Medical Oncologist, Dana-Farber Cancer Institute, and Instructor in Medicine, Harvard Medical School

Director of the Young-Onset Colorectal Cancer Center, and Director of Clinical

Colorectal cancer (CRC) is the third-most-common cancer type and the third-most-common cause of cancer-related deaths in the United States, with 147,950 new cases and 53,200 CRC-related deaths projected for 2020.

 However, approximately 10% to 11% of new cases and 6% to 7% of deaths are in patients under age 50 (defined as young-onset CRC).

 The oncology community now recognizes that young-onset CRC may involve different environmental and genetic factors compared with CRC in older patients, but the data remain limited, and much is still unknown about this concerning phenomenon.

Overall, CRC screening with colonoscopy and stoolbased tests has revolutionized the prevention and early detection of CRC; nevertheless, rates of young-onset CRC have been rising.

 The incidence of young-onset CRC grew by 22% from 2000 to 2013, and mortality increased by 13% between 2000 and 2014.

 To address these alarming trends and detect CRC in more younger patients, the American Cancer Society included in its 2018 guidelines a qualified recommendation to initiate CRC screening at age 45 for average-risk individuals.

The reasons for increased young-onset CRC remain uncertain, with a critical need for clarification.

 Genetic predisposition may be identified in 16% to 20% of patients with young-onset CRC; importantly, upward of 33% of patients without a concerning family history may still be carriers of genetic alterations, highlighting the importance of universal germline testing for this population.

 Positive germline findings may have implications for risk stratification and surveillance of relatives via cascade testing, with important downstream effects on CRC prevention.

Investigators have conducted small studies to evaluate lifestyle factors associated with young-onset CRC. Most hypotheses have focused on obesity, a known risk factor for CRC overall, particularly because the rise in young-onset CRC has seemingly paralleled the increase in obesity in the United States.

 Among 85,256 women followed prospectively in the Nurses’ Health Study II (NHSII), obese women (body mass index [BMI] 30) had a relative risk (RR) of 1.93 (95% CI, 1.15-3.25) for young-onset CRC compared with women with a BMI of 18.5 to 22.9.

 In fact, the RR was 1.20 for every 5-unit increase in BMI (95% CI, 1.05-1.38, 

 = .01). Another analysis of NHSII data found a similar, positive association between prolonged television viewing time (a marker for sedentary activity) and young-onset CRC.

Differences in the clinical and molecular features of young-onset CRC also appear to exist. Younger patients are more likely to present with advanced (stage III/IV) disease compared with older patients.

 Whether this is related to underlying biology, delays in diagnosis, or both is of ongoing interest, but tumors in younger patients may also have more aggressive pathology (including poorly differentiated and signet ring cell histologies).

 Large national databases and patient-level registries have consistently found that the majority of tumors are in the distal colon and rectum; this is intriguing in light of recent data that suggest differences in treatment response and survival outcome by primary tumor site.

 mutations are less common, and the frequency of 

 mutations and microsatellite instability is more variable.

 Further investigation into these and other mutational patterns, with larger and more diverse cohorts, is required.

To better address these unmet clinical and research needs, Dana-Farber Cancer Institute of Boston, Massachusetts, launched the Young-Onset Colorectal Cancer Center, among the first of its kind, in March 2019. The center’s mission is 3-fold: (1) to provide expert and compassionate clinical care; (2) to promote scientific discovery and innovation to elucidate underlying biological mechanisms, identify risk factors, and facilitate development of novel therapies; and (3) to improve prevention and early detection by raising public awareness of the rising burden of CRC in young adults.

To help patients navigate their cancer journey and cope with their diagnosis, the center has developed custom group programming initiatives (eg, support groups, webinars, seminars, and newsletters) tailored to this population. Finally, because many patients with young-onset CRC report feelings of isolation and a lack of contact with patient peers of similar age, the center aims to create a closeknit community of young patients and their supporters. The center’s inaugural Patient and Family Forum, scheduled for March 7, 2020, is an example of how the program is bringing young patients together.

The cornerstone of the Young-Onset Colorectal Cancer Center is a new research study called the Beyond CRC Project: Better Understanding of Young-Onset Colorectal Cancer (

). This multicenter, prospective, longitudinal cohort study is one of the first comprising exclusively patients with young-onset CRC. It is also designed to fill the gaps in existing patient cohorts, which are limited by small sample sizes, minimal racial and ethnic diversity, nonuniform collection of dietary and lifestyle data, and an absence of serial biospecimen collection, including stool samples for microbiome analyses. With comprehensive data and biospecimen collection, the Beyond CRC Project aims to identify the underlying risk factors and biology of young-onset CRC and leverage that knowledge to develop novel prevention, early detection, and treatment strategies.

