Triple-negative Breast Cancer Group Research Articles

Prognostic Value of BCL2 in Women Patients with Invasive Breast Cancer

Background:Breast cancers are heterogeneous, making it essential to recognize several biomarkers for cancer outcome predictions especially in young women where the classical prediction parameters are not suitable. The goal from this study is to evaluate the impact of B cell lymphoma 2 (BCL2), P53 and Ki-67 proteins expression on survival in young women patients with invasive ductal carcinoma.Patients and methods:Samples and clinical data from 238 patients were collected between 2003 and 2017. They were selected according to 2 criteria: age ≤40 years old and most of them are affected by an Invasive Ductal Carcinoma. We evaluated BCL2, P53 and ki-67 expression by immunochemistry test, and then we assessed correlations of these biomarkers expression with patient’s clinicopathological characteristics and survival.Results:Triple negative breast cancer group showed a high frequency among our cohort but we emphasize an almost equitable distribution among all molecular groups. Contrary to other studies which reported that luminal A was correlated with better prognosis, our analysis demonstrated that luminal A is correlated with the Scarff, Bloom and Richardson (SBR) grading 2 or SBR grading 3. To better investigate the prognosis, we analyze three biomarkers known by their impact on physiopathology behavior on breast cancer BCL2, ki-67and P53. BCL2 is the more relevant one, it was correlated with molecular subtypes (p=0.0012) and SBR grading (p=0.0016). BCL2 seems to be the good prognostic biomarker related to survival (p=0.004) with a protective role among patients when endocrine therapy is not provided and Lymph Node (LN) involvement is positive (p=0.021, p=0.000 respectively).Conclusions:The classical prognostic parameters based mainly on the molecular classification in breast cancer seem insufficient in the case of young women. BCL2 protein expression analysis provides a better prognostic value. BCL2 should be clinically associated in current practice when young women specimens are diagnosticated.

Applied value of routine ultrasound and shear wave elastography in the diagnosis of triple negative breast cancer

Objective To investigate the applied value of routine ultrasound and shear wave elastography (SWE) in the comparison between triple negative breast cancer (TNBC) and non-triple negative breast cancer (non-TNBC). Methods A total of 120 lesions in 120 patients with pathologically confirmed breast cancer were retrospectively reviewed, which were examined by routine ultrasound and SWE before surgery. According to immunohistochemical analysis, those were divided into TNBC group and non-TNBC group. The features of routine ultrasound(including shape, orientation, margin, boundary, echo pattern, microcalcification, posterior features of each lesion and blood flow characteristics) and the SWE index[including the average value of the lesion stiffness(Emean), the maximum value (Emax), the minimum value (Emin), the standard deviation (SD), and the ratio of the normal breast gland tissue (Eratio)] in the two groups were analyzed and compared. Results ①Two-dimensional ultrasound: TNBC lesions mostly showed the margin of microlobulated, abrupt boundaries and no internal microcalcification, but non-TNBC lesions were more likely to have an angular or spiculated margin, an echogenic halo of boundary and a few microcalcification in the interior, which were statistically different(P 0.05). ②The values of Emax, Emean and Eratio were statistically different(P<0.05), with AUCs of 0.811, 0.781, and 0.770, respectively. Conclusions Routine ultrasound and SWE can comprehensively analyze the morphology, blood flow and stiffness features of breast lesions, which provides more valid information to identify TNBC and non-TNBC. Key words: Ultrasonography; Shear wave elastography; Triple negative breast cancer

Identification of tRNA-derived small noncoding RNAs as potential biomarkers for prediction of recurrence in triple-negative breast cancer.

Triple‐negative breast cancer (TNBC), an intrinsic subtype of breast cancer, is characterized by aggressive pathology and shorter overall survival. Yet there is no effective therapy for these patients. Breast cancer stem cells (BCSCs) in TNBC may account for treatment failure. It is urgent to identify new therapeutic targets for TNBC. tRNA‐derived small noncoding RNAs (tDRs) represent a new class of small noncoding RNAs (sncRNA), which have been reported in some human diseases and biological processes. However, there is no detailed information about the relationship between tDRs and BCSCs. In this study, a population of CD44+/CD24−/low cells was isolated and identified by reliable BCSC surface markers. tDR expression profiles in TNBC and non‐TNBC CSCs were performed by RNA sequencing. A total of 1327 differentially expressed tDRs contained 18 upregulated and 54 downregulated in TNBC group. Furthermore, the selected tDRs were validated by quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR). tDR‐000620 expression level was consistently lower in TNBC cell lines CSCs (all P < 0.05) and serum samples (t = 2.597, P = 0.013). tDR‐000620 expression was significant association with age (P = 0.018), node status (P = 0.026) and local recurrence (P = 0.019) by chi‐square test. Kaplan‐Meier method with log‐rank test for comparison of recurrence curves. The results showed that the tDR‐000620 expression (P = 0.002) and node status (P = 0.001) group were statistically significant with recurrence‐free survival. Furthermore, multivariate Cox regression demonstrated that lymphatic metastasis (HR, 3.616; 95% CI, 1.234‐10.596; P = 0.019) and low tDR‐000620 expression (HR, 0.265; 95% CI, 0.073‐0.959; P = 0.043) were two independent adverse predictive factors for recurrence‐free survival. Finally, we found that tDR‐000620 participated in some important biological processes though GO and KEGG analysis. Taken together, our study reveals the expression profiles of tDRs in TNBC and non‐TNBC CSCs. It offers helpful information to understand the tDR‐000620 expression is responsible for the aggressive phenotype of BCSCs. It may provide predictive biomarkers and therapeutic targets for TNBC recurrence.

