Whole-Blood Fatty Acid Phenotypes and Subsequent Quality-of-Life Changes Among Cancer Survivors

Background/Objectives: Whole-blood fatty acid composition provides an objective biomarker of fatty acid status, but its relationships with nutritional characteristics and subsequent quality-of-life (QoL) changes among cancer survivors remain incompletely understood. We aimed to identify whole-blood fatty acid phenotypes and examine their associations with nutritional characteristics, cross-sectional QoL profiles, and subsequent QoL changes in an overlapping longitudinal subcohort. Methods: In this cohort study, the 2023 baseline investigation included 3175 community-dwelling adult cancer survivors with whole-blood fatty acid profiles and paired questionnaires. After excluding participants with substantial missing QoL data, implausible fatty acid measurements, or missing age, sex, or cancer type, 3009 participants comprised the baseline analytical sample. Among these, 423 overlapped with an independent longitudinal cohort contributing QoL data from June 2021 and June 2024, and 398 had complete covariate data for the core adjusted longitudinal analyses. Whole-blood fatty acid phenotypes were identified using principal component analysis and unsupervised clustering. Nutritional characteristics were assessed using habitual dietary intake, Diet Balance Index 2022 scores, and nutrition literacy measures. QoL was assessed using the EORTC QLQ-C30. Multivariable models examined cross-sectional QoL and annualised QoL changes. An open-source phenotype assignment tool was developed to support reproducible classification in future cohorts. Results: Among 3009 baseline participants (mean [SD] age, 64.9 [7.0] years; 2397 women [79.7%]), five whole-blood fatty acid phenotypes were identified. Phenotypes 2 and 3 were rarely observed in the available general-population reference sample and appeared enriched among survivors. Phenotype 2, a high-SFA/low-PUFA phenotype accompanied by higher red meat intake and greater DBI-22 excess scores for red meat and related animal foods, was associated with statistically significant worsening across multiple QoL domains over 12 months despite relatively favourable baseline QoL. Compared with the general-population-mapped reference pool (Phenotypes 1, 4, and 5), Phenotype 2 showed annualised declines in summary score (-4.66 [95% CI, -8.14 to -1.19]) and role functioning (-5.35 [-9.88 to -0.83]), and worsening pain (8.28 [2.58 to 13.98]), dyspnoea (6.83 [0.16 to 13.50]), and constipation (14.10 [7.30 to 20.90]). Prebaseline annualised QoL changes over the preceding 24 months did not differ significantly across phenotypes. Conclusions: Whole-blood fatty acid profiling identified distinct nutritional-metabolic phenotypes among community-dwelling cancer survivors. The high-SFA/low-PUFA phenotype, accompanied by higher red meat intake and greater DBI-22 excess scores for red meat and related animal foods, was associated with worsening across multiple QoL domains over the subsequent 12 months despite relatively favourable baseline QoL. These findings highlight whole-blood fatty acid phenotyping as a potentially informative framework for characterising nutritional-metabolic heterogeneity and subsequent QoL vulnerability among cancer survivors. The open-source phenotype assignment tool may facilitate reproducible phenotype assignment and external validation in future cohorts.