Triple-negative Breast Cancer Cases Research Articles

Development and verification of a novel immunogenic cell death-related signature for predicting the prognosis and immune infiltration in triple-negative breast cancer.

Insufficient understanding of the pathogenesis and tumor immunology of triple-negative breast cancer (TNBC) has limited the development of immunotherapy. The importance of tumor microenvironment (TME) in immunotyping, prognostic assessment and immunotherapy efficacy of cancer has been emphasized, however, potential immunogenic cell death (ICD) related genes function in TME of TNBC has been rarely investigated. To initially explore the role and related mechanisms of ICD in TNBC, especially the role played in the TME of TNBC, and to identify different relevant subtypes based on ICD, and then develop an ICD-related risk score to predict each TNBC patient TME status, prognosis and immunotherapy response. In this study, we identified distinct ICD-related modification patterns based on 158 TNBC cases in the TCGA-TNBC cohort. We then investigated the possible correlation between ICD-related modification patterns and TME cell infiltration characteristics in TNBC. By using univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analysis, we created a risk scoring system (ICD score) to quantifiably evaluate the impact of ICD-related modification patterns in individual TNBC patient. Two different ICD-related modification patterns were found with significant differences in immune infiltration. Lower ICD score was correlated with higher immune infiltration, tumor mutational burden and significantly enriched in immune-related pathways, indicating a strong ability to activate immune response, which might account for relatively favorable prognosis of TNBC patients and could serve as a predictor to select suitable candidates for immunotherapy. We used two independent cohorts, GSE58812 cohort and Metabric cohort to validate prognosis and immunohistochemistry for preliminary in vitro validation. This study evidenced that the ICD-related modification patterns might exert pivotal roles in the immune infiltration landscape of TNBC and ICD score might act as potential predictors of prognostic assessment and immunotherapy response. This research provides unique insights for individualize immune treatment strategies and promising immunotherapy candidates screening.

Characterizing PALB2 intragenic duplication breakpoints in a triple-negative breast cancer case using long-read sequencing.

Accurate identification and characterization of Large Genomic Rearrangements (LGR), especially duplications, are crucial for precise diagnosis and risk assessment. In this report, we characterized an intragenic duplication breakpoint of PALB2 to determine its pathogenicity significance. A 52-year-old female with triple-negative breast cancer was diagnosed with a novel PALB2 LGR. An efficient and accurate methodology was applied, combining long-read sequencing and transcript analysis for the rapid characterization of the duplication. Duplication of exons 5 and 6 of PALB2 was validated by transcript analysis. Long-read sequencing enabled the localization of breakpoints within Alu elements, providing insights into the mechanism of duplication via non-allelic homologous recombination. Using our combined methodology, we reclassified the PALB2 duplication as a pathogenic variant. This reclassification suggests a possible causative link between this specific genetic alteration and the aggressive phenotype of the patient.

Five-year survival of triple-negative breast cancer and the associated clinicopathological factors: a study in an Indonesian tertiary hospital

BACKGROUND Triple-negative breast cancer (TNBC) has a worse rate of recurrence, survival, and overall survival. This study aimed to find the survival of TNBC and its clinicopathological factors at Cipto Mangunkusumo Hospital.
 METHODS This study used survival analysis based on clinicopathology in 112 TNBC cases at Cipto Mangunkusumo Hospital, Jakarta, Indonesia, diagnosed from 2009 to 2019. Kaplan–Meier and log-rank tests were used for the analysis. Bivariate and multivariate analyses using Cox regression were performed to obtain the hazard ratios (HRs).
 RESULTS Most patients were diagnosed at the locally advanced stage (40.2%) compared to the early (33.0%) and metastatic stages (17.9%). The 5-year survival of TNBC was 81.2% with an HR value of 1.372 (p = 0.239) compared to luminal A. Bivariate analyses showed that the older age group with an HR of 6.845 (p = 0.013; CI 1.500–31.243), larger tumor size and extension (T) with an HR of 11.826 (p = 0.001; CI 2.707–51.653), broader regional lymph node involvement (N) with an HR of 8.929 (p = 0.019; CI 1.434–55.587), farther distant metastases (M) with an HR of 3.016 (p = 0.015; CI 1.242–7.322), more lymphovascular invasion with HR of 3.006 (p = 0.018; CI 1.209–7.477), and not operated-on cases with an HR of 9.165 (p<0.001; CI 3.303–25.434) significantly shortened the survival of TNBC. Multivariate analysis found that the only factor worsening the survival was not having surgery, with an HR of 6.175 (p<0.001; CI 1.518–34.288).
 CONCLUSIONS The 5-year survival rate of TNBC patients was 81.2%. Not having surgery was a clinicopathological factor that worsened survival outcomes in TNBC.

