As the second most common cause of cancer-related deaths globally, colon cancer is amongst the deadliest.

 An increasing trend in cases of early-onset colorectal cancer (EO-CRC), which is defined as younger than 50 years at the time of diagnosis, has been recognized on a global level over the last 2 decades.

 It is now estimated that EO-CRC is responsible for approximately 10% of CRC mortalities and in contrast to trends observed in later onset CRC as a whole.

 Amongst myself and colleagues, these diagnoses are amongst the most startling. A call to action has been declared, with a clear signal of receipt, as oncologists globally explore trends, challenges in diagnosis, and future directions.

Current data estimate that almost 50 new diagnoses of EO-CRC are being made today with CRC estimated to be the leading cause of cancer death in patients younger than 50 years by 2030.

 This is clearly a global phenomenon seen in countries with different lifestyles, diets, exposures, and other environmental factors and without clear urban/rural predilection.

 Increasing incidence has been most prominent amongst non-Hispanic White populations, although without clear environmental or biological.

Multiple modifiable risk factors have been posited, including Western dietary patterns (increased red meat and processed sugars, etc.), smoking, and overweight body habitus. In the Nurses’ Health Study II (1991-2015) a western style diet was associated with increased risk of EO-CRC.

 Still, a unifying cause of EO-CRC has yet to be found supporting a multifactorial cause including diet and lifestyle.

An emerging area receiving significant interest involves the gut microbiota. Gut microbiota is increasingly recognized as a moderator of obesity, age-related immunity, and inflammation.

 In one of the most robust studies to date, Yang et al explored age-related changes in more than 1,000 samples evaluating both age-related and colorectal adenoma-carcinoma sequences. They discovered several differentiating features: 1) as biological age increases, microbiota richness decreases – potentially implicating high bacterial diversity as a potential etiology and 2) Fusobacterium and Flavonifractor were consistently dominating populations of bacteria in EO-CRC. Additional investigations are ongoing.

Finally, while inherited CRC is higher in EO-CRC, still, a vast majority are still considered sporadic cases and germline variants cannot explain increases.

One of the most challenging aspects of EO-CRC is the delay in diagnosis. The reasons for this are multifactorial. First, and most obvious, is a lack of awareness by both patients and providers. CRC is most commonly associated with older age. An increase in rates in patients <50 is a relatively new phenomenon and takes time for public consciousness to catch up. A recent survey from the American Association for Cancer Research in 2019 found that a majority of patients were unaware that CRC can occur in patients younger than 50 years, saw more than 2 physicians, and waited more than 6 months to seek medical attention.

 While publicity is increasing it is often only after diagnosis that our young patients become aware of increasing rates of CRC. Similarly, patients’ first interface with the medical system is often with primary care physicians. As oncologists, we see patients with EO-CRC every day; however, this phenomenon is still somewhat rare on a population level and hard to recognize for providers who are not faced with this diagnosis on a daily basis.

Second, until recently, the recommended age at first screening was reserved for patients 50 years of age and older. The United States Preventive Services Task Force updated its recommendations in 2016 to include patients greater than 45, which was followed by the American Cancer Society in 2018.

 There is often a delay to community uptick in guideline updates and studies assessing outcome impacts have yet to be completed.

While therapies for metastatic CRC have improved significantly over the last decade, our most powerful tool is still early recognition. Efforts to increase visibility are increasing, but widespread recognition is still lagging. We are optimistic that strategies such as decreasing the colonoscopy screening age from 50 to 45 will improve outcomes but have had some resistance with uptake. Additionally, there is a bevy of EO-CRC campaign programs such as “Never Too Young.”

Identifying patients at risk of acquiring EO-CRC is of utmost importance. Patients with Lynch syndrome, which represents approximately 5% of CRC, are at the highest risk.

 Unfortunately, many patients are unaware of the syndrome, increasing the importance of testing all EO-CRC for germline mutations in an MMR gene (MLH1, MSH2, MSH6, PMS2, or EPCAM). Notably, nearly 30% of patients with EO-CRC have a first-degree relative with CRC and represent a high-risk population who can be targeted for screening.

Efforts are ongoing to identify differences between early and late-onset CRC. Patients with Lynch syndrome and other hereditary cancer syndromes represent an estimated 35% of EO-CRC, many of which are MSI-H.

 In the most comprehensive study to date, Lieu et all analyzed more than 18,000 patients with CRC with NGS sequencing comparing patients younger than 40, 40 to 49, and 50 years and older.

 The authors found that a majority of genes analyzed were similar between younger and older cohorts, but did find that 

mutations were more common in EO-CRC while 

At the 2023 ASCO Annual Meeting, there was a dedicated session exploring rising trends, potential incriminating etiologies, and molecular differentiators. First, Deepak Vadehra, MD, explored the molecular basis of EO-CRC using The Cancer Genome Atlas and the Oncology Research Information Exchange Network. They found differences in methylation, immune modulation, metabolism, and oncogenic signaling. Second, Thejus Jayakrishnan, MD, investigated differences in metabolomics between EO-CRC and average-onset CRC. They found differences in pathways of carcinogenic significance suggesting a potential etiology for EO-CRC. Finally, Eric Lander, MD, evaluated genomic differences among patients with EO-CRC, finding they were enriched with 

 and less commonly mutated with APC. We applaud these authors for contributing to the ongoing data bank needed to fight EO-CRC.

