2023 Dlin/Fischer Clinical Research Award: Social Disparities and Cancer: The Biologic Fingerprint of Stress is Transplantable and Associated with Worse Clinical Outcomes

Background: Low socioeconomic status (SES) is associated with increased serious psychological distress as well as adverse cancer outcomes. Allogeneic hematopoietic cell transplantation (HCT) carries significant risks, with low SES predictive of increased morbidity and mortality (Baker, 2009). We have demonstrated that up-regulation of the stress- and SES-related gene expression profile termed the 'conserved transcriptional response to adversity' (CTRA) is associated with low SES and worse outcomes among HCT recipients (Knight, 2016). However, previous work has not addressed the influence of donor socioeconomic factors and stress-related biology on HCT recipient outcomes.

Methods: Among matched unrelated HCT donor/recipient pairs obtained from the Center for International Blood and Marrow Transplant Research from 2000-2013, we evaluated whether donor SES (N=2,005 pairs) and CTRA gene regulation (N=263 biospecimen pairs) were associated with inferior HCT outcomes at 3 years in recipients being treated for hematologic malignancy. Multivariable models adjusted for donor and recipient characteristics evaluated associations between donor SES and CTRA and recipient clinical outcomes including overall survival (OS), treatment-related mortality (TRM), disease free survival (DFS), relapse, and acute/chronic graft versus host disease.

Results: Multivariable analyses among 2,005 donor-recipient pairs identified significant associations between a standardized donor SES composite score and DFS (p=0.009), OS (p < 0.001), and TRM (p=0.005). Recipients transplanted with cells from a donor of greater socioeconomic disadvantage experienced a 10% reduction in DFS and OS, and a 5% increase in TRM at 3 years compared with those transplanted with cells from a high-SES donor. In RNA sequencing data from a subset of 263 HCT donors, greater CTRA expression was associated with reduced OS (p=.046), an effect driven predominately by increased TRM (p=.0001). Donor cell effects on transplant outcomes derived mainly from the pro-inflammatory component of the CTRA (OS: p= 003; TRM: p=.010) and emerged above and beyond the effects of the recipients' own SES, as well as multiple other recipient disease, treatment, and demographic factors.

Discussion: For the first time, we show that low SES and gene expression patterning consistent with neighborhood SES disadvantage among HCT donors results in adverse recipient HCT outcomes. Clinical outcomes affected in both the SES and CTRA models are consistent, suggesting that the stress of low SES has a biologic impact at either the stem or immune cell level that persists even when transplanted into a new host.

Conclusions: These data demonstrate that the impact of stress on health disparities is robust enough as to be transplantable into a new host, highlighting the need for clinical interventions to reduce the stress of social health disparities and improve the outcomes of this high-risk group of cancer patients.

References:
1. Baker KS, Davies SM, Majhail NS, et al (2009). Race and socioeconomic status influence outcomes of unrelated donor hematopoietic cell transplantation. Biology of Blood & Marrow Transplantation; 15(12):1543-54.
2. Knight JM, Rizzo JD, Logan BR, et al (2016). Low socioeconomic status, adverse gene expression profiles, and clinical outcomes in hematopoietic stem cell transplant recipients. Clinical Cancer Research; 22(1):69-78.