A Pilot Study on BRCA1/2 and PI3K Mutations Across Subtypes of Triple Negative Breast Cancer in North Indian Population.

BRCA1/2 are tumor suppressor genes which regulate the DNA repair mechanism. Mutations in BRCA1/2 may increase the risk of breast cancer in patients. In the present study frequency of BRCA1/2 mutations in triple negative breast cancer (TNBC) patients was assessed and correlated with molecular subtypes of TNBC. Blood samples from 65 confirmed cases of TNBC were collected. DNA was isolated from whole blood and libraries were prepared using a BRCA1/2 custom panel. Sequencing was done on Ion torrent S5 sequencer and ion reporter was used for data analysis. Further molecular subtyping of mutation positive TNBC cases was done using immunohistochemistry markers CK5/6; CK4/14; Vimentin and E-Cadherin and androgen receptor (AR) using tissue microarray. Twenty five of 65 patients had heterozygous pathogenic mutations, alterations with conflicting interpretation of pathogenicity, variants of uncertain significance and variants of unknown significance. Nine patients had pathogenic mutation in BRCA 1 gene only and 2 patients had pathogenic mutations in BRCA2 gene. Two patients were transheterozygous for BRCA mutations, that is, had pathogenic mutations in both BRCA1/2 genes simultaneously and 5 were compound heterozygous (involving BRCA2 gene in all the cases). Prevalent subtypes among BRCA positive cases were unclassified subtype (n=4, 33%), Basal like (n=5, 41%), and mesenchymal subtype (n=3, 25%). None of the LAR subtype showed BRCA1/2 mutations. The present study observed that the BRCA1 mutation is more frequent than BRCA2 mutation in TNBC. BRCA1/2 mutations do not correspond to BRCAness or basal phenotype. Considering high incidence of breast cancer and lack of correlation of basal morphology with BRCA1/2 mutation, the molecular methods should be used for screening for BRCA1/2 mutations. This will not only help in familial screening but also in deciding targeted therapy with PARP (poly-ADP ribose polymerase) inhibitors.

Immunohistochemistry in the Differential Diagnosis of Triple Negative Breast Carcinoma and High-grade Serous Carcinoma: Old and New Markers.

Distinction of metastasis to the breast from a breast primary, particularly high-grade triple-negative breast cancer (TNBC), can be challenging due to nonspecific morphology and immunohistochemical (IHC) profiles. Among metastases to the breast, high-grade serous carcinoma (HGSC) of müllerian origin is most likely to be misdiagnosed as TNBC. We assessed breast and müllerian markers on TNBC and HGSC, including keratin 7, keratin 20, GATA3, GCDFP15, mammaglobin, p53, PAX8 (MRQ50 and BC12 clones), TRPS1, SOX10, and WT1. Of 151 TNBC cases, TRPS1 had the highest sensitivity, showing expression in 149 (98.7%) cases, followed by SOX10 (110/151; 72.8%), GATA3 (102/151; 67.5%), GCDFP15 (29/151; 19.2%), and mammaglobin (27/151; 17.9%). PAX8 positivity was seen in 40.4% (61/151) of TNBC via the MRQ50 clone but was negative in all via the BC12 clone. Of 185 HGSC cases, PAX8 via the MRQ50 clone was the most sensitive (179/185; 96.8%), followed by WT1 (171/185; 92.4%) and PAX8 via the BC12 clone (164/185; 88.6%). In addition, TRPS1 positivity was seen in 75 HGSC cases (40.5%). Aberrant p53 patterns were seen in 64.9% (98/151) of TNBC and 94.1% (174/185) of HGSC. TRPS1 positivity in HGSC and PAX8 positivity via the MRQ50 clone in TNBC represent potential pitfalls in assessing high-grade carcinoma for which the differential diagnosis includes TNBC and HGSC. However, with this knowledge, utilization of a panel of breast and müllerian markers, including preferential use of the PAX8 BC12 clone, can facilitate accurate diagnosis.

