Female Triple-negative Breast Cancer Research Articles

The prognostic impact of Her2 status in early triple negative breast cancer: a Turkish Oncology Group (TOG) study

The studies evaluating the impact of Her2 levels in neoadjuvant setting have conflicting data. The aim of the study was to evaluate the prognostic impact of Her2 status in early triple negative breast cancer(TNBC). In the study TNBC patients who were treated with neoadjuvant chemotherapy (NAC) and surgery were analyzed retrospectively. The primary aim of the study was to analyze the impact of Her2 status(Her2-0 and Her2-low) on pathological complete response (pCR). The secondary objectives were disease free survival (DFS) and overall survival (OS). 620 female triple negative breast cancer patients were evaluated. 427 patients (68.9%) had Her2-0 and 193(31.1%) had her2-low pathology. The pCR rates were similar between Her2-0 and Her2-low patients (33.0% vs. 27.5%, p = 0.098). Although Her2-0 group has better DFS (106 vs. 50 months, p = 0.002), in multivariate analysis it had a HR of 0.74 (p = 0.06). In addition, OS was similar (131 vs. 105 months, p = 0.13) with a HR of 0.88 (p = 0.61). In multivariate analysis; presence of LVI (HR:2.2 (95% CI 1.1–3.5) p = 0.001), Clinical stage T1/T2 (HR:0.39 (95% CI 0.2–0.6) p < 0.001) and lymph node negativity (HR:0.35 (95% CI 0.1–0.9) p = 0.03) were independent factors for OS. Although there were pathological and clinical differences, the pCR, DFS and OS were similar between Her2-0 and Her2-low TNBC patients. The importance of Her2 status of TNBC in neoadjuvant setting should be further studied.

Digital Whole Slide Image Analysis of Elevated Stromal Content and Extracellular Matrix Protein Expression Predicts Adverse Prognosis in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis and limited treatment options. This study evaluates the prognostic value of stromal markers in TNBC, focusing on the tumor-stroma ratio (TSR) and overall stroma ratio (OSR) in whole slide images (WSI), as well as the expression of type-I collagen, type-III collagen, and fibrillin-1 on tissue microarrays (TMAs), using both visual assessment and digital image analysis (DIA). A total of 101 female TNBC patients, primarily treated with surgery between 2005 and 2016, were included. We found that high visual OSR correlates with worse overall survival (OS), advanced pN categories, lower stromal tumor-infiltrating lymphocyte count (sTIL), lower mitotic index, and patient age (p < 0.05). TSR showed significant connections to the pN category and mitotic index (p < 0.01). High expression levels of type-I collagen (>45%), type-III collagen (>30%), and fibrillin-1 (>20%) were linked to significantly worse OS (p = 0.004, p = 0.013, and p = 0.005, respectively) and progression-free survival (PFS) (p = 0.028, p = 0.025, and p = 0.002, respectively), validated at the mRNA level. Our results highlight the importance of stromal characteristics in promoting tumor progression and metastasis and that targeting extracellular matrix (ECM) components may offer novel therapeutic strategies. Furthermore, DIA can be more accurate and objective in evaluating TSR, OSR, and immunodetected stromal markers than traditional visual examination.

DNA methylation-based biological age and time to relapse in triple negative breast cancer.

e13126 Background: Triple negative breast cancer (TNBC) represents 15% of all breast cancer cases and is one of the most aggressive forms of breast cancer with a poorer prognosis. Due to the lack of receptors, TNBC is not amendable to hormonal or anti-HER2 therapies and current gene expression arrays have limited clinical utility in TNBC. The identification of biomarkers associated with TNBC may aid in elucidating the underlying biological mechanisms of this disease and may also have implications for risk stratification, diagnosis, and prognosis of TNBC. The purpose of this study was to investigate the association between markers of biological aging and time to relapse in TNBC. Methods: DNA methylation and clinical data from a publicly available dataset (GSE141441) were used in this analysis. Breast tissue specimens in female TNBC patients who received (n=56) and who did not receive (n=110) chemotherapy underwent DNA methylation profiling using the Illumina Infinium HumanMethylation450K BeadChip. Five DNA methylation-based biological age metrics were calculated: intrinsic epigenetic age acceleration (IEAA), extrinsic epigenetic age acceleration (EEAA), PhenoAge acceleration (PhenoAA), GrimAge acceleration (GrimAA), and DunedinPACE (Pace of Aging Calculated from the Epigenome). Multiple linear and quantile regression analyses were performed to examine the association between the aging metrics and time to TNBC relapse. Interaction and stratified analyses by Ki-67 was additionally performed. Results: After adjusting for chronological age, GrimAA ( P=0.024) and DunedinPACE ( P=0.019) were negatively associated with time to relapse among patients who did not receive chemotherapy. Specifically, a 1-year increase in GrimAA and 1 unit increase in the pace of aging were associated with a 1.77-month and a 53.62-month shorter relapse of TNBC, respectively. Additionally, Ki-67 significantly modified the association between IEAA ( P=0.023) and DunedinPACE ( P=0.035) among patients who received chemotherapy with a 2.75- and a 42.17-month shorter relapse of TNBC among those with a Ki-67 index greater than 50% per unit increase in IEAA and DunedinPACE, respectively. Conclusions: We observed DNA methylation markers of biological age were associated with time to relapse in TNBC patients and these associations were modified by Ki-67. These biomarkers may have prognostic utility in TNBC relapse and potentially, may aid in oncological precision medicine efforts for personalized treatment regimens and surveillance. [Table: see text]

