Colorectal cancer is no longer a disease confined to older adults.
Across the U.S. and in my own practice at City of Hope, we are seeing a steady rise in patients diagnosed in their 20s, 30s, and 40s. Nationally, tens of thousands of people under age 50 are diagnosed each year, nearly double the proportion seen two decades ago.
Many of these younger patients arrive with advanced disease, often after months of symptoms that were dismissed or misattributed.
What makes this trend particularly troubling is that many younger patients do not fit traditional risk profiles. They are frequently active, maintain a healthy weight, and lack a family history of colorectal cancer. Genetics, diet, microbiome changes, antibiotic exposure, ultra‑processed foods, and environmental factors have all been proposed as contributors, but no single factor explains the magnitude or pace of the increase.
The reality is that we still do not fully understand why early‑onset colorectal cancer is rising. That uncertainty underscores the urgency of research.
The consequences of late detection
Because routine screening generally begins at age 45, younger adults are often diagnosed only after symptoms persist. Rectal bleeding, changes in bowel habits, or abdominal discomfort are too often attributed to benign conditions, such as hemorrhoids or irritable bowel syndrome. As a result, younger patients are more likely to present with advanced disease when treatment becomes more complex and long‑term consequences are greater.
This diagnostic gap underscores the need for more sophisticated risk stratification strategies: approaches that go beyond age alone to identify people at higher risk earlier, when interventions are more effective.
Expanding the reach of immunotherapy
From a treatment perspective, one of the greatest unmet needs in colorectal cancer lies in microsatellite‑stable disease, which accounts for approximately 95% of patients with metastatic colorectal cancer. While patients with microsatellite‑instability tumors can experience dramatic and durable responses to immunotherapy, the vast majority of patients—historically those with MSS—have not benefited from immune‑based treatments.
At City of Hope, my research has focused on changing that paradigm. City of Hope was among the first to show that carefully selected patients with MSS colorectal cancer can respond to immunotherapy when appropriate biomarkers and patterns of metastatic disease are considered.
Building on these findings, we are leading multiple clinical trials designed to improve immune responsiveness in the MSS population, including studies that combine immunotherapy with chemotherapy or novel targeted agents.
One such effort is an upcoming City of Hope clinical trial with ivonescimab, a bispecific immunotherapy agent, targeting PD1 and VEGF in combination with muzastotug, a novel CTLA-4 masked antibody. Our research at City of Hope has clearly shown that the addition of anti-CTLA-4 to anti-PD-1 in MSS metastatic colorectal cancer is essential to driving a deep response in this population. Ivonescimab, by targeting PD-1 and VEGF simultaneously, may work more effectively with muzastotug, potentially exceeding the synergies seen with other PD-1 targeting agents.
In addition, and through our participation in the HARMONi-GI3 study, we are interrogating the potential impact of ivonescimab when combined with standard systemic chemotherapy in the first-line treatment of MSS metastatic colorectal cancer. Through City of Hope’s national clinical trial network, this study is being conducted across multiple sites, expanding access to promising therapies for patients with unmet needs.
Rethinking treatment for rectal cancer
Early‑onset colorectal cancer is also notable for its high proportion of rectal tumors: approximately 40% of patients under 50 present with rectal cancer, a substantially higher rate than in older populations.
Standard treatment often involves chemotherapy, radiation, and surgery. These approaches can affect fertility, bowel and bladder function, and sexual health, particularly for younger adults.
Recognizing these long‑term implications, we are pursuing clinical trials aimed at organ preservation and treatment de‑escalation. With support from the Gateway Foundation, City of Hope is leading a study evaluating combined chemotherapy and immunotherapy as a definitive treatment for select patients with localized or locally advanced rectal cancer. The goal is to achieve complete tumor response while avoiding radiation or surgery when it is safe to do so—all without compromising cure rates.
In parallel, we are investigating novel radiosensitizers designed to enhance the effectiveness of radiation therapy with the aim of improving tumor control while potentially reducing treatment‑related toxicity.
Precision medicine with a long view
Beyond immunotherapy, advances in precision oncology are reshaping colorectal cancer care. Targeted therapies against mutations, such as KRAS G12C—once considered undruggable—are now available, with additional KRAS‑directed strategies in development.
Antibody‑drug conjugates, which deliver chemotherapy directly to cancer cells while limiting exposure to healthy tissue, are also emerging as promising tools.
At the same time, circulating tumor DNA testing is enabling more precise monitoring of treatment response and recurrence risk. While these tools continue to evolve, they hold promise for tailoring treatment duration and intensity, reducing toxicity, and maintaining efficacy.
Looking ahead
The rise of early‑onset colorectal cancer is a warning signal. Addressing it will require coordinated efforts in prevention, early detection, and therapeutic innovation.
For me, the focus is not only to cure advanced disease, but also to collaborate with researchers in developing improved detection and prevention strategies. Prevention and early detection will have the highest impact in reducing colorectal cancer mortality.
Through clinical trials, biomarker‑driven research, and a commitment to precision medicine, we are working to ensure that younger patients receive treatments designed to extend life and preserve its quality.
With continued investment in research, even the most challenging forms of colorectal cancer can become increasingly manageable and, in some cases, curable.
City of Hope® is one of the largest and most advanced cancer research and treatment organizations in the U.S. To learn more about City of Hope, visit: www.cityofhope.org.
Discover the latest innovations in cancer research on City of Hope’s new podcast, “On the Edge of Breakthrough: Voices of Cancer Research.” Available onSpotify,Apple Podcasts and atcityofhope.org/edge-of-breakthrough.