The first step in improving outcomes (and reversing the trend) is recognition followed by widespread dissemination. Our approach must be multifactorial. First, our efforts to educate increased rates of EO-CRC must be robust. Second, we need to continue ongoing epidemiologic and cancer registration studies that explore ongoing trends and potential implicating features. As more data emerge, it is essential that signal studies are followed by prospective studies. Finally, any intervention is only effective when aligned with action.

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Articles

Oncologists globally explore trends, challenges in diagnosis, and future directions in patients with colorectal cancer. 

Recent Updates in Early Onset Colorectal Cancer: What We Know and Where to Go

For many patients, there is no greater sense of promise than cancer immunotherapy and it is often the first inquiry we receive. Of course, the concept of cancer immunotherapy is not new, dating back 150 years when William B. Coley observed tumor regressions following injection of bacterial broths.

These early observations were followed by years of struggle and marginal success. In 2011, regulatory approval of the immune checkpoint inhibitor (ICI) ipilimumab (Yervoy), a monoclonal antibody targeting CTLA-4, prompted significant enthusiasm for treatments that can provide durable clinical benefits—often with limited side effects.

 Another ICI, nivolumab (Opdivo), followed in 2014, fully ushering in a new age of cancer immunotherapeutics.

Unfortunately, a majority of our patients with gastrointestinal (GI) malignancies, including those with colorectal cancer (CRC), were not included in early celebrations. CRC is a heterogenous disease driven by genomic instability with mutations in genes including 

, and mismatch repair (MMR) proteins representing the most common.

One of the earliest studies completed by Bert H. O’Neil, MD, and team investigated the antitumor activity of the PD-L1 inhibitor pembrolizumab (Keytruda) in patients with CRC. A total of 138 patients were screened for tumor PD-L1 expression with 23 patients treated. The overall response rate (ORR) was 4%, and the lone patient with a partial response had a microsatellite instability-high (MSI-H) tumor.

 A subsequent study, CheckMate-142 led by Michael Overman, MD, et al, investigated nivolumab plus or minus ipilimumab in both microsatellite stable (MSS) and MSI-H metastatic CRC and demonstrated similar findings with non–MSI-H patients, harboring a median PFS of 1.4 months.

 Emerging from these data was a sense that CRC is a cold tumor and responses with ICI are only expected for patients with MSI-H tumors.

Of course, these wins should not be dismissed, as they represent meaningful progress for a select group of patients. Mutations in MMR resulting in MMR deficiency and MSI-H account for approximately 15% of all CRCs, and are enriched in early-stage cancer.

 For patients with metastatic disease, MSI-H CRC represents about 5% of all patients and some combination of immune checkpoint blockade is expected in the first-line metastatic setting. Encouragingly, the phase 3 KEYNOTE 177 trial comparing pembrolizumab with chemotherapy demonstrated an improved PFS of 16.5 vs 8.2 months and an ORR of 43.8%.

Equally, the phase 2 Checkmate-142 trial evaluated the role of nivolumab in combination with ipilimumab, and showed an ORR of 69% with a complete response (CR) rate of 13%.

 More recently, a phase 2 study, in which single-agent dostarlimab (Jemperli) was administered to patients with MSI-H stage 2 or 3 rectal cancer, demonstrated complete clinical responses in 12/12 (100%) patients.

 This represents significant progress with lifechanging results—even if only for a select cohort of patients.

For patients with MSS CRC, renewed enthusiasm emerged when a phase 1b trial of regorafenib (Stivarga) plus nivolumab in patients with MSS CRC demonstrated a 36% ORR (n = 9/25). This exceeded historical norms for regorafenib alone and suggests a potential synergistic effect.

 In this study, the authors observed that only 2 of 13 patients with liver metastases enjoyed an objective response. While a follow-up phase 2 study demonstrated an ORR of only 7.1%, it was noted that patients without liver metastases had an ORR of 21.7%. Treatment of liver metastases with immunotherapy is challenging due to an immunosuppressive environment, local immune tolerance, and a possible metabolism effect.

What emerged was site of metastasis as a predictor of response to ICI in MSS CRC. At the 2023 Gastrointestinal Cancers Symposium, Anthony El-Khoueiry, MD, presented 1a/1b data for patients with MSS metastatic CRC treated with botensilimab (anti–CTLA-4 antibody) and balstilimab (anti–PD-1 antibody). Seventy patients were evaluated; the ORR was 23%, 11 of 16 of which were ongoing at time of presentation. All responses were seen in patients without liver metastasis. Importantly, 81% of patients without liver metastases were alive at 12 months validating our eagerness to provide patients with durable responses.

 led by Marwan Fakih, MD, et al studying a combination of regorafenib, ipilimumab, and nivolumab demonstrated differential response based on sites of disease. In their study, 39 total patients were enrolled. For the 22 patients without liver metastases, the ORR was 36.4%, while no responses were seen in patients with active liver metastases.

This is an exciting time. In an era of genomics, proteomics, and immunology a biomarker as simple as anatomy may be useful in terms of predicting responses. As we encounter patients, it is often humbling to recognize our inability to predict therapeutic benefit. While innovative therapies are essential, we must continue to examine predictive biomarkers and acknowledge that progress is not always a novel therapy, but rather novel application of an old one.

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In an era of genomics, proteomics, and immunology a biomarker as simple as anatomy may be useful in terms of predicting responses in patients with colorectal cancer. 

Jason Henry, MD

Articles

Recent Updates in Early Onset Colorectal Cancer: What We Know and Where to Go

Immunotherapy in Metastatic Colorectal Cancer: More Than Just MSI-H?