Metastasis is the major cause of death in cancer patients. Whereas colorectal cancer (CRC) incidence increases with age, metastatic spread seems to decline. Furthermore, the epidemiology of CRC is changing. There is an increase in CRC incidence in the young, presenting at an advanced stage with higher likelihood of synchronous or metachronous metastases, and a decline in CRC incidence and metastatic spread in the oldest-old. Emerging data suggest that age-related changes with regard to tumor biology (e.g. genomic instability), the tumor microenvironment (e.g. inflammaging) and the immune system (e.g. immunosenescence), complemented by interaction between the genome and exposome might contribute to the observed metastatic patterns. As aging is a key prognostic factor, this highlights the need for further studies investigating age-related patterns and underlying mechanisms of tumor growth and dissemination. Eventually, this might allow for better risk stratification, refinement of screening strategies and follow-up care as well as therapies tailored to reflect patient age and that might possibly target responsible biomarkers in a precision medicine approach. This review aims to discuss the influence of aging on metastatic spread in colorectal cancer and elucidate underlying mechanisms responsible for the observed metastatic patterns.
- • Colorectal cancer incidence increases with age whereas metastatic spread declines.
- • Age-related changes in primary tumor and microenvironment drive metastatic spread.
- • Aging impacts metastasis via changes in tumor biology, inflammaging, immunosenescence.
The single most important, non-modifiable risk factor for cancer is aging . In western countries, the majority of common cancers are diagnosed in aged patients. In colorectal cancer (CRC), incidence and mortality increase with age. In this respect, 54% of CRC patients are ≥ 65 years of age (and 88% of CRC patients are >50 years of age) at time of diagnosis and mortality ranges around 68% in this group . Given that the age of the population increases, a considerable increase in the burden of CRC is to be expected. However, even though the age-related increase in cancer risk is well established, recent studies report of two major findings suggesting that the relationship between age and cancer incidence might be nonlinear: one – there is a disproportionate drastic increase in CRC incidence in the young (generally defined as < 40 – 50 years of age) and second – there is a significant decline in CRC incidence rates in the oldest-old (>85 years), approximating zero in centenarians (≥100 years) . With regard to mortality, the major cause of death in cancer patients is metastatic spread . In CRC, about 20% of patients present with synchronous metastases and up to 60% of patients develop distant metastases within 5 years . With regards to age, about 26% of CRCs are diagnosed at the time of metastatic spread in patients younger than 50 years, compared to 23% of CRCs in patients aged 50–64 years and 19% among those ≥ 65 years . Pavlidis et al. reported that centenarians are characterised by the lowest metastatic rates and that the metastatic rate in older populations is half compared to younger populations . In developed countries, 5-year relative survival ranges around 65% . Patients younger than 50 years have higher 5-year survival rates than older patients regardless of their stage of disease. However, overall survival is similar to patients of 50–64 years due to a later stage at diagnosis. Patients ≥ 65 years have the lowest survival rates. Hypotheses for these age-related disparities in mortality and survival are that the advantage of early diagnosis in patients ≥ 65 years is outweighed by age-related disadvantages such as comorbidities and less aggressive treatment . In summary, age seems to play a pivotal role in cancer initiation and progression, however the age-related patterns of CRC are far from straight-forward. The relationship between aging, tumor biology, metastatic spread, treatment response and outcome remains largely unclear and studies investigating the influence and underlying mechanisms of age on metastatic spread are scarce. Additionally, there is a substantial underrepresentation of patients ≥ 65 years of age relative to their disease burden in clinical trials and studies of treatment for CRC . ( Table 1 ).