CD10 expression as a potential predictor of pathological complete response in ER-negative and triple-negative breast cancer patients treated with anthracycline-based neoadjuvant chemotherapy

BackgroundNeoadjuvant chemotherapy (NCT) can induce a pathological complete response (pCR) in breast cancer patients, leading to improved outcomes. However, predicting which patients will achieve pCR remains a challenge. CD10, a myoepithelial marker, has shown diagnostic and prognostic value in metastatic tumors. Its potential as a predictor of chemosensitivity to anthracycline-based NCT in breast cancer is unknown. AimThis retrospective study aimed to investigate the potential of CD10 cancer cell expression as a predictive marker of chemosensitivity in breast cancers treated with anthracycline-based neoadjuvant chemotherapy. MethodsWe analyzed 130 patients with invasive ductal carcinoma who received anthracycline-based NCT. CD10 expression was assessed by immunohistochemistry on pre-treatment biopsies. Statistical analysis evaluated the association between CD10 expression and pCR rates. ResultsUnivariate analysis revealed that ER-positive and CD10-negative tumors had lower pCR rates [OR 7.4830 (95% CI 2.7762–20.1699); p = 0.0001]. Multivariate analysis confirmed ER status as a strong predictor of poor response [OR 0.085 (95% CI 0.024–0.30); p < 0.001] and CD10 expression as a predictor of a favourable response [OR 0.11 (0.8–0.19); p = 0.049]. CD10 expression significantly predicted pCR in ER-negative cases [OR 0.1098 (0.0268–0.4503); p = 0.0022] and triple-negative breast cancer [OR 0.0966 (95% CI 0.0270–0.3462); p = 0.0003]. Concordance was observed between core biopsies and excised samples. ConclusionPositive CD10 cancer cell expression may predict increased response to anthracycline-based neoadjuvant chemotherapy in ER-negative and triple-negative breast cancer cases. Further research is needed to validate these findings in larger cohorts and determine the clinical utility of CD10 as a predictive marker.

The Diagnostic Value of a Nomogram Based on Clinical Imaging and MRIBased Radiomic Features in Triple-Negative Breast Cancer.

This study aimed to determine the utility of a radiomic nomogram combined with clinical imaging and radiomic features based on MRI for the diagnosis of triple-negative breast cancer. Multi-parametric MRI images of 136 breast cancer patients were retrospectively analyzed, 95 cases were stratified into the training cohort, and 41 cases were selected for the test group. According to the pathological molecular typing, the patients were divided into 23 cases of triple-negative breast cancer and 113 cases of non-triple-negative breast cancer. ITK software was used to manually delineate the lesion volume region of interest (VOI), and the Pyradiomics package was used to extract radiomic features for screening and model building. The platform was then used to analyze the clinical and imaging risk factors of breast cancer to build a characteristic model separately. Finally, a radiomic nomogram was constructed by integrating the radiomic and independent clinical image features. The diagnostic performance of the model was assessed using ROC curves. Univariate and multivariate analyses showed that the menstrual cycle, glandular density, and skin thickening were risk factors for clinical imaging characteristics of triple-negative breast cancer. The Area Under the Curve (AUC) was 0.839 and 0.826 for univariate and multivariate analysis, respectively. After screening, 11 radiomic features participated in the calculation of the radiomic score, and its AUC in the test set was 0.803. Combining it further with clinical models, the AUC improved to 0.899. The radiomic nomogram developed in this study has great value in the diagnosis of triple-negative breast cancer.

Detection of KRAS Mutations in Triple-negative Breast Cancers by Polymerase Chain Reaction

Abstract Background: Recently, it has been proven that KRAS gene mutation analysis is an additional in vitro diagnostic method for determining colorectal cancer patients who will not respond to anti-epidermal growth factor receptor (EGFR) therapy. KRAS mutation status assessment may be important in other EGFR-overexpressed cancers, such as breast cancer tumors. Only 5% of breast tumors are KRAS-mutated, yet 60% of triple-negative breast tumors express EGFR, making them potential targets for EGFR inhibitors. To provide a biological foundation for assessing anti-EGFR therapy, we aimed to examine the frequency of KRAS mutations in triple-negative breast cancer (TNBC). Materials and Methods: Forty breast cancer cases were evaluated. These 40 cases have undergone immunohistochemistry for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 markers which exhibited a negative reaction and were ascertained as triple negative. The mutation status of KRAS was determined by real-time polymerase chain reaction (RT-PCR) to detect wild or mutant types of KRAS. Results: In our study, we observed that, out of the total 40 cases of TNBCs, 14 (35%) cases were of wild type and 26 (65%) cases were mutant type detected by RT-PCR. Conclusion: According to our study, KRAS mutations were detected in TNBCs, and EGFR inhibitors may be effective in the treatment of these tumors, which overexpress EGFR in around 65% of cases.

