Abstract 6123: Validating cancer modulated allostatic load as a composite biomarker for mortality in patients with cancer
Authors: Fong Christopher J. , U Kaicheng , Phua Cheryl , Bai Xuechun , Waters Michele , Fu Tom , Arora Kanika , Perea-Chamblee Tomin , Jutagir Devika , Berger Michael , Schultz Nikolaus , Schoenfeld Adam , Gany Francesca , Jee Justin , Carrot-Zhang Jian 
Published: March 2024

Allostatic load (AL) is the cumulative burden of chronic stress and life events typically measured by lab and vital values routinely collected during standard care. AL has been associated with adverse socioenvironmental stressors and increased mortality rates including risk of cancer death. Despite modifications of AL as a result of progressing cancer and anti-cancer treatments, AL may serve as a valuable biomarker for cancer outcomes, and highlight similar disparities across sociodemographic groups agnostic of a history of cancer diagnosis. Recent investigations have shown associations of AL with overall mortality rates in patients with non-small cell lung cancer (NSCLC) and breast cancer, as well as various social determinants of health. The impact of AL on different malignancies, particularly in the context of genetic variations identified through genomic profiling, is yet to be thoroughly investigated.

We identified a pan-cancer cohort of 29,433 patients sequenced with the MSK-IMPACT targeted panel sequencing assay, and collected clinical, genomic, and lab data. We first studied the association of AL with patient and tumor characteristics such as tumor type, stage, cancer genomics, comorbidities, social deprivation defined by the Yost index, and genetic ancestry. We derived AL using 10 standard biomarkers across cardiovascular, metabolic, renal, and immune systems, and created a composite AL summary score with a range between 0 and 10. Composite AL summary score into quartiles for comparisons. We found that AL was increased with higher cancer stage, older age, smoking, multiple comorbidities, African ancestry, and Yost index. Multivariate logistic regression analysis showed that AL was correlated with mutations e in KRAS and anti-correlated with EGFR mutations (FDR&lt;0.02).

Next, we investigated AL as a biomarker for mortality in patients with cancer and compared its prognostic value to other biomarkers. Using a Cox proportional hazard model we found that AL was significantly associated with shorter overall survival, controlling for stage and socioeconomic variables (HR=1.7, 2.2, 2.7 in AL Quartiles 2-4 respectively). Finally, we decomposed AL into its individual markers to quantify the most important features driving outcomes. Using a Random Survival Forest model with a focus on NSCLC patients, we found that albumin and alkaline phosphatase were the strongest features of shorter survival in our AL composite model.

Our findings suggest that elevated AL is associated with a poorer prognosis across multiple cancer types, a trend observable across different stages of cancer. The association between AL and clinically actionable mutations highlights the importance of understanding the relationship between somatic alterations and social/environmental factors. The study underscores the utility of AL as a powerful prognostic tool that can be routinely collected in a clinical setting.

Citation Format: Christopher J. Fong, Kaicheng U, Cheryl Phua, Xuechun Bai, Michele Waters, Tom Fu, Kanika Arora, Tomin Perea-Chamblee, Devika Jutagir, Michael Berger, Nikolaus Schultz, Adam Schoenfeld, Francesca Gany, Justin Jee, Jian Carrot-Zhang. Validating cancer modulated allostatic load as a composite biomarker for mortality in patients with cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6123.