Colorectal Cancer Awareness Month: Exploring the Impact of Early-Onset Disease

Advances in detection and treatment of colon and rectal cancers (CRC) have transformed outcomes for patients in recent years. However, a discouraging trend has been observed, as the median age of patients being diagnosed with CRC has decreased, bringing attention to the needs of younger patients.

According to research by the American Cancer Society, 153,020 new cases of CRC are expected to be diagnosed in 2023.¹ The incidence in patients under 55 years increased by 1.9% per year from 2011 to 2019 even as the overall incidence declined, and these patients frequently present with later-stage disease. From 1995 to 2019, the proportion of patients under 55 who were newly diagnosed with CRC increased from 11% to 20%, and they made up 28% of patients with rectal cancer, growing from 15% in 1995.

This shift can partially be explained by reduction of disease prevalence and severity in older patients due to improved use of screening tests.¹ Other factors that have been linked to the rise of CRC in younger patients include trends related to lifestyle, diet, and obesity in younger people.

“I think it's a problem that faces not only oncologists but also primary care physicians and gastroenterologists, since they are typically at the front lines of dealing with this problem,” Sameh Mikhail, MD, said in an interview with Targeted Oncology^TM.

Although newer treatments have significantly improved outcomes such as 5-year survival for patients with CRC, it remains one of the deadliest cancer types, and some studies suggest that younger patients do not have better treatment outcomes than older patients.² Additionally, younger patients have to contend with different challenges such as careers and raising young children that older patients may not experience during treatment.

Improving Early Detection of CRC with Noninvasive Screening

Early detection of CRC is dependent on primary care providers and gastroenterologists, who are responsible for recognizing symptoms of CRC and conducting regular screening tests.

“In the past, medical providers did not think about colon cancer as a potential diagnosis for patients who are younger, so patients with colon cancer were diagnosed at later stages,” said Mikhail, a medical oncologist at the Zangmeister Cancer Center in Columbus, Ohio. “Oncologists have been working hard at raising awareness about the fact that the patients are diagnosed at a younger age and about potential symptoms of CRC in the young. And fortunately, our gastroenterology and primary care colleagues have done a great job in terms of improving the diagnostic workup for these patients.”

Common symptoms of CRC include anemia, change in bowel habits, and abdominal pain. Mikhail explained that in the past, these symptoms would be attributed to conditions such as stress or other factors. He said that there is now more awareness that CRC should be included in the differential diagnosis of patients who have these symptoms.

As CRC can develop asymptomatically or symptoms can be missed, colonoscopies are an essential screening tool to diagnose CRC and remove precancerous polyps in the general population. The American Cancer Society now recommends regular screening for people with average risk of cancer starting at the age of 45, lowered from 50 since 2018.¹ However, patients often do not get colonoscopies at the recommended time.

“Fifty percent of patients eligible to get a colonoscopy are actually getting them,” Mark G. Goldstein, MD, a medical oncologist at the Center for Cancer and Blood Disorders in Bethesda, Maryland, said during a Targeted Oncology^TM interview. “That means there's a whole bunch of people out there not getting appropriately screened.” Patients he has spoken to are concerned with uncomfortable preparation for colonoscopies, the use of anesthesia, and the risk of perforation, though he stressed to them that these are misconceptions since preparation and safety have improved greatly over time.

Due to the need to screen individuals in the general population for early diagnosis of CRC, noninvasive screening tests play an important role. Analysis of stool and blood samples have each demonstrated the ability to detect CRC. “Colonoscopy remains the gold standard, but these noninvasive tests are catching up very quickly,” said Mikhail.

These tests require high sensitivity to avoid missing any cancers or precancerous polyps that would be discovered by a colonoscopy. Additionally, they need to demonstrate high specificity to avoid false-positive results. For this reason, their role is screening those with average risk for CRC, and positivity on a noninvasive screening test requires confirmation by colonoscopy.

“Their sensitivity is still a little bit lower than we would like it to be,” said Mikhail. “But it's already significantly better than 5 or 10 years ago. I'm sure that just in a few years, since that field has been evolving very quickly, it will be ready for universal adoption.” The multi-stool DNA test (Cologuard^TM) in use commercially had a 92.3% sensitivity for CRC and an 89.8% specificity for negative results on colonoscopy.³ The blood-based cell-free DNA assay (Shield^TM; formerly LUNAR) evaluated in the ECLIPSE study (NCT04136002) reached a sensitivity for CRC of 83% with specificity of 90%, and was submitted for premarket approval in the United States.⁴

“I think it's probably a good thing, because we're just not screening enough people,” said Goldstein. “There are [physician] shortages out there. If you screen in this way, then you're not overwhelming the gastrointestinal [physicians] with patients…. I think they're using it more, and I think the patients are more amenable to it.”

Mikhail points out that the analysis of circulating tumor DNA (ctDNA) utilized in some noninvasive tests has other potential roles besides diagnosis. “Most recently, we've learned to possibly consider using ctDNA to determine if patients who undergo surgery for colon cancer need chemotherapy or not. Also, ctDNA can be used for monitoring of patients and early detection of recurrences.” He says that these interventions are in development, and they stand to improve patient care for those who are currently being treated for CRC. “They've been evolving and I'm fairly certain that in a few years, they're going to be routinely used in our in our day-to-day practice.”

