Profile Of Triple Negative Breast Cancer Research Articles

Integrative Multiomic Profiling of Triple-Negative Breast Cancer for Identifying Suitable Therapies.

Triple-negative breast cancer (TNBC) is a heterogeneous disease that carries the poorest prognosis of all breast cancers. Although novel TNBC therapies in development are frequently targeted toward tumors carrying a specific genomic, transcriptomic, or protein biomarker, it is poorly understood how these biomarkers are correlated. To better understand the molecular features of TNBC and their correlation with one another, we performed multimodal profiling on a cohort of 95 TNBC. Our approach involved quantifying tumor-infiltrating lymphocytes through hematoxylin and eosin staining, assessing the abundance of retinoblastoma, androgen receptor, and PDL1 proteins through IHC, and carrying out transcriptomic profiling using the NanoString BC360 platform, targeted DNA sequencing on a subset of cases, as well as evaluating associations with overall survival. Levels of RB1 mRNA and RB proteins are better correlated with markers of retinoblastoma functionality than RB1 mutational status. Luminal androgen receptor tumors clustered into two groups with transcriptomes that cluster with either basal or mesenchymal tumors. Tumors classified as PDL1-positive by the presence of immune or tumor cells showed similar biological characteristics. HER2-low TNBC showed no distinct biological phenotype when compared with HER2-zero. The majority of TNBC were classified as basal or HER2-enriched by PAM50, the latter showing significantly improved overall survival. Our study contributes new insights into biomarker utility for identifying suitable TNBC therapies and the intercorrelations between genomic, transcriptomic, protein, and cellular biomarkers. Additionally, our rich data resource can be used by other researchers to explore the interplay between DNA, RNA, and protein biomarkers in TNBC.

Clinical and histological profiling of triple-negative breast cancer at Chihuahua´s state cancer center: An observational study.

e22529 Background: Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression. This subtype is associated with a poorer prognosis and higher recurrence rates compared to other breast cancer subtypes. Understanding the histopathological and clinical characteristics of TNBC is crucial for improving early detection, clinical management, and treatment outcomes. In this context, a descriptive analysis was conducted to explore the association between TNBC and histological grade, histopathological type, and clinical stage at the State Cancer Center. Methods: A retrospective, single-center study was conducted at Chihuahua's State Cancer Center, where medical records of patients aged ≥ 18 years old diagnosed with TNBC between January 2018 and December 2022 were retrospectively reviewed. Data related to weight, histological grade, histopathological type, and clinical stage at TNBC diagnosis were collected. Frequency analysis was performed to determine the distribution of these characteristics in the TNBC patient population. Additionally, the association between histological grade and clinical stage at diagnosis was examined using appropriate statistical tests. Results: During the study period, 753 patients were diagnosed with breast cancer. Of these, 84 (11%) were diagnosed with triple-negative breast cancer and were included in the study. The mean age was 49 ± 13 years, with a mean BMI of 28 ± 5. The most common histologic subtype in this group was invasive ductal carcinoma, accounting for 78 (93%) of the TNBC cases. At the time of diagnosis, 19 (23%) were diagnosed with stage IIA, 17 (20%) with stage IIIA, 9 (11%) with stage IV, and 4 (5%) were detected in situ. Overall, the majority were identified as grade 3 tumors (44; 52%). Finally, within the stage IIA group, the majority were grade 3 tumors (58%). Conclusions: As seen in other cohorts, we found a similar frequency of TNBC among patients with breast cancer in our facility in the northwest of Mexico. The distribution of clinical stages highlights the varying degrees of disease progression at the time of diagnosis, with a considerable portion presenting at advanced stages. Moreover, these insights underscore the urgent need for improved screening strategies and early detection methods.

Prognostic and Clinical Significance of PD-L1, EGFR and Androgen Receptor (AR) Expression in Triple-Negative Breast Cancer (TNBC) Patients.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and is associated with high recurrence rates, a high incidence of distant metastases and poor overall survival. The aim of this study was to investigate the role of PD-L1, EGFR and AR expression in TNBC promotion and progression. To that end, we analyzed the immunohistochemical expression of these genes in 125 TNBC patients and their relation to clinicopathological parameters and survival. An elevated expression of PD-L1 was significantly correlated with higher tumor and nuclear grade, while a low expression was correlated with loco-regional recurrence without any influence on survival. Contrary to this, the expression of AR showed a positive impact on the DFI and a negative association with tumor grade. Furthermore, PD-L1 and AR demonstrated simultaneous expression, and further co-expression analysis revealed that a positive expression of PD-L1/AR notably correlates with tumor and nuclear grade and has a significant impact on a longer DFI and OS, while a negative PD-L1/AR expression is significantly associated with metastases. Therefore, our results suggest that positive PD-L1/AR expression is beneficial for TNBC patients. In addition, an elevated expression of EGFR contributes to metastases and a worse DFI and OS. In conclusion, we think that low PD-L1/low AR/high EGFR expression followed by high Ki67 expression constitutes a 'high risk' profile of TNBC.