Exploring novel immunotherapy biomarker candidates induced by cancer deformation.

Triple-negative breast cancer (TNBC) demands urgent attention for the development of effective treatment strategies due to its aggressiveness and limited therapeutic options [1]. This research is primarily focused on identifying new biomarkers vital for immunotherapy, with the aim of developing tailored treatments specifically for TNBC, such as those targeting the PD-1/PD-L1 pathway. To achieve this, the study places a strong emphasis on investigating Ig genes, a characteristic of immune checkpoint inhibitors, particularly genes expressing Ig-like domains with altered expression levels induced by "cancer deformation," a condition associated with cancer malignancy. Human cells can express approximately 800 Ig family genes, yet only a few Ig genes, including PD-1 and PD-L1, have been developed into immunotherapy drugs thus far. Therefore, we investigated the Ig genes that were either upregulated or downregulated by the artificial metastatic environment in TNBC cell line. As a result, we confirmed the upregulation of approximately 13 Ig genes and validated them using qPCR. In summary, our study proposes an approach for identifying new biomarkers applicable to future immunotherapies aimed at addressing challenging cases of TNBC where conventional treatments fall short.

Evolutionary Profil of Triple-Negative Breast Cancer and Influence of Histopronostic Factors: Experience of Oncology Department Chu Ibn Rochd Casablanca

Triple-negative breast cancer (TNBC) is a subgroup of breast cancer with hormone receptor and Her2 overexpression absence, accounting for 15%–20% of all breast cancers. Its unpredictable evolution, poor treatment response, and highly invasive nature warrant research interest. The main objective of this study is to assess the evolution of triple-negative breast cancer as a role for histopronostic factors. We present the evolutionary profile of triple-negative breast cancer in the role of histopronostic factors using data from a four-year retrospective study of cases of triple-negative breast cancer collected in the oncology-radiotherapy department at Chu Ibn Rochd Casablanca between January 2015 and December 2019. 232 patients were included, regardless of disease stage. The mean age was 49.54 ± 11.21 years. In 68% of cases, the disease was localized. All metastatic patients (32%) died, with a median survival of 15 months. We analyzed the evolution of triple-negative breast cancer in localized disease as a role for age, tumor size, histological type, SBR grade, lymph node invasion, and vascular invasion, with a median follow-up of 24 months (2 years). In 158 patients in our series with localized disease, local or locoregional recurrence was noted in 16% of cases, metastatic relapse in 10%, and 30% of cases were still in complete remission. Patients aged between 40 and 50 had a higher rate of local and locoregional recurrence. Patients with tumors between 2 and 6 cm in size had a high rate of metastasis and death. Grade SBR III is generally marked by a poor prognosis, with 39 patients having local or locoregional recurrence, 41 patients having metastases, and 15 patients having died. In our series, the greater the lymph node and vascular invasion, the poorer the prognosis, with a higher risk of recurrence and metastasis. These results support the role of early screening, especially for at-risk patients, adequate therapeutic management, and active surveillance of patients with triple-negative breast cancer. New research has shown the effectiveness of immune checkpoint inhibitors and anti-parp in treating advanced triple-negative breast cancer (TNBC), with encouraging findings indicating their potential benefit. Clinical studies including anatomical pathologists, oncologists, and fundamental researchers must be conducted globally to achieve this. Clinical studies involving pathologists, oncologists, and basic researchers are needed worldwide to define new therapeutic strategies for the management of this type of aggressive breast cancer.

Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer: a clinical and translational study.

p53 is mutated in half of cancer cases. However, no p53-targeting drugs have been approved. Here, we reposition decitabine for triple-negative breast cancer (TNBC), a subtype with frequent p53 mutations and extremely poor prognosis. In a retrospective study on tissue microarrays with 132 TNBC cases, DNMT1 overexpression was associated with p53 mutations (P = 0.037) and poor overall survival (OS) (P = 0.010). In a prospective DEciTabinE and Carboplatin in TNBC (DETECT) trial (NCT03295552), decitabine with carboplatin produced an objective response rate (ORR) of 42% in 12 patients with stage IV TNBC. Among the 9 trialed patients with available TP53 sequencing results, the 6 patients with p53 mutations had higher ORR (3/6 vs. 0/3) and better OS (16.0 vs. 4.0 months) than the patients with wild-type p53. In a mechanistic study, isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53. In the DETECT trial, decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line (upregulation by 16-fold) and the most responsive patient with TNBC. Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.

