Background: Breast cancer clinical management requires the assessment of hormone receptors (estrogen (ER) and progesterone receptor (PR)), human epidermal growth factor receptor 2 (HER2) and cellular proliferation index Ki67, by immunohistochemistry (IHC), in order to choose and guide therapy according to tumor biology. Many studies have reported contradictory results regarding changes in the biomarker profile after neoadjuvant therapy (NAT). Given its clinical implications for the disease management, we aimed to analyze changes in ER, PR, HER2, and Ki67 expression in paired core-needle biopsies and surgical samples in breast cancer patients that had either been treated or not with NAT. Methods: We included 139 patients with confirmed diagnosis of invasive ductal breast carcinoma from the Colombian National Cancer Institute. Variation in biomarker profile were assessed according to NAT administration (NAT and no-NAT treated cases) and NAT scheme (hormonal, cytotoxic, cytotoxic + trastuzumab, combined). Chisquared and Wilcoxon signed-rank test were used to identify changes in biomarker status and percentage expression, respectively, in the corresponding groups. Results: We did not find any significant variations in biomarker status or expression values in the no-NAT group. In cases previously treated with NAT, we did find a statistically significant decrease in Ki67 (p < 0.001) and PR (p = 0.02605) expression. When changes were evaluated according to NAT scheme, we found a significant decrease in both Ki67 status (p = 0.02977) and its expression values (p < 0.001) in cases that received the cytotoxic treatment. Conclusions: Our results suggest that PR and Ki67 expression can be altered by NAT administration, whereas cases not previously treated with NAT do not present IHC biomarker profile variations. The re-evaluation of these two biomarkers after NAT could provide valuable information regarding treatment response and prognosis for breast cancer patients.
BackgroundOur previous study reported higher mRNA levels of the human epidermal growth factor receptor 2 (HER2)-amplicon genes ERBB2 and GRB7 in estrogen receptor (ER)-positive breast cancer patients with relatively high Indigenous American (IA) ancestry from Colombia. Even though the protein expression of HER2 and GRB7 is highly correlated, they may also express independently, an event that could change the patients’ prognosis. In this study, we aimed to explore the differences in ER, HER2 and GRB7 protein expression according to genetic ancestry, to further assess the clinical implications of this association.MethodsWe estimated genetic ancestry from non-tumoral breast tissue DNA and assessed tumoral protein expression of ER, HER2, and GRB7 by immunohistochemistry in a cohort of Colombian patients from different health institutions. We used binomial and multinomial logistic regression models to test the association between genetic ancestry and protein expression. Kaplan-Meier and log-rank tests were used to evaluate the effect of HER2/GRB7 co-expression on patients’ survival.ResultsOur results show that patients with higher IA ancestry have higher odds of having HER2+/GRB7- breast tumors, compared to the HER2-/GRB7- subtype, and this association seems to be stronger among ER-positive tumors (ER+/HER2+/GRB7-: OR=3.04, 95% CI, 1.47-6.37, p<0.05). However, in the multivariate model this association was attenuated (OR=1.80, 95% CI, 0.72-4.44, p=0.19). On the other hand, it was observed that having a higher European ancestry patients presented lower odds of ER+/HER2+/GRB7- breast tumors, this association remained significant in the multivariate model (OR=0.36, 95% CI, 0.13 - 0.93, p= 0.0395). The survival analysis according to HER2/GRB7 co-expression did not show statistically significant differences in the overall survival and recurrence-free survival.ConclusionsOur results suggest that Colombian patients with higher IA ancestry and a lower European fraction have higher odds of ER+/HER2+/GRB7- tumors compared to ER+/HER2-/GRB7- disease. However, this association does not seem to be associated with patients’ overall or recurrence-free survival.