Abstract PO1-14-06: Integrated analysis reveals the impact of obesity on triple-negative breast cancer

Abstract Background: Obesity and overweight status, which has been growing rapidly over the past few decades, is considered as a risk factor for many types of cancers including breast cancer. Despite the multi-omics profile of triple-negative breast cancer (TNBC) has been comprehensively characterized, the impact of obesity on molecular features of TNBC is not fully appreciated. Methods: We applied an integrative analysis on clinicopathological data and molecular data (including genomic, transcriptomic, proteomic and metabolomic profiling) using the multi-omics database of TNBC (N = 465) from Fudan University Shanghai Cancer Center (FUSCC) for associations with patient body mass index (BMI). Patients were categorized into overweight/obese (OW/OB, BMI ≥ 24 kg/m2) and normal (NL, BMI < 24 kg/m2) group according to the Chinese criteria of BMI. The clinical and molecular differences between OW/OB and NL patients were systematically explored. We also constructed high-fat diet (HFD)-induced obese mouse tumor models and used single-cell RNA sequencing to investigate the impact of obesity on the tumor microenvironment. Furthermore, we analyzed the efficacy of anti-PD-1 immunotherapy on TNBC tumors in both obese and normal mice. Results: OW/OB patients exhibited higher proportion of metabolic syndrome, more adipose tissue in the breast and worse survival than NL patients. Among most frequently mutated genes, OBSCN showed statistically significantly less mutated in the OW/OB group (3.2% vs 9.6%), while TP53 (68.3% vs 76.9%) and PIK3CA (21.4% vs 14.1%) had tendency to be different. In terms of copy number alterations, we found OW/OB patients had a higher amplified or gained frequency of 13q14.11 (FOXO1) and a lower frequency of deletion or loss of chromosomal region 7p22.1 (FOXK1). We further dissect the expression profile of TNBC. Differentially expressed gene analysis and pathway enrichment analysis demonstrated that immune and metabolic pathways were the major distinction between OW/OB and NL tumors. OW/OB tumors were characterized with elevated inflammation of tumor microenvironment, as well as higher expression of immune checkpoints. Moreover, analyses focusing on metabolic heterogeneity using transcriptomic, proteomic and metabolomic data revealed upregulation of lipid metabolism and reactive oxygen species pathway in OW/OB group. In addition, our in vivo experiments demonstrated that TNBC in the obese mice displayed faster growth rates. Flow cytometry analysis and single-cell RNA sequencing showed that higher proportion of immunosuppressive myeloid cells and exhausted CD8+ T cells and upregulation of lipid metabolism in HFD group. Applying anti-PD-1 immunotherapy in both obese and normal mice displayed that tumors in the obese mice showed more sensitive to anti-PD-1 immunotherapy. Conclusion: Our study systematically revealed that obesity might play a significant role in the molecular heterogeneity of TNBC and showed distinct sensitivities to immunotherapy, which should be taken in account in the field of precision medicine. Keywords: triple-negative breast cancer, obesity, immune, tumor microenvironment, metabolism Citation Format: Yue Gong, Peng Ji, Huai-liang Wu, Li-Hua He, Ming-Liang Jin, Xin Hu, Yi-Zhou Jiang, Zhiming Shao. Integrated analysis reveals the impact of obesity on triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-14-06.

Novel Insights Into the Epidemiological and Clinico-Pathological Profile of Triple-Negative Breast Cancer: Dissection of an Aggressive Variant.

Objective Triple-negative breast cancer (TNBC) represents an aggressive and prognostically poor variant of breast cancer. Over the years, detailed research has been conducted and published in Western literature. However, there lacks a detailed account of TNBC cases from the perspective of a low-volume institution. This study aims to assess the clinicalfeatures of TNBC, as well as their prognostic implications in a tertiary care centre. Methods and materials This prospective observational studytook place at a tertiary health centre for two years, spanning from 2021 to 2023. The study aimed to investigate various clinicopathological and epidemiological parameters, thereby highlighting the shortcomings in the existing knowledge about the subject in the context of a low-volume centre, as well as additional contributing factors in developing countries like India.A group of 150 participants diagnosed with TNBC through biopsy and immunohistochemistry and >40 years of age were included in the study. Patients who tested positive for hormonal receptors and who refused to give consent for participation were excluded from the study. The study subjectswere categorized according to their clinical TNM (cTNM) stage and eventually segregated into two primary heads, namely pre-surgery chemotherapy with breast-conserving surgery (BCS) after a good response, or modified radical mastectomy (MRM) upfront. Important demographic details, including age, socioeconomic status, and education, were also recorded. A comprehensive follow-up assessment post-treatment was performed to detect early recurrence. After data collection, the recurrence rates were correlated with the TNBC status to establish the aggressiveness of the cancer. Statistical analysis of the data was done using the Statistical Package for Social Sciences (SPSS) -16version software. Results The average age of the 150 participants in the study was 52.21 years (SD±4.89 years). The highest recorded age was 64 years, while the lowest recorded age was 45 years. In the study, it was observed that 41% of the participants diagnosed with TNBChad stage III disease, whereas 33.5% had stage I disease, 22% had stage IV disease and 3.6% had stage II disease. A total of 27.5% of individuals with TNBCexhibited metastases in various anatomical sites, whereas the other 72.5% did not show any signs of metastasis. Conclusion Triple-negative breast cancer has earned its position as a unique subtype of breast cancer due to its unusual molecular characteristics, aggressive behavior, limited treatment options, and poor prognosis. The lower per-capita income and limited knowledge pertaining to this variant, along with the absence of more specific treatment options, contribute to the already high levels of morbidity and mortality associated with this illness. To effectively address this unique and very virulent ailment and customize our strategies, it is imperative to do further comprehensive investigations, thereby enabling us to deliver the highest quality of medical attention to individuals afflicted by this pathology.