Evaluation of MMP-13 and Micro RNA-138 as prognostic biomarkers for breast cancer in Egyptian women patients

BackgroundElevated serum levels of MMP-13 are linked to tumor growth and metastasis, while miR-138 dysregulation is observed in breast cancer cases. The aim of this study is to investigate the expression of miR-138 and MMP-13 levels as potential biomarkers for the prognosis of breast cancer. Patients and MethodIn this retrospective case-control study, 119 female subjects were recruited and divided into three groups. MMP-13 level was measured using Enzyme Linked Immunosorbent Assay (ELISA), while real-time PCR technique was employed to quantify miR-138 expression. ResultsBoth non-metastatic and metastatic groups showed significantly higher levels of serum MMP-13 compared to other groups. MMP-13 levels are significantly increased among patients with advanced tumor size, lymph node metastasis, and triple-negative breast cancer cases. An inverse significant association between MMP-13 levels and response to treatment was observed. Expression of miR-138 underwent a significant down-regulation in breast cancer patients, and a statistically significant association was established between miR-138 expression and triple-negative breast cancer cases. A positive association was detected between the increase in miR-138 expression and the good response to treatment. The expression of miR-138 was inversely correlated with the MMP-13 levels. ConclusionMMP-13 levels were significantly higher in breast cancer, especially in advanced cases, suggesting its role in promoting tumor invasion and metastasis. MiR-138 was down-regulated in breast cancer, especially in triple-negative breast cancer patients, rendering it a promising biomarker for triple-negative breast cancer. Modulation of miR-138 expression and MMP-13 levels may represent therapeutic targets for breast cancer.

Pigmented Microbial Extract (PMB) from Exiguobacterium Species MB2 Strain (PMB1) and Bacillus subtilis Strain MB1 (PMB2) Inhibited Breast Cancer Cells Growth In Vivo and In Vitro.

Breast cancer (BC) continues to be one of the major causes of cancer deaths in women. Progress has been made in targeting hormone and growth factor receptor-positive BCs with clinical efficacy and success. However, little progress has been made to develop a clinically viable treatment for the triple-negative BC cases (TNBCs). The current study aims to identify potent agents that can target TNBCs. Extracts from microbial sources have been reported to contain pharmacological agents that can selectively inhibit cancer cell growth. We have screened and identified pigmented microbial extracts (PMBs) that can inhibit BC cell proliferation by targeting legumain (LGMN). LGMN is an oncogenic protein expressed not only in malignant cells but also in tumor microenvironment cells, including tumor-associated macrophages. An LGMN inhibition assay was performed, and microbial extracts were evaluated for in vitro anticancer activity in BC cell lines, angiogenesis assay with chick chorioallantoic membrane (CAM), and tumor xenograft models in Swiss albino mice. We have identified that PMB from the Exiguobacterium (PMB1), inhibits BC growth more potently than PMB2, from the Bacillus subtilis strain. The analysis of PMB1 by GC-MS showed the presence of a variety of fatty acids and fatty-acid derivatives, small molecule phenolics, and aldehydes. PMB1 inhibited the activity of oncogenic legumain in BC cells and induced cell cycle arrest and apoptosis. PMB1 reduced the angiogenesis and inhibited BC cell migration. In mice, intraperitoneal administration of PMB1 retarded the growth of xenografted Ehrlich ascites mammary tumors and mitigated the proliferation of tumor cells in the peritoneal cavity in vivo. In summary, our findings demonstrate the high antitumor potential of PMB1.

Eliciting the antitumor immune response with a conditionally activated PD-L1 targeting antibody analyzed with a quantitative systems pharmacology model.

Conditionally activated molecules, such as Probody therapeutics (PbTx), have recently been investigated to improve antitumoral response while reducing systemic toxicity. PbTx are engineered to be proteolytically activated by proteases that are preferentially active locally in the tumor microenvironment (TME). Here, we perform an exploratory study using our recently published quantitative systems pharmacology model, previously validated for other drugs, to evaluate the effectiveness and targeting specificity of an anti-PD-L1 PbTx compared to the non-modified antibody. We have informed the model using the PbTx dynamics and pharmacokinetics published in the literature for anti-PD-L1 in patients with triple-negative breast cancer (TNBC). Our results suggest masking of the antibody slightly decreases its efficacy, while increasing the localization of active therapeutic component in the TME. We also perform a parameter optimization for the PbTx design and drug dosing regimens to maximize the response rate. Although our results are specific to the case of TNBC, our findings are generalizable to any conditionally activated PbTx molecule in solid tumors and suggest that design of a highly effective and selective PbTx is feasible.