Discordance of the PAM50 Intrinsic Subtypes Compared with Immunohistochemistry-Based Surrogate in Breast Cancer Patients: Potential Implication of Genomic Alterations of Discordance.

PurposeWe aimed to analyze the discordance between immunohistochemistry (IHC)-based surrogate subtyping and PAM50 intrinsic subtypes and to assess overall survival (OS) according to discordance.Materials and MethodsA total of 607 patients were analyzed. Hormone receptor (HR) expression was evaluated by IHC, and human epidermal growth factor receptor 2 (HER2) expression was analyzed by IHC and/or fluorescence in situ hybridization. PAM50 intrinsic subtypes were determined according to 50 cancer genes using the NanoString nCounter Analysis System. We matched concordant tumor as luminal A and HR+/HER2–, luminal B and HR+/HER2+, HR–/HER2+ and HER2–enriched, and triple-negative breast cancer (TNBC) and normal- or basal-like. We used Ion Ampliseq Cancer Panel v2 was used to identify the genomic alteration related with discordance. The Kaplan-Meier method was used to estimate OS.ResultsIn total, 233 patients (38.4%) were discordant between IHC-based subtype and PAM50 intrinsic subtype. Using targeted sequencing, we detected somatic mutation–related discordant breast cancer including the VHL gene in the HR+/HER2– group (31% in concordant group, 0% in discordant group, p=0.03) and the IDH and RET genes (7% vs. 12%, p=0.02 and 0% vs. 25%, p=0.02, respectively) in the TNBC group. Among the luminal A/B patients with a discordant result had significantly worse OS (median OS, 73.6 months vs. not reached; p < 0.001), and among the patients with HR positivity, the basal-like group as determined by PAM50 showed significantly inferior OS compared to other intrinsic subtypes (5-year OS rate, 92.2% vs. 75.6%; p=0.01).ConclusionA substantial portion of patients showed discrepancy between IHC subtype and PAM50 intrinsic subtype in our study. The survival analysis demonstrated that current IHC-based classification could mislead the treatment and result in poor outcome. Current guidelines for IHC might be updated accordingly.

Triple Negative Breast Cancer, Clinicopathologic Study of Egyptian Patients, NCI Experience

AbstractBackground: Triple negative breast cancer category is a challenging group of breast cancer. It needs more detailed clinical and pathological studies.Aim of Study: To study the clinicopathologic characteristics of triple-negative breast cancer of Egyptian patients.Patients and Methods: A retrospective study was done included 59 women with triple negative breast cancer collected from Pathology Department at NCI, Cairo University, Egypt. Clinical data and pathological data were revised, then follow-up of the cases with a median follow-up time 40.5 months (range: 8-67).Results: Most cases were equal or below 50 years old, post-menopausal, and unilateral. According to pathological characters, majority of cases represented grade 2, T2, positive lymph nodes, and stage 2. As regards outcome three cases underwent recurrence, seven cases underwent metastasis, and two cases show metastasis and recurrence. At the end of the study 44 cases were alive, ten died, and five show lost follow-up. There was a significant relationship found between grade and DFS, as well as OS with grade, stage, occurrence of metastasis and node positivity.Conclusion: Triple negative breast cancer group were more noticed among age group less than 50 years, with tendency to express high grade, large tumor size, high stage and node positivity, with significant relationship between grade and DFS, as well as OS with grade, stage, occurrence of metastasis and node positivity.

Morphological and Semiquantitative Kinetic Analysis on Dynamic Contrast Enhanced MRI in Triple Negative Breast Cancer Patients

The aim of this study was to retrospectly investigate the association between different breast cancer (BC) immunohistochemical subtypes and morphological and semiquantitative kinetic analysis on breast magnetic resonance imaging (MRI) performed before surgery treatment. Specifically we aimed to assess MRI features of triple-negative breast cancer (TNBC) compared to the other BC subtypes (nTNBC). Patients undergone to breast MRI and then diagnosed with BC by core-needle biopsy were included. The MRI morphological and kinetic features were studied. Parametric and non-parametric tests were used, as appropriate. Seventy-five BC patients were considered, 30 patients included in TNBC Group and 45 patients included in nTNBC Group. We found in TNBC Group a greater mean lesion size (P <0.001), a rim enhancement imaging (P=0.003), and a higher intratumoral signal intensity on T2-weighted images (P=0.03) with respect to nTNBC Group. We noticed that TNBC patients presented a lower grade of BPE when compared to the nTBC Group (P< 0.02). TNBC Group showed lower EPeak values (P=0.003) and higher SER values (P=0.02) with respect to the nTNBC Group. In addition, stratifying kinetics parameters according to the tumor grade, the TNBC Group presented higher tumor grade (G3) (P< 0.005) and this subgroup had higher SER values when compared to TNBCs showing a lower tumor grade (G1 and G2) (P=0.03). After validation by large-scale studies, the morphological and semiquantitative kinetic analysis on dynamic contrast enhanced MRI may help in the pretreatment risk stratification of patients with TNBC and in evidence-based clinical decision support.

