HER2 Status in Breast Cancer in Relation to Age and Tumor Category: A Cross-Sectional Clinicopathological Study from Karbala, Iraq

Abstract

Background: Human epidermal growth factor receptor 2 (HER2) overexpression defines an aggressive, biologically distinct subset of breast carcinomas with critical therapeutic relevance. Epidemiological and pathological profiles from central Iraq, particularly Karbala Province, re- main scarce. This study evaluates HER2 immunohistochemical (IHC) expression profiles across age cohorts and clinicopathological tumor categories in Iraqi breast cancer patients.

Materials and Methods: In this retrospective cross-sectional study, clinicopathological data from 99 consecutive women with histologically confirmed invasive breast carcinoma diagnosed at a tertiary diagnostic center in Karbala Province were evaluated. Patients were categorized into four age deciles (28–39, 40–49, 50–59, and 60–69 years). Tumor category was documented based on standardized diagnostic practice incorporating histological types (invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), clinical stage/extent (locally advanced breast cancer (LABC), metastatic breast cancer (MBC), and receptor-defined molecular subtype (triple-nega- tive breast cancer (TNBC). HER2 expression was scored by IHC according to 2013 ASCO/CAP guidelines (0, 1+, 2+, 3+). Categorical distributions were analyzed using Pearson χ² and exact Monte Carlo tests. Multivariable logistic regression and continuous-age sensitivity analyses were conducted to identify independent predictors of HER2 3+ positivity.

Results: The median cohort age was 48 years, with the 40–49-year decile representing the largest patient stratum (33.3%, 33/99). Invasive ductal carcinoma was the predominant tumor category (56.6%, 56/99), followed by LABC (16.2%, 16/99), ILC (12.1%, 12/99), MBC (8.1%, 8/99), and TNBC (7.1%, 7/99). Overall, 47.5% (47/99) of tumors scored IHC 0 and 13.1% (13/99) scored IHC 1+ (total HER2-negative = 60.6%), while 13.1% (13/99) were equivocal (IHC 2+), and 26.3% (26/99) exhibited definitive HER2 3+ overexpression. Accounting for unresolved equivocal cas- es, potential cohort HER2 positivity ranges from 26.3% to 39.4%. HER2 IHC score demonstrated no significant association with patient age (χ² = 3.43, df = 9, p = 0.94). In contrast, tumor cate- gory distribution varied significantly across age cohorts (χ² = 151.50, df = 12, exact Monte Carlo p < 0.00001), reflecting earlier presentation for IDC and clustering of advanced/TNBC cases in older cohorts. In multivariable logistic regression, neither age group nor tumor category inde- pendently predicted HER2 3+ status (IDC adjusted OR = 1.67, 95% CI: 0.20–14.05, p = 0.64; age 40–49 adjusted OR = 0.90, 95% CI: 0.25–3.28, p = 0.87).

Conclusions: Over half of the cohort exhibited detectable HER2 expression, with a definitive IHC 3+ rate of 26.3% that aligns with regional Middle Eastern series and exceeds Western histor- ical averages. The presence of 13.1% unresolved equivocal cases underscores the clinical impera- tive for establishing onsite reflex in-situ hybridization (ISH). Tumor category varied significantly across age groups, whereas HER2 expression was age-independent. Standardized synoptic re- porting and multi-center molecular profiling are warranted.