Introduction: Distant metastases following standard treatment for locally advanced rectal cancer (LARC) are typically associated with poor disease-free survival. We report on a 52-year-old Australian male of Dutch ancestry with no family history of colorectal cancer or significant medical history who experienced bleeding per rectum for several months prior to a colonoscopy in July 2010. He was subsequently diagnosed with Stage IIb LARC.
Case presentation: Despite treatment with curative intent, a distant recurrence to his left lung was detected in May 2012, upstaging him to Stage IV rectal cancer. He had repeated distant metastatic recurrences over the next 8 years, and treatment included multiple surgeries, chemotherapies, radiation treatments, a “watch and wait” period of 20 months, and personalised dietary management. Genetic and nutrigenomic testing identified that the case had KRAS and MTHFR mutations. As part of his dietary management, the case also had his levels of folate, vitamin B12, and vitamin D regularly monitored because of his genetic predisposition and history of deficiency for these key nutrients. Apart from changes in his CEA levels, sudden increases in the patient’s folate levels, inconsistent with dietary exposures preceded detection of each new distant recurrence, with significant decreases in the levels at the next follow-up measurement.
Conclusion: A multimodal approach to this patient’s management appeared to contribute to his long-term survival of nearly 10 years from the initial diagnosis. Multidisciplinary management, including the use of additional biomarkers, may enhance survival rates in other similar cases with advanced disease resistant to differing therapies, and with potentially poor prognosis.
Introduction
Over the past few decades, there has been an increasing trend in the number of younger cases diagnosed with advanced colorectal cancer (CRC) (1). Rectal cancer comprises around one-third of all CRC cases and is a distinct and heterogeneous disease presenting with different metabolic and genetic profiles, disease patterns, and responses to available treatments (2). While standard treatment for LARC, such as neoadjuvant combined chemotherapy (usually fluoropyridines) and radiotherapy (nCRT), along with surgery, has improved local disease control, distant metastatic recurrence reportedly occurs in approximately 30% of patients (3, 4). Distant metastasis is the leading cause of cancer-related death among LARC patients with a median survival between 24 to 36 months (5). The 5-year relative survival rate for Stage IV rectal cancer has been estimated at around 14% (6).
One of the biomarkers that have been associated with aggressive disease, poor treatment responses, and low overall survival rates is the Kirsten Rat Sarcoma viral oncogene homolog (KRAS) gene mutation (3, 7, 8). Epigenetic factors, such as DNA methylation patterns, are also reported to be associated with an increase in the number of younger patients with non-hereditary disease (9). Methylation is a dynamic process involved in regulation of gene expression by the addition of a methyl group to the 5-carbon position of the cytosine ring of DNA (10). DNA methylation can be modified by environmental factors, such as diet, with abnormal methylation patterns associated with cancer development and progression (10). Methylenetetrahydrofolate reductase (encoded by the MTHFR gene) is an enzyme involved in methylation and can influence DNA synthesis and repair (11). Genetic variations in the MTHFR gene have been associated with differing responses to treatments of rectal cancer as well as influencing folate metabolism and bioavailability (3, 11).
The effect of folate on colorectal carcinogenesis is complex and appears to have a “dual modulatory” role, with both high and low levels having been implicated in cancer risk, dependent on timing, dosing, and form of the nutrient (12, 13). This was evident from the varying responses to different folate levels reported in animal models (12). One animal study on rats found that folate deficiency led to a reduced risk of CRC (14), while another study on rats reported that low folate status increased the risk of CRC and that moderate increases in dietary folate were shown to be protective against developing the disease (13). It was also reported that no appreciable differences were observed at slightly higher folate doses (greater than 4 times the dose), while exceptionally high levels (1,000 times the dose) led to the development of neoplasms (13). Human intervention studies have investigated the effect of supplementation with folic acid (FA), the synthetic form of the nutrient for prevention of recurrent colorectal adenomas (CRAs) (12). One randomised clinical trial (RCT) allocated participants to either 1 mg/day of FA or a placebo for 3 years and found that this did not reduce the risk of CRAs (15). After an additional intervention and follow-up period, participants in the FA group had a higher incidence of advanced and multiple CRAs suggesting that FA supplementation may increase the risk of neoplasia (15). Two other RCTs using FA supplementation at 1 mg/day (16) and 0.5 mg/day (17) reported no effect on the risk of CRA recurrence or increased risk of advanced or multiple CRAs. The results from these RCTs highlight potential metabolic differences with FA, which may affect folate metabolism and biological pathways (12). Additionally, when administered at higher doses, FA, in some circumstances, may increase the risk of recurrence and disease progression, e.g., in participants with undetected microscopic CRAs (12).
While not all (18–20), several early epidemiological studies have reported inverse associations between folate levels and colorectal cancer (21–25). A large Danish cohort study reported that dietary folate had a protective effect against developing both colon and rectal cancer among those who consumed more than 10 g of alcohol per day (26). Variations in the potential effect of folate on CRC risk according to body site, gender, and genetic polymorphisms were also noted in a large Dutch study (27). In this study, dietary intakes of folate (pre folic acid fortification era) were associated with a decreased risk of rectal cancer but not colon cancer. Reduced risk was also observed for men but not women, and this association was most pronounced in those with KRAS mutated tumours (27).
We present a 52-year-old male of Dutch ancestry who was diagnosed with LARC and had nCRT, surgery, and adjuvant chemotherapy (aCT). He also had KRAS (G13D) and MTHFR (C667T rs1801133 and A198C rs1801131) mutations and had his first distant recurrence in his left lung within 2 years of initial diagnosis and treatment. Following this first distant recurrence, a nutritional assessment of the case identified potential nutritional deficiencies and metabolic issues based on nutrigenomics testing and a review of his medical history (vitamin D deficiency) and dietary intake, e.g., high alcohol and low folate intakes. From this point onward, he had personalised dietary management focussing on his folate, vitamin B12, and vitamin D levels, all of which were monitored and managed along with his standard medical care. The patient survived nearly 10 years, with eight of these years having multiple distant recurrences to both lungs, and later his liver.