The unique risk factor profile of triple-negative breast cancer: a comprehensive meta-analysis.

Triple-negative breast cancer (TNBC) has a poor prognosis compared with other breast cancer subtypes. This systematic review and meta-analysis examines whether known risk factors for breast cancer are also associated with TNBC in adult women. EMBASE, Medline, SCOPUS, and gray literature were queried with no limit on the date or language of publication. The exposures of interest included parity, breastfeeding, duration of breastfeeding, age at menarche, age at first live birth, oral contraceptive (OC) use, duration of OC use, use of menopausal hormone therapy (MHT), family history, body mass index (BMI), alcohol use, smoking, and breast density. The main outcome of interest was TNBC. Study quality was determined using the Newcastle-Ottawa scale for case control studies and cohort studies. We estimated weighted odds ratios from random effects models to study the exposure-outcome associations. Protocol was registered under the number: PROSPERO 2021 CRD42021254594. Thirty-three studies were included. Family history, longer duration of OC use, and higher breast density were significantly associated with increased risk for TNBC, whereas later age at menarche, later age at first birth, and breastfeeding were protective against TNBC. Parity, MHT, alcohol, smoking, and BMI were not significantly associated with TNBC overall, but higher parity was associated with higher risk among Black women. Our findings highlight that TNBC has a distinct risk factor profile compared with overall breast cancer. This can be the foundational work in identification of actionable TNBC risk factors to improve prevention and early detection of these poor prognosis breast tumors.

Clinical Profile of Triple-Negative Breast Cancer: A Hospital-Based Study.

Introduction Triple-negative breast cancer (TNBC) is a new concept and an important area of investigation. In Western country's literature, different studies reported on TNBC and all indicated the poor prognostic aspect of this molecular subtype over other types of breast cancer.However, there is a scarcity of comprehensive data from India. Hence, the present study was carried out to look at the epidemiological and clinical characteristics of TNBC in the Indian population. Methods The present study was performed between January 2020 and June 2021 at a tertiary care hospital in Eastern India. A total of 150 patients with TNBC were enrolled in the study. The epidemiological and clinical features of enrolled patients were collected and reviewed. Results The median age of patients at TNBC presentation was 45.53 years (24 to 74 years). The median tumor size was reported to be 5.32 cm. Of 150 patients, 94(62.67%) showed enlarged lymph nodes and 56 (37.33%) patients had no lymph node enlargement. In the present study, 85 (56.67%)patients were in the pre/perimenopausal stage at presentation, whereas 65 (43.33%) patients were in the postmenopausal stage.Upon evaluating the spread of TNBC, it was observed that a maximum of patients 60 (40%) were at the T4 stage and 56 (37.33%) at the N0 condition. The clinical staging of TNBC reported a maximum of 74 (49.33%) patients at the IIA, and IIB stages followed by 53 (35.33%) patients at the IIIA, IIIB, and IIIC stages and a minimum of 11 (7.33%) patients at stage IV. Only five (3.33%) patients were reported with a family history of breast cancer.Of all patients, 126 (84%) had detected early breast cancer thereby applicable for surgery at the time of presentation, whereas 71 (47.33%) patients were eligible for radiation therapy and 138 (92%) patients received chemotherapy. A total of 112 (74.67%) patients were found alive after 24 months of follow-up, 22 (4.67%) patients were observed with remission, and 11 (7.33%) patients died due to TNBC progression. During the course of follow-up, five (3.33%) patients were lost in the study. Conclusion TNBC is an aggressive malignancy that has a high risk of systemic relapses in the first two years after diagnosis. For more mature evidence on TNBC, longer follow-up of patients is necessary.

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.