Personalized chemotherapy selection for patients with triple-negative breast cancer using deep learning.

Potential uncertainties and overtreatment exist in adjuvant chemotherapy for triple-negative breast cancer (TNBC) patients. This study aims to explore the performance of deep learning (DL) models in personalized chemotherapy selection and quantify the impact of baseline characteristics on treatment efficacy. Patients who received treatment recommended by models were compared to those who did not. Overall survival for treatment according to model recommendations was the primary outcome. To mitigate bias, inverse probability treatment weighting (IPTW) was employed. A mixed-effect multivariate linear regression was employed to visualize the influence of certain baseline features of patients on chemotherapy selection. A total of 10,070 female TNBC patients met the inclusion criteria. Treatment according to Self-Normalizing Balanced (SNB) individual treatment effect for survival data model recommendations was associated with a survival benefit (IPTW-adjusted hazard ratio: 0.53, 95% CI, 0.32-8.60; IPTW-adjusted risk difference: 12.90, 95% CI, 6.99-19.01; IPTW-adjusted the difference in restricted mean survival time: 5.54, 95% CI, 1.36-8.61), which surpassed other models and the National Comprehensive Cancer Network guidelines. No survival benefit for chemotherapy was seen for patients not recommended to receive this treatment. SNB predicted older patients with larger tumors and more positive lymph nodes are the optimal candidates for chemotherapy. These findings suggest that the SNB model may identify patients with TNBC who could benefit from chemotherapy. This novel analytical approach may provide debiased individual survival information and treatment recommendations. Further research is required to validate these models in clinical settings with more features and outcome measurements.

MYC Deregulation and PTEN Loss Model Tumor and Stromal Heterogeneity of Aggressive Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) patients have a poor prognosis and few treatment options. Mouse models of TNBC are important for development of new therapies, however, few mouse models represent the complexity of TNBC. Here, we develop a female TNBC murine model by mimicking two common TNBC mutations with high co-occurrence: amplification of the oncogene MYC and deletion of the tumor suppressor PTEN. This Myc;Ptenfl model develops heterogeneous triple-negative mammary tumors that display histological and molecular features commonly found in human TNBC. Our research involves deep molecular and spatial analyses on Myc;Ptenfl tumors including bulk and single-cell RNA-sequencing, and multiplex tissue-imaging. Through comparison with human TNBC, we demonstrate that this genetic mouse model develops mammary tumors with differential survival and therapeutic responses that closely resemble the inter- and intra-tumoral and microenvironmental heterogeneity of human TNBC, providing a pre-clinical tool for assessing the spectrum of patient TNBC biology and drug response.

Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer

Chemotherapy prior to immune checkpoint blockade (ICB) treatment appears to improve ICB efficacy but resistance to ICB remains a clinical challenge and is attributed to highly plastic myeloid cells associating with the tumor immune microenvironment (TIME). Here we show by CITE-seq single-cell transcriptomic and trajectory analyses that neoadjuvant low-dose metronomic chemotherapy (MCT) leads to a characteristic co-evolution of divergent myeloid cell subsets in female triple-negative breast cancer (TNBC). Specifically, we identify that the proportion of CXCL16 + myeloid cells increase and a high STAT1 regulon activity distinguishes Programmed Death Ligand 1 (PD-L1) expressing immature myeloid cells. Chemical inhibition of STAT1 signaling in MCT-primed breast cancer sensitizes TNBC to ICB treatment, which underscores the STAT1’s role in modulating TIME. In summary, we leverage single-cell analyses to dissect the cellular dynamics in the tumor microenvironment (TME) following neoadjuvant chemotherapy and provide a pre-clinical rationale for modulating STAT1 in combination with anti-PD-1 for TNBC patients.

Loss of the receptors ER, PR and HER2 promotes USP15-dependent stabilization of PARP1 in triple-negative breast cancer.