One study estimates that in 2030, the incidence of young-onset CRC will increase by over 90% for individuals aged 20 to 34 and more than 27% for those aged 35 to 49.

 Given that this phenomenon is only growing, focused and targeted investigation is imperative to both inform effective treatment strategies and stratify those most at risk who might benefit from additional screening. Additional dedicated centers are needed, and we welcome ongoing collaboration to better facilitate research endeavors and provide the best comprehensive care for our patients with young-onset CRC.

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The Young-Onset Colorectal Cancer Center offers several unique features and resources. All patients at the center receive multidisciplinary evaluation and up-front genetic counseling and testing at their initial visit. Each patient’s tumor is genomically profiled using the OncoPanel next-generation sequencing platform, the results of which are reviewed by a multidisciplinary molecular tumor board through a novel program called GI TARGET (Treatment Assistance Regarding Genomic Evaluations of Tumors). The result is a comprehensive report detailing personalized therapy options and clinical trial matches, which is shared with the treating oncologist to facilitate a precision medicine approach to care. The center has a dedicated research and program coordinator to help expedite referrals to critical support services (including fertility, sexual health, nutrition, and integrative medicine) and to act as the patient’s liaison to the clinical and research team. To provide comprehensive psychosocial support, the center also has its own social worker with clinical expertise in young patients with cancer.

Articles

Dana-Farber Cancer Institute launched the Young-Onset Colorectal Cancer Center, among the first of its kind, in March 2019 to provide expert and compassionate clinical care, promote scientific discovery and innovation to elucidate underlying biological mechanisms, identify risk factors, and facilitate development of novel therapies, and improve prevention and early detection by raising public awareness of the rising burden of CRC in young adults.

Dana-Farber Tackles Rising Incidence of Young-Onset Colorectal Cancer

Epidemiologic and scientific research indicates that diet and other lifestyle factors have a significant influence on the risk of developing colorectal cancer. Little is known, however, about how these factors may impact the survival of patients with established colorectal cancer, many of whom seek to understand which diet and lifestyle behaviors—beyond standard treatment with surgery, chemotherapy, or radiation&mdash;will improve their outcome.

Following on the recommendation of an American Cancer Society consensus panel highlighting the urgent need for more research on the effect of nutrition and physical activity on the prognosis of cancer survivors, the Center for Gastrointestinal Oncology at Dana-Farber Cancer Institute has developed an innovative, crossdisciplinary, translational research program to elucidate the role of diet and lifestyle behaviors in the survival of colorectal cancer patients.

Among the factors that we have identified as being potentially protective are exercise,

 and vitamin D status. For vitamin D, in particular, abundant data from the laboratory as well as epidemiologic studies support a potential antineoplastic effect. Efforts are underway to further understand the biologic mechanisms by which vitamin D may contribute to colorectal cancer pathogenesis and the potential clinical impact of supplementation on patient management.

The hypothesis that vitamin D status is related to colorectal cancer has received strong experimental support over the past two decades, based on the almost ubiquitous expression in colon cancer cells of the vitamin D receptor (VDR)

 which converts plasma 25-hydroxyvitamin D

[25(OH)D] into 1,25-dihyroxycholecalciferol [1,25(OH)2D], the active metabolite. Binding of VDR by 1,25(OH)2D leads to transcriptional control of target genes, resulting in induction of differentiation and apoptosis,

Vitamin D inhibits growth and promotes differentiation of colorectal cancer cell lines and xenografts.14,18-21 Rats maintained on a diet enriched in 1,25(OH)2D develop fewer intestinal tumors and metastases compared to control animals.

 Treatment of ApcMin mice with vitamin D or a synthetic analog reduces the size of intestinal adenomas,

 and epidemiologic data also suggest that vitamin D plays a role in colorectal cancer carcinogenesis. A meta-analysis of nine prospective studies showed that individuals with higher plasma levels of 25(OH)D, the best indicator of vitamin D status, have a significantly reduced risk of developing colorectal cancer.

The influence of vitamin D on survival of patients with established colorectal cancer remains uncertain, however, and we conducted several studies to try and address this knowledge gap.

		Figure. Plasma 25(OH)D and Survival in 304 Colorectal Cancer Patients (NHS/HPFS)

		Adjusted for age, gender, stage, grade, site, year of diagnosis, season of blood draw, BMI, and post-diagnosis physical activity. (Ng K, et al. 