Molecular genetic clusters of triple-negative breast cancer and their prognostic significance

Background. Triple-negative breast cancer is a group of tumors with different clinical and morphological features, prognosis, and response to therapy. There are from 4 to 6 molecular genetic varieties of this type of malignant neoplasm.
 Aim. Identification of individual clusters of triple-negative breast cancer that differed in terms of overall and disease-free survival.
 Material and methods. On the basis of the Regional Clinical Oncological Dispensary (Ulyanovsk) and National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of Russia (Moscow) in the period from 2017 to 2021, a molecular genetic analysis using a 45-gene signature in 246 patients with triple-negative breast cancer, confirmed by immunohistochemical method, was performed. Using the K-means clustering method, it was possible to form 4 molecular genetic clusters. When comparing clusters according to clinical and morphological features, the Student's t-test, MannWhitney U-test, Fisher's exact test, Pearson's 2 test were used. Survival analysis was performed using the construction of KaplanMeier curves (the observation period was 3 years and 8 months). Comparison of clusters in terms of survival was carried out using a long-rank test. Multivariate analysis was used to determine the significance of variables affecting overall and disease-free survival. Differences between groups were considered statistically significant at p 0.05.
 Results. Cluster 1 included patients with clinical stage IIA, invasive nonspecific subtype, G3, N0, Ki67 31%, with hypoexpression of most genes, unstable prognostic outcome: high survival rate at stage IV (62%) and zero survival rate at stage IIIB. Patients of the 2nd cluster were associated with stage IIA, medullary histological subtype, G3, N0, Ki67 31%, overexpression of genes for hormone receptors, growth factor receptors and transcription factors and a favorable prognosis: the best indicators of overall (100% in stage I, 66% in stage IV) and relapse-free (75% in stage I, 33% in stage IV) survival. Patients of the 3rd cluster more often had stage IA, invasive lobular and special histological tumor subtypes, N+, Ki67 14%, high expression of genes responsible for the regulation of proliferation, mitosis, spindle formation and regulation of the cell cycle, genes that regulate cell transport, the processes of replication and repair of deoxyribonucleic acid, tumor cell differentiation markers, and genes that regulate immune processes, had a regular prognosis with an increase in the clinical stage, a decrease in survival occurred. Cluster 4 patients correlated with stage IV, invasive non-specific subtype, G1G2, N0, Ki67=1530%, mean values of most genes, and worse overall and recurrence-free survival (64% in stage I, 0% in stage IV).
 Conclusion. Based on the data of molecular genetic profiling of triple-negative breast cancer, it is possible to identify individual clusters that are statistically significantly different from each other in terms of survival rates.

Frequency and Clinicopathologic Characteristics of Triple-Negative Breast Cancer Among Breast Cancer Patients Presenting to Medical Oncology Department, Hayatabad Medical Complex Peshawar, Pakistan.

Breast cancer is one of the most common cancers affecting females.The outcomes of this study will aid future research and policy suggestions by giving a rapid local burden and clinicopathologic profile of triple-negative breast cancer (TNBC) patients. This cross-sectional study was carried out at the Department of Oncology, Hayatabad Medical Complex Peshawar, Pakistan, from April 21, 2022, to October 21, 2022. The sample size was 120 using a 95% confidence level, 18.7% proportion of TNBC frequency in patients with breast cancer, and 7% absolute precision. All patients who presented with newly diagnosed breast cancer and were between the ages of 30-60 yearswere included in the study. The study excluded male patients and patients with a history of surgical intervention on the breast during the previous six months. A total of 120 patients were evaluated. Age ranged between 30-60 years with a mean age of 45 years. Thirty-four (28%) patients were in the age range of 30-45 years and 86 (72%) patients were in the age range of 46-60 years. Fifty-six (47%) patients had BMI ≤27 kg/m2 while 64 (53%) had BMI >27 kg/m2. The use of oral contraceptives was noted in 25 (21%) patients. A total of 62 (52%) patients had breast cancer on the right side while 58 (48%) had it on the left side. According to the results of our study, 14% of breast cancer patients had triple-negative disease.

Investigating the prognosis gene profile of triple-negative breast cancer

Background: Current therapeutic strategies have poor effects in triple-negative breast cancer (TNBC) patients due to lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 expression. Identification of novel genes of TNBC prognosis aids in the development of effective treatment strategies. Aim: We aim at explore key genes related to TNBC recurrence. Methods: RNAseq and clinical characteristics data were derived from The Cancer Genome Atlas Breast Invasive Carcinoma project. Ninety-seven TNBC patients were included. We used DESeq2 and Cox regression to identify significant genes to TNBC recurrence. Pathway enrichment analysis and protein–protein interaction plot were conducted to understand the functions of target genes. Results: We discovered top nine important genes for TNBC recurrence. Lower mRNA expression of potassium voltage-gated channel subfamily Q member 5, H3 clustered histone 10, and ADP-ribosylation factor-like protein 17 and higher mRNA expression of synuclein beta, interleukin 6 (IL-6), casein kappa, RHOC, phosphodiesterase 8B, and laminin subunit alpha 3 (LAMA3) were associated with higher risk of recurrence. IL-6, LAMA3, and Ras homolog family member V (RHOV) genes out of nine candidate genes can make the best prediction of TNBC recurrence (area under receiver operating characteristic curve: 0.95, sensitivity: 0.89 and specificity: 0.97). The top three significant Gene Ontology (GO) pathways are nucleosome, ion gated channel activity, and epidermis development. Significant GO pathways can be categorized into four functions: cell–cell adhesion, cell transportation, cell proliferation, ion channel and transporter, and immune. Conclusion: We discovered that the gene set of IL6, LAMA3, and RHOV can accurately predict TNBC recurrence. These genes warrant further study to confirm their causal association with TNBC prognosis and possible treatment targets.