Poly(ADP-ribose) polymerase 1 (PARP1) is essential for the progression of several types of cancers. However, whether and how PARP1 is stabilized to promote genomic stability in triple-negative breast cancer (TNBC) remains unknown. Here, we demonstrated that the deubiquitinase USP15 interacts with and deubiquitinates PARP1 to promote its stability, thereby stimulating DNA repair, genomic stability and TNBC cell proliferation. Two PARP1 mutations found in individuals with breast cancer (E90K and S104R) enhanced the PARP1-USP15 interaction and suppressed PARP1 ubiquitination, thereby elevating the protein level of PARP1. Importantly, we found that estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) inhibited USP15-mediated PARP1 stabilization through different mechanisms. ER bound to the USP15 promoter to suppress its expression, PR suppressed the deubiquitinase activity of USP15, and HER2 abrogated the PARP1-USP15 interaction. The specific absence of these three receptors in TNBC results in high PARP1 levels, leading to increases in base excision repair and female TNBC cell survival.

Abstract 1451: BRCA1 and BRCA2 germline mutational spectrum in Algerian triple negative breast cancer (TNBC) patients

Abstract Background: Breast cancer is currently the leading cause of cancer morbidity and mortality among Algerian women. To date, triple negative breast cancer (TNBC) shows substantial overlap with basal type cancer and it is associated with aggressive tumor behavior, poor prognosis and BRCA1 mutations. In the present study, we screened for the prevalence of BRCA1 and BRCA2 germline mutations in a cohort of 169 TNBC patients using PCR-Sanger sequencing and NGS with a cancer panel of 30 hereditary cancer genes or BRCA1/BRCA2 genetic test. Materials and Methods: 169 TNBC patients and their relatives were referred trough several public hospitals from six years (2013-2019). BRCA1 germline mutation was screened using PCR-Sanger sequencing in 66 TNBC patients with strong family history of breast and ovarian cancer and 103 sporadic TNBC patients including all exons where a mutation was previously found in Algerian population (exons 2, 3, 4, 10, 17 and 19). BRCA2 germline mutation was screened using PCR-Sanger sequencing in 24 TNBC patients with strong family history of breast cancer including all exons where a mutation was previously found in Algerian patients (exons 10 and 22). In addition, nine (9) TNBC patients with strong family history of breast and ovarian cancer were analyzed by NGS using BRCA1 and BRCA2 test or a cancer panel of 30 hereditary genes (Colors genomics). Results: The analysis of the genomic DNA samples of 169 TNBC patients revealed that 15 patients carried pathogenic germline variants in BRCA1 gene and three patients carried pathogenic variants in BRCA2 gene (10.65%). Eight distinct germline mutations in BRCA1 have been detected in this study: c.83_84delTG, c.181T&amp;gt;G, c.798_799delTT, c.505C&amp;gt;T, c.923_924delGC, c.2125_2126insA, c.5257A&amp;gt;G and deletion of exon 15. Interestingly, the recurrent and specific mutation c.83_84delTG has been detected in 4 unrelated TNBC patients. The pathogenic variant c.2125_2126insA has been detected in three unrelated families and also in the first relatives of 2 patients. The rare likely pathogenic variant BRCA1 c.5257A&amp;gt;G/p.Arg1753Gly has been detected in young female TNBC patient. The Del exon 15 in BRCA1 has been detected in two unrelated patients. Three distinct germline mutations in BRCA2 have been detected in three TNBC patients: c.1813dupA, c.7654dupA and c.8485C&amp;gt;T. Interestingly, these three mutations are reported for the first time in Algerian population. The c.1813dupA and c.8485C&amp;gt;T pathogenic variants have been detected in two young female TNBC patients with a family history of male breast cancer. Conclusions: In the current study, we detected recurrent germline mutations in BRCA1 gene in early onset TNBC patients. BRCA2 pathogenic variants have also been detected in young female TNBC patients. TNBC immunophenotype should be considered as an additional criterion for genetic counselling and testing of BRCA genes in Algerian women with early onset breast cancer. Citation Format: Farid Cherbal, Chiraz Mehemmai, Hadjer Gaceb, Hassen Mahfouf, Kada Boualga. BRCA1 and BRCA2 germline mutational spectrum in Algerian triple negative breast cancer (TNBC) 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 1451.

Effectiveness of the Sanyin Formula Plus Chemotherapy on Survival in Women With Triple-Negative Breast Cancer: A Randomized Controlled Trial.

