Advancing early onset colorectal cancer research: research advocacy, health disparities, and scientific imperatives.

Early onset colorectal cancer (EOCRC) emerged as the fourth foremost contributor to cancer-related mortality among both genders in the late 1990s. Presently, EOCRC (<50) ranks as the leading cause of cancer mortality in men and the second leading cause in women within the United States. Similar trends are now also evident globally, particularly in developed countries. Furthermore, there is strong evidence confirming that health disparities persist in the diagnosis and treatment of EOCRC, with signs indicating that these gaps may worsen in specific cases. These alarming trends highlight the critical need for research to inform evidence-based interventions to reduce the burden of EOCRC globally. Fight Colorectal Cancer (Fight CRC) is the leading patient advocacy group in the United States providing information on colon and rectal cancer research, prevention, treatment, and policy. It is the opinion of Fight CRC that an international, coordinated effort with the medical, research, scientific, advocacy, industry and funding community is needed to advance impactful research. Fight CRC, in partnership with José Perea, MD, PhD, of the Institute of Biomedical Research of Salamanca (IBSAL) in Spain, and partners, are working together to address this global phenomenon and are presenting a multi-faceted research approach to move the field forward.

Addressing the Rising Trend in Early-Age-Onset Cancers in Canada.

A multi-disciplinary symposium on early-age onset cancer (EAOC) was held in October 2023 to explore challenges experienced by this rapidly growing population. A major outcome of the symposium was recognition of the remarkable similarities of EAOC patients' journeys across cancer sites. Prevention and early detection of cancer are hindered by a lack of awareness among patients and family doctors that cancer can and does occur in younger persons. Distinct characteristics of the disease-such as a later stage at diagnosis and more aggressive tumor biology-require more potent treatments, which result in profound physical and psychosocial consequences that are unique to this age group. EAOC patient empowerment emerged as another key theme of the symposium. The development of a greater number of specialized clinics was called for, and patient support groups were recognized for the vital role they play in empowering patients and their families. Leading-edge medical advancements hold tremendous hope across the spectrum of EAOC care. New technologies based on genomic profiling, immunotherapy and microbiome alteration contribute to the development of highly effective, personalized approaches to treatment. All symposium participants expressed their commitment to speak with one resounding voice to advocate for equitable access to leading care practices for EAOC patients; thus, a fourth symposium is planned for November 2024.

Understanding Colorectal Cancer Patient Experiences with Family Practitioners in Canada.

Despite ongoing screening efforts, colorectal cancer (CRC) remains a leading cause of death in Canada. The aim of this study was to better understand the experiences of Canadian CRC patients with their family practitioners (FPs) during and after their CRC diagnosis. Patient-reported data were collected through an online questionnaire to understand their CRC diagnosis experiences and identify potential gaps in care. Various factors contributing to challenges throughout a patient's CRC diagnosis (e.g., delayed CRC diagnosis) were determined using descriptive, qualitative, and inferential analyses. These factors could be targeted to optimize CRC care. This study found that 40.6% of the 175 respondents were unaware of at least one of the following aspects of CRC prior to their diagnosis: early-age onset (EAO), symptoms, and screening procedures. While 84.6% had access to a family physician (FP) before their diagnosis, only 17.7% were diagnosed by FPs. Higher proportions of younger individuals experienced misdiagnoses and felt dismissed compared to older individuals. Only half felt fully informed about their diagnosis when it was explained to them by their FP, while 53.1% had their diagnosis explained in plain language. Transitioning towards patient-centred care would promote pre-diagnosis CRC awareness, address differences in management of CRC care (e.g., dismissal and support), and accommodate for age and health-literacy-related disparities, thereby improving CRC care pathways for patients. Future research should investigate FPs experiences in detecting CRC cases to develop educational resources and recommendations, enhancing early detection and improving patient outcomes (1).

The health-related quality of life of early-onset colorectal cancer patients: an Australian cross-sectional study.