Abstract LB561: Germline mutational profiling of TNBCs in an Indian cohort

Abstract Breast cancer is the most common cancer in Indian women with a high incidence of triple negative breast cancer (TNBC), an aggressive subtype of breast cancer associated with poor prognosis. The high TNBC prevalence (>25%) in India as compared to the western population (10-15%) remains to be a challenge in clinical management. The association of germline BRCA1/2 mutations in TNBCs is well-established as a predisposing factor for hereditary breast cancer risk. However, these studies are predominantly from germline profiling of TNBCs representative of western population. Therefore, we aimed to investigate the germline profiles of breast cancer patients in India using a multi-institutional TNBC cohort based on ACMG consensus multi-gene NGS panel. Of 193 TNBC patients, we identified 57 pathogenic mutations (diagnostic yield = 29.53%) from various genes of which BRCA1 (41/57, 71.93%) and BRCA2 (8/57, 14.03%) were most commonly mutated. We observed a high prevalence of BRCA1 mutations (41/193, 21.24%) and BRCA2 mutations (8/193, 4.14%) in our cohort as compared to published literature. Additionally, 8 pathogenic mutations were also reported in non-BRCA cancer pre-disposing genes associated with the HR pathway like ATM, CHEK2, PALB2. 10 novel mutations were identified in 3 genes namely BRCA1, BRCA2 and PALB2. The most common type of mutations was found to be frame-shift which may cause protein truncation and loss of function. Furthermore, we identified 48 variants of unknown significance (24.9%) of which about 7% were in the BRCA1/2 genes. Data mining from global databases like TCGA, Genome Asia indicated that the novel mutations were unique to the Indian population compared to the germline profiles of different ethnicities. Our study confirms the major contribution of BRCA1/2 genes in TNBCs as reported in the literature. A high percentage of the women were found to be associated with young age onset which may be attributed to BRCA mutations. We have also assessed the association of clinicopathological parameters such as tumor grade, stage, recurrence to the germline mutational status. Our analysis shows significant association of germline mutational status with family history thus underlin the importance of multi-gene panel testing as recommended by NCCN guidelines. Moreover, our results also emphasize the need for designing/implementing guidelines specific to Indian population. In summary our results indicate that Indian TNBCs have a high prevalence of BRCA1/2 mutations. Large scale studies in future are warranted to validate these preliminary findings. Citation Format: Chaitanyanand Koppiker, Ashwini Bapat, Siddharth Gahlaut, Naveen Luke, Jisha John, Rupa Mishra, Aishwarya Konnur, Namrata Namewar, Ruhi Reddy, Shaheen Shaikh, Rituja Banale, Smeeta Nare, Laleh Busheri, Asha Reddy, Ashraf Mannan, Sabarinathan Radhakrishnan, Selvi Radhakrishna, Santosh Dixit. Germline mutational profiling of TNBCs in an Indian cohort [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 LB561.

Triple negative breast cancer presentation in Afro-Caribbean women in New York City.

e18726 Background: In the United States, triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancers. It also has a higher incidence and worse prognosis in black women. There is paucity of information on the incidence and presentation of breast cancer in black women from the Caribbean. The clinical and pathologic profile of TNBC in this immigrant underrepresented patient group is described here. Methods: This is a retrospective study performed at Kings County Hospital (KCH), a safety net hospital in Central Brooklyn, New York City with a predominantly Afro-Caribbean patient population. Data from patients diagnosed with breast cancer from 2015-2018 were collected from the institution’s tumor registry and the clinical and pathologic data of these patients were collected and analyzed with descriptive statistics and chi square testing. Results: Of the total 299 female patients with a breast cancer diagnosis, 60 patients (20%) had TNBC with median age 57 and Nottingham grade 3 in 90% (54) of the patients. At presentation, 43% (26) presented with localized disease, 55% (33) with lymph node involvement (regional), and 2% (1) with distant metastasis. When stratified by menopausal status, 46 patients (77 %) were post-menopausal and remainder pre-menopausal. Premenopausal women presented with higher rates of regional disease at 64% with compared to 50% in the postmenopausal women (p = 0.5444). BMI was similar in both groups (p = 0.9879). Of the 37 patients with documented country of origin, 84% (31) were from the Caribbean, and 27% of these patients identified as medical tourists from the Caribbean. 25% (15) of all patients reported 1st or 2nd degree relative with breast cancer and 18% (11) reported a first degree relative with malignancy other that breast cancer. 100% of patients younger than 44 years reported a family history of cancer. Genetic testing information was unavailable to these patients. Of the twenty patients (33%) that received neoadjuvant chemotherapy with standard treatment, two achieved complete response, 15 partial response, and 3 without response to treatment. Conclusions: In our study of African-Caribbean patients with breast cancer, the incidence of TNBC was high at 20% with most presenting with high-grade tumors, regional lymph node involvement, and young age at diagnosis. Notably this represents a high-risk cohort with significant family history of breast and other cancers suggestive of inherited or familial cancers. Response to standard neoadjuvant chemotherapy was less than expected, encouraging the need to consider neoadjuvant immunotherapy in these patients.