PurposeTo evaluate the efficacy of the Sanyin formula (SYF) plus conventional standard chemotherapy in operable triple-negative breast cancer (TNBC) patients, a randomized controlled trial was implemented at 5 hospitals and cancer centers in China between May 23, 2016, and October 31, 2019.Materials and MethodsFemale patients aged 18 to 80 years with operable TNBC after definitive surgery were screened and enrolled. The exclusion criteria included metastatic disease, other tumors, or locally advanced disease. Patients were randomly divided into groups SYF plus conventional standard chemotherapy and placebo plus conventional standard chemotherapy at a ratio of 1:1. The primary endpoint of the investigation was disease-free survival (DFS), and secondary endpoints included overall survival (OS) and toxicity.ResultsA total of 252 operable female TNBC patients were randomized to receive SYF plus conventional standard chemotherapy (N = 127) or a placebo plus conventional standard chemotherapy (N = 125). At a median follow-up of 51 months, 5-year DFS time was longer in those assigned to SYF plus conventional standard chemotherapy compared with placebo plus conventional standard chemotherapy (94.2%vs 85.5%, hazard ratio [HR] = 0.40; 95%CI, 0.17-0.97; P = 0.034). The absolute benefit for 5-year DFS was 8.7% in the SYF plus conventional standard chemotherapy group. No statistically significant difference was observed in OS between the two groups (P = 0.23). Patients with negative node status benefited more from SYF plus conventional standard chemotherapy treatment (HR = 0.21, P-interaction = 0.013) in accordance with the exploratory subgroup analyses of DFS.ConclusionsThe results of the present study suggest that the traditional Chinese medicine SYF plus conventional chemotherapy regimens is an effective alternative adjuvant chemotherapy strategy for female operable TNBC patients.Clinical Trial Registrationhttps://www.chictr.org.cn/searchproj.aspx, identifier ChiCTR-IPR-16008590.

Prediction for pathological and immunohistochemical characteristics of triple-negative invasive breast carcinomas: the performance comparison between quantitative and qualitative sonographic feature analysis.

Sonographic features are associated with pathological and immunohistochemical characteristics of triple-negative breast cancer (TNBC). To predict the biological property of TNBC, the performance using quantitative high-throughput sonographic feature analysis was compared with that using qualitative feature assessment. We retrospectively reviewed ultrasound images, clinical, pathological, and immunohistochemical (IHC) data of 252 female TNBC patients. All patients were subgrouped according to the histological grade, Ki67 expression level, and human epidermal growth factor receptor 2 (HER2) score. Qualitative sonographic feature assessment included shape, margin, posterior acoustic pattern, and calcification referring to the Breast Imaging Reporting and Data System (BI-RADS). Quantitative sonographic features were acquired based on the computer-aided radiomics analysis. Breast cancer masses were manually segmented from the surrounding breast tissues. For each ultrasound image, 1688 radiomics features of 7 feature classes were extracted. The principal component analysis (PCA), least absolute shrinkage and selection operator (LASSO), and support vector machine (SVM) were used to determine the high-throughput radiomics features that were highly correlated to biological properties. The performance using both quantitative and qualitative sonographic features to predict biological properties of TNBC was represented by the area under the receiver operating characteristic curve (AUC). In the qualitative assessment, regular tumor shape, no angular or spiculated margin, posterior acoustic enhancement, and no calcification were used as the independent sonographic features for TNBC. Using the combination of these four features to predict the histological grade, Ki67, HER2, axillary lymph node metastasis (ALNM), and lymphovascular invasion (LVI), the AUC was 0.673, 0.680, 0.651, 0.587, and 0.566, respectively. The number of high-throughput features that closely correlated with biological properties was 34 for histological grade (AUC 0.942), 27 for Ki67 (AUC 0.732), 25 for HER2 (AUC 0.730), 34 for ALNM (AUC 0.804), and 34 for LVI (AUC 0.795). High-throughput quantitative sonographic features are superior to traditional qualitative ultrasound features in predicting the biological behavior of TNBC. • Sonographic appearances of TNBCs showed a great variety in accordance with its biological and clinical characteristics. • Both qualitative and quantitative sonographic features of TNBCs are associated with tumor biological characteristics. • The quantitative high-throughput feature analysis is superior to two-dimensional sonographic feature assessment in predicting tumor biological property.

An evaluation of gender discrepancies in genetic referrals for BRCA testing for indicated malignancies.

