Rising Rates, Screening Gaps, and Emerging Therapeutic Targets in CRC: Your Key Clinical Questions Answered

During colorectal cancer (CRC) awareness month, OncLive® sat down with Jeremy Kortmansky, MD, to discuss frequently asked questions about the complexities of CRC management and the rising incidence of CRC in young adults. The following FAQ, adapted from the conversation, provides clinical insights into potential risk factors for CRC in young adults, gaps in screening and early symptom identification contributing to this phenomenon, and the evolving landscape of molecularly targeted therapies in the space.

Kortmansky is an associate professor of clinical medicine (medical oncology), associate chief medical officer of Network Medical Services, chief of ambulatory services, clinical director of the Division of GI Medical Oncology at Yale Cancer Center, and the chief network officer for the Smilow Cancer Hospital, Yale School of Medicine in New Haven, Connecticut.

Read on to learn more about the shifting demographics and molecular complexities of CRC.

Q: What are the current demographic trends regarding CRC incidence and mortality?

A: Although cancer rates in patients over 65 are declining, there is a troubling increase in younger populations.¹ According to a recent report by the American Cancer Society, CRC is currently:

• The third leading cause of cancer in the United States, with an estimated 158,850 new cases of CRC in 2026.
• The second leading cause of cancer-related death in the US, with an estimated 55,230 deaths from CRC in 2026.
• Increasing in incidence by 3% annually in adults aged 20 to 49 years and by 0.4% annually in those aged 50 to 64 years, despite decreasing by 2.5% in adults aged 65 and older.

Mortality has decreased in adults 65 years and older by 2.3% annually since 2012; however, it has increased by approximately 1% annually in adults younger than 50 years old since 2004.

“What is upsetting is that it is now the No. 1 cause of cancer mortality in patients under 50 years old,” Kortmansky stated. He highlighted that nearly 50% of new cases now occur in patients under the age of 65 years, a significant jump from 27% approximately 30 years ago.

Furthermore, most patients diagnosed under age 50 (75%) are presenting with either advanced-stage or metastatic disease, including 27% with distant metastases vs 21% to 23% of older patients, Kortmansky observed.¹

Q: What factors are driving the increase in early-onset CRC?

A: The rise in early-onset CRC may be attributed to a combination of lifestyle, dietary, and environmental factors¹:

• Diet and Lifestyle: High consumption of processed foods, sugar-sweetened beverages, rising obesity rates, and high alcohol consumption.
• The Gut Microbiome: Changes in the microbiome, potentially linked to antibiotic use in health and food production, are a major area of interest. Specifically, certain bacterial species, including Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis, have been implicated in promoting inflammation, DNA damage, and tumor progression.²
• Environmental Exposures: Emerging concerns include microplastics and other factors that create proinflammatory environments.
• Hereditary Causes: Although the incidence of genetic syndromes is elevated for patients under 35 vs older than 35, heredity is not the primary factor driving this overall increase in the under-50 population.

Q: Is early-onset CRC considered a biologically distinct entity?

There is growing evidence that CRC in younger patients may be a different disease biologically, characterized by different frequent mutations and more aggressive behavior, Kortmansky shared.¹

Kortmansky provided an example involving patients with resectable liver metastases: “The prognosis in the younger population was still worse... it was the same stage, the same distribution, but clearly a difference in how the disease behaved.”

Additionally, there is a notable dominance of tumors in the distal colon and rectum in younger patients, leading to differences in clinical presentation compared with older patients.

Q: What are the primary challenges in screening and early diagnosis for younger patients?

A: In 2021, the US Preventive Services Task Force lowered the recommended starting age for average-risk screening from 50 to 45 years in response to epidemiologic data demonstrating a 15% rise in cases among younger adults over approximately 15 years and modeling data supporting benefit in the 45- to 49-year age group.³

Despite these updated recommendations to begin screening at 45 years old, Kortmansky noted that uptake remains low. Many younger patients have busy lives with full-time jobs and families, making it difficult to find time for traditional screening, he explained.

Kortmansky emphasized the need for primary care physicians and gastroenterologists to be more proactive: “We can’t chalk [abdominal pain and bleeding] up to hemorrhoids or irritable bowel. We need to be a bit more proactive and say, ‘let’s make sure this isn’t cancer at an earlier group.’"

He also suggested leaning into noninvasive techniques, such as the Cologuard Plus screening test, to improve screening prevalence. As of October 2024, this next-generation multitarget stool DNA test has been indicated for adults aged 45 or older who are at average risk of developing CRC.⁴ This regulatory decision was supported by findings from the observational BLUE-C trial (NCT04144738), in which, among a subset of 20,176 evaluable adults undergoing screening colonoscopy, Cologuard Plus showed⁵:

• 93.9% (95% CI, 87.1%-97.7%) overall CRC sensitivity
• 90.6% (95% CI, 90.1%-91.0%) specificity for advanced neoplasia
• 43.4% (95% CI, 41.3%-45.6%) sensitivity for advanced precancerous lesions
• 92.7% (95% CI, 92.2%-93.1%) specificity for nonneoplastic findings or negative colonoscopy

Q: Why is molecular profiling essential in the current CRC treatment landscape?