Abstract 5392: Exosomal miRNA expression profiling in triple-negative breast cancer

Abstract Exosomes are extracellular vesicles that are present in body fluids and known to play key roles in intercellular signaling communication. Exosomes carry several types of molecules of their tumor of origin, including miRNAs, and therefore present potential as biomarkers for cancer prognosis and treatment. Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer, associated with treatment resistance, recurrence and high mortality rates. These tumors are molecularly heterogeneous, which impairs the identification of effective prognostic molecular markers and target therapies. The main objective of this study was to characterize the miRNA expression profile of exosomes derived from TNBC cells in comparison to normal controls and to the luminal A (LA) breast cancer subtype. The exosomal miRNAs were isolated from 19 serum samples of breast cancer patients (10 with the LA and 9 with the TNBC subtype) and 10 serum samples of healthy women (control group) using the exosome precipitation method. Exosome characterization and quantification was assessed by Western blot using the exosomal surface markers, CD6 and CD9, and Nanotracking analysis. The tumor and normal exosomal samples were combined into 6 different pools (of at least 4 samples in each group) and sequenced in the Ion Torrent Proton platform (Applied Biosystems). RNA-seq analysis revealed differentially expressed (DE) levels of exosomal miRNAs, with log2FC ranging from 1.2 to 3.6, among the four groups studied (control, cancer (TNBC+LA), TNBC and LA groups): 22 DE miRNAs were observed in the cancer vs. control, 19 in the LA vs control, 30 in the TNBC vs. control and 7 in the LA vs. TNBC groups. Eleven miRNAs were commonly DE in the cancer, LA and TNBC groups when compared to the control group, which included miRNAs, such as miR-103a-3p, miR-107 and miR-423-5p, involved in the biosynthesis of unsaturated fatty acids and neutrophin signaling pathways. Nine miRNAs were only observed DE in the TNBC group (vs. control), with the majority of them being downregulated. The top 10 significant functional enriched pathways affected by these miRNAs included proteoglycans, pathways in cancer and TGF-beta signaling pathways. Only three miRNAs were observed DE in the TNBC vs. LA groups, all with downregulated expression in the TNBC group. These miRNAs were observed mostly involved in fatty acid biosynthesis, proteoglycans in cancer and TGF-beta signaling pathways. In conclusion, our results indicate that expression alterations of exosomal miRNAs affect critical cancer-associated signaling pathways, suggesting their potential use as noninvasive cancer biomarkers. Additional studies should be performed to determine whether the expression patterns of these exosomal miRNAs reflect the ones observed in the corresponding patients' TNBC tissue. Funding: CAPES, PPSUS-Fundação Araucária, Brazil. Citation Format: Patricia M. Ozawa, Débora S. Lemos, Evelyn Vieira, Ingrid L. Souza, Silvio M. Zanata, Vânia C. Pankievicz, Thalita R. Tuleski, Emanuel M. Souza, Rosiane V. Silva, Pryscilla F. Wowk, Rodrigo C. Almeida, Iglenir J. Cavalli, Danielle M. Ferreira, Luciane R. Cavalli, Enilze M. Ribeiro. Exosomal miRNA expression profiling in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5392.

Pre-menopausal triple-negative breast cancer at HAM hospital medan

Triple-negative breast cancers (TNBC) are a type of breast cancer that does not have any or lack expression of the three receptors of estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER-2). This cross-sectional study was performed on patients TNBC in HAM hospital Medan from 2013 to 2016 by immunohistochemistry stained. A total 60 invasive breast cancer samples with TNBC. The more frequent in TNBC group were 51-60 years (19 cases, 31.66%) and pre-menopause (34 cases, 57%). Tumor size T3 and T4 with staging IIIA and IIIB, histology sub-type IC-NOS and ILC with grade 2 and grade 3 of histologic was more common in TNBC.

Abstract P5-07-12: miR-34a as a prognostic biomarker for overall survival triple negative breast cancer within Tunisian patients