10584 Background: Tumor suppressing genes BRCA1 and BRCA2 were discovered in 1990 and 1994, respectively, with mutations linked to hereditary breast-ovarian cancer syndromes (HBOCs). The discovery of these mutations has led to screening of at-risk patient populations and their family members. Women with BRCA1 or BRCA2 mutations are generally recommended to have prophylactic bilateral mastectomies and oophorectomies to decrease their future risk of cancer. While the initial discovery mostly focused on cancers in women, research has shown that BRCA mutations increase the risk of other cancers such as prostate cancer and pancreatic cancer, that also affect men. Previous research suggests that men are three times less likely to receive genetic testing in cancer driven by a 10:1 disparity in HBOC genetic testing. This was thought to be due to the lack of information on the importance of HBOC testing along with social roles in health. We wanted to evaluate the magnitude of the potential gender gap in BRCA testing in men compared to women. Methods: This was an IRB-approved, single center retrospective study to evaluate the rate of referrals to genetics for BRCA testing. Eligible patients had a personal history of cancer meeting criteria for BRCA testing per NCCN recommendations. Chart review was performed for patients with ovarian cancer, female breast cancer 45 years and younger, female triple negative breast cancer 60 years and younger, metastatic prostate cancer, all male breast cancer that have made an office visit since 2017, and pancreatic cancer since 2019. Rates of referral for genetic testing was the primary outcome and the groups were compared via the Chi-Square test. Results: 1,320 patients were included in the study, of which 664 were men and 656 were women. 128/664 (19.3%) of men were referred to genetics for screening compared to 527/656 (80.3%) for women ( p &lt;.001). Additionally, 42/128 (32.8%) men who were referred for screening did not complete genetic screening compared to 72/527 (13.7%) women ( p &lt;.001). A total of 62/541 (11.5%) patients who completed screening had either a BRCA1 or BRCA2 mutation. Conclusions: In our study, men were referred for BRCA testing significantly less than women for primary cancers, despite recommendation from the NCCN. In addition, men were also more than twice as likely not to complete genetic screening even if referred. The integration of genetics and oncology will continue to grow as personalized medicine continues to drive more treatment options. Closing this gender gap is important not only for familial screening purposes but also for treatment implications as patients with germline BRCA mutations are eligible for poly ADP ribose polymerase (PARP) inhibitors (e.g. olaparib) in both metastatic prostate cancer and pancreatic cancer. Further quality improvement initiatives are needed in order to close this gap by increasing education of the importance of BRCA testing in men.

Socioeconomic status variables contribute to the disparities in female triple negative breast cancer outcome in the United States, 2011-2015: A population study based on NCI Surveillance, Epidemiology and End Results (SEER) database.

6521 Background: Cancer disparities pertinent to socioeconomic status (SES) still exist in the American healthcare system. How SES variables impact the outcome of triple negative breast cancer (TNBC) needs identification. Methods: We enrolled 22,434 women diagnosed with invasive TNBC in 2011 – 2015 from the SEER 18 program. The primary outcome was to identify SES risk factors for TNBC cause specific survival (TNBCCSS)and overall survival (OS) via the Cox Proportional Hazard Regression Model. SES information was collected: race, insurance status, marital status, and percentage of families with incomes below the poverty level and adults with less than high school graduate (&lt;HSG) in a county of the patient’s residency; all analyses were also adjusted for clinicopathological characteristics. We categorized rates of poverty and &lt;HSG as quartiles. Results: 18,578 (82.8%) women were insured or insured/ no specifics (NS), and 3,360 (15.0%) received Medicaid upon TNBC diagnosis; only 496 (2.2%) patients were uninsured. The TNBCCSS rates of insured, insured/ NS, Medicaid, and uninsured cohorts were 86.6%, 83.6%, 77.4% and 73.2%, respectively. In multivariable adjusted analyses, the TNBC cause specific mortality risk of patients who were uninsured or receiving Medicaid was significantly higher than that of women who were insured (Hazard ratio [HR] = 1.60, 95% confidence interval [CI]: 1.34-1.92 and HR = 1.29, 95% CI: 1.18-1.41, respectively). Women residing in a county with a high poverty rate (the 3rd quartile [rate of 11.1 – &lt;14.3%]) had significantly worse TNBC cause specific mortality risk as compared to women with residency of the lowest poverty rate (HR = 1.25, 95% CI: 1.10-1.41). Single and widowed cohorts had better HR of TNBCCSS compared with the married population (HR = 0.86, 95% CI: 0.79-0.95 and HR = 0.82, 95% CI: 0.73-0.93, respectively). Notably, we observed a synergistic effect among race, insurance status and TNBC OS: black women receiving Medicaid had significantly lower HR compared with their non-Hispanic white counterparts (HR = 0.86, 95% CI: 0.74-0.98). Rate of &lt;HSG was marginally correlated with the TNBCCSS. Conclusions: SES variables contribute to the disparities in TNBC survival. TNBC cause specific mortality risk of patients without insurance or with Medicaid at the time of TNBC diagnosis is 60% and 29% higher compared with insured women (Table). Race and insurance status act synergistically upon TNBC OS.[Table: see text]

Characteristics of male triple negative breast cancer: A population-based study.