Introduction: Socioeconomic disadvantages can contribute to breast cancer health disparities among populations. However, it has been shown that other factors related to the etiology of breast cancer and the biology of the tumor, might also act as determinants of health disparities, as they can impact the patients’ treatment. To date, the relationship between these factors with genetic ancestry in a highly admixed population from Latin-America, has not yet been explored. Based on this, we aimed to assess contributing factors to breast cancer health disparities according to genetic ancestry in Colombian patients from a national cancer reference center. Methods: We revised clinical-pathological and socioeconomic data from breast cancer patients diagnosed at the National Cancer Institute (NCI) of Colombia and classified variables into the following groups: etiology-related factors (e.g., age of diagnosis), tumor-biology factors (e.g., tumor size), and socioeconomic factors (e.g., health insurance), each of which reflects potential sources of racial/ethnic disparities of breast cancer. We also considered variables related to treatment administration (e.g., neoadjuvant therapy) as an indicator of disease management. We applied a Kruskal–Wallis test to assess differences in genetic ancestry fractions according to each of the variables distribution. Results: A total of 308 Colombian breast cancer patients were included. Etiology-related factors analysis showed higher European ancestry fraction in patients diagnosed at older ages (>50 years: 50% vs. ≤50 years: 46%, p=0.017), and with smaller tumors (<20mm: 52% vs. ≥20mm: 48%, p=0.038). Higher Indigenous American (IA) ancestry was observed in patients with HER2-positive tumors compared to HER2-negative cases (44% vs. 40%. p=0.011). Additionally, patients with higher IA ancestry were more frequently treated with neoadjuvant therapy (NAT) (43% vs. no-NAT: 40%, p=0.050). Moreover, socioeconomic variables showed that patients that benefit from the government public health insurance, known in Colombia as subsidized regime, and those who are covered under their relative’s health insurance, known as beneficiaries, have a higher IA ancestry (43% and 43%, respectively, vs. 37%, p=0.016), compared to patients that do afford their own health insurance (contributory regime in Colombia); conversely, these patients presented a higher European ancestry (55% vs. subsidized: 47% and beneficiaries: 49%, p=0.011). Conclusions: Our results indicate that genetic ancestry is related to several potential sources of breast cancer health disparities that cover from tumor-biology factors like tumor size and HER2 expression to socioeconomic determinants like health insurance affiliation regime. Consequently, it is possible that genetic ancestry may partially reflect some differences in the disease management and in healthcare attention given to breast cancer patients in Colombia. Citation Format: Silvia J. Serrano-Gómez, Laura Rey-Vargas, Lina Bejarano, Juan Carlos Mejía-Henao, Maria Carolina Sanabria-Salas. Genetic ancestry is related to potential sources of breast cancer health disparities among 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 A072.
Purpose: Breast cancer (BC) is the leading cause of morbidity and mortality in women in Colombia, constituting a major public health issue. Importantly, not all breast cancer patients respond to neoadjuvant chemotherapy (NAC), leading to an incomplete pathological response and suggesting that there are tumor characteristics that may explain the differences in response. The overarching goal of this study is to identify gene expression profiles associated with an incomplete pathological response to NAC in Colombian women with invasive BC. Design: An integrative transcriptome analysis using Illumina high-throughput RNA sequencing was performed from 63 baseline and post-NAC (follow-up) paraffin-embedded samples from 46 different female patients with locally advanced BC (stage IIB to IIIC) treated at the Colombian National Cancer Institute. Gene expression data were obtained from 42 baseline and 21 follow-up samples. Two comparison analyses were conducted to identify differentially expressed genes (DEGs) first comparing baseline vs follow-up samples from nonresponders to NAC and second comparing to baseline samples from nonresponders vs responders to NAC. Additionally, enrichment analyses were performed in both comparative analyses. Results: From 46 patients included, 20 had a pathological complete response (pCR), while 26 did not show pCR. By investigating the gene expression profiling, 1546 significantly DEGs and 174 DEGs were identified among non-responders and Baseline analyses, respectively. From these analyses, 24 DEGs were found in common and apoptosis as the only shared enrichment pathway (p=0.001). In both analyses, Histone associated genes were downregulated in nonresponders (Histone 3, p=0,001 and Histone 2B, p<0,001). In addition, downregulation of Granzyme B and perforin were also found differentially expressed in apoptosis network pathways. CD8+ naïve T-cells, hematopoietic stem cells, Macrophages, Macrophages M1, Neurons, Th1 cells, activated dendritic cells and pro B cells were defined by the xCell algorithm and showed statistically significant association with non-response to NAC. Conclusions: Changes in histones and tumor microenvironment cell populations elicits local immune response, which contributed to therapeutic efficacy. Downregulation of Granzyme B and perforin could block mechanism of resistance to carcinogenesis, leading to non-response to NAC. Furthermore, patients with tumors containing higher gene signatures of these DEGs may benefit from NAC. Additional validations are needed to confirm these data. If confirmed, these data may be relevant in elucidating the mechanisms that lead to therapy resistance as well as in selecting patients that will benefit from NAC in Latino (Colombian) patients. Citation Format: Hedda Michelle Guevara-Nieto, Rafael Parra-Medina, Juan Carlos Mejia-Henao, Patricia Eugenia López-Correa, José Ismael Guío-Avila, Sandra Diaz-Casas, Jone Garai, Jovanny Zabaleta, Liliana López-Kleine, Alba Lucia Cómbita. Identification of predictive biomarkers for neoadjuvant chemotherapy response in invasive breast cancer Latino patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1255.
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