Challenges of Younger-Onset CRC

Some clinical distinctions have been identified in early-onset disease, including more frequent appearance of symptoms like hematochezia and abdominal pain. Younger patients also receive a diagnosis of later-stage disease more often, with 27% of patients under 50 having distant metastases at diagnosis vs 20% in older patients.¹ Patients diagnosed under 50 are also more likely to be women.

Patients under 50 years of age tend to wait longer between experiencing symptoms and seeking medical attention; however, this delay has been shown to not significantly impact staging on presentation or 5-year survival outcomes.⁵ Once CRC has been diagnosed, in general, patient age does not significantly influence treatment selection for therapy. Goldstein said that disease stage, patient frailty, and performance status are more important factors than age, though older patients often have more challenges with tolerating multiple chemotherapy agents.

Younger patients may have better tolerance for chemotherapy and complicated surgeries, according to Mikhail. However, their outcomes are not always better. Investigators performed an analysis of patients younger than 50 years vs older than 50 years enrolled in the CALGB/SWOG 80405 trial (NCT00265850) of monoclonal antibody plus chemotherapy regimens in 2326 patients with advanced CRC. They found no difference in respective overall survival (adjusted HR, 0.98; 95% CI, 0.88-1.10; P = .78) or progression-free survival (adjusted HR, 1.02; 95% CI, 0.92-1.13; P = .67).⁶

Overtreatment may be an issue in younger patients. Increased use of adjuvant chemotherapy in younger patients was found to result in no benefit for patients with stage II colon cancer and minimal benefit for stage III and IV compared with older patients who received less chemotherapy after surgery.⁷

Mikhail said that other data suggest CRC occurring in younger patients can be more aggressive, though CRC associated with hereditary Lynch syndrome can have a lower risk of recurrence than non-hereditary cancers.⁸ Patients whose cancer can be attributed to Lynch syndrome would also be eligible for immunotherapy, making it crucial to identify.

Genetic Testing Guides Use of New Therapy Options

The rise of universal genetic testing has also impacted how younger patients with CRC are able to be evaluated for treatment. “It used to be that if you were younger, [with] no family history of colon cancer, but you developed a colon cancer, you didn't meet the criteria to get genetic counseling and testing,” Goldstein said. “But that paradigm has shifted, so now for everybody—regardless of age—who gets diagnosed with colon cancer, the pathologist will do a screening test.”

More than half of patients who have metastatic CRC have tumors with molecular profiles that can be treated with targeted therapies or immunotherapies.⁹ Disease subtypes are based on features such as KRAS, NRAS, and BRAF mutations, microsatellite instability (MSI) or mismatch repair abnormalities, HER2 amplification, and NTRK fusions. The availability of targeted therapies for these subtypes is especially important for patients whose cancers go undiagnosed until later stages.

Patients with MSI-high/mismatch repair–deficient (dMMR) tumors stand to benefit from immunotherapy. Results from a phase 2 trial (NCT04165772) of dostarlimab (Jemperli) showed a 100% complete response rate with no evidence of disease in 14 patients with MSI-high/dMMR rectal cancer in 2022.¹⁰ “This trial is being expanded to include more patients, and I suspect that this will be a practice-changing trial,” said Mikhail.

“I definitely think that's going to be the next development in rectal cancer as a new standard,” Goldstein said of this trial. “Because it helps you avoid chemotherapy and radiation therapy and surgery. Theoretically, it is a great advance for some of those select patients.”

Another shift in the role of genetic testing is that next-generation sequencing (NGS) is becoming standard for all stage IV cancers, according to Goldstein. “I would encourage physicians to look at the NGS platform of their choice. That's important because it can sometimes open up treatment options for patients that they otherwise would not know about. I think it’s best for the patient to do that to inform them of what their options are going forward,” Goldstein said.

Looking Ahead in CRC

As screening and treatment for CRC improve, oncologists and other providers have new challenges to look out for. One that is often overlooked is the adjustment for physicians taking care of a greater proportion of younger patients.

“CRC has been an ever-changing field, partly because we're seeing younger patients, and we have learned that different patients will have different challenges,” says Mikhail. “The younger patients that I see have completely different challenges in terms of balancing, many times, the responsibilities towards younger families and towards trying build their careers while undergoing treatment for CRC. This is a new challenge that is different for us medical oncologists since many of our patients are traditionally older and possibly retired.”

Researchers continue to investigate the causes of earlier-onset CRC. Since treatment options can differ dramatically based on disease stage, early detection plays the biggest role in improving outcomes for patients. Better screening techniques offer a promising approach to ensuring CRC diagnoses are not overlooked. Additionally, the value of genetic testing should be recognized at every stage in the treatment process, from identifying hereditary disease to treating patients with advanced CRC.

Goldstein stresses that encouraging more participation in clinical trials can make a huge difference for the continued development of oncology research. “If you have a patient who is in need of therapy, in particular for stage IV [disease], clinical trials should be top of your mind, because that's how we made the advances we made, and that's the only way we're going to make more advances.”

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