Male triple negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is a very rare entity, comprising only a very small percentage of all male breast cancer cases. Management strategies are typically based off research conducted in female TNBC patients; however, there is still much that remains unknown in the male cohort, such as risk factors for developing these malignancies, the optimal treatment approach, and both short-term and long-term outcome data. In this retrospective cohort study, we aimed to address these concerns by assessing both the characteristics of male patients who develop TNBC as well as their outcomes. We harnessed data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program and identified 66 male patients diagnosed with TNBC between 2010 and 2016. Patients were stratified by several variables including age, insurance status, time period of diagnosis, histology, nodal status, tumor grade, tumor stage at diagnosis, and treatment strategy employed for the assessment of overall survival (OS) differences. Our analysis demonstrated that stage remains the most important prognostic factor for OS, with higher stage corresponding to worse OS. A significant OS benefit was also identified in men undergoing a total mastectomy, compared to partial mastectomy or no surgery at all. We also identified that male patients are more likely to present with more advanced disease stages compared to their female counterparts and, therefore, have worse outcomes on average. This may be due to various factors, including the rarity of male TNBC cases and less clear screening guidelines for male breast cancer in general. Trends toward poorer OS with higher tumor grade, higher tumor T stage, advanced age, earlier time period of diagnosis, and ductal histology were also identified, but did not achieve statistical significance. The remaining variables did not appear to influence outcomes in a meaningful manner. In summary, our study suggests, similar to population studies of women with TNBC, that tumor stage is a major prognostic factor of OS in men with TNBC. The data also suggest that the surgical treatment strategy employed is also likely of significance, with improved OS being seen with total mastectomies over partial mastectomies. Other variables such as tumor grade and T stage also likely play a role, but did not achieve statistical significance owing to the small population size. Owing to the rarity of cases, further studies of male TNBC are needed to better understand this rare entity and guide future management strategies.

EPR20-075: Clinicopathological Features as a Predictor of Female Triple-Negative Breast Cancer Metastasis and Survival in the United States, 2010-2015: a Logistic Regression Model From NCI Surveillance, Epidemiology and End Results (SEER) Database

EPR20-075: Clinicopathological Features as a Predictor of Female Triple-Negative Breast Cancer Metastasis and Survival in the United States, 2010-2015: a Logistic Regression Model From NCI Surveillance, Epidemiology and End Results (SEER) Database

Abstract P2-08-19: Disparities in triple negative breast cancer survival in the United States by patient characteristics: A population-based study from SEER database, 2010 - 2015

Abstract Introduction: Efforts to improve the outcomes of triple negative breast cancer (TNBC) have been hampered by the inability to identify the key risk factors for prognosis. We focus solely on female TNBC and explored its survival by age, marital status, treatment and race. Data from Surveillance, Epidemiology and End Results Program (SEER) Database 18 of National Cancer Institute were used to assess TNBC survival by the above factors. Results: A total of 26,413 female patients diagnosed with TNBC from 2010 to 2015 were included in the current study, including 15840 (60.0%) Non-Hispanic white women. The follow up time ranges: 0 to 83 months. Younger (≤ 49) and elderly (≥ 65) age is associated with poorer survival, with reference to middle age group (50-64). The breast cancer specific survival (BCSS) rate for the three age groups (≤ 49, 50-64 and ≥ 65) are 78.6%, 81.0% and 78.1%, respectively; hazard ratio (HR) (95% confidence interval [CI]): 1.17 (1.08-1.27) in ≤ 49 and 1.24 (1.15-1.34) in ≥ 65 patients, individually. We further categorized elderly group into two strata: aged 65 -74 (age group recommended by U.S. Preventive Services Task Force to have breast cancer [BC] screening) and ≥75 (not recommended for BC screening). Our data revealed that the BCSS rate of 65-74 cohort rises to 81.9%; HR (95% CI): 0.97 (0.88-1.07), not significantly different from group aged 50-64. In contrast, the ≥75 group, as against middle age cohort, has the worst BCSS rate of 71.6%; HR (95% CI): 1.74 (1.58-1.92). In patients ≥75, there is highest proportion of metastatic disease (2.9%) at diagnosis and advanced lymph node involvement (N2 + N3 = 11.9%); their percentage of receiving perioperative chemotherapy (CT) and radiation therapy (RT) is lowest across all age groups: 33.3% and 43.6%, respectively. The mean age of single (never married), married and widowed patients at diagnosis was 52 ± 13, 56 ± 12 and 72 ± 11, respectively. The single cohort has the second worst BCSS rate of 76.1% [HR (95% CI): 1.46 (1.34-1.59)], in comparison with married women (BCSS rate of 81.6%). The BCSS rate of single patients is only better than that of widowed population (74.7%), who have significantly advanced age. Our analyses also showed that single patients have the highest percentage of Black women (37.7%) that are known to have unfavorable prognosis of TNBC. Also, single female patients have high proportion of large tumor (T3 + T4 = 18.5%, highest among all women in study) and metastatic disease (2.9%, secondary to widowed group only). Single group compared with married group, tends to have lower percentage of completing RT: 49.9% versus 53.4%, respectively. Conclusion: Advanced age is associated with worse BCSS. However, discontinuation of BC screening may partly account for the phenomenon that ≥ 75-year-old patients lost survival benefits (i.e., highest metastatic disease at diagnosis and worst BCSS), that is maintained in patients aged 65-74, who are recommended for BC screening. Further, low adherence to receive or complete adjuvant therapy may attenuate the survival in elderly patients aged ≥ 75. The poor outcome in single women with relatively young age indicates that both biological and socioeconomic factors and their interactions (e.g., high proportion of black women and low proportion of receiving RT) may influence TNBC prognosis. Our findings suggest a greater need for early and extended BC screening in the above two populations. Citation Format: Zikun Wang, Zheyu Lu, Maitri Kalra, Zhongxue Chen, Yi Dong. Disparities in triple negative breast cancer survival in the United States by patient characteristics: A population-based study from SEER database, 2010 - 2015 [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 P2-08-19.