Abstract Introduction: miR-34a has been recently introduced to clinical trials especially in breast cancer depending on its crucial role as microRNA suppressor tumors since it regulates several oncogenes. We explore here the prognostic effect of miR-34a on triple negative breast cancer (TNBC) overall survival compared to no triple negative (NTNBC) group and its effect on PARP-1 and BRCA1 protein expression. Methods: 76 patients with TNBC and NTNBC were recruited for this study. miR-34a was quantified using qPCR Syber Green technique. PARP-1 and BRCA1 were analyzed by IHC using Tissue Micro-Array method. Results: PARP-1 is more expressed in TNBC compared to NTNBC; P = 0.04; RR= 1.8 (1.1-3.1), however, BRCA1 is less expressed in TNBC; P = 0.03; RR= 2 (1.2-12.6). Furthermore, we evaluated the relationship between miR-34a and clinicopathological features with survival rate of both studied groups, we found that miR-34a is more expressed among patients with distance metastases in TNBC group P = 0.001; RR = 6.5 (2.1-19.6). Survival analysis showed that miR-34a low expression in TNBC was remarkably related to overall survival; P=0.012. Furthermore, multivariate survival test suggested that the absence of miR-34a was linked to the poor survival within TNBC according to the presence of distance metastasis; P=0.048; HR= 2.69. Our results showed that miR-34a is decreased in triple negative breast cancer patients with a very poor prognosis. Conclusion:Our results give mechanistic insights in miR-34a as a prognostic biomarker for overall survival Triple Negative Breast Cancer within Tunisian patients through its effect on PARP-1 and BRCA1 protein expression which may open potential new strategies towards prevention and therapeutic inhibition of PARP-1 positive within mammary tumors. Citation Format: Medimegh I, Ayari H, Baraudi O, Majoul H, Omrane I, Yousef E, Benayed F, Benromdhan K, Gaboury L, Mader S, Benammarelgaaied A. miR-34a as a prognostic biomarker for overall survival triple negative breast cancer within Tunisian patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-07-12.

Histological scoring of immune and stromal features in breast and axillary lymph nodes is prognostic for distant metastasis in lymph node-positive breast cancers.

The prognostic importance of lymph node (LN) status and tumour‐infiltrating lymphocytes (TILs), is well established, particularly TILs in triple negative breast cancers (TNBCs). So far, few studies have interrogated changes in involved and uninvolved LNs and evaluated if their morphological patterns add valuable information for the prediction of disease progression in breast cancer. In a cohort of 309 patients enriched for TNBCs (170/309), we histologically characterised immune and stromal features in primary tumours and associated involved and uninvolved axillary LNs on routine haematoxylin and eosin stained sections. Of the 309 patients, 143 had LN‐positive disease. Twenty‐five histopathological features were assessed, including the degree of TIL presence, quantitative and qualitative assessment of germinal centres (GCs) and sinus histiocytosis. Multivariate and cross‐validated proportional hazard regression analyses were used to identify optimal covariate sets for prediction of distant metastasis‐free survival (DMFS). The degree of intratumoural and peritumoural immune infiltrate was associated with architectural changes in both uninvolved and involved LNs. By including clinicopathological characteristics as well as tumour and LN histopathological features in L2‐regularised proportional hazard models, the prediction of 5‐year DMFS was improved by 3–15% over the baseline in all cancers and in TNBCs. In LN‐positive cancers, the combination of Salgado's classification, lymphocytic lobulitis, size and number of GCs in the uninvolved LNs and location of GCs in the involved LNs carried significant prognostic information. From these features, a multivariate cross‐validation‐stable risk signature was constructed, which identified low‐risk groups within both LN‐positive breast cancers and the LN‐positive TNBCs group with a 10‐year DMFS probability of 78 and 87%, respectively. This study illustrates that, by incorporating histopathological patterns of involved and uninvolved LNs combined with primary tumour immune and stromal features, the prediction of developing distant metastasis in LN‐positive breast cancers can be estimated more accurately.

Health Disparity or Bad Biology? An Analysis of Triple Negative Breast Cancer Patients in an Urban Academic Hospital

Background: 10-25% of patients diagnosed with breast cancer have triple negative breast cancer (TNBC). TNBC is more aggressive than receptor-positive breast cancer. Objective: The objective of this study is to examine the demographics of this patient population. Methods: The Commission on Cancer tumor registry was queried for breast cancers from 2006 to 2013. The tumors were divided into groups according to receptor status. Patient demographics were then analyzed along with TNM staging defined by the American Joint Committee on Cancer. Results: Breast cancer tumors were identified (n=3267) and complete receptor data was available for 1238 tumors. Of these, 83% (1028/1238) of tumors were non-TNBC, while 17% (210/1238) were TNBC. Patients with TNBC were more likely be <40 years of age (p=0.018) and African American (p<0001). No significant difference was found comparing insurance type, median household income, or duration from diagnosis to definitive treatment between the TNBC and non-TNBC groups. Conclusion: TNBC is more common among African-American and younger women, but not more common among uninsured patients or those below the poverty level. This suggests an actual difference in tumor biology and not simply a health disparity

Prognostic significance ofandrogen receptor expression in HER2-positive and triple-negative breast cancer.

Triple-negative breast cancer (TNBC) and HER2-positive breast cancer are more aggressive than other subtypes ofbreast cancer. Due to thelimited number oftreatment alternatives and theabsence oftarget receptors in TNBC, and because ofprogression in theHER2-positive group despite targeted treatments, new treatment targets and therapeutic combinations are required. In this context, thepresent study aims to evaluate theprognostic importance ofimmunohistochemical androgen receptor (AR) expression in HER2-positive breast cancer and TNBC subtypes. AR nuclear staining density was evaluated immunohistochemically. Atotal of111 operated patients with breast cancer were included in thestudy; 44 (39.6%) belonged to theHER2-positive breast cancer subgroup and 67 (60.4%) belonged to theTNBC subgroup. AR expression was 34.3% and 79.5% in TNBC and HER2-positive groups, respectively. The5-year overall survival (OS) was 76% and 58% for thegroup with anAR-expression>7.5% and AR-expression<7.5%, respectively, in theTNBC subgroup (p=0.042). In theHER2-positive patient group, thesubgroups characterised by anAR-expression>7.5% and AR-expression<7.5% had 5-year OS rates of57.6% and 63.5%, respectively (p=0.91). Including theassessment ofAR expression in theroutine pathological examination will contribute to our understanding oftherelevance ofAR in thebiology and prognosis ofbreast cancer.

