The Impact of Diabetes and HER2 Expression on Recurrence Risk and Survival in a Diverse Prostate Cancer Patient Population Restricted; Files Only
Mavingire, Nicole Ursula Rumbidzai (Spring 2026)
Abstract
Background: Prostate cancer (PC) disproportionately burdens Black men and is frequently complicated by metabolic comorbidities. Diabetes mellitus (DM) is paradoxically associated with reduced PC incidence yet worse PC outcomes. Human epidermal growth factor receptor 2 (HER2/ERBB2), mechanistically linked to insulin signaling, has been proposed as a bridge between metabolic disease and aggressive PC. We evaluated whether DM is associated with recurrence and survival, whether HER2 mediates these risks, and whether DM and HER2 interact to modify outcomes in a racially diverse cohort.
Methods: We conducted a retrospective cohort study of 517 men with Stage I–III PC who underwent radical prostatectomy (2009–2020), combining data from the Department of Defense Prostate Cancer Biorepository Network and UAB Tissue Biorepository. DM was defined by clinical records. HER2 was assessed by immunohistochemistry on tissue microarrays. West African ancestry (WAA) was estimated from 105 ancestry-informative markers using ADMIXTURE. A directed acyclic graph guided covariate selection (confounders: age, WAA, BMI). Logistic regression evaluated clinical recurrence; Cox proportional hazards models assessed time to recurrence (TTR) and overall survival (OS). Firth penalized regression examined DM × HER2 interactions.
Results: DM (8.1%) was more prevalent among older, Black men with higher WAA and BMI (all p<0.05). DM was not associated with recurrence (OR range 0.59–0.99, all p>0.3), TTR, or OS, and HER2 did not mediate any DM–outcome relationship. Paradoxically, HER2-positive status was associated with reduced recurrence risk in univariate analysis (OR=0.49, p=0.004) but independently predicted nearly five-fold higher mortality in adjusted OS models (HR=4.71, p=0.031), with trends toward shorter TTR (HR=1.48, p=0.2). Kaplan–Meier analyses confirmed significantly different TTR distributions by HER2 status (log-rank p<0.05). Exploratory interaction analyses suggested DM may be protective against recurrence in HER2-negative patients (TTR HR=0.10, p=0.022), an effect abolished in HER2-positive disease (interaction HR=9.79, p=0.053).
Conclusions: DM was not associated with PC recurrence or survival in this surgically treated cohort. HER2-positive status emerged as a novel independent predictor of mortality, potentially reflecting PSA-independent lethal progression. A hypothesis-generating DM × HER2 interaction warrants validation in larger cohorts. These findings support HER2 as a clinically meaningful prognostic biomarker and therapeutic target in PC.
Table of Contents
INTRODUCTION AND BACKGROUND 1
METHODS 7
RESULTS 16
DISCUSSION 27
CONCLUSIONS 41
TABLES & FIGURES 42
List of Figures 43
List of Tables 44
Figure 1. Study flow diagram illustrating the selection of participants from the PCBN and UAB 45
Biorepository databases of prostate cancer patients who underwent radical prostatectomy,
2009 – 2020.
Figure 2. Directed acyclic graph model of the relationship of diabetes and clinical recurrence (relapse) 46
among prostate cancer patients who underwent radical prostatectomy.
Figure 3. The association of diabetes with time-to-recurrence using Cox proportional hazards 46
model 2A (base model).
Figure 4. The HER2-mediated association of diabetes with time-to-recurrence using Cox 47
proportional hazards model 2B (HER2-mediated model).
Figure 5. The association of diabetes with time-to-recurrence after adjusting for tumor characteristics 47
using Cox proportional hazards model 2C (fully-adjusted model).
Figure 6. The association of diabetes with overall survival using Cox proportional hazards model 2A 47
(base model).
Figure 7. The HER2-mediated association of diabetes with time-to-recurrence using Cox 48
proportional hazards model 2B (HER2-mediated model).
Figure 8. The association of diabetes with time-to-recurrence after adjusting for tumor characteristics 48
using Cox proportional hazards model 2C (fully-adjusted model).
Figure 9. Kaplan-Meier analysis of Recurrence-Free Survival stratified by diabetes status (unadjusted). 49
Figure 10. Kaplan-Meier analysis of Recurrence-Free Survival stratified by HER2 status (unadjusted). 49
Figure 11. Kaplan-Meier analysis of Recurrence-Free Survival stratified by diabetes/HER2 status 50
(unadjusted).
Figure 12. Kaplan-Meier analysis of overall survival stratified by diabetes status (unadjusted). 50
Figure 13. Kaplan-Meier analysis of overall survival stratified by HER2 status (unadjusted). 51
Figure 14. Kaplan-Meier analysis of overall survival stratified by diabetes/HER2 status (unadjusted). 51
Table 2.1 The six primary regression models employed across both study aims. 52
Table 3.1 The baseline characteristics of study participants stratified by diabetes status at the time of 53
radical prostatectomy.
Table 3.2 The individual variable effects on recurrence risk by univariate model analysis. 54
Table 3.3 The total effect of diabetes on recurrence risk: multivariate model 1A (base model). 55
Table 3.4 The HER2-mediated effect of diabetes on recurrence risk: multivariate model 1B. 55
Table 3.5 The “controlled” directed effects of diabetes on recurrence risk: combined 56
univariate and fully-adjusted multivariate model 1C.
Table 3.6 The diabetes × HER2 interaction effects on recurrence risk (base model 1A with 57
interaction).
Table 3.7 The diabetes × HER2 interaction direct effects on recurrence risk (fully-adjusted 58
model 1C with interaction).
Table 3.8 The stratified diabetes effects due to interaction (OR_Diabetes main effect × OR_Interaction) 59
on recurrence risk (Base and fully-adjusted models with interaction).
Table 3.9 The total effect of diabetes on time-to-recurrence: Cox proportional hazards multivariate 59
model 2A.
Table 3.10 The HER2-mediated effect of diabetes on time-to-recurrence: Cox proportional hazards 60
multivariate model 2B.
Table 3.11 The “controlled” direct effect of diabetes on time-to-recurrence: Cox proportional hazards 61
multivariate model 2C (fully-adjusted).
Table 3.12 The total effect of diabetes on overall survival: Cox proportional hazards multivariate 62
model 2A.
Table 3.13 The HER2-mediated effect of diabetes on overall survival: Cox proportional hazards 62
multivariate model 2B.
Table 3.14 The “controlled” direct effect of diabetes on overall survival: Cox proportional hazards 63
multivariate model 2C (fully-adjusted).
Table 3.15 The diabetes × HER2 interaction effects on time-to-recurrence (base model 2A with 64
interaction).
Table 3.16 The diabetes × HER2 interaction effects on overall survival (base model 2A with 64
interaction).
Table 3.17 The diabetes × HER2 interaction effects on time-to-recurrence (fully-adjusted model 65
2C with interaction).
Table 3.18 The diabetes × HER2 interaction effects on overall survival (fully-adjusted model 66
2C with interaction).
Table 3.19 The stratified diabetes effects due to interaction (HR_Diabetes main effect × 66
HR_Interaction) on survival outcomes, time-to-recurrence, and overall survival
(base and fully-adjusted models with interaction).
Table 3.20 The complete case analysis of fully-adjusted “controlled” direct effects of diabetes on 67
recurrence (model 1C).
Table 3.21 The complete case analysis of fully-adjusted “controlled” direct effects of diabetes on 67
time-to-recurrence (model 2C).
Table 3.22 The complete case analysis of fully-adjusted “controlled” direct effects of diabetes on 68
overall survival (model 2C).
REFERENCES 69
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