Evidence Emerges Showing External Stressors Adversely Affect Cancer Outcomes

A measure of environmental stress had a significant association with mortality risk in patients with breast cancer, a large retrospective cohort study showed.

Patients with a high allostatic load (AL) had almost a 50% higher all-cause mortality risk versus patients with a low AL. Stratification of AL scores showed that patients in the highest (fourth) quartile had almost an 80% greater risk than those in the lowest (first) quartile. Patients in the third quartile had a 56% greater relative risk as compared with the first quartile.

“There was a significant dose-dependent association between increased AL and a higher risk of all-cause mortality,” reported Samilia Obeng-Gyasi, MD, MPH, of the Ohio State University in Columbus, and co-authors in JAMA Network Open. “Furthermore, AL remained significantly associated with higher all-cause mortality after adjusting for the Charlson Comorbidity Index.”

“These findings suggest increased AL is reflective of socioeconomic marginalization and associated with all-cause mortality in patients with breast cancer,” they concluded.

The results added to a growing body of evidence that external stressors may adversely affect outcomes in cancer and other diseases.

“The authors are to be commended for creating a measure of allostatic load that can be derived from the routine biomarkers in an institutional breast cancer cohort,” Anurag Singh, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, told MedPage Today via email. “The correlation of these findings with socioeconomic factors is fascinating and consistent with our data showing that household income was significantly associated with gene-based recurrence scores and survival in breast cancer. Similarly, we found that socioeconomic factors can impact DNA methylation.”

AL reflects cumulative physiologic damage secondary to cognitive-emotional responses to socioenvironmental stressors, such as low-socioeconomic status. Early researchers in the field defined AL as the “cost of chronic exposure to fluctuating or heightened neural or neuroendocrine response resulting from repeated or chronic environmental challenge that an individual reacts to as being particularly stressful.”

AL combines primary mediators of the hypothalamic-pituitary-adrenal axis (such as cortisol) and sympathetic adrenal medullary pathway, secondary outcomes of the hypothalamic-pituitary-adrenal axis and sympathetic adrenal medullary pathway (such as C-reactive protein), and tertiary outcomes (such as cancer) into a composite score. Emerging literature suggests elevated AL (an indicator of physiologic dysregulation) is associated with exposure to adverse socioenvironmental stressors, an increased risk of chronic diseases, and worse all-cause mortality.

In patients with cancer, elevated AI has been associated with worse all-cause and disease-specific mortality and other adverse outcomes. Obeng-Gyasi and colleagues previously reported an association between elevated AL at diagnosis of metastatic lung cancer and worse all-cause mortality. The same study showed associations between elevated AL and stressors such as limited mobility, worse self-care, problems engaging in social and daily activities, and a greater number of stressful life events.

With respect to breast cancer, high versus low AL has been associated with larger tumor size and unfavorable tumor characteristics. In addition, high AL has been associated with marital dissolution, low educational attainment, and unhealthy behaviors.

No previous studies had shown an association between high AL and all-cause mortality in patients with breast cancer. To examine the issue, investigators queried an institutional electronic medical record and a cancer registry at the National Cancer Institute Comprehensive Cancer Center. They identified patients with newly diagnosed stage I-III breast cancer from January 2012 through December 2020.

Currently, no reference standard exists for biomarkers to include when calculating AL, the authors noted. For their study, they limited data collection to biomarkers routinely collected in clinical practice and frequently used in AL literature. The biomarkers represented four physiologic systems: cardiovascular, metabolic, renal, and immune. The AL score ranged from 0-10, and AL values were stratified into quartiles.

The primary outcome was all-cause mortality, defined as the time from breast cancer diagnosis to date of death. Data analysis included 4,459 patients, who had a median age of 59; 87% were non-Hispanic white. The overall mean AL was 2.6 and the median was 2.0. A high AL was defined as a value exceeding the median.

Patients with a high AL were older and more likely to be single (relative ratio [RR] 2.76), widowed/separated/divorced (RR 2.78), have government insurance (Medicaid RR 2.8; Medicare RR 2.9), and identify as non-Hispanic Black (RR 3.08).

The data showed that 2,257 patients had a low AL, and 99 died during follow-up, translating into a mortality per 100 person-years of 1.04. The remaining 2,202 patients had a high AL, and 180 died during follow-up, which translated into a mortality of 1.99 per 100 person-years. Mortality increased in linear fashion with AL quartiles:

• Q1: 0.89 per 100 person-years
• Q2: 1.22
• Q3: 1.78
• Q4: 2.59

“These results support existing studies suggesting patients experiencing persistent socioeconomic marginalization … have higher biological correlates of stress, operationalized as AL, than their socioeconomically privileged counterparts,” Obeng-Gyasi and colleagues wrote.

“This study shows that vital signs … and routine laboratory assessments … collected in clinical practice can be used to calculate a robust AL measure,” they added.