Magnetic resonance (MR) features in triple negative breast cancer (TNBC) vs receptor positive cancer (nTNBC)

Few reports in literature describe triple negative breast cancer (TNBC) imaging findings. Aim of the study is to determine MR-features of TNBC compared to receptor positive cancer (nTNBC).From May 2014 to May 2015, we retrospectively enrolled 31 consecutive patients with histological diagnosis of TNBC and a control group of 31 consecutive nTNBC observed in the same period, out of 602 cancer, diagnosed in our department in the same year.Histopathological analysis and MR-features of TNBC (31 patients) were compared to nTNBC (31 patients). MR-features included dimension, fibroglandular tissue (FGT), background parenchimal enhancement (BPE), mass shape, margins, presence of rim, intratumoral signal intensity in T2w, uni-multifocality, kinetic curves. All patients were examined with MR 1,5T (Magnetom Simphony Tim, Siemens Healthcare) performing T2w fat-sat and contrast enhanced high temporal and spatial resolution T1w before and after injection of Gadolinium.62 staging MR were reviewed. Median age was 50 (30-78ys) with a standard deviation of 10,9. TNBC showed 3 MR features in concordance with current literature: rim enhancement, hyperintensity in T2 sequence and unifocality. Rim enhancement was shown in 67.7% of TNBC (21/31) and 29% of nTNBC (9/31). Higher T2w values were shown in 83.9% of TNBC (26/31) and 58.1% of nTNBC (18/31). Cancer was multifocal in 7/31 (22.6%) of TNBC and 19/31 (61.3%) nTNBC.No correlation was found for dimension (p=0.12), FGT (p=0.959), BPE (p=0.596), homogeneity of enhancement (p=0.43), margins (p=0.671) and kinetic (p=0.37).Multivariate analysis demonstrated that rim enhancement and unifocality correlated independently with TNBC group. Area under ROC curve of our model is 0.835.Furthermore, we evaluated the clinical outcome of all 31 TNBC patients in a follow-up time ranging from 24months to 36months separating them in a free-survival group (23 women) and a recurrence group (8 women with local recurrence or distant metastasis): only kinetic curves resulted to be significantly higher in recurrence group (p=0.042).

The role of BRCA1-IRIS in the development and progression of triple negative breast cancers in Egypt: possible link to disease early lesion

BackgroundBreast cancer is the most globally diagnosed female cancer, with the triple negative breast cancer (TNBC) being the most aggressive subtype of the disease. In this study we aimed at comparing the effect of BRCA1-IRIS overexpression on the clinico-pathological characteristics in breast cancer patients with TNBC or non-TNBC in the largest comprehensive cancer center in Egypt.MethodsTo reach this goal, we conducted an observational study at the National Cancer Institute (NCI), Cairo University (Cairo, Egypt). The data on all diagnosed breast cancer patients, between 2009 and 2012, were reviewed. BRCA1-IRIS expression measured using real time RT/PCR in these patients’ tumor samples was correlated to tumor characteristics, such as to clinico-pathological features, therapeutic responses, and survival outcomes.Results96 patients were enrolled and of these 45% were TNBC, and 55% were of other subtypes (hereafter, non-TNBC). All patients presented with invasive ductal carcinomas. No significant difference was observed for risk factors, such as age and menopausal status between the TNBC and the non-TNBC groups except after BRCA1-IRIS expression was factored in. The majority of the tumors in both groups were ≤5 cm at surgery (p = 0.013). However, in the TNBC group, ≤5 cm tumors were BRCA1-IRIS-overexpressing, whereas in the non-TNBC group they were BRCA1-IRIS-negative (p = 0.00007). Most of the TNBC patients diagnosed with grade 1 or 2 were BRCA1-IRIS-overexpressing, whereas non-TNBCs were IRIS-negative (p = 0.00035). No statistical significance was measured in patients diagnosed with grade 3 tumors. Statistically significant difference between TNBCs and non-TNBCs and tumor stage with regard to BRCA1-IRIS-overexpression was observed. Presence of axillary lymph node metastases was positively associated with BRCA1-IRIS overexpression in TNBC group, and with BRCA1-IRIS-negative status in the non-TNBC group (p = 0.00009). Relapse after chemotherapy (p < 0.00001), and local recurrence/distant metastasis after surgery (p = 0.0028) were more pronounced in TNBC patients with BRCA1-IRIS-overexpressing tumors compared to non-TNBC patients. Finally, decreased disease-free survival in TNBC/BRCA1-IRIS-overexpressing patients compared to TNBC/BRCA1-IRIS-negative patients, and decreased overall survival in TNBC as well as non-TNBC patients was driven by BRCA1-IRIS overexpression.ConclusionsTNBC/BRCA1-IRIS-overexpressing tumors are more aggressive than TNBC/BRCA1-IRIS-negative or non-TNBC/BRCA1-IRIS-overexpressing or both negative tumors. Further studies are warranted to define whether BRCA1-IRIS drives the early TNBC lesions growth and dissemination and whether it could be used as a diagnostic biomarker and/or therapeutic target for these lesions at an early stage setting.

