AS695 - Impact of allostatic load and neighborhood contextual factors on breast cancer in the Women’s Health Initiative

Investigator Names and Contact Information

Adana Llanos (al4248@cumc.columbia.edu)

Lucile Adams-Campbell

Introduction/Intent

Non-Hispanic Black (NHB) and Hispanic/Latinx women are disproportionately diagnosed with breast cancers that exhibit more aggressive clinicopathologic features compared to non-Hispanic White (NHW) women. Incidence of breast cancers that exhibit aggressive phenotypes contribute to increased risk of breast cancer mortality, which is strikingly high among NHBs. While the causes are not well understood, they are likely a function of complex, sociobiological influences. To date, few studies have specifically explored the combined impacts of biological and contextual factors on breast cancer, particularly in diverse study samples. While data support a link between individual-level and neighborhood contextual factors and breast cancer, it remains unclear how these factors “get under the skin” and biologically impact breast cancer risk and phenotype. One hypothesis is that some of the downstream effects of detrimental contextual factors, particularly at the neighborhood-level (e.g., poverty, racial residential segregation) exacerbate the wear and tear on the body, leading to dysregulation across major regulatory systems. Such dysregulation, measured as allostatic load, serves as an indicator of the body’s cumulative physiologic response to chronic stressors. As postulated by the “weathering hypothesis” higher allostatic load – caused in part by the effects of lower socioeconomic status (SES) – increases risk of adverse health outcomes. Although there is no gold-standard for estimating allostatic load, it has been operationalized as an index of various combinations of cardiovascular, metabolic, and immune system biomarkers (ranging from 7 to 20 markers in total), and shown to be associated with breast cancer.

In a cross-sectional analysis of NHANES data published in 2013, Parente et al. showed that higher allostatic load was associated with increased breast cancer risk among NHBs, but not NHWs. Preliminary data from our analysis of data from the Women’s Circle of Health Study (WCHS – published in 2020) showed that higher allostatic load up to 12 months before breast cancer diagnosis predicted more aggressive breast tumor features in Black women. In WCHS, we also found that neighborhood contextual factors (neighborhood SES and racial composition) were associated with triple-negative subtype. These findings led to our central hypothesis, which is that incidence of breast cancer, particularly tumors exhibiting more aggressive phenotypes, are attributable to a combination of higher allostatic load and neighborhood contextual factors indicative of neighborhood deprivation and racial/ethnic segregation. We further hypothesize that these associations differ by race/ethnicity.

The goal of this proposal is to examine the impact of allostatic load and objectively measured neighborhood contextual factors on breast cancer incidence and phenotype in the Women’s Health Initiative (WHI), using a nested case-control study of 4,800 NHB, NHW, and Hispanic breast cancer cases and controls (1,600 cases and 3,200 controls). Key data will include: 1) allostatic load scores – estimated using existing baseline data on cardiovascular [e.g., systolic and diastolic blood pressure, total cholesterol, high-density lipoprotein, triglycerides], metabolic [e.g., BMI, WHR, glucose], and immune biomarkers [e.g., CRP, IL-6]; 2) existing neighborhood-level social environment measures; 3) breast cancer incidence; and 4) tumor clinicopathology (adjudicated at diagnosis). Our strong, transdisciplinary investigative team will leverage WHI’s large, longitudinal study, rich epidemiologic and clinical data, and long-term follow-up, to address these aims:

The Specific Aims of this study are:

Aim 1. Investigate the association of allostatic load with breast cancer risk and tumor phenotype. H1a: Higher allostatic load score (ALS) is associated with increased risk of breast cancer. H1b: Higher ALS is associated with increased risk of aggressive tumor features (e.g., higher grade, larger size, HR-, HER2+, TN subtype).

Aim 2. Investigate the association of neighborhood contextual factors with breast cancer risk and tumor phenotype. H2a: Detrimental neighborhood contextual factors (e.g., lower nSES, racially/ethnically segregated) are associated with increased risk of breast cancer and aggressive tumor features. H2b: Allostatic load mediates the association between detrimental neighborhood context and breast cancer risk. H2c: Allostatic load mediates the association between detrimental neighborhood context and risk of aggressive breast tumors.

Aim 3. Evaluate whether independent associations of allostatic load and neighborhood context with breast cancer differ by race/ethnicity. H3a: Magnitudes of associations observed for allostatic load and breast cancer differ by race/ethnicity, with strong associations observed in NHB and Hispanic/Latinx than NHW women. H3b: Magnitudes of associations observed for neighborhood context and breast cancer differ by race/ethnicity with larger associations observed in NHB and smaller in Hispanic/Latinx than NHW women.