Among 304 colorectal cancer patients in the Nurses’ Health Study (NHS) and the Health Professionals Follow- Up Study (HPFS) who had blood samples available, we measured 25(OH)D concentrations prior to colorectal cancer diagnosis and assessed for a correlation with survival. We found that higher plasma 25(OH)D levels were associated with a significant reduction in overall mortality (

 This finding was subsequently confirmed in another study of 1017 colorectal cancer patients in the NHS and HPFS, where higher postdiagnosis vitamin D scores calculated from known clinical determinants of vitamin D status were found to be significantly associated with improved cancer-specific (adjusted hazard ratio [HR] = 0.50; 95% CI, 0.26-0.95; 

 trend = .02) and overall survival (HR = 0.62; 95% CI, 0.42- 0.93; 

 trend = .002).28 In subgroup analyses, the benefit of higher plasma 25(OH)D seemed greater in stage III and IV patients than stage I and II (adjusted HR = 0.40 vs 0.90, respectively, comparing extreme quartiles).

To further test the benefit of vitamin D in advancedstage colorectal cancer, we conducted an analysis of plasma 25(OH)D levels drawn at study registration in 515 stage IV colorectal cancer patients enrolled in a completed, National Cancer Institute-sponsored clinical trial of palliative chemotherapy (North Central Cancer Treatment Group N9741).

 We found extremely low circulating concentrations of 25(OH)D in this population, with a median level of 20.0 ng/ mL. Indeed, only 10% of the cohort had levels ≥33 ng/mL, the threshold believed to be required for a protective effect of vitamin D on colorectal cancer risk.

 These low levels of plasma 25(OH)D are especially concerning in light of laboratory and epidemiologic evidence that higher levels are associated with improved outcome.

Given the prevalence of vitamin D deficiency and insufficiency among metastatic colorectal cancer patients, the hypothesis-generating finding of a greater benefit of vitamin D among advanced-stage patients, and preclinical studies revealing potential synergy between vitamin and cytotoxic drugs such as platinums

 we are now translating our observational findings into a clinical intervention for patients.

We are currently conducting a multicenter, randomized, blinded, placebo-controlled phase II study of FOLFOX + bevacizumab in combination with either standard-dose vitamin D

 at 400 IU/day versus higher- dose vitamin D

 at 4000 IU/day in previously untreated, stage IV colorectal cancer patients, with a primary endpoint of progression-free survival (ClinicalTrials.gov identifier NCT01516216). Approximately 120 patients will be enrolled on the study, and accrual is actively ongoing at multiple centers across the United States. Serial plasma and DNA samples and archival tumor tissue will be collected from all patients and banked for future correlative studies.

These correlative studies will be critical to fully understanding the role of vitamin D in colorectal cancer pathogenesis. Despite the abundant laboratory and observational data discussed above, the exact molecular and genetic mechanisms underlying vitamin D’s antineoplastic effects are unknown. Consequently, an entire project in our Dana-Farber/Harvard Cancer Center SPORE (Specialized Programs of Research Excellence) in gastrointestinal cancer is devoted to investigating the transcriptional targets of VDR in cell lines, xenograft mouse models, and human primary colon tumor samples. Moreover, multiple analyses of germline polymorphisms in vitamin D pathway genes are ongoing to determine if genetic variation significantly affects response to vitamin D supplementation as well as colorectal cancer patient outcome.

The potential to modulate the progression of colorectal cancer through nutritional and lifestyle factors is very real but insufficiently studied, and a clinical and translational approach that steps beyond purely observational studies is required to establish causality. In addition, elucidation of a biological mechanism underlying these clinical findings would enhance the acceptability of vitamin D as critical for cancer prevention and treatment.

In this era of expensive and often toxic antineoplastic drugs, vitamin D represents an attractive treatment option for patients and oncologists with respect to both safety and cost, and improving understanding of vitamin D in colorectal cancer could potentially shift the paradigm in managing this disease.

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			Meyerhardt JA, Giovannucci EL, Holmes MD, et al. Physical activity and survival after colorectal cancer diagnosis. 

			Meyerhardt JA, Niedzwiecki D, Hollis D, et al. Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer. 

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			Meggouh F, Lointier P, Saez S. Sex steroid and 1,25-dihydroxyvitamin D3 receptors in human colorectal adenocarcinoma and normal mucosa. 

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			Zehnder D, Bland R, Williams MC, et al. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. 

			Vandewalle B, Wattez N, Lefebvre J. Effects of vitamin D3 derivatives on growth, differentiation and apoptosis in tumoral colonic HT 29 cells: possible implication of intracellular calcium. 

			Diaz GD, Paraskeva C, Thomas MG, Binderup L, Hague A. Apoptosis is induced by the active metabolite of vitamin D3 and its analogue EB1089 in colorectal adenoma and carcinoma cells: possible implications for prevention and therapy. 