Epidemiological Study of Triple-Negative Breast Cancer Patients in North Indian Population: a Hospital-Based Study.

Triple-negative breast cancer (TNBC) accounts for 10-25% of all breast tumors. This makes it more difficult to treat, so triple-negative cancers often require targeted therapies. We studied the prevalence of TNBC in a hospital-based study and compared the clinicopathological characteristics of triple-negative and non-triple-negative breast tumors. One hundred three patients were included in the study that underwent modified radical mastectomy. The procedure of immunostaining was performed using formalin-fixed, paraffin-embedded tissue sections. These sections were stained immunohistochemically for ER, PR, and HER2 neu by using ready-to-use monoclonal antibody detection system with 3'-3' diaminobenzidine hydrochloride (DAB) as chromogen. Of all 103 patients, 35 (34%) were triple negative. The average age of patients of TNBC and non-TNBC group was found as 44.16 and 40.73years, respectively. Patients of post-menopausal state were higher than premenopausal in TNBC (22/35; 62%) and non-TNBC groups (45/68; 66%). Further, TNBC patients reported at clinically early stages I and II (18/35; 51.4%) while non-TNBC patients predominantly reported at later stages III and IV (44/68; 64.7%). It was also observed that breast tumor size in majority of the patients in both groups lies between 2 to 5cm (TNBC=23/35; 65.7% and non-TNBC=35/68; 51.5%). Lymph node metastases were present in 51.5% (18/35) cases in TNBC patients and 64.7% (44/68) cases in non-TNBC group. Despite the limitation of less number of breast cancer cases, we analyzed that TNBC tumors have aggressive clinical values than non-TNBC, though having no statistically significant difference between the prognostic clinical parameters of two groups.

Health-related quality of life in Black breast cancer survivors with and without triple-negative breast cancer (TNBC).

Black women are more likely to develop early-onset (≤50years) breast cancer (BC) and have the lowest five-year, cause-specific survival rate of any United States (U.S.) racial or ethnic group. These disparities can be attributed partially to the higher rate of triple-negative BC (TNBC) in Blacks. Yet, little is known about health-related quality of life (HRQOL) among Black women with TNBC. Black women with invasive BC≤50years were recruited via the Florida Cancer Data System as part of a population-based case-only study of etiology and outcomes of early-onset invasive BC. Of 460 consented participants, a subset of 355 self-reported sociodemographic, clinical, and psychosocial variables. Descriptive analyses included participants with known TNBC (n=85) or non-TNBC (n=245) disease. Univariable and multivariable analyses were conducted to examine differences in factors associated with HRQOL. In unadjusted analyses, TNBC participants had significantly lower FACT-B total scores (90.1±27.9) compared to non-TNBC (98.5±27.6) participants (p<0.05). For the TNBC group, multivariable analyses indicated five individual-level, and three systemic-level factors explain 80% of the response variation in HRQOL. For the non-TNBC group, seven individual-level factors and three systemic-level factors account for 76% of the variation in HRQOL scores. Compared to Black women with non-TNBC, TNBC women have worse HRQOL. There are key individual and systemic-level factors that are unique to both groups. Findings can inform future HRQOL interventions to support young Black BC survivors.

A Comparative Study of Clinical Profile and Relapse Patterns in TRIPLE-NEGATIVE and Non-Triple-Negative Breast Cancer Patients Treated with Curative Intent.

Molecular subtyping in breast cancer is recently emerging as an important determinant of treatment and outcomes, and triple negative breast cancer (TNBC) has been established as a distinct clinical entity with unique features and adverse outcomes. A retrospective analysis of a prospectively maintained computerized breast cancer database was performed, and all the non-metastatic female breast cancer patients undergoing potentially curative multimodality treatment between 2005 and 2012 were included for analysis. Patients with incomplete information regarding ER, PR, and HER2/neu status were excluded. All the eligible patients were divided into TNBC and non-TNBC group based on molecular subtyping. A comparative analysis between the two groups was performed to analyze the clinical spectrum and patterns of relapse. A total of 861 patients qualified for the final analysis and the proportion of TNBC was 254 (29.5%) and non-TNBC was 607 (70.5%). Patients in the TNBC group were slightly younger than the non-TNBC group (median age 46 vs. 49, p value=0.006). TNBC group had a higher breast conservation surgery (BCS) rate, and there was no difference in the need for chemo and radiotherapy between two groups. The overall recurrence rates were significantly higher in TNBC group compared to non-TNBC group (26.8 vs. 19.3%, p value=0.01). Local disease recurrences were significantly higher in TNBC compared to non-TNBC (7.9 vs. 3.1%, p value=0.002). Both the regional and systemic recurrences were higher in TNBC group compared to non-TNBC, though the difference failed to attain statistical significance (for regional recurrences 2.4 vs. 1.5%, p value=0.36; for systemic recurrences 23.2 vs. 17.8%, p value=0.06). The brain metastasis was significantly higher in TNBC group (6.7 vs. 3.3%, p value=0.02). In addition, time to relapse was also significantly less in TNBC cohort (16.1 vs. 22.1months). TNBC accounts for almost one-third of the breast cancer patients with a relatively younger age at presentation, higher volume of disease burden and high breast conservation rates. Despite a standard multimodality therapy the local, systemic, and CNS recurrence rates are high in TNBC and majority relapse within first 2years after completion of therapy.