Role of PTEN, PI3K, and mTOR in Triple-Negative Breast Cancer.

Breast cancer is the most commonly occurring malignancy and the leading cause of cancer-related death in women. Triple-negative breast cancer (TNBC) is the most aggressive subtype and is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival. The aim of this study was to investigate the PI3K/PTEN/Akt/mTOR pathway as one of the most frequently deregulated pathways in cancer. We aimed to explore the impact of PI3K and mTOR oncogenes as well as the PTEN tumor suppressor on TNBC clinical behavior, prognosis, and multidrug resistance (MDR), using immunohistochemistry and copy number analysis by quantitative real-time PCR. Our results revealed that loss of PTEN and high expression of PI3K and mTOR proteins are associated with poor outcome of TNBC patients. PTEN deletions appeared as a major cause of reduced or absent PTEN expression in TNBC. Importantly, homozygous deletions of PTEN (and not hemizygous deletions) are a potential molecular marker of metastasis formation and good predictors of TNBC outcome. In conclusion, we believe that concurrent examination of PTEN/PI3K/mTOR protein expression may be more useful in predicting TNBC clinical course than the analysis of single protein expression. Specifically, our results showed that PTEN-reduced/PI3K-high/mTOR-high expression constitutes a ‘high risk’ profile of TNBC.

Functional Proteomic Profiling of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that comprises various disease entities, all of which share a set of common features: a lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, respectively. Because of their receptor status, conventional chemotherapy remains the main therapeutic option for TNBC patients. We employed a reverse phase protein array approach (RPPA), complemented by immunohistochemistry, to quantitatively profile the activation state of 84 actionable key signaling intermediates and phosphoproteins in a set of 44 TNBC samples. We performed supervised and unsupervised approaches to proteomic data analysis to identify groups of samples sharing common characteristics that could be amenable to existing therapies. We found the heterogenous activation of multiple pathways, with PI3 K/AKT/mTOR signaling being the most common event. Some specific individualized therapeutic possibilities include the expression of oncogenic KIT in association with cytokeratin 15 and Erk1/2 positive tumors, both of which may have clinical value.

The metabolic foibles of triple negative breast cancer

Metabolic profiling of triple-negative breast cancers may advance personalized therapies.

Abstract C092: Immune characteristics of triple-negative breast cancer (TNBC) in Latin American women from Colombia

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive form of the disease with limited treatment options and poor survival. A series of retrospective studies established the presence of tumor-infiltrating lymphocytes (TILs) in most primary breast cancers, the number of which affect the response rate to chemotherapy in both neoadjuvant and adjuvant treatment contexts. A subset of TNBC is highly immunogenic, and recent studies have shown that understanding the specific immune profiles of tumors has implications both for treatment and prognosis. Most studies have been conducted in samples of women of European origin, and little is known about the immune profile of TNBCs in Hispanic/Latinas. The specific goal of our study was to test the association between immune characteristics of TNBC from Colombian patients and genetic ancestry proportions, to determine if genetic ancestry could be a relevant factor in defining the immune characteristics of TNBC. Methods: We obtained 41 TNBC tissues through collaboration with the National Cancer Institute in Colombia along with demographic and clinical information. Genetic ancestry was estimated with a panel of 106 ancestry informative markers and the program STRUCTURE. RNA was extracted from FFPE tissues, qualified using Agilent chips, and used for sequencing at the Translational Genomics Core at the Stanley S. Scott Cancer Center. Using the TNBCtype program we confirmed 33 samples as TNBC. The program xCell was used for cell-signature identification based on RNAseq data. We explored associations between genetic ancestry and scores obtained for different immune cell-types and an overall immune score using linear regression. We analyzed the association for the following specific cells: Th1 cells, Th2 cells, Treg, CD4 T cells, CD4 TEM, CD4 memory T cells, CD8 T cells, CD8 TCM, CD8 TEM, CD8 naive T cells, macrophages, macrophages M1, macrophages M2, and mast cells. Results: The overall immune score was positively associated with the proportion of African ancestry (p=0.049). Interestingly, we observed that Indigenous American ancestry was inversely associated with the Treg cell score while African ancestry was positively associated with it. Levels of these regulatory cells have been correlated with prognosis in ER- and triple-negative disease. We also found that CD4 T cell and CD4 memory T-cell scores were positively associated with African ancestry (P=0.006 and P=0.049 respectively). Conclusions: Our results suggest that genetic ancestry among Latina women from Colombia is associated with certain immune characteristics of breast cancer. We need to further test these associations in a larger sample to confirm the findings, obtain additional insights, and understand their implications for TNBC treatment and prognosis among Latin American women. Citation Format: Valentina A. Zavala, Laura C. Carrasquilla, Silvia J. Serrano-Gomez, Maria C. Sanabria-Salas, Melody C. Baddoo, Jone Garai, Jovanny Zabaleta, Laura Fejerman. Immune characteristics of triple-negative breast cancer (TNBC) in Latin American women from Colombia [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C092.

