Introduction: HER2-low expression tumors, either with weak or incomplete membrane expression (immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization (ISH) result), are considered and treated as HER2-negative tumors. However, recent clinical trials have shown promising results in the application of antibody-drug conjugates (ADCs) for patients with HER2-low breast tumors, highlighting the need to characterize the clinical phenotype of this group. This is the first study in Colombia aiming to explore the clinical-pathological features and survival of women affected with HER2-low breast cancer, compared with HER2-negative (0+) and HER2-positive groups (2+ with ISH+ or 3+). Methods: We included 516 breast cancer patients from different health institutions in Colombia, diagnosed at clinical stages that ranged between I-III. Protein expression of HER2, Ki67, and hormone receptors (estrogen (ER) and progesterone (PR) receptor) was evaluated by IHC in a paraffin block with tumoral tissue by a single pathologist. We defined HER2 expression as positive (3+ or 2+ with positive ISH test), low (1+/2+ with negative ISH result), and negative (0+). We applied a Chi-square or Fisher’s exact test to evaluate clinical-pathological features for HER2-low cases, compared with HER2-negative (low vs. negative) and HER2-positive tumors (low vs. positive). Differences in overall survival (OS) and risk of mortality were assessed using the Kaplan-Meier and log-rang test, and a Cox proportional hazard model. Results: 325 cases (63%) were classified as HER2-negative, 97 (18.8%) as HER2-low, and 94 (18.2%) as HER2-positive. We encountered more clinical-pathological significant differences between HER2-low and HER2-positive tumors than with HER2-negative cases. A higher proportion of patients diagnosed after the age of 50 (79.4% vs. 62.4%, p=0.018), with better-differentiated tumors (Bloom Richardson II: 58.8 vs. 41.2%, p=0.025), and a lower proliferation index (Ki67 <20%: 50.5 % vs. 21.2%, p<0.001) was observed for HER2-low tumors, compared to the HER2-positive group; these characteristics were not significantly different between HER2-low and HER2-negative tumors. The proportion of ER-positivity was significantly higher in the HER2-low group, compared to both HER2-positive (89.7% vs. 62.4%, p<0.001) and negative groups (89.7% vs. 79.7%, p=0.039). Moreover, although longer OS rates were found in HER2-low patients, compared to the negative group (5.5 vs. 5.0 years, p=0.0032), the multivariate Cox model adjusted by ER status showed no statistically significant differences between these groups (HR=0.62, 95% CI, 0.34 – 1.13, p=0.122). Conclusions: HER2-low tumors represent an important proportion of all breast cancer cases diagnosed in Colombian women. Our results are consistent with other reports that show differences in ER expression between HER2-low tumors and both HER2-positive and negative subtypes, although it seems that the prognosis of HER2-low patients is not different than of the other groups. Citation Format: Laura Rey Vargas, Lina Maria Bejarano, Juan Carlos Mejia Henao, Diego Felipe Ballen Lozano, Maria Carolina Sanabria Salas, Silvia Juliana Serrano Gomez. Characterization of HER2-low breast tumors among a cohort of Colombian women [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C015.
Introduction: Breast cancer is the most prevalent cancer in women worldwide. It is a heterogeneous disease that has been classified into intrinsic subtypes based on gene expression analyses. Previous studies have reported a higher proportion of HER2-positive (HER2+) tumors in Hispanics/Latinas, compared to Non-Hispanic White women, characterized by their aggressive phenotype. A gene expression analysis of breast tumor tissues from Colombian women reported that patients with a higher Indigenous American (IA) ancestry expressed higher mRNA levels of ERBB2, and of other genes in the HER2-amplicon region (17q12) such as GRB7. Although the expression of HER2 and GRB7 is highly correlated, it has been reported that these proteins might also be expressed independently. It is still unclear whether IA ancestry is associated with the co-expression of HER2/GRB7, or only with one of these two proteins. Aim of the study: To explore differences in HER2 and GRB7 protein expression according to genetic ancestry and the presentation of clinical-pathological features in Colombian women with breast cancer. Methods: A total of 517 Colombian breast cancer patients from different health institutions were included. For genetic ancestry estimation, 106 ancestry informative markers were genotyped from non-tumoral DNA. The protein expression of HER2 and GRB7 was evaluated in paraffin blocks with tumoral tissue by immunohistochemistry by a single pathologist. We tested the association between genetic ancestry and protein expression of HER2, GRB7, and the co-expression of both using logistic and multinomial logistic regression models. Results: Higher IA ancestry fractions were observed in patients with HER2+ compared to HER2- tumors (46% vs 41%, respectively, p = 0.013). We found higher odds of having HER2+ (OR=1.65, 95% CI, 1.05-2.63, p=0.0293) and GRB7+ tumors (OR=1.92, 95% CI, 1.03-3.56, p=0.0376) for every 25% increase in the IA ancestry proportion. The association between IA ancestry and HER2/GRB7 co-expression was influenced by estrogen receptor (ER) status. Patients with a higher IA ancestry (>42%) and with ER+ subtypes presented higher odds of having HER2+/GRB7- breast tumors (OR=3.59, 95% CI, 1.11-11.65, p=0.0327), whereas ER- patients with high IA ancestry tended to have HER2+/GRB7+ tumors (OR=2.27, 95% CI, 0.69 - 7.45, p=0.1730). The co-expression of these proteins was found associated with advanced clinical stages (p=0.018), less differentiated tumors (p=0.005), and a higher proliferation index (p<0.001), compared to HER2+/GRB7- and HER2-/GRB7- tumors. Conclusions: Our results confirm the previously reported association between IA ancestry and HER2 expression in breast tumors and suggest that HER2/GRB7 co-expression in patients with high AI ancestry may change according to the ER status. This event also correlates with unfavorable clinical-pathological features. Citation Format: Laura Rey Vargas, Lina Maria Bejarano, Juan Carlos Mejia Henao, Luz Fernanda Sua Villegas, Jhon Faustino Bastidas Andrade, Carlos Andrés Ossa Gómez, Laura Fejerman, Maria Carolina Sanabria Salas, Silvia Juliana Serrano Gomez. Association of HER2/GRB7 co-expression with Indigenous American ancestry and breast cancer clinical-pathological features [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PR-04.
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