Abstract P2-04-20: PD-L1 expression in triple negative breast cancer (TNBC) is associated with improved outcomes

Abstract Background: Breast cancer (BC) evolution is influenced by tumor microenvironment. Presence of CD8+ cytotoxic T lymphocytes (TILs) has been proposed as surrogate marker of adaptive immune response, and programmed death ligand-1 (PD-L1) is a negative regulator of the tumor immune microenvironment. However, whether PD-L1 expression adversely affects breast cancer outcome is unknown (Oncotarget 2014; 6:5449). Tumor-associated macrophages (TAMs) in the tumor microenvironment may contribute to BC progression and metastagenicity. We assessed the potential correlations between PD-L1 expression, the presence of TAMs and TILs, and BC outcomes. Methods: 59 primary BCs (16 HR+, 16 HER2+, and 27 TNBC) with known clinical and pathological features and patient (pt) follow-up for a median of 3.9 years were evaluated by immunohistochemistry for expression of CD8, CD68, and PD-L1 within tumor and stroma. The average number of CD8+ cells within 10 high power fields was determined separately for invasive tumor cell nests and for stroma within each sample, and the median number of CD8+ cells within tumor vs stroma was calculated (Breast Cancer Res Treat 2011 128:703–711). Non-lymphocyte mononuclear cells in tumor and stroma were used in counting CD68+ TAMs. BCs were positive for CD8+ TILs (Cell Marque clone #C8144B) or CD68+ TAMs (Cell Marque clone #KP1) if the number of cells positive in the sample was greater than the median. PD-L1 (Dako 28-8 pharmDx) was positive if at least 1% of tumor cells expressed PD-L1. The log-rank was used to compare the survival and progression free survival between groups and Spearman's rank-order correlation tests were conducted to determine associations between CD8, CD68, and PD-L1. Results: 57% of TN, 26% of HER2+ and 13% of HR+ BCs expressed PD-L1 in tumor. TNBC pts received anthracycline/ taxane chemotherapy (62%) or taxane therapy alone (22%). HR+ and HER2+ pts received standard endocrine therapy and trastuzumab-based therapy. Stromal CD8+ TILs were associated with improved OS in the overall population (log rank p=0.026). In TNBC, PD-L1 expression was positively correlated with the presence of TILs (p=0.0002) and TAMs (p=0.0005) as well as with improved 3 year PFS and OS (log rank p=0.04 and p=0.03, respectively). Furthermore, stromal CD8+ TILs and stromal CD68+ TAMs correlated positively with each other in the TNBC group (p=0.0094). Conclusions: PD-L1 expression correlated with TILs and TAMs in TNBC and was associated with a favorable outcome. PD-L1+ TNBCs with high levels of TILs and TAMs may be primed for exceptional response to immunogenic chemotherapy alone. Whether some pts with PD-L1+ TNBCs with high TILs/TAMs will benefit additionally from an anti-PD-L1/PD-1 agent is being investigated currently. Citation Format: Mardones MA, Grosser D, Levin MK, Daoud Y, Palucka K, O'Shaughnessy J, Osborne C. PD-L1 expression in triple negative breast cancer (TNBC) is associated with improved outcomes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-04-20.

Abstract ES9-3: ES9-3 (Neo)adjuvant systemic therapy of TNBC: How much is enough?