AIM: Early-onset colorectal cancer (EOCRC) patients are more likely to have advanced disease and undergo more aggressive treatment modalities. However, current literature investigating the health-related quality of life (HRQoL) of EOCRC patients is scarce. This study aimed to determine the HRQoL of an Australian cohort of EOCRC patients including a subset who underwent pelvic exenteration (PE) or cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHOD: A cross-sectional study of EOCRC patients treated at the Royal Prince Alfred Hospital, Sydney Australia was performed. Patients were divided into groups based on the time interval from their index operation: ≤2 years and >2 years. HRQoL was evaluated using the SF-36v2 questionnaire. RESULTS: A total of 50 patients were included. For patients ≤2 years from surgery, the median physical component summary (PCS) and mental health component summary (MCS) scores were 53.3 (36.4-58.9) and 47.3 (37.5-55.7). In the >2 years group, the median PCS and MCS scores were 50.6 (43.3-57.7) and 50.2 (39.04-56.2), respectively. Stage I (vs. stage II) disease and emergency (vs. elective) surgery conferred poorer PCS scores in patients ≤2 years from surgery. No other variables impacted PCS or MCS scores in EOCRC patients in either group. CONCLUSIONS: HRQoL of EOCRC patients was equivocal to the Australian population. Having an earlier stage of diagnosis and emergency index operation was associated with poorer levels of physical functioning in patients ≤2 years from surgery. However, because of the limitations of this study, these findings require validation in future large-scale prospective research.

The diagnostic yield of colonoscopic surveillance following resection of early age onset colorectal cancer.

BACKGROUND: The primary benefit of post-colorectal cancer (CRC) colonoscopic surveillance is to detect and remove premalignant lesions to prevent metachronous CRC. Current guidelines for long-term colonoscopic surveillance post early age onset CRC (EOCRC) resection are based on limited evidence. The aims of this study were to assess the diagnostic yield of colonoscopic surveillance post-EOCRC resection and identify molecular and clinicopathological risk factors associated with advanced neoplasia. METHODOLOGY: A retrospective cohort study of prospectively collected data was conducted at St Mark's hospital, London, United Kingdom, for patients diagnosed with EOCRC who underwent at least one episode of post-CRC colonoscopic surveillance between 1978 and 2022. We collected clinicopathological data including tumour molecular status and neoplasia detection rates. RESULTS: In total, 908 colonoscopic surveillance procedures were performed in 195 patients over 2581.3 person-years of follow-up. The diagnostic yields of metachronous CRC, advanced adenomas and non-advanced adenomas were 1.76%, 3.41% and 22.69% respectively. Sixteen patients (8.21%) developed metachronous CRC, and the majority (87.5%) were detected more than 3 years post index EOCRC diagnosis. Detection of advanced neoplasia was significantly higher in EOCRC patients with Lynch syndrome (26.15%) compared with those in whom Lynch syndrome was excluded (13.13%) (OR, 2.343; 95% CI, 1.014-5.256; p = 0.0349). CONCLUSIONS: During colonoscopic surveillance post-EOCRC resection, the long-term risk of developing metachronous advanced neoplasia remains high in the context of Lynch syndrome, but this trend is not as clearly evident when Lynch syndrome has been excluded.

Breaking Down Barriers to Detection and Care in Early-Age-Onset Colorectal Cancer in Canada.

The second Early-Age-Onset Colorectal Cancer Symposium, convened in October 2022, sought solutions to the barriers to early detection and care for colorectal cancer in Canada. This meeting built on a previous symposium, held in 2021 and reported in this journal. Early-age-onset colorectal cancer (EAOCRC) affects increasing numbers of people under the age of 50 in Canada and throughout the developed world. Two main themes emerged from the meeting: the importance of timely detection, and the need for a tailored approach to the care of EAOCRC. Early detection is crucial, especially in light of the later stage at diagnosis and unique tumour characteristics. Symposium participants were strongly in favour of reducing the age of eligibility for screening from 50 to 45, and promoting the development of non-invasive screening techniques such as testing for circulating tumour DNA and biomarkers. Leading approaches to care were described and discussed, which meet the unique treatment needs of younger CRC patients. Multidisciplinary practices within and outside Canada address such factors as fertility, family roles, education, careers and financial responsibilities. These models can be applied in treatment centres across the country.

Lights and shadows in the early-onset colorectal cancer management and research: An integrative perspective - Physician scientist with patient advocates.