			Scaglione-Sewell BA, Bissonnette M, Skarosi S, Abraham C, Brasitus TA. A vitamin D3 analog induces a G1-phase arrest in CaCo-2 cells by inhibiting cdk2 and cdk6: roles of cyclin E, p21Waf1, and p27Kip1. 

			Iseki K, Tatsuta M, Uehara H, et al. Inhibition of angiogenesis as a mechanism for inhibition by 1alpha-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 of colon carcinogenesis induced by azoxymethane in Wistar rats. 

			Fernandez-Garcia NI, Palmer HG, Garcia M, et al. 1alpha,25-Dihydroxyvitamin D3 regulates the expression of Id1 and Id2 genes and the angiogenic phenotype of human colon carcinoma cells. 

			Lamprecht SA, Lipkin M. Cellular mechanisms of calcium and vitamin D in the inhibition of colorectal carcinogenesis. 

			Evans SR, Shchepotin EI, Young H, Rochon J, Uskokovic M, Shchepotin IB. 1,25-dihydroxyvitamin D3 synthetic analogs inhibit spontaneous metastases in a 1,2-dimethylhydrazine-induced colon carcinogenesis model. 

			Shabahang M, Buras RR, Davoodi F, et al. Growth inhibition of HT-29 human colon cancer cells by analogues of 1,25-dihydroxyvitamin D3. 

			Eisman JA, Barkla DH, Tutton PJ. Suppression of in vivo growth of human cancer solid tumor xenografts by 1,25-dihydroxyvitamin D3. 

			Giuliano AR, Franceschi RT, Wood RJ. Characterization of the vitamin D receptor from the Caco-2 human colon carcinoma cell line: effect of cellular differentiation. 

			Zhao X, Feldman D. Regulation of vitamin D receptor abundance and responsiveness during differentiation of HT-29 human colon cancer cells.

			Beaty MM, Lee EY, Glauert HP. Influence of dietary calcium and vitamin D on colon epithelial cell proliferation and 1,2-dimethylhydrazine-induced colon carcinogenesis in rats fed high fat diets. 

			Huerta S, Irwin RW, Heber D, et al. 1alpha,25-(OH)(2)-D(3) and its synthetic analogue decrease tumor load in the Apc(min) Mouse. 

			Zheng W, Wong KE, Zhang Z, et al. Inactivation of the vitamin D receptor in APC(min/+) mice reveals a critical role for the vitamin D receptor in intestinal tumor growth. 

			Larriba MJ, Ordonez-Moran P, Chicote I, et al. Vitamin D Receptor Deficiency Enhances Wnt/beta-Catenin Signaling and Tumor Burden in Colon Cancer. 

			Ma Y, Zhang P, Wang F, Yang J, Liu Z, Qin H. Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies. 

			Ng K, Meyerhardt JA, Wu K, et al. Circulating 25-hydroxyvitamin d levels and survival in patients with colorectal cancer. 

			Ng K, Wolpin BM, Meyerhardt JA, et al. Prospective study of predictors of vitamin D status and survival in patients with colorectal cancer. 

			Ng K, Sargent DJ, Goldberg RM, et al. Vitamin D Status in Patients With Stage IV Colorectal Cancer: Findings From Intergroup Trial N9741. 

			Gorham ED, Garland CF, Garland FC, et al. Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis. 

			Cho YL, Christensen C, Saunders DE, et al. Combined effects of 1,25-dihydroxyvitamin D3 and platinum drugs on the growth of MCF-7 cells. 

			Moffatt KA, Johannes WU, Miller GJ. 1Alpha,25dihydroxyvitamin D3 and platinum drugs act synergistically to inhibit the growth of prostate cancer cell lines. 

			Kulkarni AD, van Ginkel PR, Darjatmoko SR, Lindstrom MJ, Albert DM. Use of combination therapy with cisplatin and calcitriol in the treatment of Y-79 human retinoblastoma xenograft model. 

			Light BW, Yu WD, McElwain MC, Russell DM, Trump DL, Johnson CS. Potentiation of cisplatin antitumor activity using a vitamin D analogue in a murine squamous cell carcinoma model system. 

			Liu G, Hu X, Chakrabarty S. Vitamin D mediates its action in human colon carcinoma cells in a calcium-sensing receptor-dependent manner: downregulates malignant cell behavior and the expression of thymidylate synthase and survivin and promotes cellular sensitivity to 5-FU.

Epidemiologic and scientific research indicates that diet and other lifestyle factors have a significant influence on the risk of developing colorectal cancer.

Kimmie Ng, MD, MPH

Articles

Dana-Farber Tackles Rising Incidence of Young-Onset Colorectal Cancer

Examining the Role of Vitamin D in Colorectal Cancer Survival