Abstract P6-11-05: Tumor mutational profile of triple-negative breast cancer amongst hispanics of Mexican descent

Abstract Introduction: Triple negative breast cancer (TNBC) is biologically defined by the absence of expression of ER, PR, and Her-2neu receptors and clinically has a poor prognosis. Racial disparities in breast cancer are well recognized with African-Americans and Hispanics having a higher prevalence of TNBC as compared to Caucasians. Advances in characterization of the molecular drivers of cancer hold the promise of better targeting TNBC and addressing some of the disparities in outcomes noted amongst minorities. However, based on the data from the cancer genome atlas (TCGA), the mutational landscape of TNBC in African-Americans was found to be similar to that of Caucasians. There is a remarkable lack of data regarding the genomic aberrations (GA) in TNBC in Hispanics. Of the more than 1000 breast cancer cases in the TCGA, only 37 are identified as Hispanic. Of these 37, only 4 had TNBC. Objective: Aim of the current study is to describe the GA seen in triple negative breast cancer patients, diagnosed at the Garbar Breast Cancer Center (GBCC) at TTUHSC-EP which serves a predominantly Mexican-American Hispanic population. Methods: Medical records of patients diagnosed with triple negative breast cancer at GBCC were reviewed. Of these, ones who had undergone next generation sequencing of the tumor were selected for review. Clinical, pathological and demographic data was extracted. Results were compared with the GA reported in the TCGA basal like subtype and the METABRIC (molecular taxonomy of breast cancer international consortium) triple negative cohorts. Results: Next generation sequencing data of representative tumor specimen for the detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens was available for 17 patients. All were Hispanic females of Mexican-American heritage. Median age is 54 years (range 23-88). 14 (82.3%) had stage IV and 3 (17.7%) had stage III cancer. Of the 11 patients who underwent germ-line testing for inherited cancer predisposition syndrome, only one was found to have a pathogenic BRCA mutation. Tumor mutational burden(TMB) could not be determined in 3 cases. The average TMB in the remaining 14 cases was 4.7 mutations/Mb (Range: 1-10). All tumors were micro satellite stable. The top 5 gene mutations seen and their corresponding frequency in TCGA and METABRIC database are shown in the following tables. Conclusions: In a predominantly Hispanic cohort of advanced TNBC, we found a 100% prevalence of TP53 mutations and an increased frequency of NF1 and PTEN mutations as compared to reported frequencies in TCGA and METABRIC database. All cases were micro satellite stable and had low TMB. This suggests that molecular drives of cancer may be different in Hispanics and a better understanding of these may help address some of the disparities seen in outcomes in this group of patients. Frequency of 5 most commonly mutated genes seen at GBCC versus TCGAGeneGBCC (n=17)(%)TCGA(n-93)(%)pTP5310082.80.06NF117.62.150.004PIK3CA17.67.50.18PTEN17.61.080.0008RB111.74.30.21 Frequency of 5 most commonly mutated genes at GBCC vs METABRIC databaseGeneGBCC (n-17)(%)METABRIC (n-245)(%)pTP53100800.04NF117.63.270.004PIK3CA17.618.370.9PTEN17.66.50.08RB111.74.90.22 Citation Format: Sumit Gaur, Alexander Philipovskiy, Meghan McAlice, Onyedika V Umeanaeto, Kiran Ghimire. Tumor mutational profile of triple-negative breast cancer amongst hispanics of Mexican descent [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-11-05.

Abstract P4-06-24: Microenvironment heterogeneity of triple-negative breast cancer reveals distinct immune escape mechanisms and potential driver events

