ZIP Code to Genomic Code: Neighborhood Disadvantage, Aggressive Breast Cancer Biology, and Breast Cancer Outcomes

Neha Goel; Alexandra E Hernandez; Michael H Antoni; Susan Kesmodel; Paulo S Pinheiro; Erin Kobetz; Nipun Merchant; Steve Cole

doi:10.1097/SLA.0000000000006283

ZIP Code to Genomic Code: Neighborhood Disadvantage, Aggressive Breast Cancer Biology, and Breast Cancer Outcomes

Ann Surg. 2024 Mar 28. doi: 10.1097/SLA.0000000000006283. Online ahead of print.

Authors

Neha Goel^{1

2

3}, Alexandra E Hernandez^{1

2}, Michael H Antoni^{2

4}, Susan Kesmodel^{1

2}, Paulo S Pinheiro⁵, Erin Kobetz^{2

5

6}, Nipun Merchant^{1

2}, Steve Cole⁷

Affiliations

¹ Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, Florida, USA.
² Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA.
³ Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
⁴ Department of Psychology, University of Miami, Coral Gables, Florida, USA.
⁵ Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida, USA.
⁶ Division of Internal Medicine, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
⁷ Department of Psychiatry/ Biobehavioral Sciences and Medicine, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA, USA.

PMID: 38545788
DOI: 10.1097/SLA.0000000000006283

Abstract

Objective: To determine the association between objective (geospatial) and subjective (perceived) measures of neighborhood disadvantage (ND) and aggressive breast cancer (BCa) tumor biology, defined using validated social adversity-associated transcription factor (TF) activity and clinical outcomes.

Summary background data: ND is associated with shorter BCa recurrence-free survival (RFS), independent of individual, tumor, and treatment characteristics, suggesting potential unaccounted biological mechanisms by which ND influences RFS.

Methods: We quantified TF-binding motif prevalence within promoters of differentially expressed genes for 147 tissue samples prospectively collected on protocol. Covariate-adjusted multivariable regression analyzed objective and subjective ND scores with 5 validated TFs of social adversity and aggressive biology-pro-inflammatory activity (NF-kB, AP-1), sympathetic nervous system (SNS) activity (CREB), and protective cellular responses (IRF, STAT). To clinically validate these TFs as prognostic biomarkers of aggressive biology, logistic regression and multivariable Cox proportional-hazards models analyzed their association with Oncotype DX scores and RFS, respectively.

Results: Increasing objective ND was associated with aggressive tumor biology (up-regulated NF-kB, AP-1, down-regulated IRF, STAT) and SNS activation (up-regulated CREB). Increasing subjective ND (e.g., threat to safety), was associated with up-regulated NF-kB and CREB and down-regulated IRF. These TF patterns were associated with high-risk Oncotype DX scores and shorter RFS.

Conclusions: In the largest human social genomics study, objective and subjective ND were significantly associated with TFs of aggressive biology and SNS activation. These TFs also correlated with worse clinical outcomes, implicating SNS activation as one potential mechanism behind ND survival disparities. These findings remain to be validated in a national cohort.