Abstract C047: Multiomics approaches to identify African-ancestry specific phenotypes of triple negative breast cancer

Abstract Despite recent convergence of breast cancer (BC) incidence among African American (AA) and European American (EA) women, BC mortality remains 40% higher among AA women. This disparity is driven partly by BC heterogeneity, where distinct subtypes have differing prognosis and treatment modalities, defined by presence of estrogen and/or progesterone receptor (HR+), overexpression of HER2, or lack of all three biomarkers (triple negative BC (TNBC)). TNBC is the most aggressive subtype, diagnosed as late-stage disease and lacking targeted therapeutic options. TNBC represents ~10% of annual diagnoses, however prevalence is significantly higher among AA women. Our work in the International Center for the Study of Breast Cancer Subtypes (ICSBCS) revealed significant association of west African (AFR) ancestry and TNBC, where we report that Ghanaian and AA women have increased frequency of TNBC, compared to Ethiopian and EA women, and that TNBC patients have higher percentages of quantified AFR ancestry. To characterize AFR ancestry-specific TNBC phenotypes, we have employed transcriptomics and whole genome sequencing (WGS) methods. Our recent publication from an AFR ancestry enriched TNBC transcriptomics cohort (n = 26) leveraged genetic ancestry to identify 600+ AFR and 2000+ AFR sub-continental ancestry associated genes. Pathway analysis showed enrichment of immune cell trafficking and indicates distinct AFR ancestry phenotypes that can be leveraged for future therapeutic opportunities. Recently, we have completed WGS on 80+ AFR ancestry patients with TNBC disease (n = 59) and HR+ disease (n = 23); representing AA (n = 71), Ethiopian (n = 8) and Ghanaian patients (n = 3). TP53 was the most mutated gene, more commonly mutated among TNBC cases (83%) compared to HR+ cases (35%) (p &amp;lt; 0.0001). HR+ had significantly more GATA3 (26%) and PIK3CA (30%) mutations compared to TNBC (0% and 9%, p &amp;lt; 0.05). Prevalence of COSMIC mutational signatures shows higher Signature 1 among HR+ cases, and higher Signature 3 among TNBC cases (both p &amp;lt; 0.05). Signature 3 is associated with DNA double-strand break repair and germline BRCA1/2 mutation status, where 9 TNBC cases have elevated homologous repair deficiency status. Our genomic work utilizes the reference genome, which is primarily sequenced from a single individual. With the African Pan Genome (APG), a set of 125,000+ contigs distinct from the reference genome, we have aligned RNAseq reads to the APG that failed to map to the reference genome. Successful APG alignment of a subset of reads indicates that genes are expressed from these distinct AFR sequences. We also identified CpG sites in contigs with gene expression, showing AFR ancestry specific regulatory regions in the previously unmapped genome. We are working to determine the significance of these in the tumor microenvironment. This work represents a comprehensive, AFR ancestry enriched cohort with multiple genomic data approaches that will allow us to further characterize TNBC disease and define actionable biomarkers and targets for women of African ancestry. Citation Format: Rachel Martini, Max Chao, Timothy Chu, Brian Stonaker, Ishmael Kyei, Ernest Adjei, Mahteme Bekele, Kofi Gyan, Olivier Elemento, Nicolas Robine, John Carpten, Lisa Newman, Melissa Davis. Multiomics approaches to identify African-ancestry specific phenotypes of triple negative breast cancer [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C047.

