients have metastatic colorectal cancer, and about 40% of patients have a recurrence after their previously treated local disease. So we're talking about patients who may have earlier stage colorectal  cancers with risks of getting colorectal cancer again, upwards of 50%. The prognosis of metastatic colorectal cancer is poor, with a 5-year survival rate of less than 20%. Some of our chemotherapeutic drugs, such as fluoropyrimidines, haven't changed in the last 50 years. Advances in the use of molecular profiling to select therapy matching the biological features of the tumor have the potential to improve prognosis.

What’s new in colorectal cancer treatment?

RS: The most exciting advance is molecular profiling, which is genetic testing conducted on a patient’s tumor that enables us to better identify druggable targets for an optimum treatment plan. We use molecular profiling for all stages of colorectal cancer, but in particular, it's  critical for metastatic disease, or patients with advanced cancer that has spread outside of the colon or the rectum to another site of the body.

What does molecular profiling enable?

RS: Molecular profiling allows us to identify tumor subtypes for which targeted therapy may be available. All colorectal tumors should be tested for mismatch repair deficiency or something called microsatellite instability-high (MSI-H). Mismatch repair proteins help to make sure DNA replication occurs correctly, but a faulty mismatch repair process may result in the accumulation of errors in the DNA, often in regions of microsatellites, that can lead to cancer. Five percent of metastatic colorectal cancer tumors are mismatch repair deficient or MSI-H and may respond to immunotherapy. Immunotherapy is treatment that uses a person’s own immune system to fight cancer.&

In addition, we’re also testing for mutations in different genes such as KRAS, NRAS, and BRAF. Knowing whether or not these genes are mutated has treatment implications. For example, EGFR inhibitors (drugs like cetuximab and panitumumab) are only effective for patients who do not have mutations in KRAS or NRAS, and patients with a BRAF mutation should receive targeted therapy. Most insurers also cover multi-gene panel tests for metastatic colorectal cancer, and with these tests, we can potentially identify additional genetic targets to treat with specific drugs.

How have surgical methods changed?

DB: Surgery still remains the cornerstone for curative treatment of colorectal cancer. Our surgical  techniques, however, have changed considerably. Over the past decade, a laparoscopic approach, which uses much smaller incisions and a tiny camera to guide the surgeon, has become the standard for colon cancer. There are several developments, including robotic-assisted surgery that are evolving. Robotic surgery has the potential to overcome some of the limitations of laparoscopic surgery. It offers improved ergonomics, due to the unique wristed articulated instruments, and produces higher resolution, more precise images and a three-dimensional view. In comparing robotic versus conventional laparoscopic technique, the results are comparable in terms of the rates of disease-free survival, mortality, and recurrence-free survival.

Is immunotherapy the future of colorectal cancer treatment?

RS: Immunotherapy has the potential in the future to change colorectal cancer treatment but for now, it’s only used in the treatment of a small percentage of patients who have advanced disease with mismatch repair deficient/MSI-H tumors. There are three immunotherapy drugs that are FDA-approved. In 2020, the FDA approved the immune checkpoint inhibitor, pembrolizumab, for patients with newly diagnosed mismatch repair deficient/MSI-H colorectal cancer based on results of the phase 3 KEYNOTE-177 trial. This study, which randomized over 300 patients with untreated mismatch repair deficient/MSI-H metastatic colorectal cancer to first-line pembrolizumab or standard chemotherapy, showed that the length of time that a patient lives with cancer but it does not get worse doubled with pembrolizumab. That was a very exciting advance; patients had improvement in disease control and also fewer side effects from pembrolizumab compared to chemotherapy.

Unfortunately, the vast majority of metastatic colorectal cancer patients are not eligible for immune therapy because their tumors are microsatellite stable. Novel therapeutic approaches are needed to render this group sensitive to immune therapy. Many critical questions remain, and we’re studying the tumor and its immune microenvironment to better understand the complex interactions between cancer cells and the immune system. This will lead to new immunotherapy combinations for patients with metastatic colorectal cancer.