A: Molecular profiling is critical because it identifies targetable mutations and informs treatment selection based on tumor location (left-sided vs right-sided), Kortmansky explained. Surprisingly, many patients still start treatment before these results are available.

Key molecular targets for drug development include:

• KRAS Mutations: KRAS G12C is now targetable with approved therapies, and G12D is currently under intense study.
• MET Amplification: Approximately 50% of patients show some increase in MET expression.
• Mismatch Repair Status: Although immunotherapy is effective for patients with microsatellite instability–high disease, researchers continue to struggle with bringing these benefits to the mismatch repair-proficient (pMMR) population.

Q: What emerging trials or therapies are most influential in the field right now?

A: Beyond work with KRAS and MET inhibitors, Kortmansky noted the following developments:

• Bispecific Antibodies: Amivantamab (Rybrevant), which targets both MET and EGFR, has shown potential to address resistance to traditional anti-EGFR therapies.⁶ Investigated in studies like the phase 1b/2 OrigAMI-1 trial (NCT05379595), it demonstrated antitumor activity against RAS/BRAF wild-type CRC and a manageable safety profile when combined with chemotherapy.
• Antibody-Drug Conjugates (ADCs): The MET-directed ADC telisotuzumab adizutecan (Temab-A; formerly ABBV-400) has shown promise in heavily pretreated patients, regardless of the level of MET expression.⁷ In a first-in-human phase 1 study (NCT05029882), Temab-A demonstrated antitumor activity across multiple dose levels in patients with BRAF wild-type, microsatellite-stable, or pMMR CRC who experienced disease progression on prior therapies. The agent is currently being evaluated in a phase 2 clinical trial (NCT07023289) in patients with ctDNA-positive CRC after adjuvant therapy.⁸
• Immunotherapy Combinations: The phase 3 STELLAR-303 trial (NCT05425940) investigated the combination of zanzalintinib plus atezolizumab vs regorafenib (Stivarga) in patients with previously treated CRC in the third-line setting; however, it showed only modest overall survival improvements accompanied by significant toxicity.⁹

Kortmansky concluded that although biological differences are recognized, these have not yet fully translated into standard treatment differences, making ongoing clinical trials and toxicity management essential for the future of CRC care.

References

1. Siegel RL, Wagle NS, Star J, Kratzer TB, Smith RA, Jemal A. Colorectal cancer statistics, 2026. CA Cancer J Clin. 2026;76(2):e70067. doi:10.3322/caac.70067
2. Gomes de Sousa R, Guerreiro CS, Santos I, Cravo M. The knowledge gap in gut microbiome characterization in early-onset colorectal cancer patients: a systematic scoping review. Cancers (Basel). 2025;17(11):1863. doi:10.3390/cancers17111863
3. US Preventive Services Task Force. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(20):1965-1977. doi:10.1001/jama.2021.6238
4. FDA approves Exact Sciences’ Cologuard Plus test, setting a new benchmark in non-invasive colorectal cancer screening. News release. Exact Sciences. October 4, 2024. Accessed March 30, 2026. https://www.exactsciences.com/newsroom/press-releases/fda-approves-exact-sciences-cologuard-plus-test
5. Imperiale TF, Porter K, Zella J, et al. Next-generation multitarget stool DNA test for colorectal cancer screening. New Engl J Med. 2024;390(11):984-993. doi:10.1056/NEJMoa2310336
6. Rybrevant (amivantamab-vmjw) longer-term results show promising and durable responses in difficult-to-treat colorectal cancer. News release. Johnson & Johnson. January 10, 2026. Accessed March 30, 2026. https://www.investor.jnj.com/investor-news/news-details/2026/RYBREVANT-amivantamab-vmjw-longer-term-results-show-promising-and-durable-responses-in-difficult-to-treat-colorectal-cancer/default.aspx
7. Sharma MR, Strickler JH, Sommerhalder D, et al. First-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors: results in colorectal cancer. J Clin Oncol. 2024;42(suppl 16):3515. doi:10.1200/JCO.2024.42.16_suppl.3515
8. Raghav KPS, Bando H, Ke TW, et al. A phase 2 randomized study comparing telisotuzumab adizutecan monotherapy with standard of care in patients with post-adjuvant circulating tumor DNA-positive colorectal cancer. J Clin Oncol. 2026;44(suppl 2):TPS265. doi:10.1200/JCO.2026.44.2_suppl.TPS265
9. Hecht JR, Park YS, Tabernero J, et al. Zanzalintinib plus atezolizumab versus regorafenib in refractory colorectal cancer (STELLAR-303): a randomised, open-label, phase 3 trial. Lancet. 2025;406(10517):2360-2370. doi:10.1016/S0140-6736(25)02025-2