Chronic stress may impact treatment and survival outcomes in patients with breast cancer

Allostatic load is the "wear and tear" on the body caused by lifelong exposure to stressors—such as social isolation, poverty, and racism—many of which are common among racial/ethnic minorities. Elevated allostatic load has been associated with various health problems, such as high blood pressure, increased body mass index, kidney disease, inflammation, arthritis, and other conditions.

"Patient behavior and clinical outcomes cannot be isolated from the effects of their social environment," said presenter Samilia Obeng-Gyasi, MD, MPH, a surgical oncologist at The Ohio State University Comprehensive Cancer Center. "Allostatic load provides us with a way to evaluate the effects of social and environmental stressors on a patient's physiology."

In this study, Obeng-Gyasi and colleagues in the ECOG-ACRIN Cancer Research Group sought to understand whether allostatic load or genetic ancestry (identified by DNA) impacted patients' survival and their likelihood of completing chemotherapy. Prior studies suggested that allostatic load and genetic ancestry each plays a role in poor breast cancer outcomes; however, no studies have looked at both factors at the same time in a study population.

"We observed that people with a high allostatic load at the beginning of the study had a greater likelihood of stopping chemotherapy early and a higher risk of death," said Obeng-Gyasi. "In contrast, we did not observe an association between genetic ancestry and survival or chemotherapy completion. This suggests that allostatic load may be better than genetic ancestry at predicting chemotherapy completion and overall survival."

The researchers analyzed data from the ECOG-ACRIN E5103 phase III clinical trial, one of the first large breast cancer treatment trials to assemble a biorepository and database of patient information, including demographics and DNA, for future research. The trial examined the effect of adding bevacizumab into sequential anthracycline and paclitaxel chemotherapeutic regimens in patients with lymph node-positive or high-risk lymph node-negative HER2-negative breast cancer.

Using genomic analyses and other patient information from the E5103 repository, Obeng-Gyasi and colleagues examined chronic stress, measured by allostatic load, across three broad categories of genetic ancestry—African, European, and other. Among the 348 patients included in the analysis, approximately 80 percent had European ancestry, 10 percent had African ancestry, and 10 percent had other ancestry.

Allostatic load was measured in patients in E5103 using biomarkers of the cardiovascular, immune, and metabolic systems collected prior to starting treatment. Examples of the biomarkers included body-mass index, blood pressure, creatinine, and several cytokines.

After adjusting for genetic ancestry, the researchers found that each 1 unit increase in allostatic load score was associated with a 15 percent reduction in the likelihood of completing chemotherapy and a 14 percent increase in the risk of death.

"These results suggest that long-term exposure to chronic social and environmental stress may contribute to poor outcomes in patients with breast cancer," said Obeng-Gyasi.

She explained that with further research, measuring allostatic load may be a useful tool to predict which patients with breast cancer may be at increased risk for stopping chemotherapy early and/or having poor survival. "Future prospective clinical trials with repeated measures of allostatic load may provide greater insight into its relationship to treatment and survival, especially if allostatic load is collected multiple times during the active treatment and survivorship phases of care," she added.

A limitation of the study is that the analyses included only a subpopulation of patients with breast cancer; therefore, the results may not apply to all patients. An additional limitation is the small sample size.

This study was conducted by the ECOG-ACRIN Cancer Research Group and was supported by the National Cancer Institute of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Obeng-Gyasi declares no conflicts of interest.

Abstract

Title: The implications of genetic ancestry and allostatic load on clinical outcomes in the ECOG-ACRIN adjuvant breast cancer trial E5103

Introduction: Elevated allostatic load (AL) has been associated with poor tumor prognostic features in Black breast cancer patients and worse disease specific and overall survival among cancer patients. To date, there are no studies evaluating the relationship between genetic ancestry, allostatic load and clinical trial endpoints such as completion of chemotherapy per protocol or overall survival. Prior evaluations of the ECOG-ACRIN adjuvant breast cancer trial E5103 suggests African ancestry is associated with a worse invasive disease-free survival and lower odds of chemotherapy completion. The objective of this study is to evaluate the association of genetic ancestry and AL with trial completion per protocol and with overall survival among patients in E5103.

Methods: ECOG-ACRIN E5103 was a clinical trial that compared doxorubicin and cyclophosphamide (AC) for four cycles, followed by 12 weeks of weekly paclitaxel with placebo (Arm A) to the same chemotherapy with either concurrent bevacizumab (Arm B) or with concurrent plus sequential bevacizumab (Arm C) among women with node positive or high-risk node negative HER2 negative disease. Genetic ancestry groups of African ancestry (AA), European ancestry (EA) and other ancestry (OA) were determined using genome-wide single nucleotide polymorphisms. AL, at trial entry, was comprised of the biomarkers body mass index, systolic blood pressure, diastolic blood pressure, creatinine, IL6, IL10, and TNF alpha. To calculate AL, patients were awarded a point if their biomarker value was above the 75 percentile of the study sample.  Logistic regression and Cox-Proportional Hazard models (odds ratio(OR) and hazard ratio (HR) estimates with corresponding 95% confidence intervals (CI)) were used to assess association with chemotherapy completion and with overall mortality. Estimates for AL were adjusted for genetic ancestry.

Results: There were 348 patients in the study. The majority of the sample was of EA (EA 80%, AA 10%, OA 10%). Median (range) of AL was 2(0-6). Patients of AA (2.1(1.3)) and EA (1.88(1.4)) had a higher mean (SD) AL score compared to OA patients (0.91(1.1). On adjusted analysis, a 1 unit increased in AL was associated with a 15% reduction in the odds of completing chemotherapy per protocol (OR 0.85, 95% CI 0.72-0.99). Additionally, a 1 unit increase in AL was associated with a 14% increase in the hazard of death (HR 1.14, 95%CI 1.02-1.29). There was no association between ancestry and chemotherapy completion (AA OR 0.95, 95%CI 0.47-1.93; OA 1.82, 95%CI 0.78-4.23; ref EA) or survival (AA HR 1.40, 95% CI 0.85-2.31), OA 0.89 (0.46-1.73; ref EA). Moreover, there was no interaction between AL and ancestry.

Conclusion: Among patients enrolled in E5103, AL appeared to be a better predictor of chemotherapy completion and overall survival than genetic ancestry. These results suggest life course exposure to chronic stress has implication in clinical outcomes even within the context of equivalent access to and quality of care.