Metabolomics-Based Discovery of Molecular Signatures for Triple Negative Breast Cancer in Asian Female Population

Triple negative breast cancer (TNBC) is a devastating cancer disease characterized by its poor prognosis, distinct metastatic patterns, and aggressive biological behavior. Research indicates that the prevalence and presentation of TNBC varies among races, with Asian TNBC patients more commonly presenting with large invasive tumors, high node positivity, and high histologic grade. In this work, we applied ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS)-based metabolomics to discover metabolic signatures in Asian female TNBC patients. Serum samples from 31 TNBC patients and 31 healthy controls (CN) were involved in this study. A total of 2860 metabolic features were detected in the serum samples. Among them, 77 metabolites, whose levels were significantly different between TNBC with CN, were confirmed. Using multivariate statistical analysis, literature mining, metabolic network and pathway analysis, we performed an in-depth study of the metabolic alterations in the Asian TNBC population. In addition, we discovered a panel of metabolic signatures that are highly correlated with the 5-year survival rate of the TNBC patients. This metabolomic study provides a better understanding of the metabolic details of TNBC in the Asian population.

Analysis of clinicopathological characteristics and prognostic factors of patients with triple negative breast cancer in Shanxi province

Objective To discuss the clinicopathological features and prognostic factors of patients with triple negative breast cancer (TNBC) in Shanxi province. Methods The medical records of 958 female TNBC patients who were admitted to Shanxi Provincial Cancer Hospital and the First Hospital of Shanxi Medical University from January 2005 to December 2015 were retrospectively analyzed. The clinicopathological features and prognostic factors were summarized. Results The median age of TNBC patients in Shanxi province was 46 years old (21-87 years old), the median body mass index (BMI) was 24.42 kg/m2 (15.0-37.5 kg/m2), and the rural population was slightly more. The left breast cancer was more than the right breast cancer, and 492 patients (51.4%) were in stage T2. The main histological type was invasive ductal carcinoma. The main surgical method was modified radical mastectomy. Univariate Cox regression analysis showed that the patient's place of residence, fertility status, age at first birth, breastfeeding history, tumor size, American Joint Committee on Cancer Staging, lymph node metastasis, and surgical approach were associated with the risk of death in TNBC patients (all P 0.05). Multivariate Cox regression analysis showed that rural residents (HR = 1.46, P = 0.044), positive lymph node metastasis (HR = 2.51, P < 0.01), non-fertility (HR = 1.08, P =0.009) and no surgery (HR = 2.53, P = 0.004) were independent risk factors affecting the risk of death, a history of breastfeeding was a protective factor affecting the risk of death in TNBC patients (HR = 0.44, P = 0.013). Conclusions In Shanxi province, TNBC is more common in premenopausal women and the main pathological type is invasive ductal carcinoma. Rural population, lymph node positive, non-fertility, and no surgical treatment are independent risk factors for the prognosis of TNBC patients. Key words: Triple-negative breast cancer; Prognosis; Clinicopathological features

BRCA1 and BRCA2 Germline Mutation Analysis in Hereditary Breast/Ovarian Cancer Families from the Aures Region (Eastern Algeria): First Report.

Breast cancer is currently the leading cause of cancer morbidity and mortality among Algerian women. In this study, we aimed to investigate the mutation spectrum of BRCA1 and BRCA2 genes in hereditary breast/ovarian cancer (HBOC) families from the Aures region (eastern Algeria). High risk breast/ovarian cancer families were selected from overall 1162 consecutive patients collected from cancer registry of anticancer center of Batna. Breast cancers were diagnosed between 2011 and 2015. Recurrent mutations on BRCA1 and BRCA2 previously found in Algerian patients were screened using PCR-direct sequencing in 113 HBOC families. In addition, for the first time in Algeria, HBOC patients were analyzed by NGS using a cancer panel of 30 hereditary cancer genes or BRCA1/2 genetic test. Six distinct deleterious mutations in BRCA1 and BRCA2 and a new VUS in PALB2 were detected in ten patients. Two distinct BRCA2 pathogenic variants c.1813dupA and c.8485C > T detected in two young female triple negative breast cancer (TNBC) patients, respectively, with a family history of male breast cancer, are reported here for the first time in Algerian population. Interestingly, we also detected a BRCA exon 15 deletion in two unrelated young female TNBC patients with strong family history of breast/ovarian cancer. Our study showed differences in the distribution of the mutation spectrum of BRCA genes between the Aures region and the north central region of Algeria. Our results will contribute in the implementation of genetic counseling and testing for patients and families at risk of hereditary breast and ovarian cancer.

