Background: Frailty, a dynamic construct with reduced physiological reserve, is a state of extreme vulnerability to stressors that leads to adverse health outcomes. Although frailty is more common in older people, it may also affect the middle-aged and even younger population. The intensifying aging trend of the global population imposes an ever-increasing incidence of multiple chronic diseases, including cancer, resulting in decreased quality of life and increased health care burden. Cancer remains a leading cause of death and an immense barrier to increasing life expectancy in countries around the world. Better recognition of frailty and cancer will favor clinical practice and public health. In the clinical setting, the assessment of frailty has been widely used to classify cancer patients at risk of poor prognosis and to identify cancer survivors at risk of early morbidity and death after cancer treatments. However, research and evidence regarding the associations of frailty status with cancer incidence and mortality in the general population are controversial and insufficient. Given the limited and controversial evidence in this regard, we aimed to examine whether physical pre-frailty and frailty were linked with risks of subsequent cancer as well as survival from cancer in middle and older age.

Methods: This prospective study included 348,144 participants free of cancer at baseline from the UK Biobank. Frailty phenotypes, classified as non-frailty (0 scores), pre-frailty (1 to 2 scores), and frailty (≥3 scores) were constructed from 5 components: weight loss, exhaustion, low physical activity, slow gait speed, and low grip strength. The outcomes of interest were the incidence and mortality of overall cancer and 24 specific cancer types. The hospital admission and mortality data were available until March 31, 2021 and February 28, 2021, respectively. We censored analysis at this date or the date of first-time cancer incidence or death, whichever came first. We calculated unadjusted rates by dividing the number of events by the person-years using an exact Poisson model. We performed multivariable Cox proportional hazard model to examine hazard ratios (HRs) and 95% confidence intervals (CIs) for the overall and sex-stratified association of frailty phenotypes with cancer incidence and mortality. Missing values of covariates were treated as dummy variables. The restricted cubic spline model presented the overall and sex-stratified dose-response relationship of frailty index with cancer incidence and mortality. We further examined associations between the five frailty components and cancer with mutual adjustment for other frailty components. Secondary analyses were performed. First, we examined the association of frailty with the primary outcome of cancer across strata of all covariates. The joint test was used to examine the statistical significance of the difference between subgroups. Second, to minimize the potential reverse causation, we excluded subjects who developed cancer or died within 2 years from baseline and re-ran the primary analyses. Third, we considered competing for risk by using the Fine and Gray sub-distribution hazard model to examine the association between frailty phenotypes and incidence and mortality of cancer.

Results: A total of 43,304 incident cancer cases and 10,152 cancer deaths were documented during a median of 12.0 years of follow-up. Participants with pre-frailty (12.7%) and frailty (14.8%) tended to develop cancer compared to non-frailty (12.0%). Meanwhile, pre-frailty (3.1%) and frailty (5.0%) were more likely to die of cancer than those with non-frailty (2.6%). Pre-frail and frail participants were more likely to be older, female, non-White, more deprived, less educated, obese, current smokers, have a lower income and an unhealthier diet but drink less alcohol, have more long-term conditions and be free of a family history of cancer, compared to non-frail ones. For overall cancer, compared with the incidence rate of overall cancer of 11.32 per 1000 person-years among those with non-frailty, the risk of overall cancer incidence increased by 4% (HR 1.04, 95% CI: 1.02-1.06) for pre-frailty, and 11% (HR 1.11, 95% CI: 1.06-1.17) for frailty. There were significant associations of pre-frailty (2.65 per 1000 person-years; HR 1.11, 95% CI: 1.07-1.16) and frailty (4.41 per 1000 person-years; HR 1.39, 95% CI: 1.28-1.52) with increased risk of cancer mortality, in contrast to non-frailty with the mortality rate of 2.19 (per 1000 person-years). Individuals with pre-frailty and frailty phenotypes carried a significantly higher incidence risk of site-specific cancers, including bone, oral, liver, and lung cancers, as well as the higher mortality risk of the cancers above except bone in a dose-dependent manner and with a gender-specific pattern. We observed a synergetic association of frailty phenotypes and smoking with overall cancer incidence and mortality risk.

Conclusions: Our findings indicated that frailty phenotypes were significantly associated with a higher risk of overall and some site-specific cancers incidence and mortality in a dose-dependent manner, and we observed gender differences in these associations. Meanwhile, frailty phenotypes and smoking had synergetic effects on overall cancer incidence and mortality. Assessment for physical frailty may be integrated into risk stratification for cancer prevention in the general population, favoring evidence-based and lifestyle-targeted preventive measures.