Early-onset colorectal cancer (age under 50 years) (EOCRC) is an entity of undeniable importance, both because of its growing incidence, and the population it affects. Other current reviews emphasize the essential points regarding the clinical management and knowledge of its molecular bases. However, we intend to go one step further. With the increased significance of patient participation and disease experience in mind, we have integrated the voice of the patient to show the weaknesses and the needs, and next steps in the advancement of knowledge and management of EOCRC. This integrative review of the different perspectives, clinical, research and the patients themselves, can therefore be defined as an integrative needs assessment. Hence, this may be a first step in working towards an essential homogeneity of definitions and action.

Colorectal Cancer in the Young: Research in Early Age Colorectal Cancer Trends (REACCT) Collaborative.

Background: The incidence of colorectal cancer (CRC) is increasing in the young (under 50). Defining the clinicopathological features and cancer-specific outcomes of patients with early-onset CRC is important to optimize screening and treatment strategies. This study evaluated disease-specific features and oncological outcomes of patients with early-onset CRC. Methods: Anonymized data from an international collaboration were analyzed. The inclusion criteria for this study were patients aged <50 years with stage I-III disease surgically resected with curative intent. Overall and disease-free survival were calculated using the Kaplan-Meier method. Results: A total of 3378 patients were included, with a median age of 43 (18-49) and a slight male preponderance (54.3%). One-third had a family history of colorectal cancer. Almost all (>95%) of patients were symptomatic at diagnosis. The majority (70.1%) of tumors were distal to the descending colon. Approximately 40% were node positive. Microsatellite instability was demonstrated in one in five patients, representing 10% of rectal and 27% of colon cancers. A defined inherited syndrome was diagnosed in one-third of those with microsatellite instability. Rectal cancer displayed a worse prognosis stage for stage. Five-year disease-free survival for stage I, II, and III colon cancer was 96%, 91%, and 68%, respectively. The equivalent rates for rectal cancer were 91%, 81%, and 62%. Conclusions and relevance: The majority of EOCRC would be captured with flexible sigmoidoscopy. Extending screening to young adults and public health education initiatives are potential interventions to improve survivorship.

Early-Age-Onset Colorectal Cancer in Canada: Evidence, Issues and Calls to Action.

The inaugural Early-Age-Onset Colorectal Cancer Symposium was convened in June 2021 to discuss the implications of rapidly rising rates of early-age-onset colorectal cancer (EAO-CRC) in Canadians under the age of 50 and the impactful outcomes associated with this disease. While the incidence of CRC is declining in people over the age of 50 in Canada and other developed countries worldwide, it is significantly rising in younger people. Canadians born after 1980 are 2 to 2.5 times more likely to be diagnosed with CRC before the age of 50 than previous generations at the same age. While the etiology of EAO-CRC is largely unknown, its characteristics differ in many key ways from CRC diagnosed in older people and warrant a specific approach to risk factor identification, early detection and treatment. Participants of the symposium offered directions for research and clinical practice, and developed actionable recommendations to address the unique needs of these individuals diagnosed with EAO-CRC. Calls for action emerging from the symposium included: increased awareness of EAO-CRC among public and primary care practitioners; promotion of early detection programs in younger populations; and the continuation of research to identify unique risk factor profiles, tumour characteristics and treatment models that can inform tailored approaches to the management of EAO-CRC.

Identification of a novel de novo KMT2B variant in a Greek dystonia patient via exome sequencing genotype-phenotype correlations of all published cases.

Mutations in Lysine-Specific Histone Methyltransferase 2B gene (KMT2B) have been reported to be associated with isolated and complex early-onset generalized dystonia. We describe clinico-genetic features on a Greek patient with a novel de novo variant and demonstrate the phenotypic spectrum of KMT2B variants. We performed whole exome sequencing (WES), in a Greek patient with sporadic generalized dystonia. Additionally, we performed a systematic review of all published cases with KMT2B variants. The patient presented with isolated and mild generalized dystonia. We identified a novel splice site variant that was confirmed by Sanger sequencing and was not found in parents. This is the first reported KMT2B variant, in the Greek population. This case report further highlights the growing trend of identifying genetic diseases previously restricted to few cases in many different ethnic groups worldwide via exome sequencing. In the systematic review, we evaluated the mutation pathogenicity in all previously reported cases to investigate possible phenotype-genotype correlations. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various KMT2B variants.