The influence of marital status and race/ethnicity on risk of mortality for triple negative breast cancer.

PurposeTo assess the effect of marital status and the role of race/ethnicity on breast cancer specific mortality in women with triple negative breast cancer (TNBC).MethodsThe study utilized the California Cancer Registry to identify 22,812 cases of first primary female TNBC. Unadjusted Kaplan-Meier breast cancer specific survival was computed. Cox Proportional Hazards modeling was used to compute the adjusted risk of breast cancer specific mortality for women who were single, separated, divorced, and widowed when compared with women who were married. Models were adjusted for age, stage, tumor grade, SES, and treatment with surgery, chemotherapy, hormone therapy, and radiation therapy. Hazard ratios (HR) and 95% confidence intervals (CI) were reported.ResultsSeparated (HR: 1.45; 95% CI: 1.14–2.01) and widowed (HR: 1.39; 95%CI: 1.23–1.57) white women had a higher risk of mortality than white married women whereas single and divorced white women had the same risk of mortality. For Asian/Pacific Islanders (API), only single (HR: 1.55; 95% CI: 1.17–2.06) and divorced (HR:1.81; 95% CI:1.26–2.60) women had a higher risk of mortality than married women. Marital status had no influence on risk of mortality for either black or Hispanic women.ConclusionsThe risk of mortality associated with marital status is dependent on race/ethnicity. Only white and API women with TNBC have a marital advantage.

Abstract CT058: A phase 2 open-label study to evaluate the efficacy and safety of VT-464 in patients with androgen receptor positive triple-negative breast cancer patients, and men with ER positive breast cancer

Abstract Background: The androgen receptor (AR) is expressed in 20-30% of patients with triple negative breast cancer (TNBC). In phase 2 trials androgen blockade with bicalutamide demonstrated a clinical benefit rate (CBR = Partial Response + Complete Response + Stable Disease) of 19% at 24 weeks and enzalutamide showed a CBR of 35% at 16 weeks. VT-464 is an oral non-steroidal, small molecule that is a potent anti-androgen through both inhibition of CYP17 lyase and through direct inhibition of AR. Studies in breast cancer cell lines have shown that VT-464 inhibits growth in a soft agar assay of MCF7 (ER positive/low AR expression), tamoxifen-resistant MCF7, and MDA-MB-453 (ER negative/AR positive) cells in a dose dependent manner and with higher potency than enzalutamide. Patients with AR+ TNBC may benefit from treatment with VT-464. In addition, since VT-464 will deplete androgen available for aromatization, men with ER-positive (ER+) breast cancer may benefit from use of VT-464. Methods: This is a Phase 2, open label study evaluating the potential benefit of VT-464 in female patients with TNBC with AR 1 to 9% (cohort 1) and AR ≥ 10% (cohort 2), and men with ER+ breast cancer (cohort 3) (NCT02130700; NIH 14-c-0090). VT-464 will be administered once daily in continuous 28-days cycles. Due to differences in drug metabolism, women with TNBC will receive VT-464 450mg by mouth daily while men with ER+ breast cancer will receive VT-464 600mg by mouth daily. In the two female TNBC cohorts the primary endpoint is CBR at 16 weeks. In the ER+ male breast cancer cohort the primary endpoint is progression free survival at 24 weeks. Secondary objectives include evaluation of response rate and the safety profile of the drug in both populations. Women with TNBC with &amp;gt; 1% AR expression per IHC are eligible. Males with ER+ breast cancer, who have failed at least one prior endocrine therapy and are undergoing gonadal suppression using LHRH agonists or antagonists are eligible for the study. All patients must be at least 18 years old and have a ECOG of 0 to 1. Consenting patients must have biopsiable disease which will be used for genomic and transcriptomic evaluation before and after treatment with VT-464. Correlative studies including serum hormone levels, circulating tumor cells, and immune subset will be analyzed. Patients must also have adequate hematopoietic, hepatic and renal function. Exclusions include symptomatic CNS metastases, radiotherapy within 28 days of study entry and active HIV, hepatitis B or hepatitis C infection. This trial opened in December 2016. While no patients have been enrolled at this time, multiple patients are currently being screened. Citation Format: Alexandra Zimmer, Margaret E. Gatti-Mays, Stan Lipkowitz, Fatima Karzai, James Gulley, William Dahut, Seth Steinberg, William D. Figg, Ravi Madan. A phase 2 open-label study to evaluate the efficacy and safety of VT-464 in patients with androgen receptor positive triple-negative breast cancer patients, and men with ER positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT058. doi:10.1158/1538-7445.AM2017-CT058