Mismatch Repair Protein Deficiency in Triple Negative Breast Carcinomas: Clinicopathological Features

Abstract Introduction/Objective Female breast cancer has now surpassed lung cancer as the most commonly diagnosed cancer worldwide. Triple-negative breast cancer (TNBC) accounts for approximately 10–15% of all breast cancers. Chemotherapy remains the mainstay of systemic treatment for patients with TNBCs. Studies of mismatch repair (MMR) deficiency in TNBC reported variable prevalence ranging, from 0.2% to 18.6%. Recent studies described an excellent response in a patient with metastatic breast cancer treated with anti-PD1 illustrating the urgent need to test for MMRP deficiency as a predictive biomarkers to select those patients who could benefit from immunotherapy. The aim of the study is to detect MMRP deficiency in a cohort of TNBC Jordanian patients using the immunohistochemical methods. Methods/Case Report This study targeted cases of TNBC diagnosed and treated at King Hussein Cancer Center from 2015 until 2021. Clinicopathological data was obtained from 152 patients’ records. Immunohistochemistry for MLH1, MSH2, MSH6 and PMS2 proteins were performed on paraffin embedded tissue containing carcinoma. Results (if a Case Study enter NA) The median age of patients at diagnosis was 49 years. A total of 14 out of 152 (9.2%) cases showed deficient MMR (dMMR) expression. Loss of expression of PMS2 was seen in 13 cases, 5 of which showed also loss of MLH1 expression. Loss of expression of both MSH6 and MSH2 was seen in one case. Positive family history of cancer was present in 5 of 12 patients with available data, three of whom had isolated loss of PMS2 and two had combined loss of PMS2 and MLH1. One pt. with loss of MSH6 and MSH2, had a personal history of a second malignancy (Lung cancer). The median duration of follow-up was 27 months. The overall (OS) and event- free survival (EFS) were better for dMMR despite the lack of statistically significant differences. At 24 months EFS and OS were 77.9% and 85.7% for dMMR and 63.9% and 56.9% for pMMR respectively. Conclusion The prevalence of dMMR in TNBC is 9% with most of the cases apparently related to Lynch syndrome. dMMR tumors tend to be associated with better outcomes compared to pMMR cases. dMMR can serve as a biomarker for better prognosis. These results are of value in directing the clinical management.

A Study on the Factors and Prediction Model of Triple-Negative Breast Cancer for Public Health Promotion.

This study was conducted to identify the risk causes and predictive models based on the clinical features of patients with breast cancer classified as triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBCs) using Korean cancer statistics. A total of 2045 cases that underwent three types of hormone receptor tests were obtained from Korean cancer data in 2016. Research data were analyzed with the software SPSS Ver. 26.0. TNBC and non-TNBCs accounted for 12.4% and 87.6% of the data, respectively. Tubular and lobular tumors occurred most frequently in the external quadrant of the breast (C50.4-C50.5; 43.1%). Compared to non-TNBCs, the incidence of TNBC was the most common in patients under the age of 39 (19.5%), followed by those over the age of 70 (17.3%). Tumors larger than 2 cm accounted for 16.0%, which was higher than the number of tumors smaller than 2 cm. Cases in stage IV cancer represented 21.7% of the data. Additionally, 21.0% of the patients were in the SEER stage of distant metastasis, which was the most prevalent SEER (surveillance, epidemiology, and end outcomes) stage. Neoadjuvant therapy was administered more frequently, with a rate of 24.1%. In the logistic regression and decision-making tree model, the variables that affected TNBC were age, differentiation grade, and neoadjuvant therapy. The predictive accuracies of logistic regression and decision-making tree models were 87.8% and 87.6%, respectively. In a decision-marking tree model, the differentiation grades of TNBC affect neoadjuvant therapy, and neoadjuvant therapy affects the cancer stage. Therefore, in order to promote the health of breast cancer patients, it is urgent to apply an intensive early health check-up program for those in their 40s and 50s with a high prevalence of TNBC. For patients with breast cancer, in TNBC cases, except for poorly differentiated cases, neoadjuvant therapy must be applied first at all differentiation grades. The establishment of a policy system is necessary for the success of this process.

A Multiscale Spatiotemporal Epidemiological Analysis of Neighborhood Correlates of Triple-Negative Breast Cancer.