Abstract The use of neoadjuvant chemotherapy in ER-negative cancers has become quite popular in patients with stage II and III breast cancers, since it gives us important information on long-term prognosis, based on the amount of residual disease burden at the time of definitive surgical resection. Two relatively large phase II randomized neoadjuvant clinical trials have explored the addition of carboplatin to an anthracycline/taxane based chemotherapy regimen for patients with stage II or III triple-negative breast cancers (TNBC): GeparSixto, in Europe, and CALGB40603, in the US. Despite significant differences in chemotherapy backbone, and frequency and duration of carbo administration, both trials showed that the addition of carboplatin significantly increased the rate of pCR from ∼ 40% to 54%. Both trials also reported a significant amount of added toxicity for the carboplatin arms, with a significant amount of patient not being able to complete their planned treatment. However, whereas the GeparSixto trial reported an improvement in 3-year disease-free survival (DFS), the CALGB40603 did not. Since neither of these studies was powered to address disease-free or overall survival benefit from the addition of carboplatin to neoadjuvant systemic chemotherapy, lack of precision from small sample sizes are likely responsible for the difference seen in DFS between these two trials. Additionally, there's not yet a confirmed correlation between increases in frequency of pCR and event-free survival (EFS). A recently pooled analysis by Cortazar et al. could not validate pCR as a surrogate endpoint for improved EFS and overall survival (OS): as some patients who achieve a pCR go on to relapse and many with residual disease never experience a recurrence, small differences in pCR may never translate to improvements in EFS. Long term effects of the added toxicity of carboplatin are also not known. At present, upon completion of neoadjuvant therapy, the standard of care for patients with TNBC (who have no clinical evidence of metastatic disease after surgical excision of the cancer regardless of burden of residual disease) is observation. But recently, preliminary data from a Japanese phase III trial (CREATE-X) that randomized patients with HER2-negative breast cancer with lack of pCR post-neoadjuvant chemotherapy to observation or capecitabine x 8 cycles showed that the addition of capecitabine provided a statistically significantly higher 5-year DFS and OS in the TNBC group. EA1131, an ongoing adjuvant randomized phase III clinical trial seeks to address if patients with basal-like TNBC, with high risk of recurrence due to residual disease post completion of neoadjuvant chemotherapy, have a higher DFS benefit from a platinum agent than from capecitabine. The results of this trial will ultimately help avoid exposing upfront unselected patients, many of whom will never relapse, to toxic therapy in the absence of long-term known benefit. In summary, the addition of a platinum agent routinely in the neoadjuvant setting in TNBC is still an individualized decision and not yet standard of care for all patients. The decision to use capecitabine in patients with residual disease post-neoadjuvant chemo may still be slightly premature, confirmatory results of EA1131 are eagerly awaited. Citation Format: Mayer IA. ES9-3 (Neo)adjuvant systemic therapy of TNBC: How much is enough? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES9-3.

Abstract B26: Health-related quality of life in black breast cancer patients with Triple Negative Breast Cancer (TNBC)

Abstract Purpose: Black women are more likely to develop early onset (age ≤50 years) breast cancer and have the lowest five year cause specific survival rate of any U.S. racial or ethnic group. The disparity in incidence and survival can be attributed partially to the higher rate of triple negative breast cancer (TNBC) in Blacks. Yet, little is known about health-related quality of life (HRQOL) among Black women with TNBC. Guided by the Contextual Model of HRQOL, the purpose of these analyses is to examine factors associated with HRQOL in patients with TNBC and non-TNBC. Methods: Black women with invasive breast cancer at age ≤50 years and diagnosed between 2009-2012 were recruited through the Florida State Cancer Registry as part of a population-based case-only study to investigate etiology and outcomes of early-onset invasive breast cancer (n=456). A subset of participants (n=355) consented to complete additional study questions assessing those sociodemographic, clinical, and psychosocial variables selected based on the Contextual Model. The Functional Assessment of Cancer Treatment-Breast (FACT-G) was used to assess HRQOL. Descriptive analyses included those participants confirmed to have either TN or non-TN disease (n=330); univariable and multivariable analyses included participants who met the aforementioned criteria and completed baseline HRQOL data (n=299). Results: Participants in the TNBC and non-TNBC group were similar (p&amp;gt;0.05) with respect to age (TNBC: 41.4 ±5.9 years; non-TNBC: 42.2 ±6.5) and time since diagnosis (TNBC: 18.5 ±7.0 months; non-TNBC: 19.8±10.1). TNBC participants had lower mean FACT-G total scores (71 ± 22.3) compared to non-TNBC (77 ± 21.6) participants (p&amp;lt;0.05). In the TNBC group, variables significantly associated in multivariable analysis with FACT-G scores included: current health, role limitation, anxiety, income, life stress, collectivism, and fatalism (p&amp;lt;0.05). These three individual-level factors (current health, role limitation, and anxiety) and four systemic-level factors (income, life stress, collectivism, and fatalism) explained 80% of the response variation in HRQOL. In the non-TNBC group, factors significantly associated in multivariable analysis with FACT-G scores included: current health, role limitation, anxiety, depressed affect, cancer worry, income, life stress, social support, and birth country (p&amp;lt;0.05). These five individual-level factors (current health, role limitation, anxiety, depressed affect, and cancer worry) and four system-level factors (income, birth country, life stress, and social support) accounted for 76% of the variation in HRQOL scores. Conclusions: The Contextual Model of HRQOL provides a useful framework for evaluating HRQOL in Black breast cancer patients; differences based on triple negative disease status suggest possible intervention targets to improve HRQOL in these women. Effective interventions should focus on reducing anxiety at the individual level, with additional consideration for depressed affect, cancer worry, and social support in the non-TNBC group. For patients with TNBC, interventions may include addressing fatalistic cognitions and collectivist attitudes that may adversely affect HRQOL. Citation Format: Susan T. Vadaparampil, Juliette Christie, Kristine Donovan, Jongphil Kim, Bianca Augusto, Cheryl Holt, Kimlin Ashing, Chanita Hughes Halbert, Tuya Pal. Health-related quality of life in black breast cancer patients with Triple Negative Breast Cancer (TNBC). [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B26.