Epidemiology and Mechanisms of the Increasing Incidence of Colon and Rectal Cancers in Young Adults.

In contrast to the decreasing incidence of colorectal cancer (CRC) in older populations, the incidence has nearly doubled in younger adults since the early 1990s. Approximately 1 in 10 new diagnoses of CRC are now made in individuals 50 years or younger. Patients' risk of CRC has been calculated largely by age and family history, yet 3 of 4 patients with early-onset CRC have no family history of the disease. Rapidly increasing incidence rates in younger people could result from generational differences in diet, environmental exposures, and lifestyle factors. We review epidemiologic trends in CRC, data on genetic and nongenetic risk factors, and new approaches for determining CRC risk. These may identify individuals likely to benefit from early screening and specialized surveillance.

Colorectal Cancer in the Young: Does Screening Make Sense?

PURPOSE OF REVIEW: Colorectal cancer (CRC) screening is recommended to reduce CRC mortality. This review outlines key factors to consider when recommending screening, including disease burden, screening benefits and harms, and remaining knowledge gaps. RECENT FINDINGS: In response to increasing rates of CRC incidence among younger (age < 50 years) adults, the American Cancer Society published guidelines in May 2018 recommending average-risk CRC screening beginning at age 45 (vs. 50) years. Rates of young-onset CRC have increased in the USA since the early 1990s. However, there is very little empirical evidence of screening effectiveness in younger adults, and few studies have reported harms of routine screening in this age group. Further, we know little about the natural history of CRC in younger adults. Uncertainty surrounding the efficacy of CRC screening in younger adults suggests the benefits may be small. Precision cancer screening-or modified screening regimens based on risk-may improve the balance of screening benefits and harms beyond conventional age-based strategies.

Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma.

Multiple factors, including host genetics, environmental factors, and Epstein-Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage-stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying the MST1R pathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating that MST1R germline variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, five MST1R missense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%, P = 7.94 × 10(-12)). The validation study, including 2,160 cases and 2,433 controls, showed that the MST1R variant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0). MST1R is predominantly expressed in the tissue-resident macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation of MST1R was identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation at MST1R were often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways.

Colorectal cancer in patients under 50 years of age: a retrospective analysis of two institutions' experience.

AIM: To investigate the epidemiological characteristics of colorectal cancer (CRC) in patients under 50 years of age across two institutions. METHODS: Records of patients under age 50 years of age who had CRC surgery over a 16 year period were assessed at two institutions. The following documents where reviewed: admission notes, operative notes, and discharge summaries. The main study variables included: age, presenting symptoms, family history, tumor location, operation, stage/differentiation of disease, and post operative complications. Stage of disease was classified according to the American Joint Committee on Cancer TNM staging system: tumor depth; node status; and metastases. RESULTS: CRC was found in 180 patients under age 50 years (87 females, 93 males; mean age 41.4 ± 6.2 years). Young patients accounted for 11.2% of cases during a 6 year period for which the full data set was available. Eight percent had a 1(st) degree and 12% a 2(nd) degree family CRC history. Almost all patients (94%) were symptomatic at diagnosis; common symptoms included: bleeding (59%), obstruction (9%), and abdominal/rectal pain (35%). Evaluation was often delayed and bleeding frequently attributed to hemorrhoids. Advanced stage CRC (Stage 3 or 4) was noted in 53% of patients. Most tumors were distal to the splenic flexure (77%) and 39% involved the rectum. Most patients (95%) had segmental resections; 6 patients had subtotal/total colectomy. Poorly differentiated tumors were noted in 12% and mucinous lesions in 19% of patients of which most had Stage 3 or 4 disease. Twenty-two patients (13%) developed recurrence and/or progression of disease to date. Three patients (ages 42, 42 and 49 years) went on to develop metachronous primary colon cancers within 3 to 4 years of their initial resection. CONCLUSION: CRC was common in young patients with no family history. Young patients with symptoms merit a timely evaluation to avoid presentation with late stage CRC.