Women living in disadvantaged neighborhoods present with increased prevalence rates of triple-negative breast cancer (TNBC). This study takes a spatiotemporal epidemiological approach to understand the impact of socioenvironmental contextual factors on TNBC prevalence rates. We analyzed 935 TNBC cases from a major cancer center registry, between 2005 and 2017, to explore spatial and space-time clusters of TNBC prevalence rates at the census tract and neighborhood scales. Spatial regression analysis was performed to examine relationships between nine socioenvironmental factors and TNBC prevalence rates at both ecological scales. We observed spatial clustering of high TNBC prevalence rates along a north-south corridor of Miami-Dade County along Interstate 95, a region containing several majority non-Hispanic Black neighborhoods. Among the ecologic measures, the percent of a region designated as a brownfield was associated with TNBC prevalence rates at the tract-level (β = 4.27; SE = 1.08; P < 0.001) and neighborhood-level (β = 8.61; SE = 2.20; P < 0.001). Our spatiotemporal analysis identified robust patterns of hot spots of TNBC prevalence rates in a corridor of several disadvantaged neighborhoods in the northern half of the county. These patterns of TNBC align with the literature regarding at-risk groups and neighborhood-level effects on TNBC; however, remain to be validated in a population-based sample. Spatial epidemiological approaches can help public health officials and cancer care providers improve place-specific screening, patient care, and understanding of socioenvironmental factors that may shape breast cancer subtype through gene-environment and epigenetic interactions.

The prognostic value of a combined immune score in tumor and immune cells assessed by immunohistochemistry in triple-negative breast cancer

BackgroundThis study aimed to develop a novel combined immune score (CIS)-based model assessing prognosis in triple-negative breast cancer (TNBC).MethodsThe expression of eight immune markers (PD-1, PD-L1, PD-L2, IDO, TIM3, OX40, OX40L, and H7-H2) was assessed with immunohistochemistry on the tumor cells (TCs) and immune cells (ICs) of 227 TNBC cases, respectively, and subsequently associated with selected clinicopathological parameters and survival. Data retrieved from The Cancer Genome Atlas (TCGA) were further examined to validate our findings.ResultsAll immune markers were often expressed in TCs and ICs, except for PD-1 which was not expressed in TCs. In ICs, the expression of all immune markers was positively correlated between one another, except between PD-L1 and OX40, also TIM3 and OX40. In ICs, PD-1, PD-L1, and OX40L positive expression was associated with a longer progression-free survival (PFS; p = 0.040, p = 0.020, and p = 0.020, respectively). In TCs, OX40 positive expression was associated with a shorter PFS (p = 0.025). Subsequently, the TNBC patients were classified into high and low combined immune score groups (CIS-H and CIS-L), based on the expression levels of a selection of biomarkers in TCs (TCIS-H or TCIS-L) and ICs (ICIS-H or ICIS-L). The TCIS-H group was significantly associated with a longer PFS (p < 0.001). Furthermore, the ICIS-H group was additionally associated with a longer PFS (p < 0.001) and overall survival (OS; p = 0.001), at significant levels. In the multivariate analysis, both TCIS-H and ICIS-H groups were identified as independent predictors of favorable PFS (p = 0.012 and p = 0.001, respectively). ICIS-H was also shown to be an independent predictor of favorable OS (p = 0.003). The analysis of the mRNA expression data from TCGA also validated our findings regarding TNBC.ConclusionOur novel TCIS and ICIS exhibited a significant prognostic value in TNBC. Additional research would be needed to strengthen our findings and identify the most efficient prognostic and predictive biomarkers for TNBC patients.

Spatial Distribution of Immune Cells Drives Resistance to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer.

Neoadjuvant chemotherapy (NAC) alone or combined with target therapies represents the standard of care for localized triple-negative breast cancer (TNBC). However, only a fraction of patients have a response, necessitating better understanding of the complex elements in the TNBC ecosystem that establish continuous and multidimensional interactions. Resolving such complexity requires new spatially-defined approaches. Here, we used spatial transcriptomics to investigate the multidimensional organization of TNBC at diagnosis and explore the contribution of each cell component to response to NAC. Starting from a consecutive retrospective series of TNBC cases, we designed a case-control study including 24 patients with TNBC of which 12 experienced a pathologic complete response (pCR) and 12 no-response or progression (pNR) after NAC. Over 200 regions of interest (ROI) were profiled. Our computational approaches described a model that recapitulates clinical response to therapy. The data were validated in an independent cohort of patients. Differences in the transcriptional program were detected in the tumor, stroma, and immune infiltrate comparing patients with a pCR with those with pNR. In pCR, spatial contamination between the tumor mass and the infiltrating lymphocytes was observed, sustained by a massive activation of IFN-signaling. Conversely, pNR lesions displayed increased pro-angiogenetic signaling and oxygen-based metabolism. Only modest differences were observed in the stroma, revealing a topology-based functional heterogeneity of the immune infiltrate. Thus, spatial transcriptomics provides fundamental information on the multidimensionality of TNBC and allows an effective prediction of tumor behavior. These results open new perspectives for the improvement and personalization of therapeutic approaches to TNBCs.