Abstract Background The microenvironment phenotypes strongly affect the immunotherapeutic strategies for triple-negative breast cancer (TNBC). Although the multi-omics profile of TNBC has been comprehensively characterized, few studies have focused on the microenvironment phenotypes of TNBC. Methods With multi-omics data for the largest single-center TNBC cohort (n=386), we first established a TNBC-specific microenvironment cell signature. We further used single sample gene set enrichment analysis to calculate the relative number of microenvironment cell subsets in each sample. Then, we performed k-means clustering to classify the TNBC microenvironment phenotypes into heterogeneous clusters. Furthermore, we systematically analyzed the extrinsic and intrinsic immune escape mechanisms of different TNBC microenvironment clusters. In addition, we explored genomic alterations that might decrease immune infiltration in certain TNBC microenvironment clusters. Results We classified the TNBC microenvironment phenotypes into three heterogeneous clusters. Cluster 1 (type 1 “cold tumor”) had low microenvironment cells infiltration. Cluster 2 (type 2 “cold tumor”) was characterized by resting innate immune cells, fibroblasts and endothelial cells infiltration. Cluster 3 (“hot tumor”) was featured by adaptive immune cells infiltration. Analysis of immune escape mechanism revealed that an incapability to attract innate immune cells (resulting in failure of adaptive immunity) led to immune escape of cluster 1. The chemotaxis but inactivation of innate immunity (also leading to failure of adaptive immunity) and low tumor antigen burden resulted in immune escape of cluster 2. High expression of immune checkpoint molecules contributed to immune escape of cluster 3. In addition, we found that tumor infiltrating lymphocytes (TILs) were positively correlated with immune checkpoint molecules expression, while mutation load was negatively correlated with those indicators in triple-negative breast cancer. Analysis of enrichment pathways, mutations and somatic copy number variations between the “cold tumor” and “hot tumor” clusters revealed that amplification of MYC and activation of MYC-related pathways might decrease the immune infiltration of cluster 1. Mutations in PI3K-AKT pathway members and activation of fibroblasts-related pathways might decrease the immune infiltration of cluster 2. Conclusion Utilizing the largest single-center TNBC cohort with multi-omics data, our study first revealed the heterogeneity of the TNBC microenvironment, with translational significance both clinically and biologically. First, we identified a subtype of “hot tumor” in TNBC (cluster 3), for which immune checkpoint blockers (ICBs) might be effective. TILs and immune checkpoint molecules expression but not mutation load might predict the efficacy of ICBs. Second, we presumed some genomic alterations that might drive “cold tumor” formation in TNBC. Our study represents a step toward personalized immunotherapy for TNBC patients. Key Words triple-negative breast cancer, multi-omics, microenvironment heterogeneity, immune escape Citation Format: Xiao Y, Ma D, Zhao S, Jiang Y-Z, Shao Z-M. Microenvironment heterogeneity of triple-negative breast cancer reveals distinct immune escape mechanisms and potential driver events [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-24.

Abstract P3-07-55: Predictive value of O6-methylguanine-DNA methyltransferase (MGMT) promoter gene methylation in triple-negative breast cancer patients receiving carboplatin

Abstract Background: The epigenetic profile of triple-negative breast cancer (TNBC) showed a wide prevalence of MGMT promoter methylation.Aberrant methylation of MGMT seems to be an independent predictor of poor survival in patients with basal-like breast cancer. Moreover, patients with MGMT-negative basal-like tumors who received cyclophosphamide had asignificantly improved DFS and OS compared with MGMT-positive tumors.However, the impact of MGMT methylation in the context of modern therapy concepts is not clear. Methods: We retrospectively evaluated 174 TNBC tumors of patients enrolled into the neoadjuvantGeparSixtotrial from 08/2011 to 12/2012. Patients were randomized to receive 18 weeks of neoadjuvant treatment with paclitaxel (80mg/m2/week) and non-pegylated liposomal doxorubicin (20mg/m2/week) with or without addition of carboplatin (AUC 2.0-1.5/week).Hormone-receptor status, HER2status, and Ki67 were centrally confirmed prior to randomization. We defined pathological complete response (pCR)as ypT0/is ypN0. MGMT promoter methylation status was determined by PCR using EZ DNA Methylation Kit™ (Zymo Research); TNBCtumors were considered to be methylated if they had an average methylation ≥10%, some tumors were considered borderline due to high heterogeneity among GpC islands.We investigated the effect of MGMT methylation on pCR and its correlation with baseline characteristics. Results: A total of210 tumors from the TNBC cohort of the GeparSixtotrial(n=315) were available with a tumor content >20%. In 174 tumors the methylation assay was performed successfully. The number of tumorswith methylated MGMT was similar in carboplatin vs. non-carboplatin treated cohorts. In the carboplatin group 19.3% (17/88) of TNBC were methylated, 65.5% (58/88)unmethylated, and 14.8% (13/88) borderline.In the non-carboplatin group 20.9% (18/86) of TNBC were methylated, 62.8% (54/86)unmethylated, and 16.3% (14/86) borderline.In the entire cohort,there was no association between MGMT methylation status and pCR (p=0.522).Non-carboplatin cohort: 33.3% (6/18) of patients with methylated MGMT achieved pCR vs. 51.9% (28/54) of unmethylatedand 21.4% (3/14) of borderline (p=0.079).Carboplatin cohort: 52.9% (9/17) of patients with methylated MGMT achieved pCR vs. 55.2% (32/58) of unmethylatedand 76.9% (10/13) of borderline (p=0.320). In TNBC patients with methylated MGMT, the addition of carboplatin resulted in a 20% increased pCR rate (p=0.241). Conclusion: In this study no statistically significant association between MGMT methylation andpCR was found.Patients with MGMT methylation seemed to have a lower possibility to achieve a pCR and the addition of carboplatin seemed to reverse this effect. However, a clear classification of the borderline MGMT samples and further studies in larger series of TNBC are warranted. Citation Format: Fontanella C, Gehlhaar C, Denkert C, Schneeweiss A, Heppner B-I, Koch I, Blohmer J-U, Jackisch C, Lederer B, Fasching PA, Müller V, Untch M, Aprile G, Puglisi F, Nekljudova V, Heppner F, von Minckwitz G, Loibl S. Predictive value of O6-methylguanine-DNA methyltransferase (MGMT) promoter gene methylation in triple-negative breast cancer patients receiving carboplatin. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-55.